Personalized medicine describes medical practices that use information about a person’s genes, proteins, and environment to prevent, diagnose and treat disease. Science-based practice has routinely incorporated environmental advice (e.g., diet and exercise) into medical management. And there are a number of genetic tests in routine use that are well established, clinical validated, and are highly predictive of future outcomes, such as tests for Huntington’s disease and hereditary breast cancer.

Predicting how well drugs will work is another area of personalized medicine. Cancer cells have specific genetic mutations that lead to uncontrolled growth. Identifying the mutation, and then developing drugs to target it, means more targeted treatments. Trastusumab (Herceptin) works only in patients overexpressing the Her-2/neu oncogene. Panitumumab (Vectibix) and cetuximab (Erbitux) effectively treat colorectal cancer, but only in patients whose tumors have wild-type KRAS oncogenes. And gefitinib (Iressa) a drug that initially didn’t look that promising, seems to offer a much better risk/benefit perspective in patients with EGFR mutations. Tumor testing for these specific genetic markers helps predict patient response, guides drug selection, and spares the costs and consequences of ineffective therapies.

Whole-genome testing, offered directly to the public, is the latest development in personalized medicine. Companies typically offer to test for genetic traits that predict the risk of disease or estimate the effectiveness of drug therapies. In a typical test, up to a million single nucleotide polymophisms (SNPs) may be analyzed. A customized report is generated, describing the SNPs and your individual risk factors, usually based on population-level studies of what these SNPs mean.

But our understanding of the correlation between SNPs and the risks they identify is still in its infancy. It’s fair to say we only have a preliminary understanding of the relationship between SNPs, environmental factors, and other influencers of illness. It’s not even clear that SNP variants provide meaningful information on risk, beyond what we already know. For example, a study published earlier this year concluded that adding ten additional genetic variants to to a standard breast cancer risk assessment model had little effect on improving the accuracy of predictions. It adds to a growing list of variants which don’t seem give us any actionable information. But the science doesn’t seem to be stopping the vendors of these tests from making unsubstantiated claims about their accuracy and relevance.

The GAO and the FDA

The US Government Accountability Office (GAO) recently released the results of an investigation into 15 companies offering DTC genetic testing. And it raised some serious questions about the accuracy and validity of information currently available to consumers. The GAO purchased ten tests from four companies, and sent duplicate samples to each company, changing the demographic information each time. The results were alarming:

GAO’s fictitious consumers received test results that are misleading and of little or no practical use. For example, GAO’s donors often received disease risk predictions that varied across the four companies, indicating that identical DNA samples yield contradictory results. One donor was told that he was at below-average, average, and above-average risk for prostate cancer and hypertension.

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Although the experts GAO spoke with believe that these tests show promise for the future, they agreed that consumers should not rely on any of the results at this time. As one expert said, “the fact that different companies, using the same samples, predict different directions of risk is telling and is important. It shows that we are nowhere near really being able to interpret [such tests].” GAO also found 10 egregious examples of deceptive marketing, including claims made by four companies that a consumer’s DNA could be used to create personalized supplement to cure diseases. Two of these companies further stated that their supplements could “repair damaged DNA” or cure disease, even though experts confirmed there is no scientific basis for such claims. One company representative even fraudulently used endorsements from high-profile athletes to convince GAO’s fictitious consumer to purchase such supplements. Two other companies asserted that they could predict in which sports children would excel based on DNA analysis, claims that an expert characterized as “complete garbage.” Further, two companies told GAO’s fictitious consumer that she could secretly test her fiance’s DNA to “surprise” him with test results–though this practice is restricted in 33 states. Perhaps most disturbing, one company told a donor that an above average risk prediction for breast cancer meant she was “in the high risk of pretty much getting” the disease, a statement that experts found to be “horrifying” because it implies the test is diagnostic.

To be clear, this was not a scientific study, and the results can’t be interpreted to be a comprehensive analysis of the state of the marketplace. But they do give consumers and health professionals cause for concern. Not only did the investigation raise questions about whether these tests are are accurate, there is mixed information about what the results actually mean. The marketing goes well beyond the robust evidence that’s needed to draw stronger correlations between SNPs and specific risk factors. And while some companies are offering legitimate tests (albeit of questionable use), other companies are selling snake oil diagnostics, wrapped in a double helix.

Not surprisingly, the FDA recently took action, sending warning letters to several companies, informing them that these tests require regulatory approval before they can be marketed. While the letters and the FDA’s intent has been subject to considerable scrutiny, the message is clear: the FDA intends to regulate this marketplace.

Expert Opinion – Also Pessimistic

If anyone should be enthusiastic about genetic testing, it would be Craig Venter, who was the first to sequence the human genome. Yet in an intriguing interview in Der Speigel magazine, he is decidedly skeptical about its utility, as noted in a few exchanges:

SPIEGEL: Why is it taking so long for the results of genome research to be applied in medicine?

Venter: Because we have, in truth, learned nothing from the genome other than probabilities. How does a 1 or 3 percent increased risk for something translate into the clinic? It is useless information.

SPIEGEL: Do you think there will be a time when you can extract all this information to yield real medical results?

Venter: For that to happen we need a lot more information: Information about your body’s chemistry, your physiology, your complete medical history, your brain and your entire life. We would need to do that a million times on different people and correlate that data with their genetic information.

SPIEGEL: Will that lead in the end to the kind of personalized medicine that genetic researchers have always touted? Each person would get his or her own personal treatment that is tailored precisely to that person’s genetic make-up?

Venter: That was another one of these silly naïve notions that was out there. It’s not, ‘Oh, we know your genome, we’re going to make this drug for you.’ That will never happen. It is more important that you use the information in the genome about your personal risks and reduce them through intelligent behavior.

It’s anecdote, yes. But when one of the world’s leading scientists is this pessimistic, it doesn’t send a positive signal.

The British Approach

In the United Kingdom, the Human Genetics Commission is taking a different approach than the FDA. Rather than move forward with regulatory intervention, it recently published the Common Framework of Principles for direct-to-consumer genetic testing services, which supports industry self-regulation, while focusing on consumer interests. Here are the highlights:

1. Scope: The framework is intended to ensure good practices; meeting consumer expectations while safeguarding their interests. The principles apply to tests ordered directly by consumers or by a non-medical intermediary.
2. Marketing and Advertising: Validity claims should be supported by peer reviewed evidence, and references should be provided. This evidence must be presented fairly and transparently (i.e., no cherry-picking).
3. Regulatory: Evidence for the association between a genetic marker and a disease, condition or trait identified in the test must be provided. “Associations should be validated at genome wide significance level in more than one large case control study and in a cohort of the ethnic/geographic background relevant to the client. The associations should be published in peer-reviewed scientific journals, they should be undertaken in line with the recommendations made in the STREGA statement, and the provider should supply standard references for these publications.” Accepted and transparent statistical methodologies should be documented to document how the risk of the disease, condition or trait was calculated.
4. Information for Consumers: Clear and transparent information should be provided to consumers about the tests offered, their scientific basis, counselling offered, how samples will be handled post-test, possible consequences to future decisions (e.g., life insurance), etc. Data shall be presented in easy-to-understand formats. If a test provider intends to recommend products such as supplements, then information about lifestyle modification and other strategies should be provided. Depending on the type of test being offered, a health professional should oversee the information provided under this principle.
5. Counselling and Support: “Where the test is a genetic test in the context of inherited or heritable disorders, that test should only be provided to consumers who are given a suitable opportunity to receive pre- and post-test counselling.”
6. Consent: “A genetic test should be carried out only after the person concerned has given free and informed consent. Informed consent can only be provided when a consumer has received sufficient relevant information about the genetic test to enable them to understand the risks, benefits, limitations and implications (including the implications for purchasing insurance) of the genetic test.” “Genetic tests in respect of children when, according to applicable law, that child does not have capacity to consent should normally be deferred until the attainment of such capacity, unless other factors indicate that testing during childhood is clinically indicated.”
7. Data Protection: All genetic information must be protected as per any other medical or personal health information.
8. Sample Handling: All handling of genetic samples must be carried out in accordance with legal, medical and professional standards.
9. Laboratory Processes: Laboratories performing tests should be accredited for quality assurance in molecular genetic testing.
10. Interpretation of Test Results: Depending on the test, interpretation should be carried out under guidance of an appropriately trained and accredited professional. When information is provided related to risk assessment, the differences between relative and absolute risks should be made clear.
11. Provision of Results: Information should be provided in an easy-to-understand format. When testing for conditions or traits, non-genetic factors should be identified.
12. Continuing Support: Depending on the test, ongoing access to consultation should be offered.
13. Complaints: A robust process for dealing with complaints should be in place.

In order for the DTC market to avoid strict regulation, the Framework looks like a good place for the industry to start. It allows full access by consumers to their own genetic information, while requiring a full disclosure when any interpretation of that information is offered.

Towards a Science-Based Approach

Our access to genetic information currently exceeds our understanding of what that information actually means. The science underlying these tests is still evolving, and that means the interpretations of this data will continue to evolve. Until better and more conclusive data emerges to correlate SNPs with actual health outcomes, consumers will be dealing with probabilities that are largely irrelevant for health decisions. Luckily, there’s a more powerful and far simpler approach: You can make far more substantial reductions in your risk of cardiovascular disease, cancer, or diabetes without any genetic testing at all: simply follow science-based prevention and treatment guidelines.

The World Health Organization (WHO) and the International HIV/AIDS Alliance are teaming up with the Traditional Health Practitioners Association of Zambia (THPAZ) to address the first problem – the lack of health services. Most Zambians use traditional healers for primary health care. The WHO has therefore decided to utilize traditional healers in the fight against AIDS. There are interesting pros and cons to this policy, but it must first be recognized that there is no ideal solution to the problem. The resources to provide optimal modern health care to treat and prevent HIV/AIDS (which would need to include a massive education program) in Zambia and the rest of Africa simply do not exist. One might argue that the world should provide those resources, but let’s put that issue aside and focus on what to do in the meantime.

The arguments given in favor of this WHO strategy are:

Traditional healers far outnumber biomedical workers in the rural areas.

They are consulted, not only because they are closer and more affordable than their Western-trained counterparts, but also because they are embedded, extensively and firmly, within Ugandan culture.

Traditional healers are highly respected and widely consulted by communities.

In the various articles I read discussing this issue, even those entirely favorable to the idea, conspicuously absent is any mention of whether or not the interventions provided by traditional healers are safe and effective. It’s not even an afterthought – it’s as if it is a non-issue.

However, if we are to focus on the potential benefits of such a policy we could envision a program to train traditional healers essentially to implement a science-based program of counseling and basic health care while also using them to funnel patients to modern health treatments. In addition traditional healers could be trained how not to interfere with modern treatments – for example by not giving herbs that might reduce the effectiveness of anti-HIV drugs. Also they will need to be educated so that they do not spread myths and misconceptions, and in fact so that they can help to counter them. Until such an education program is in full swing, however, the policy of using traditional healers is likely to be counter-productive. As one report notes:

According to the 2006 survey by THPAZ, only 13 percent of the traditional healers in the country had been in contact with modern medical doctors or facilities.

In essence the goal is to use an existing infrastructure of trusted primary care providers (traditional healers) to get them to help the HIV/AIDS program, rather than hinder it. The only alternative strategy would be to replace this infrastructure with a modern science-based medical system – ideal but not realistic. These two strategies are also not mutually exclusive – efforts can be made to maximize the availability of modern health care in the region, while using traditional healers to fill the gap, or at least make sure they are not working against the system.

But there are significant pitfalls to using traditional healers. I have already stated some – most have had no contact with modern medical doctors. By all accounts traditional healers in the region rely upon treatments that are worthless at best, and may even be harmful. There is every likelihood that despite some modern medical education, many traditional methods will be retained.

The biggest pitfall of a partnership is that it will be used as a sign of validation of traditional healing methods, whether or not they are safe and effective. Already there are attempts to validate herbal treatments for HIV/AIDS in Africa. Dr Sekagya Yahaya Hills is a dentist and traditional healer who is promoting herbal remedies as effective in treating HIV/AIDS. Not surprisingly we are seeing the same pattern as elsewhere with the promotion of herbs as drugs – preliminary small studies of poor design being used to justify unlikely treatments. Many herbs are, in fact, drugs but they contain a mixture of chemicals that are not purified, are not quantified, and have unknown bioavailability (as well has half-life and other pharmacological properties). This makes them very poor drugs. The experience in the US is likely to be typical – herbs that seemed promising in preliminary studies have almost all been useless when studied in large well-controlled trials.  In addition they have drug-drug interactions and potential side effects and toxicities that were not apparent before being carefully studied.

Treating HIV is very challenging, and it is also a recent plague on humanity. It seems very unlikely that any traditionally used herb would be safe and effective against HIV. Despite the low probability, it is reasonable to test candidate herbs (as long as it is done ethically) but only well-controlled studies should be performed.

A more plausible research program would be to screen hundred of candidate herbs for in vitro activity – demonstrating that there is some biological activity that could plausibly fight HIV. Then follow up with animal testing of those herbs that seem promising on the screening test. And finally conduct preliminary then definitive testing in humans – and once you have a product that is proven safe and effective, recommend it for usage. This, of course, all s0unds suspiciously like pharmacognacy and drug development. But this is not what is happening. Rather, the preliminary research is bypassed and we have only preliminary and unreliable clinical studies.

What is very likely to happen is that traditional healers, propped up by an alliance with the WHO, will stick to their traditional methods, supported by those like Dr. Sekagya Yahaya Hills, who will use bad science as a rubber stamp to endorse traditional treatments.

It is a real dilemma – a devil’s bargain. It seems necessary and potentially useful to enlist the help of traditional healers, given the realities on the ground in Africa. But the potential to do more harm than good is extreme. The WHO should therefore go into any such collaboration with their eyes wide open, and not naive to the power of cultural belief, the highly sophisticated anti-scientific propaganda of the CAM movement, and the potential for reliance upon bad science. The WHO should therefore focus on regulation, which is an admitted problem:

The other concern is a weak regulation of traditional medicine, leaving people living with HIV open to abuse by unscrupulous healers who promote cures for AIDS or persuade their patients to cease life-prolonging drugs such as the antiretroviral treatment.

Therefore any such partnership should be contingent on careful scientific scrutiny and improved regulations.

Conclusion

Given the cultural and health care realities in Africa, it does seem necessary for the WHO to partner with local traditional healers in order to implement any widespread public health program. The endorsement of traditional healers may be necessary to achieve public acceptance of “Western” medicine. It is also necessary to counter myths and misconceptions about HIV/AIDS, and this must begin with the locally recognized health authorities – the traditional healers.

But the WHO should resist pressures to “respect” local traditions themselves as if they are acceptable alternatives to science-based medicine. In the promotion of health, which is the WHO’s mandate, utilizing treatments that are safe and effective is the only ethical option. Promoters of unscientific treatments, however, often resort to an appeal to cultural sensitivity and a false dichotomy between “Western” science and the beliefs of other cultures. Whether or not Dr. Hill’s herbs are an effective alternative to proven anti-HIV drugs will be determined by objective science, not culture, and bad science should not be excused with appeals to cultural sensitivity.

Without maintaining a strong dedication to science-based medicine this WHO program will likely become an epic example of the axiom that the road to ruin is paved with good intentions.

Kaiser Permanente Mid Atlantic States and Mid-Atlantic Permanente Group recently announced the elimination of neck manipulation from their chiropractic coverage. The revised policy states,

Given the paucity of data related to beneficial effects of chiropractic manipulation of the cervical spine and the real potential for catastrophic adverse events, it was decided to exclude chiropractic manipulation of the cervical spine from coverage. 

Their decision was applauded by some  but was predictably attacked by chiropractors.

The American Chiropractic Association (ACA) promptly responded with a letter to Kaiser outlining “the extensive data that supports cervical spinal manipulation as both beneficial and safe.” I have not yet been able to find a copy of that letter online. I don’t doubt that they presented data to support their beliefs. I do doubt that they presented a balanced view of the entire body of published evidence, the body of evidence that Kaiser relied on in making its decision. When the BCA (British Chiropractic Association) tried to defend itself against Simon Singh’s criticism, it provided a list of allegedly supporting studies but these were readily demolished in the blogosphere. Several previous posts on SBM including this one by a chiropractor have examined the evidence for neck manipulation and concurred with Kaiser that there is a “paucity of data related to beneficial effects of chiropractic manipulation of the cervical spine” and a “real potential for catastrophic adverse events.” That’s what the science says. It is encouraging that Kaiser followed the science.

The ACA also released the following statement, signed by ACA President, Dr. Rick McMichael :

The American Chiropractic Association is aware that Kaiser Permanente Mid Atlantic States and Mid-Atlantic Permanente Medical Group have revised their Chiropractic Manipulation Medical Coverage Policy to exclude cervical Chiropractic Manipulative Treatment (CMT) from coverage.  This restriction, if allowed to stand, will be harmful to chiropractic patients and doctors. We have contacted Kaiser to express our grave concern over this change, and we await its reply. ACA will expend every effort to encourage Kaiser to reverse this new restriction, and we will keep our members and the profession informed along the way.  

Chiropractors are not doing well. 20-25% of chiropractors leave the field within 10 years of graduation. Their average income has dropped from $97,892 annually in 1992-1993 to only $48,900 in 2002-2003.

The new Kaiser policy threatens their livelihood, especially the livelihood of the many practitioners who use neck manipulation on virtually all patients regardless of the presenting complaints. So of course they will protest and will try everything possible to convince Kaiser to change its mind. Such lobbying has been effective in previous cases.

In 2007, United Healthcare decided to stop reimbursing chiropractic care for children and for headaches. A joint letter from various chiropractic organizations chastised them:

Attached is an analysis which demonstrates that the above policy is not only flawed but more importantly, poses a threat to the health of children, adolescents and those individuals suffering with headache pain who may be insured or otherwise covered under United Healthcare programs and policies. We view your recent policy determination to be a material denial of essential benefits and coverage paid for by employers and other insureds. The broad stroke elimination of these important benefits is, in our view, not only unconscionable but is an abrogation of the promises made to cover chiropractic services to employees, individuals and their dependants.

The chiropractors contended that they are “uniquely qualified to address all types of childhood and adolescent ailments [not true].” They provided their evidence that chiropractic treatment was effective for headache [not convincing]. They said a number of other things that those of us on SBM would disagree with. United Healthcare backed down and rescinded the policy.

Kaiser made a good, science-based decision that will protect patients and also save money. They are to be commended. I hope they will stick to their guns and withstand the pressure that will be exerted against them by non-science-based chiropractors and health consumers. I hope other insurance and health care organizations will follow suit. In another action earlier this year, Saskatchewan deleted chiropractic subsidies from its health budget to save $10 million.   

Note: this policy change does not restrict patients’ rights to choose any treatment they want. It does not prevent chiropractors from doing neck manipulation; it only means that patients will have to pay for it out of pocket. Their approach seems entirely reasonable for a large organization that is trying to reduce costs for everyone by refusing to pay for treatments of questionable efficacy and safety.

Of course, I specifically mentioned Avastin because it’s been in the news a lot recently with respect to my area of clinical specialty, breast cancer. Specifically, beginning in July there started appearing a spate of stories about the FDA considering revoking the approval of Avastin for advanced breast cancer based on recent studies that demonstrate that it does not prolong survival in these patients. Many lay people and patients find this reconsideration of Avastin to be quite puzzling, given that the drug was granted accelerated approval in 2008 and has since gone on to be used fairly widely. Given that the case of Avastin in breast cancer is rapidly becoming a classic case study of how messy science-based medicine can be when practiced in the public eye and debated among pharmaceutical companies, the government, and patient advocacy groups.

The promise of angiogenesis inhibitors

Avastin (generic name: bevacizumab) is a class of drug that attacks cancer by attacking its blood supply. Basically, Avastin targets a protein called vascular endothelial growth factor (VEGF), which is growth factor that stimulates the cells lining the blood vessels to undergo a process of angiogenesis, sprouting out new blood vessels in the direction of the cells secreting VEGF. Angiogenesis is a normal physiological function used during embryogenesis and pregnancy, wound healing, during the proliferative phase of the female menstrual cycle, and a variety of other processes. Diffusion of oxygen and nutrients through an aqueous medium is limited to around 1 mm, and malignant tumors get around this limitation by hijacking the normal process of angiogenesis by secreting large amounts of pro-angiogenic factors like VEGF in order to provide themselves with the oxygen and nutrients that they need to grow. During the 1990s, largely inspired by the work of one of my scientific heroes, Judah Folkman, scientists discovered strategies to target the process of angiogenesis to treat cancer. After spectacular results in mouse models of various cancers, however, as is all too often the case the use of angiogenesis inhibitors in humans produced far less dramatic results and, in some cases, didn’t work at all. However, for some cancers, such as colorectal cancer, combining Avastin with conventional chemotherapy has been effective. To those of us “in the biz” since the mid-1990s, this is not a revelation or surprise. In fact, I was involved with some of the first research demonstrating that combining anti-angiogenic therapy with radiation resulted in synergistic anti-tumor effects.

Over the last decade, Avastin has tended to be a magnet for controversy. The major reason that Avastin has attracted a lot of attention is that it’s so expensive (up to $100,000 a year per patient), and part of the reason it’s so expensive is that it is a protein rather than a small molecule. Basically, Avastin is an antibody directed against human VEGF. More specifically, it’s a humanized monoclonal antibody against VEGF. What that means is that the antibody has been modified to get rid of most of the mouse sequences that can provoke an immune reaction against the protein in humans. In any case, developing and producing such a molecule, which is a large protein, are not cheap. Even so, there has been considerable criticism of Genentech, the manufacturer of Avastin, for allegedly overpricing it. In addition, Genentech has pulled some very questionable stunts to protect its profits with regard to some off-label uses of Avastin, for example, for macular degeneration.

Be that as it may, the number of uses of Avastin have expanded to a number of cancers, now including colorectal, lung, breast, and renal cell cancers. Perhaps the most controversial expansion occurred in 2008, when the FDA approved Avastin on what is known as the “fast track” for use in metastatic breast cancer. This allows certain promising drugs for life-threatening conditions to be granted in essence provisional approval quickly, so that patients can have access to them before the usual large phase III randomized, double-blind trials are completed. To understand why this decision was controversial and why it is now being reconsidered, a brief review of terminology is required.

How to evaluate an anticancer therapy

Cancer therapies are generally evaluated using a number of endpoints. The most commonly used include overall survival (OS) and progression-free survival (PFS). There are, of course, other endpoints related to survival that are measured, but these two are the most relevant for this discussion. Overall survival is what it sounds like: How long do patients survive their cancer after diagnosis? Period. It’s hard for an endpoint to be more objective than that: Either the patient is alive or he is dead. This number is usually expressed in terms of median survival, which is the period of time after which half of the patients under study are still alive and half have died. This includes all causes, not just cancer. If a patient with cancer under study dies of a heart attack that is not related to his cancer or his cancer treatment, that counts. Traditionally, OS has been the “gold standard” endpoint in measuring the efficacy of a cancer therapy, because the primary goal has been to prolong survival, the ideal case being prolonging survival to the point where it is indistinguishable from life expectancy if the patient never had cancer in the first place. PFS is survival without progression; i.e., how long the patient with cancer survives before his or her tumor starts measurably growing again or metastasizes. While PFS is often measured as well as OS, it’s generally considered less useful because it is entirely possible for a treatment to prolong PFS without prolonging OS. This sort of result can happen when the treatment is effective at shrinking a tumor or slowing its growth but its toxicities can result in death. Thus, PFS improves with no improvement in OS.

Which brings us to Avastin.

In 2008, that’s exactly the sort of data upon which the FDA’s fast track approval of Avastin was based. Back in 2005, the National Cancer Institute (NCI) announced that in a randomized trial Avastin combined with paclitaxel had increased PFS approximately 4 months over the use of paclitaxel alone. Eventually, by the time an FDA panel voted to approve Avastin in 2007, the E2100 study published in the New England Journal of Medicine had reported encouraging results that Avastin improved PFS in women with metastastic breast cancer. Unfortunately, E2100 also failed to find any benefit in terms of OS. Specifically, Paclitaxel plus Avastin significantly prolonged progression-free survival compared to paclitaxel alone (median, 11.8 vs. 5.9 months; hazard ratio for progression, 0.60; P<0.001). Adding Avastin to paclitaxel also increased the objective response rate (36.9% vs. 21.2%, P<0.001). Unfortunately, however, the overall survival rate (median, 26.7 vs. 25.2 months; hazard ratio, 0.88; P=0.16). Complications were also more frequent in the group receiving Avastin. Grade 3 or 4 hypertension (14.8% vs. 0.0%, P<0.001), proteinuria (3.6% vs. 0.0%, P<0.001), headache (2.2% vs. 0.0%, P=0.008), and cerebrovascular ischemia (1.9% vs. 0.0%, P=0.02), all complications common from antiangiogenic therapies, were more frequent in patients receiving paclitaxel plus Avastin. Infection was more common in patients receiving paclitaxel plus Avastin (9.3% vs. 2.9%, P<0.001).

These data were thin gruel indeed to approve Avastin for the indication of metastatic breast cancer, which the FDA did in February 2008. Although the increase in PFS was impressive, the lack of effect on OS was very disturbing, strongly suggesting that drug toxicity was "taking back" all the benefit the addition of the drug was providing against the cancer. However, based on a program to "fast track" promising drugs that was developed in 1990s, the FDA gave provisional approval to Genentech to market Avastin for metastatic breast cancer with the condition that Genentech had to perform additional studies to verify the results upon which the original approval had been based. At the time, there was a great deal of argument over whether this was a wise decision, particularly given how expensive Avastin is and the lack of evidence that it improved quality of life or overall survival. Indeed, I recall attending a talk at ASCO in June 2008 in which the approval of Avastin was strongly defended and the speaker (who it was now escapes me) attacked the use of OS as the basis upon which to approve drugs and argued that PFS should be enough, given the potential improvements in quality of life that can result from a longer period of time without tumor progression.

In the press at the time, Dr. Kathy Albain at Loyola University defended the approval of Avastin thusly:

Dr. Kathy Albain, a breast cancer specialist at Loyola University Medical Center in Maywood, Ill., polled colleagues and patients and found overwhelming support for approving drugs based on delaying tumor progression. It would be ideal to show that a drug also prolongs life, but that may not be realistic, she said. The reason is that when a woman’s cancer progresses, doctors change the drugs they use, hoping to slow the cancer. That dilutes any impact of the first drug — in this case Avastin.

Personally, although I can see where Dr. Albain is coming from, I’ve always been uneasy with this view. Yes, I can see the utility of a drug that slows tumor progression but does not prolong survival. However, I can see its usefulness in only one situation: There must also be good evidence that that drug also improves quality of life, evidence that was lacking for Avastin. In fact, the evidence that existed was suggestive of increased complications due to Avastin. Now, it may be a bit of a judgment call whether it is worth it to slow down tumor progression if there is no improvement in survival and there are drug-related complications, but I remained unenthusiastic about a drug that didn’t prolong OS but did appear to produce markedly more complications. How is that improving the quality of life of a cancer patient? I can also understand the argument, which was made in 2008, that perhaps Avastin benefits certain subsets of patients; we just don’t know who they are yet. My response to that would be that we should be doing the studies to identify those patients rather than exposing large numbers of women to the risk of the drug outside the auspices of clinical trials that could identify them.

The promise is not confirmed

In any case, the followup studies, known as the AVADO and RIBBON-1 trials were indeed performed, and the results published. The AVADO trial was a phase III randomized double-blind clinical trial (N=736 subjects) comparing docetaxel with docetaxel plus Avastin in women with stage IV HER2-negative breast cancer. Its results were less than impressive. While it did demonstrate a decrease in PFS due to the addition of Avastin, PFS did not improve anywhere near the five months it did in the E2100 trial; rather it improved from 8.2 months to 9.0 months, a mere 0.8 month or 24 days. As in E2100, there was no detectable effect on OS. There was, however, a troubling trend towards a shorter OS in women who received Avastin. Even though the difference was not statistically significant, women who did not receive Avastin survived a median of 31.9 months; those who received the lower dose survived a median of 30.8 months; and those who received the higher dose level of Avastin survived a median of 30.2 months. In contrast to E2100, in the AVADO study Avastin did not increase the toxicity of treatment measurably. In the discussion, the authors of the AVADO study concluded:

Taken together with the results of the E2100 study, these data suggest that the combination of bevacizumab with taxane chemotherapy should be considered as an option for the first-line treatment of HER2-negative MBC.

The initial results of the RIBBON-1 trial were reported at the American Society of Clinical Oncology (ASCO) meeting last year and were similarly disappointing. In the trial, Avastin was tested in a randomized, double-blind study enrolling 1,237 patients. Oncologists could choose from capecitabine, taxane, or anthracycline-based chemotherapy, and patients would be randomized to that plus or minus Avastin. The results were that Avastin improved PFS by 2.9 months when added to capecitabine, and 1.2 months when added to anthracycline-based chemotherapy. Again, there was no improvement in OS in women receiving Avastin. In fact, it was these studies that led the FDA advisory panel to vote 12-1 to revoke FDA approval for Avastin for use in breast cancer:

An FDA advisory committee voted 12 to 1 on July 20 to withdraw Avastin’s authorization for advanced breast cancer based on two new studies that the advisers concluded had not shown that the drug extends life. Not only that, the committee concluded that the studies indicated the drug slowed tumor growth for even less time — perhaps as little as about a month. “The vast majority opinion of the committee was that the drug was not doing very much, and what it was doing was more than offset by the negative,” said Wyndham Wilson of the National Cancer Institute, who chaired the committee. Avastin can cause a variety of potentially serious side effects, including blood clots, bleeding and heart failure. “In our best judgment, we did not feel this drug was safe to give relative to its benefits,” Wilson said.

The recommendation has been praised by many cancer experts and by advocates for breast cancer patients.

“The FDA should never have approved Avastin for breast cancer to begin with,” said Fran Visco of the National Breast Cancer Coalition. “We don’t see evidence of benefit, but we do see evidence of harm.”

I tend to agree, although I must admit that back in 2008 I was ambivalent about the FDA approval of Avastin rather than necessarily opposed to it. Now, I’m more of the opinion that the FDA would be justified, based on science alone, in revoking Avastin’s approval, although I can also understand, if not agree, with a lot of the multitude of opinions in the breast cancer oncology world regarding the FDA’s decision. However, there is more than science at work, which is why where the rubber hits the road practicing science-based medicine in intersection with public policy can be so messy and contentious. Just practicing SBM alone is contentious enough, but add a biotech company trying to protect its profits and expand its market, regulatory agencies trying to fulfil their mandate in the case of ambiguous data, and advocacy organizations trying, well, to advocate for their members, and the whole debate can turn into a huge kerfuffle in a hurry. In this case, the FDA is scheduled to make a final determination in September. In the meantime, patients receiving Avastin are afraid, because if the FDA revokes its approval using Avastin for breast cancer will become and off-label use, and insurance companies will no longer pay for it.

Politics intrudes

The whole controversy, where science, economics, politics, and dying cancer patients intersect in what are sometimes very ugly ways, is taking an even uglier turn, thanks to the entire healt insurance reform debate and the intrusion of partisan politics and the unrelenting opposition of Republicans to what they often derisively term “Obamacare.” The reason is that right wing bloggers have jumped on the bandwagon of criticizing the FDA’s decision on Avastin as “evidence” of the impending arrival of socialized medicine-style rationing, thanks, of course, to “Obamacare.” For example, Senator Dave Vitter (R-LA) characterized the decision thusly:

Reviving allegations of government death panels, Sen. David Vitter of Louisiana said Wednesday that an FDA advisory panel’s negative recommendation on a contested breast cancer drug amounts to rationing health care. “I shudder at the thought of a government panel assigning a value to a day of a person’s life,” Vitter said in a press release about the drug Avastin. “It is sickening to think that care would be withheld from a patient simply because their life is not deemed valuable enough.”

Several right wing and rightward-leaning blogs, such as Red State, Hot Air, and Big Government characterized the decision as the FDA being made complicit in “rationing” health care. Perhaps the most despicable post I’ve seen about the matter is this one by Moe Lane at Red State, entitled Obamacare worth 17.5K dead women a year? This is, of course, utter demagoguery of the most vile and despicable sort, as my previous discussion of the evidence demonstrates and the simple observation that Avastin, even under the most optimistic scenario imaginable, only prolongs disease-free survival; it does not save lives of breast cancer patients, at least not as far as we can tell. Also at Red State, Ed Morrissey resorted to exaggerating the benefits and downplaying the results of clinical trials that failed to find much, if any, benefit and did find potential evidence of harm, even going so far as to accuse the FDA thusly:

With the new ObamaCare regime in place, the issue of cost has now become openly part of the FDA process. This is a perversion of their mission, which is supposed to only involve product safety and effectiveness, not bean-counting. If Medicare doesn’t want to cover Avastin, that should be a separate issue handled by CMS and HHS. This strongly suggests that the FDA has become politicized to a degree where their recommendations lose credibility — a dangerous situation for consumers and providers alike.

The Wall Street Journal chimed in with a fallacy- and demagoguery-filled editorial whose deconstruction would be worthy of a separate post of its own (perhaps an exercise for my more “insolent” friend elsewhere?), entitled The Avastin Mugging, in which the anonymous editorialist harped on the earlier E2100 trial and cherry picked the very best numbers out of the AVADO and RIBBON-1 trial, completely ignoring the fact that OS was no different with Avastin and that it might even be worse. He or she made liberal use of straw men arguments and even misquoted findings, at one point even claiming, “At any rate, even the 31% reduction in the risk of disease progression or death is better than the status quo.” The problem is that none of the studies showed a 31% decrease in the risk of death–or any decrease in the risk of death for that matter. The editorialist also referred to to chemotherapy as “savagery” and asserted:

The Avastin mugging is really an attempt to undermine regulatory modernization like accelerated approval that offends the FDA’s institutional culture of control and delay. It is also meant to discourage innovations like Avastin that the political and medical left has decided are too costly, with damaging implications for the next generation of cancer drugs.

No, the reconsideration of decisions like the decision to approve Avastin is an absolutely necessary part of the fast track approval of drugs. If we are going to approve drugs on the basis of relatively scarce preliminary evidence with the quite reasonable requirement that more studies be done and the issue of FDA approval be revisited after those studies are completed, we have to expect that we will find in at least some cases where follow up studies will suggest that FDA approval wasn’t justified, that the drug isn’t particularly useful, and that FDA approval should be revoked. If that doesn’t happen from time to time, then why bother requiring additional studies? Just use fast track approval and forget it, which is, of course, what the pharmaceutical companies would very much like to see.

Although it may not be unreasonable to be concerned that the law may evolve to consider cost more strongly, as the law exists now and as has been reported in the Wall Street Journal and the AP, FDA advisory panels do not consider the costs of the drugs they are evaluating, only the evidence. Whether they should or not is certainly something we as a nation will have to decide. I don’t consider it at all unreasonable to ask whether it’s worth over $8,000 a month to produce a 1.2 month increase in DFS, no increase in OS, and an increased risk of complications such as bleeding, stroke, hypertension, and bowel perforation.

FDA approval, science-based medicine, and politics

So how will this all play out on September 17, which is when the FDA is expected to make its final determination. The FDA could decide to side with the panel recommendation to revoke approval for Avastin, ignore the recommendation, or chart a middle course, continuing approval and asking for still more studies. It wouldn’t surprise me if the FDA chose that last option.

Whatever the FDA decides in this particular case, determining which drugs to approve for metastatic breast cancer (or nearly all metastatic solid malignancies) is a particular challenge to SBM because SBM cannot cure the disease. Consequently, the goals in treatment must be palliative; i.e., to relieve symptoms and prolong survival as much as possible. Sometimes these goals are in conflict. In the case of Avastin, this may well be the case. The drug improves PFS very modestly, but there must be a cost in terms of complications that decrease quality of life. The Avastin saga is a saga the likes of which we are probably going to see with increasing regularity.

Another lesson of the ongoing Avastin saga is about the very nature of science-based medicine itself. We have stated that we believe that medical care should be science-based. However, although medicine should be based on science, medicine itself can never be a pure science because so many non-science-based considerations impact on it. On the patient level, there is patient choice and how the doctor and patient weigh the patient’s personal situation and personal considerations in choosing from among science-based therapies. At the national level, considerations of cost, politics, and values cannot be separated from medical policy considerations. Science can tell us that Avastin does not prolong overall survival in breast cancer patients and that it only very modestly prolongs progression-free survival. It can tell us that even that modest increase in PFS comes at a cost of complications that prevent improved PFS from translating to improved OS. What science can’t tell us is whether that modest benefit is worth the cost. That’s a value judgment that must be made both at the level of society as a whole and at the level of each patient and physician.

With more research, I can only hope that science will soon be able to tell us which women with breast cancer are most likely to benefit the most from Avastin.

Can the parents of an unvaccinated child be held liable if their child becomes infected with a vaccine-preventable disease which then spreads from their child to another child or children?

Yes, they can.

In fact, for over 125 years, courts in this country have recognized a cause of action for negligent transmission of an infectious disease. In the first reported case (New York, 1884) the defendant infected the plaintiff with whooping cough. Cases since then have run the gamut: smallpox, tuberculosis, unspecified “venereal disease,” typhoid fever, scarlet fever, diphtheria, hepatitis, herpes, gonorrhea, HIV. If your favorite infectious disease is not on this list, don’t worry. The disease may vary, but the legal principles remain the same.

You’ve got WHAT?

As the previous paragraph suggests, one need look no further than plain old negligence for an entrée to the courts — the same legal principle that forms the basis of actions arising out of automobile accidents and slip and fall cases.

Here’s how the Court of Appeals of Maryland described the basic law of negligence and its application to infectious diseases:

The traditional elements of a cause of action in negligence may be stated as:

1. A duty, or obligation, recognized by the law, requiring the person to conform to a certain standard of conduct, for the protection of others against unreasonable risks.
2. A failure on the person’s part to conform to the standard required: a breach of the duty ….
3. A reasonably close causal connection between the conduct and the resulting injury ….
4. Actual loss or damage resulting to the interests of another ….

The notion of duty is founded on the ‘responsibility each of us bears to exercise due care to avoid unreasonable risks of harm to others.’ … ‘When a reasonable person knows or should have known that certain types of conduct constitute an unreasonable risk of harm to another, he or she has the duty to refrain from that conduct.’ …

One who knows he or she has a highly infectious disease can readily foresee the danger that the disease may be communicated to others with whom the infected person comes into contact. As a consequence, the infected person has a duty to take reasonable precautions—whether by warning others or by avoiding contact with them—to avoid transmitting the disease. ‘[As an example] if defendant knew that he was afflicted with smallpox it then became and was his duty to keep away from other persons, or should other persons approach him to notify them of the fact so that they might protect themselves.’

B.N. v. K.K., 538 A.2d 1176 (Md. Ct. App. 1988)(citations omitted)(emphasis added).

In this case, K.K., a doctor, transmitted genital herpes to B.N., a nurse with whom he worked at Johns Hopkins Hospital. (Hence the discrete initials instead of the names of the parties, although that privilege is not always granted to the litigants in STD cases.) Dr. K.K. and Nurse B.N. had a sexual relationship of several months’ duration during which time Dr. K.K. — rather ungallantly — failed to tell Nurse B.N. about his infection, even though he knew his diagnosis and on at least one particular occasion knew that he had an active case.¹

While the facts were unique to the case under consideration, the Maryland appellate court correctly stated the law of negligence generally applicable in the 50 states. Some courts have added that the duty to exercise due care not to infect others is also grounded in the state’s interest in the prevention and control of disease. (Caveat: each state’s courts have the jurisdiction to create variations on the law of negligence, so, as has been said on this blog before, your results may vary.)

But what if one doesn’t know he has a contagious disease?

Actual knowledge is not required, although it makes for easier proof. Courts have found that in certain circumstances the infected person should have known, or, as it is sometimes put, he had constructive knowledge of his disease. This can be established on the basis of symptoms alone, without a confirming medical diagnosis, particularly where symptoms of the disease are well publicized, such as is true of HIV/AIDS infection and genital herpes.

Note that a “reasonable person” is the standard — what a reasonable person knew or should have known. Thus, being merely unaware (in cases where the “reasonable person” would have known) or willfully ignorant of the disease is no excuse.

Once a duty to act with due care is established through actual or constructive knowledge of one’s disease, the infected person is charged with, at the least, warning those with whom he comes in contact that he has a communicable disease (allowing them to choose to stay away) or himself choosing not to engage in activity which would spread the disease to others. If he fails to do so, the second element of negligence — breach of his duty — is established.

A tougher problem might be to show that the diseased person’s conduct was the cause in fact of the plaintiff’s injury, the third element of proof in a negligence case. Even though she catches the same infectious disease as is suffered by the defendant, the plaintiff must still show the defendant was in fact the source of her disease. Depending on the disease, this can be accomplished through expert testimony concerning, for example, how contagious the disease is, the incubation period, and DNA testing of the disease strains.

Finally, there must be actual damages, and there usually are, in the form of medical expenses. (The collateral source rule prevents the offset of health insurance payments against the plaintiff’s recovery.) In cases where the defendant’s conduct was particularly egregious, punitive damages might be awarded. Other types of damages are discussed below.

No two negligence cases are exactly alike. There will always be factual variations to weigh in determining liability. In general, however, negligent transmission of infectious disease cases will turn on two issues: (1) Did the defendant know, or should he have known, he was contagious, and (2) Was he the cause in fact of plaintiff’s disease. Once those two are established, the defendant’s lack of due care will almost always be a given, as will at least some damages. Of course, in some cases the facts may show contributory negligence, or even consent, by the plaintiff.

While negligence is the most common, and easiest to prove, claim against a defendant who has transmitted an infectious disease, it’s not the only one. Actions for fraud, intentional infliction of emotional distress, the tort of battery, other forms of intentional tort, and actions based on premises liability (for failure to warn of a communicable disease on one’s property) have all been the subject of suits based on the contraction of an infectious disease.

Some states have a law making it a crime to intentionally transmit HIV to another through sexual contact. If that is not the case, the crimes of battery and reckless endangerment may offer the possibility of prosecution for any infectious disease transmission given the requisite proof of intentional or reckless conduct.

So sue me! 

So let’s apply these lessons to a perennial topic at SBM — parents who refuse to vaccinate their children because of unwarranted fears about vaccine safety. What part such children might be playing in the current pertussis epidemic is a question under investigation by public health authorities, as pointed out in a recent post by Dr. Steve Novella.

First, note that in the case of vaccine-preventable childhood diseases, it’s not the child who is calling the shots. (Sorry!) Children under a certain age (usually 18) are deemed legally incapable of making decisions about their health care. The parents make those decisions and it is the parents who are legally responsible for the consequences of their decisions.

Of course, as the standard for determining negligence is what a “reasonable person” in the same or similar circumstances would do, how could that standard ever be applied to children? The “reasonable toddler?” No such thing.

Second, it does not matter WHY the parent chose not to vaccinate in establishing liability. The parent may have exercised his statutory privilege of opting out for religious or philosophical reasons, but that’s not the equivalent of a “get out of jail free” card for all the consequences of that decision.

In fact, it can help the plaintiff establish liability by showing that the parent knew, or should have known, her child was vulnerable to vaccine-preventable diseases and that this, in turn, made it more likely that her child would transmit these diseases to unvaccinated, not fully vaccinated and even vaccinated children.

In one New England Journal of Medicine² article the authors point out:

• Children with non-medical exemptions are at a greatly increased risk for acquiring and transmitting vaccine-preventable diseases;
• In one study, at least 11% of nonexempt children who acquired measles were infected through contact with an exempt child;
• Outbreaks of vaccine-preventable disease often start among persons who refused vaccination, spread rapidly within unvaccinated populations, and then to other subpopulations, such as vaccinated children.

In cases where there is not a confirmed diagnosis, I would argue that reasonable parents should have been on high alert for symptoms, given their child’s increased susceptibility. While the parent of a vaccinated child could be excused for not thinking his child, broken out in little blisters, might have chicken pox, the argument can be made that the parent of an unvaccinated child shouldn’t be given that consideration.

As one treatise states:

The defendant’s membership in a group at high risk for development of a particular infectious or contagious disease, his or her involvement in patterns of behavior likely to result in contraction of a disease, and/or his or her exposure to a disease in circumstances likely to lead to contraction of the disease are additional factors which may assist the plaintiff in establishing constructive knowledge. If any combination of the factors stated above would put a reasonable person on notice of the need to inquire further, the defendant will be charged with constructive knowledge of any facts reasonable inquiry would have disclosed.

22 Causes of Action 1, at 18 (Westlaw, accessed June 4, 2010).

“Group at high risk?” “Behavior likely to result in contraction of a disease?” Sounds like a description of the unvaccinated child.

An insolent question

With all of this in mind, we turn to a hypothetical posed by Dr. David Gorski:

What would the liability be of the parents of a child who refused to vaccinate if their child infected other children, leading to serious harm (such as measles encephalitis). Let’s say the causation could be proven very strongly, for instance by the sequence of the measles virus in the unvaccinated child matching exactly the measles that infected and harmed other children. Say the children who were harmed were fully vaccinated against MMR (remember, MMR is not 100% effective).

Slam dunk, Dr. Gorski! With a few caveats.

Certainly, if the parents knew, or should have known from symptoms, that their child was infected with measles and then put him into a position where he might infect other children, and causation has been established as you suggest, then the parents would be liable to the injured children for their pain and suffering and to their parents for all medical and other expenses incurred in taking care of their ill children. If the encephalitis had lasting effects, the defendant parents would also be liable for the continuing care of the children, the children’s future wages, and the parents’ loss of their children’s help and support. If any of the children actually died, the amount of loss would depend on the wrongful death law of the state where this occurred as the method for calculating those losses varies from state to state. Then there is the possibility of punitive damages.

In other words, this could run into hundreds of thousands, even several million, dollars, depending on the number of children injured and the extent of their injuries.

But … factual variations might influence the outcome. If the parents of the unvaccinated child knew the other children were vaccinated, the finder of fact (either the jury or, if a bench trial, the judge) might determine they were not negligent. It would depend on whether a reasonable person should know the vaccine is not 100% effective. If the parents of the injured children knew or should have known the unvaccinated child had the measles, and the uncertain effectiveness of the vaccine, then their own negligence might reduce their recovery, but not that of the children. And so on.

“Chicken pox parties” present an interesting case. For the parent supplying the diseased child to the “party” the prospect of liability should be particularly troubling. She is not negligently spreading her child’s disease — she is intentionally spreading it. Intentional torts automatically subject the defendant to the possibility of punitive damages, which are usually based on the defendant’s net worth. The whole point is to make sure the defendant is financially punished for her actions — in other words, to take enough money that it hurts.

Punitive damages are on top of actual damages, such as medical bills, and pain and suffering. As in the above hypothetical, while the recovery of parents subjecting their children to the virus can be reduced — perhaps eliminated in this case — because of their actions, the award to the children cannot, and it is the children who are entitled to punitive damages. It could turn out to be a very expensive party.

And what about the physician? What role does he or she play? Well, possibly the role of “defendant.” Courts in a number of jurisdictions have found that in certain circumstances a physician is liable to a third party who contracts a contagious disease from the physician’s patient. One of these circumstances is the physician’s failure to inform the patient how to avoid the spread of the disease, such as by avoiding specific at-risk conduct. Another is giving the patient inadequate or incorrect information. The physician does not need to know that this third person even exists and the third person does not have to rely on the physician’s incorrect advice to hold the physician liable.

As one court in Pennsylvania said,

the duty of the physician treating a patient with a communicable disease is to prevent the spread of the disease, not for the benefit of the patient, whose health has already been compromised, but for the benefit of those third parties ‘within the foreseeable orbit of risk of harm.’

Troxel v. A.I. DuPont Institute, 450 Pa.Super. 71, 675 A.2d 314 (Pa. Super. 1996)(citations omitted).

I would argue that this duty to third parties requires a physician to warn the vaccine-refusing parent, and the parent who chooses the “alternative” vaccine schedule (a la Dr. Bob), of not only the heightened risks to her child resulting from vaccine refusal or delay, but also the risks to other persons to whom her child could spread disease. This information would include the symptoms of the preventable disease and how to avoid infecting others. Otherwise, beware of small third parties bearing service of process coming at you from “the foreseeable orbit of risk of harm.”

Closing argument

In sum, the state’s interest in preventing the spread of communicable diseases manifests itself not only in mandatory vaccine laws, but also in impressing a duty to avoid the spread of disease on those who are infected with, or who are at high risk for contraction of, a communicable disease. Where the diseased are children, the responsibility for fulfilling this duty falls on the parents. As well, physicians of high risk or infected patients must properly instruct patients in avoiding transmission of disease to others. Those who breach their duty to avoid the spread of communicable disease may be liable to those injured for damages.

Parents who refuse vaccination may be willing to forsake their children’s health for their religion or their philosophy, but once that choice adversely affects someone else’s child, they will have to pick up the tab.

Notes

1. I have no sympathy for Dr. K.K., but do note that it must be a huge bummer for one’s negligent transmission of genital herpes case go all the way to the state court of appeals and be immortalized in published case law.  Future defendants in such cases might want to consider settlement.

2. Omer SB, Salmon DA, Orenstein WA, et al., Vaccine Refusal, Mandatory Immunization, and the Risks of Vaccine-Preventable Diseases, N Engl J Med 2009; 360:1981-1988.

We tell many versions of the same story over and over, not just to entertain each other, but to refine our thinking, to convince those who can be convinced, and to point out the weakness in thinking apparent in others.  We do this not to be “dicks” but because repeated assaults on reason require repeated defense.   Scientific medicine gives us a powerful tool for analyzing new ideas and old ones dressed up in new clothes.  It allows us to find ourselves to be wrong in particular facts, if not in our overall approach.

A common theme in many of our writings at Science-Based Medicine is that science-based practitioners are willing to be proved wrong, and that altmed supporters are not.  The history of medicine is littered with the corpses of abandoned therapies, while altmed fetishizes the past, preferring to recycle old ideas rather than discard them in the face of overwhelming negative evidence.

This can be done in many ways.  I recently examined a paper that purported to support the use of a homeopathic preparation to treat sinus infections.  Leaving aside the nearly-miraculous reported results, there was a fundamental error in thinking at the very beginning of the paper.

The present trial was designed to demonstrate the efficacy and safety of Sinfrontal compared with placebo in patients with AMS confirmed by sinus radiography. As well as measuring the clinical efficacy of this homeopathic medication, the study also investigated the ability of subjects to work and/or to follow their usual activities of daily living—both during and following treatment with active medication compared with placebo—to assess the treatment success of this homeopathic medication as an integrated symptomatic therapy for AMS.

Compare this to another study on sinusitis treatment:

The value of antibiotics in acute rhinosinusitis is uncertain. Although maxillary sinusitis is commonly diagnosed and treated in general practice, no effectiveness studies have been done on unselected primary-care patients. We used a randomised, placebo-controlled design to test the hypothesis that there would be an improvement associated with amoxycillin treatment for acute maxillary sinusitis patients presenting to general practice.

The difference is dramatic.  All studies build on pre-existing knowledge, but good studies start with a question, not an answer.

Many in the altmed movement aren’t persuaded either by absence of evidence or evidence that directly refutes their hypotheses.  When that evidence is overwhelming, or when it is noted that their for their hypothesis to be true, we would have to toss out all we know of chemistry and physics, they fall back to one of their weakest arguments: “our magic is too clever for your science.”

This was demonstrated recently  in a blog post at the New York Times (and ably eviscerated by Orac). I wrote about it as well, especially regarding this particular complaint.   In the Times piece, an acupuncture supporter specifically complained that:

There is a body of literature that argues that the whole approach to studying acupuncture doesn’t lend itself to the Western reductionist scientific method.

What does that even mean?  We’ve seen this argument many times before, and what it usually means is, “we cannot prove our magic works, and rather than abandon it, we are going to abandon all of science, and we demand you do the same.”  That is obviously an untenable position, and to see why, one needs only to ask one question: are the altmed practitioners claiming it works?

If they are claiming their magic does something, then “something” can be measured.  If they are claiming that acupuncture treats arthritis, then we can ask patients if it is so, record their answers, and do some math.  That’s the Big Secret to “Western reductionist scientific method”.  If you are going to claim an effect on a subject, that effect can be recorded and measured.  Period.

Stepping back to examine basic principles and to critique basic errors is not some masturbatory exercise, and it does not have to descend into “dickishness”, but neither does it need to compromise or pull punches.  Some ideas are so laughably stupid that laugher is inevitable. Some are so demonstrably dangerous that scorn is not only appropriate but mandatory.

Back to business. Science-based medicine (SBM) business, that is.

What happened while I was away could almost be characterized by the New England Journal of Medicine (NEJM) singing “Oops, I did it again.” Three weeks ago, the hallowed pages of the NEJM hosted a truly execrably credulous review article about acupuncture. So bad was the article that it “merited” the incredibly rare triple beat-down from this very blog, with posts by Steve Novella, the ever-irascible Mark Crislip, and myself in rapid succession applying the clue-by-four. As I was preparing to leave for Chicago on Thursday, I happened to look at the very latest issue of the NEJM hot off the presses, and what to my wondering (and watering–it is ragweed season) eyes should appear but an article reporting a study on the use of tai chi in treating fibromyalgia. Entitled A Randomized Trial of Tai Chi for Fibromyalgia, the study comes out of the Tufts University School of Medicine and the Newton-Wellesley Hospital in Boston and was carried out by a team led by Chenchen Wang, MD, MPH. Not surprisingly, the study has gotten a lot of play in the media, for example, in this story in the L.A. Times, which is at least reasonably restrained, probably because it an AP wire story by Marilynn Marchione, who has written some excellent articles about “alternative” medicine before. Even the usually reliable GoozNews seems smitten with this study beyond what it rates, characterizing it as “rare victory for the National Institute of Health’s National Center for Complementary and Alternative Medicine and Sen. Tom Harkin (D-IA), who routinely comes under fire for pushing funding for these types of studies.”

I’m less impressed. You’ll see what I mean in a few minutes, I hope. First, however, let’s look at the study itself.

Fibromyalgia, like many chronic conditions, truly sucks. If there’s one condition or disease (or whatever you want to call it) that is poorly understood by medical science thus far, it’s fibromyalgia. Indeed, like some diseases that are also not well understood, there has even been some debate whether or not fibromyalgia exists as a distinct disease. Although that debate appears to have been largely settled in favor of fibromyalgia as a clinical entity, unfortunately, the pathogenesis and pathobiology of fibromyalgia remain “incompletely” understood (meaning not well understood at all), and there is considerable controversy over the precise diagnostic criteria to use to define the syndrome. The authors of this study describe fibromyalgia thusly:

Fibromyalgia is a common and complex clinical syndrome characterized by chronic and widespread musculoskeletal pain, fatigue, sleep disturbance, and physical and psychological impairment.

“Common and complex” usually means that a lot of people have it; we don’t understand it; and we don’t have any good treatments for it. An accompanying editorial by Gloria Y. Yeh, M.D., M.P.H., Ted J. Kaptchuk, and Robert H. Shmerling, M.D. entitled Prescribing tai chi for fibromyalgia: Are we there yet? describes fibromyalgia thusly:

Fibromyalgia is a common and poorly understood pain disorder that afflicts an estimated 200 million or more people worldwide.¹ The lack of objective abnormalities detected on physical examination and standard blood and imaging tests has led many physicians to question the existence of this disorder.² However, for those experiencing the pain and other associated symptoms (including fatigue, stiffness, and nonrestorative sleep), there is little doubt that the condition is real — and so is the need for relief. Studies over the past decade suggest that fibromyalgia may be due, at least in part, to an alteration in pain sensitivity in the central nervous system.³ Other potential mechanistic contributors include a genetic predisposition, emotional or physical stress, disordered sleep, and neurohormonal dysfunction.

These sorts of conditions are the most frustrating of conditions to deal with, particularly for patients but also for doctors. After all, no one goes into medicine to tell patients that there’s not much he can do for them; yet that’s what doctors all too often end up having no choice but to tell fibromyalgia patients. Not surprisingly, patients are neither happy nor satisfied with this, nor should they be. They’re suffering, and they want relief. Also not surprisingly they’re willing to try almost anything, including the rankest forms of quackery peddled by unscrupulous quacks.

Let me hasten to add right here that I am most definitely not saying that tai chi is a rank form of quackery pedaled by unscrupulous quacks. It’s a martial art that combines slow, deliberate, graceful stretching and isometric exercises with breathing exercises, relaxation, and visualization. I was merely using the reference to quacks to explain why it’s not surprising that physicians might consider tai chi as an intervention in patients with fibromyalgia, given that currently the standard interventions recommended consist of exercise, sleep hygiene, and medications. Unfortunately, all of these interventions have problems, particularly the pharmacological interventions, which in general aren’t all that effective. One might even say that demonstrating their efficacy to be greater than that of placebo interventions has been difficult. Although exercise is helpful in fibromyalgia, it is not known what kind, intensity, or combination of exercise modalities works, and, of the ones that may work, which one works the best. Tai chi, therefore, would appear to be at least as good a candidate exercise regimen as any because of its gentleness, requirement for control, and relaxation. It is not at all unreasonable to hypothesize that tai chi might benefit patients with fibromyalgia, although not for any reasons of “energy flows” or alterations of the flow of qi.

In this particular study, the design was fairly straightforward and is summarized below (click for a larger image):

Basically, the study examined 66 patients diagnosed with fibromyalgia by the time randomization was complete, of which 33 were assigned to the tai chi group and 33 to a sham group that underwent stretching exercises. The specific tai chi intervention used for this clinical trial was described thusly:

The tai chi intervention took place twice a week for 12 weeks, and each session lasted for 60 minutes. Classes were taught by a tai chi master with more than 20 years of teaching experience. In the first session, he explained the theory behind tai chi and its procedures and provided participants with printed materials on its principles and techniques. In subsequent sessions, participants practiced 10 forms from the classic Yang style of tai chi¹⁸ under his instruction. Each session included a warm-up and self-massage, followed by a review of principles, movements, breathing techniques, and relaxation in tai chi. Throughout the intervention period, participants were instructed to practice tai chi at home for at least 20 minutes each day. At the end of the 12-week intervention, participants were encouraged to maintain their tai chi practice, using an instructional DVD, up until the follow-up visit at 24 weeks.

The control intervention consisted of this:

Our wellness education and stretching program similarly included 60-minute sessions held twice a week for 12 weeks.¹⁹ At each session, a variety of health professionals provided a 40-minute didactic lesson on a topic relating to fibromyalgia, including the diagnostic criteria; coping strategies and problem-solving techniques; diet and nutrition; sleep disorders and fibromyalgia; pain management, therapies, and medications; physical and mental health; exercise; and wellness and lifestyle management.²⁰ For the final 20 minutes of each class, participants practiced stretching exercises supervised by the research staff. Stretches involved the upper body, trunk, and lower body and were held for 15 to 20 seconds. Participants were instructed to practice stretching at home for 20 minutes a day.

One can certainly argue whether the sham control intervention was an appropriate sham control or not. It would depend to some extent what sort of stretching exercises were included, as well as other factors, such as the quality of the instructional material and the attention paid to the patients by the wellness education instructor. Also, one might imagine that the self-massage part of the tai chi intervention might have some benefit. It’s hard to say.

What one can say about this is that there does appear to be a suspicious difference between the two groups. Note that the protocol specifies that one tai chi master with over 20 years of teaching experience instructed the tai chi group, while multiple members of the research staff did the control instruction. More worrisome, note that the control group only underwent 20 minutes of exercise during its 60 minute sessions. It’s not specified how long the tai chi group exercised during its 60 minute sessions, but it would not be unreasonable to speculate that most of the 60 minute session was spent doing tai chi. Be that as it may, there was no blinding at all, and it’s a pretty fair bet that the subjects in the tai chi group knew that they were receiving tai chi.

That problem aside, subjects were evaluated before starting the trial and then periodically for the severity of their fibromyalgia symptoms. The primary outcome measure was the change in the score on the Fibromyalgia Impact Questionnaire, a 100-point scale that estimates intensity of pain, physical functioning, fatigue, morning tiredness, stiffness, depression, anxiety, job difficulty, and overall well-being at 12 weeks. Secondary outcomes included the FIQ score at each week, as well as a number of other measures of fibromyalgia severity, chronic pain, and quality of life. Participants continued their regular medications and treatments, making note of any changes that occurred during the study period.

The results demonstrated improvement in FIQ scores in the tai chi group from 62.9±15.5 to 35.1±18.8, with an improvement in the control group from 68.0±11 to 58.6±17.6, with a highly statistically significant p-value. Investigators also noted improvements in other measures of pain and quality of life, all in favor of the tai chi group. More patients in the tai chi group had discontinued their medications to treat fibromyalgia by the end of the study period, but the difference was not statistically significant.

As you might expect, this study had a number of limitations. First, it isn’t very large. Another problem is that it looked at fairly short term outcomes. Fibromyalgia is a chronic condition for which 12 to 24 weeks do not represent a sufficiently long period of time to judge whether any potential responses will be durable. Previous studies have found that exercise can help fibromyalgia but that the effects are not always durable. This is particularly true given that fibromyalgia, like many chronic pain syndromes, is prone to placebo effects due to interventions, regardless of whether they’re effective or not. That’s one aspect of the condition that makes fibromyalgia so difficult to study.

More importantly, I must reiterate that this study was not double-blind. The authors justify this lack of blinding by arguing that there is no accepted and validated sham tai chi intervention. Fair enough. It took many years before scientists studying acupuncture managed to develop and validate various forms of sham needles that successfully blinded both patient and practitioner as to whether they were undergoing “true” or sham acupuncture. The authors also point out that investigators told study subjects that tai chi was being tested. Rather, they told subjects that they were testing the effects of two different exercise training programs, one of which was combined with education. Fair enough as well, but whether this “deemphasis” of tai chi worked or not to minimize expectations and placebo effects is highly arguable. Do the investigators really think that most of the tai chi group didn’t realize they were doing some form of “Eastern” martial art? Yeh et al sum up the difficulty in coming up with an adequate sham intervention for tai chi very well:

The authors state that they tried to minimize any a priori differences between expectations for tai chi and the control intervention, which consisted of stretching and health education, and they report that expectations in the two groups were similar at baseline. However, it seems likely that when a persuasive and enthusiastic teacher of tai chi first explained its potential benefits to the class, expectations in this group were heightened. The authors dutifully suggest that a sham tai chi intervention would have been desirable as a control. Ideally, a placebo control matches all aspects of the therapeutic intervention except for the “active” element of that intervention. But what is the active element of a complex, multicomponent therapy such as tai chi?¹¹ Is it rhythmic exercise, deliberate and deep breathing, contemplative concentration, group support, relaxing imagery, a charismatic teacher, or some synergistic combination of these elements? If so, would the matched control include awkward movements, halted breathing, participant isolation, unpleasant imagery, or a tepid teacher? Would the resulting sham intervention be credible, valid, or even genuinely inactive?

These are all excellent questions. Unfortunately, Yeh et al then strongly imply that a “quixotic” search for the “ideal sham” would be a waste of time, which is rather annoying because such a search doesn’t have to be quixotic, nor would it be a waste of time. All you have to do is to break down tai chi into its key elements: the slow, graceful stretching and isometric exercises, the breathing exercises, the relaxation exercises. If it’s possible to break down tai chi into its important elements, then it would be possible to determine which aspects of tai chi are providing the benefit and which are not.

On the other hand, maybe Yeh et al have a point–except that they didn’t go far enough. I’ll show you what I mean.

Let’s for the moment and for the sake of argument accept the findings of Wang et al. Let’s say that tai chi is the greatest thing since sliced bread and that it alleviates fibromyalgia pain and stiffness better than anything we’ve yet come up with. Let’s assume all of those things are true, just for the moment and then think about it. What thought comes to mind to you? I know what thought comes to mind to me. In fact, I put this thought on a slide that I used when I spoke to the assembled throngs of Chicago Skeptics:

That’s right. Why on earth is this result “provocative” (as Yeh et al describe it) or even the least bit surprising? Why on earth is it in the least bit “alternative” or “complementary”? Stripped to its essence and particularly stripped of its woo elements about qi, all tai chi is is exercise and relaxation, and we already know that exercise can be useful for fibromyalgia! The only question is what type, intensity, and regimen does the most good, and this study answers that question to the extent that it tells us that an exercise regimen resembling tai chi seems to work pretty well. Excellent! Science-based medicine can build on that! But why is this finding “alternative”? It shouldn’t be. Why was this study funded by the National Center for Complementary and Alternative Medicine (NCCAM) and why is it being touted by NCCAM (and GoozNews) as a “success”? It’s a study that had no reason to be done at NCCAM. It could have and should have been funded by the appropriate Institute in the NIH.

As I’ve written time and time again, exercise and relaxation interventions have been completely co-opted by the CAM movement as “alternative” when there is no a priori reason that they should be considered anything other than science-based interventions. Just because they are difficult to study doesn’t make them any less science-based. It just means they are difficult to study and that science has to work harder to validate them. However, CAM supporters know that co-opting less controversial modalities with some degree of prior plausibility that have no real reason not to fall under the mantle of science-based medicine allows them to slip the woo in alongside it. The Trojan horse is diet, exercise, and natural products derived from plants (i.e., herbal medicine). The Greeks jumping out of the belly of the horse are the woo, including acupuncture, “energy medicine” (including the “qi” aspect of tai chi), and even homeopathy. It also helps if the Trojan horse is something “Eastern,” because that’s so much cooler than ancient Western medicine, such as leeches and trying to balance the four humors, although apparently homeopathy, as German and therefore “Western” as it is, is still “cool enough.”

When it comes to the infiltration of quackademic medicine into medical academia, language and how various “alternative” or “complementary” treatment modalities are framed are everything. That’s how CAM can co-opt nutrition as somehow being “alternative.” It’s how CAM can claim exercise as being “alternative.” It’s how CAM can take the long-respected field of pharmacognosy, infuse it with the woo that is herbalism, and suddenly make the whole field suspect. None of these modalities should not be considered “science-based,” but CAM has claimed them as its own and used them as the Trojan horse to enter stealthily the bastions of medical academia. Once there, the horse disgorges the real woo, like acupuncture, reiki, and homeopathy, “integrating” quackery with science-based medicine until it’s hard to tell the difference between the two.

This issue is very relevant to Science-Based Medicine as this is in part an experiment – an attempt to produce a high quality, editorially filtered, but not peer-reviewed, online journal. Our process here is simple. Outside submissions are reviewed by two or more editors and typically are either accepted with minor revisions or rejected. In addition we have a staff of regular contributors – those who have a proven track record of producing high quality articles. There is no pre-publication review for their submissions, and they are able to post directly to SBM.

Because many of the issues we cover are timely, we emphasize speed of publication. Therefore copy-editing is done post-publication – the notion being that our readers can tolerate a few typos in order to gain access to material more quickly.

In addition our pieces are, essentially, crowd sourced. SBM editors and readers provide feedback in the comments, often pointing out ambiguous wording or even outright errors, which can then be quickly fixed or clarified. Editors also provide direct feedback to authors if a more serious issue emerges (which is rare, but happens) and steps are taken to transparently fix such issues. This is, in a way, post-publication peer-review.

By contrast, traditional peer-review is designed to take a long time to produce the highest quality article prior to going to print (even if “print” is online). The strength of this process is that several editors and peer-reviewers have thoroughly gone over the submission, corrected errors, fixed ambiguities, added missing insights, reviewed methodology, checked references, and made sure that the author’s conclusions do not overstep the data. At least this is the ideal – we often write about peer-reviewed publications on SBM that fall far short of this ideal. In the end, peer-review is only as good as the editors and reviewers. I have both been a writer and reviewer, and the process does have many strengths. In the end the article that gets printed is much improved over the original submission.

The weaknesses of the process, however, are the long delay to publications – months or even years. Further, the process is a bit hit or miss and depends largely on the quality of the reviewers. Individuals are quirky, and they may have biases or missing information that will hamper the quality of their review. The more people there are involved in the process the better the quality is likely to be.

As academia grapples with the internet age, the challenge is to rethink the process of peer-review. Specifically, are there ways to leverage the power of the internet to make the review process faster and better? This has happened in the technical sense – the traditional process of peer review is now often done online. For the last article I reviewed I was not sent a hard copy or even an electronic copy. I signed onto a secure website where I had access to the article, and I submitted my review entirely online. This was convenient and also a time-saver. But still the process was slowed by the need to choose reviewers, wait for them to accept and then for those specific reviewers to review the paper. And in the end opinions were solicited from only two reviewers.

Imagine an alternate process by which an article is published online, either on an open site or a secure site that only experts have access to. Then dozens or hundreds of experts can comment on the paper, providing feedback directly to the authors in addition to the editors, who can also respond to the commenters. The result would be more of a dynamic conversation than you get with the current review process. But most importantly, in my opinion, is that you would get a broader range of opinions, and a far greater chance to detect error or bias. An editor or editors can oversee the process, and once it has played itself out the final version of the paper can be published to the public, and become part of the official literature.

Now is the time for experimentation, in my opinion. I don’t know yet what the optimal system would be, but I think a hybrid of peer-review and open publication will emerge. There still needs to be some filter, and some editorial process selecting articles, overseeing feedback and revisions, and approving the final version. Feedback from many experts should be solicited in some fashion, and the process should be interactive.

There are many details to experiment with, however. Should commenters be named or anonymous? Anonymous feedback may be more candid, but people should be held accountable for their expert opinions as well. How should commenters be limited, if at all? Should there be a period of feedback open to the public, or should pre-publication access only be granted to experts, and how should that be limited? (How narrow a field of experts should apply?)

There is also the issue of presenting new research in an open forum prior to adequate review. Will the press troll these pre-review sites looking for juicy stories based upon flawed research that would never ordinarily make it to publication?

The strengths and weaknesses of any new process of peer-review will not be fully appreciated until it is implemented, which is why we are in a period of experimentation. But the experiment is worth doing. In the end we may gain a better, faster and more transparent review process.

There is evidence that antioxidant vitamin supplementation may slow the progression of the dry type when it is already established and moderately severe, but the published evidence does not support the use of these supplements for prevention or for patients with early stages of the disease. Some people are using it for prevention, but there is concern that the risks might exceed any benefit. Of more concern, it appears that a manufacturer’s (Bausch & Lomb’s) advertising has gone way beyond the available evidence. 

This review by the American Academy of Ophthalmology covers the subject well. 

A Cochrane review  found that the evidence for effectiveness of antioxidant vitamin supplements comes mainly from one large trial, the AREDS trial, that was funded by the manufacturer Bausch & Lomb. The AREDS study used vitamin C, 500 mg; vitamin E, 400 IU; beta-carotene, 15 mg (approximately 25,000 IU vitamin A); zinc 80 mg as zinc oxide; and copper, 2 mg, as cupric oxide. (The copper was added to prevent copper-deficiency anemia, an adverse effect of high-dose zinc.)  

The effect was statistically significant but modest. Patients taking the antioxidant and zinc supplement had a 23% chance of developing vision loss from advanced AMD compared to a 29% chance of developing vision loss from advanced AMD for patients taking a placebo pill.

The Cochrane review concluded

The generalisability of these findings to other populations with different nutritional status is not known. Further large, well-conducted randomised controlled trials in other populations are required. Long-term harm from supplementation cannot be ruled out. Beta-carotene has been found to increase the risk of lung cancer in smokers; vitamin E has been associated with an increased risk of heart failure in people with vascular disease or diabetes.

Bausch & Lomb has been selling a product called PreserVision Eye Vitamin AREDS Formula. It contains the same combination of vitamins C, E, beta carotene and zinc that was shown to slow the progression of moderate to advanced macular degeneration in the AREDS trial.  The authors of that trial recommended this treatment for patients with extensive intermediate size drusen (deposits seen on ophthalmoscopy that are characteristic of AMD), at least one large druse, noncentral geographic atrophy in one or both eyes, or advanced AMD or vision loss due to AMD in one eye, and without contraindications such as smoking.

Bausch & Lomb has tried to improve their formula to reduce the risk associated with beta carotene. Their PreserVision Eye Vitamin AREDS 2 Formula omits the beta carotene and adds lutein and zeaxanthin, as well as omega-3 fatty acids. Is the new formula better? We don’t know, because the results of the AREDS 2 trial to test it will not be available until 2013. The product has already been recalled  for reformulation after some patients reported difficulty swallowing the soft gels or experiencing a choking sensation. The recall affects only the US: the product is still available in Europe and other parts of the world, and we can expect to see it back on our shelves as soon as it is put into an easier-to-swallow form.

Bausch & Lomb has been advertising their AREDS 2 Formula as “the latest scientific advancement in eye vitamin therapy” and has urged ophthalmologists to give it to their patients. A recent article in The Medical Letter criticized them, saying “That seems premature at best.” Much harsher words could be used.

Bausch & Lomb also sells other products (Ocuvite, Ocuvite Lutein, etc.) that contain lower amounts of the vitamins and minerals used in the AREDS trial, sometimes with other ingredients added, like lutein and omega-3. The rationale for products with these dosages is hard to fathom.

Is this Big Pharma or Big Supplement? The products carry the FDA warning “not intended to diagnose, treat, cure or prevent any disease,” yet they are clearly being marketed to treat a disease.

Should everyone with moderately severe AMD be taking antioxidant supplements?  I’m not sure. Since there is little else to try, if I had advanced AMD I might be tempted. But I think caution is warranted due to the following red flags: 

• Evidence boils down to one study funded by manufacturer.
• Not replicated.
• Concerns about harmful side effects; no long-term safety data.
• Modest effect.
• No clear rationale for the particular combination and dosage of ingredients.
• Hype by the manufacturer.

High fructose corn syrup (HFCS) has, over the past few decades, gradually displaced cane and beet sugar as the sweetener of choice for soft drinks, candy and prepared foods. In recent years, there have been a growing number claims that HFCS is a significant health risk to consumers, responsible for obesity, diabetes, heart disease and a wide variety of other illnesses. 

In fact, there are large amounts of experimental data supporting the claims that high levels of fructose in the diet can cause hyperlipidemia (high levels of fats — triglycerides primarily — in the blood), obesity and insulin resistance and may lead to cardiovascular disease and type 2 diabetes (for a good recent review, see [1]). A high-fructose diet is thought to cause hyperlipidemia (and probably visceral obesity) because fructose is preferentially “sent”  to fatty acid synthesis and it also reduces the activity of lipoprotein lipase (for a good review, see [2]). The mechanisms by which fructose causes insulin resistance and cardiovascular disease are less clear (see, for example [3], [4] and [5]), but there is no shortage of hypotheses. Despite the fact that some of the underlying mechanisms are not clear, the evidence seems pretty solid that there are real risks to high fructose consumption.

However, the question remains — is HFCS more of a health risk than other sweeteners? Many of the sources that demonize HFCS list alternative sweeteners — cane sugar, honey, agave syrup, etc. — that they claim are healthier than HFCS, but those claims usually rest primarily on the fact that these alternatives to HFCS are “natural” rather than any actual data showing that they are safer than HFCS. 

Sugar 101:

Before we can properly analyze these claims, we need to understand a bit about sugar. To begin with, what is sugar? To most people, sugar is the white granulated solid that they find in the sugar bowl. In reality, sugar is a much broader term. There are two general classes of sugars — aldose and ketose — and over twenty individual sugars (monosaccharides), if you limit yourself to only those found in nature. Of these, only a few play any significant role in human nutrition, primarily glucose, fructose and galactose (ribose, a sugar that forms the backbone of DNA and RNA, also plays a minor nutritional role). 

Further complicating the issue, there are also sugars — disaccharides — that are compounds made of two monosaccharides covalently bound together. The most common of these is sucrose, a compound made by joining one molecule of glucose to one molecule of  fructose. Sucrose is the sugar in the average sugar bowl. It is also the sugar in brown sugar, molasses, cane sugar, beet sugar and is the major component of maple syrup (and maple sugar). Another common disaccharide is lactose (milk sugar), which is a combination of glucose and galactose. Less commonly encountered is maltose, a combination of two molecules of glucose. 

Starches, such as corn starch, are also sugar. They are made up of long interlinked chains (polymers, also known as polysaccharides) of individual sugars (usually glucose). Cellulose, the major component of paper and wood, is also a polymer of glucose (with different bond geometries). Insect and crustacean shells are made of a sugar polymer known as chitin (also a major component of fungal cell walls). We literally live in a world of sugar. 

One final note about sugars — humans only absorb monosaccharides; no matter what form the sugar enters the digestive tract, it is only absorbed after it is broken down to its component monosaccharides (there are, as usual in biology, a few minor exceptions to this rule). There are a variety of enzymes — amylases, disaccharidases, etc. — that perform this function. Any disaccharide or polysaccharide that isn’t broken down (such as the raffinose and stachyose in beans and many other gas-causing foods) remains inside the gut, providing food for our gut bacteria.

“Natural” Sweeteners:

Now, let’s take a look at some of the sugar-based sweeteners in common use today. Honey was probably the first sweetener — at least in the part of the world where honey bees are native. Honey is about 82% sugar, with almost all the remainder being water. The sugar in honey is 43% glucose,  50% fructose, 4% galactose, 2% maltose, 1% sucrose and trace amounts of other sugars [6]. As mentioned earlier, it is considered by many to be a natural sweetener that is a healthy alternative to HFCS. 

Another sweetener used in ancient times — especially in regions where honey bees were not native — is tree sap. The most famous of these is the sap of sugar maple trees, used to make maple syrup and, when crystallized, maple sugar. Natural maple syrup is 60% sugar, with that sugar being 95% sucrose, 4% glucose and 1% fructose [6]. 

Fruit juices also have an ancient history of use as sweetening agents and — not surprisingly — are often cited as natural and healthy alternatives to HFCS. The sugar content of fruits varies with the type of fruit and even with the variety. Apples, for instance, are a bit over 10% sugar by weight, with that sugar being 57% fructose, 23% glucose and 20% sucrose. Peaches, in contrast, are 8.4% sugar by weight with that sugar being 57% sucrose, 23% glucose and 18% fructose. Pears – the most common fruit juice used in sweetening - are 9.8% sugar, with that sugar being 64% fructose, 28% glucose and 8% sucrose. Table grapes are about 15% sugar, with the sugars being 53% fructose and 47% glucose [6]. 

Sucrose, the disaccharide in common table sugar, was originally obtained in ralatively pure form from sugar cane, which can only grow in the tropics. The high cost of cane suger led to a search for alternative sources. As early as the 1700’s, sucrose was being extracted from sugar beets, but it took both selective breeding of sugar beets to increase their sucrose content and improvements in the extraction process to make beet sugar economically viable. By the late 1800’s and early 1900’s, sucrose from sugar beets had outstripped cane sugar in Europe and the U.S. Sugar beets have the advantage of growing throughout the temperate zone, closer to the demand. Just to be clear, beet sugar and case sugar are indistinguishable — they are exactly the same chemical compound (sucrose).

The rise of HFCS:

So, with all of these sugar-based sweeteners available, what prompted the development of HFCS?

Corn syrup is a relatively recent arrival as a sweetener; it had to wait until food processors discovered how to take corn starch (which, like most starches, is a polymer composed of long interlinked chains of glucose molecules) and break it down into isolated glucose molecules using the enzymes amylase and maltase. Commercial amounts of corn syrup were available by the middle of the 20^th century [7]. Corn syrup was so much cheaper than sucrose that it saw extensive use as a sucrose substitute for thickening foods and to help retain moisture. It wasn’t much used solely as a sweetener because it isn’t as sweet as sucrose.

The fact is that not all sugars are equally sweet. If we assign sucrose (table sugar) a sweetness of 100%, glucose has a sweetness of 60 – 75% (on a gram-per-gram basis) and fructose has a sweetness of 140 – 170% [8][9][10]. (Note: the sweetness of fructose varies with its conformation, and so will differ under different circumstances [11]) Candy and soft drink manufacturers exploited the greater sweetness of fructose even before HFCS was available by using what is called “invert sugar”. Invert sugar is sucrose that has been treated with a weak acid solution and then recrystallized (to get rid of the acid). This treatment causes a portion of the sucrose to break apart into fructose and glucose. Although the glucose part is less sweet than sucrose, the fructose is so much sweeter that the overall effect is to get more sweetness with less sugar. This allowed the manufacturers to use less sugar and thereby save money, even though invert sugar was more expensive than plain sucrose.

In 1957, a process was developed to convert some of the glucose in corn syrup to fructose, yielding a product that was 42% fructose and 58% glucose [12]. This dramatically increased its sweetness, making a product that was a commercially viable competitor to sucrose as a sweetener. This was HFCS 42, which has a sweetness — gram-per-gram — slightly greater than sucrose (110%).

The primary advantage of HFCS 42 to food manufacturers was its low cost — much lower than the cost of sucrose. Secondary advantages were that it retained moisture better than sucrose (twice as many molecules), was slightly sweeter than sucrose (so less was needed), was in a liquid form and didn’t caramelize as readily as sucrose (this last one could be an advantage or a disadvantage, depending on the use).

Later, HFCS manufacturers began putting some of their HFCS 42 through separation columns to produce syrup that was 90% fructose (HFCS 90) [5]. Today, the bulk of the HFCS 90 production is used to make corn syrup with 55% fructose, known as HFCS 55, although a very small amount is used in some reduced-calorie confections (HFCS 90 is about 60% sweeter per gram than sucrose, which allows a 35% reduction in the amount of sugar used). 

With the introduction of HFCS 55, which is 25% sweeter than sucrose, food manufacturers found that the slightly increased price (which was still less than sucrose) was more than offset by the fact that they needed less of it to get the same level of sweetness. 

That’s right, HFCS allowed food manufacturers to use less sugar — and thus fewer sugar calories — in their products without compromising sweetness. Using sucrose — cane or beet sugar — would require 20% more sugar (and 20% more sugar calories) than using HFCS 55. 

How safe are other sweeteners compared to HFCS?:

Still, none of this alters the fact that a diet high in fructose has been shown to cause — or at least contribute to — hyperlipidemia, obesity, insulin resistance and cardiac disease. However, those who have been paying attention will have noticed that HFCS is not the ONLY sweetener that contains significant amounts of  fructose.

In fact, sucrose — even “natural” cane sugar — is 50% fructose once it is digested and absorbed. While this is 20% less than the fructose content of HFCS 55, food manufacturers need to use less (about 20% less) HFCS 55 to get the same sweetness, so it’s a wash as far as fructose content.

Honey, long touted as a “healthy” and “natural” alternative to evil HFCS, is also 50% fructose. Agave syrup (also called agave nectar), often promoted as a healthy alternative to HFCS (especially in diabetics),  is very high in fructose, although there is some disagreement over how much fructose it contains. According to the USDA, the sugar in cooked agave is 87% fructose (due to breakdown of fructans — a starch-like polymer of fructose — in the plant when it is cooked) [6]. A wholesale supplier of agave syrup, however, lists the fructose as 70 — 75% of the total sugar in their syrup [13]. Either way, agave syrup is higher in fructose than any other natural sweetener (and any form of HFCS except HFCS 90). 

Even fruit juices (and what could be more natural and healthy than fruit juice?) are 40 — 70% fructose, if you count the fructose in sucrose. And for those who argue that ingesting sucrose delays the absorption of fructose, Monsivais et al (2007) showed that sucrose breaks down spontaneously in carbonated beverages (and, presumably, all acid solutions), with 50% of the sucrose being hydrolyzed to fructose and glucose within the first 30 days after bottling [14].

Finally, a study that directly compared the short-term effects of fructose, HFCS and sucrose showed that they are indistinguishable [15]. 

What does all this mean?:

So, what are the take-home messages from all of this? 

1. HFCS 42 and HFCS 55 have essentially the same amount of fructose, as a fraction of their total sugar, as honey, sucrose (cane or beet sugar) or maple syrup/sugar (to be agonizingly precise, HFCS has slightly less, and HCFS 55 has slightly more).
2. HFCS 42 and HFCS 55 have an equal or smaller amount of fructose, as a fraction of their total sugar, as many commonly consumed fruits.
3. Agave syrup has higher fructose content than any type of HFCS except HFCS 90. 

For people who are worried about their health or their children’s health — and who isn’t, these days — the data suggest that the best choice is to reduce intake of all sweeteners containing fructose. That includes not only the evil HFCS, but also natural cane sugar, molasses (which is just impure cane sugar), brown sugar (ditto) and honey. Even “unsweetened” (no added sugar) fruit juices need to be considered when limiting your family’s fructose intake. 

Finally, the best nutritional advice is to eat everything in moderation — and that includes sweets. While a diet high in fructose may increase your risk of obesity, diabetes and heart disease — maybe — a fructose-free diet is not guaranteed to prevent those diseases. Eat a variety of foods, including a small amount of sweets, get enough exercise, watch your (and your children’s) weight and see your doctor for regular health check-ups. 

And stop worrying that HFCS is poisoning you and your children. 

Until later,

Jim Laidler

 Jim Laidler, MD graduated from USC School of Medicine and went on to do an internship in Pediatrics before spending four years as a flight surgeon in the US Army. After his military service, he completed a residency in Anesthesiology and a fellowship in Pain Medicine at the University of Illinois. He practiced for several years in Alaska and Oregon before deciding to take up a new career in research. He is currently finishing his PhD thesis in Molecular Biology in Portland, Oregon.

DISCLAIMER:  The opinions expressed by Dr. Laidler are his own and not those of any organization or institution he is affiliated with. His writings are not meant to diagnose or treat any diseases or disorders except ignorance and misinformation.

References

1. Stanhope KL and Havel PJ. Fructose consumption: recent results and their potential implications. Ann. NY Acad. Sci. 2010 Mar;1190(1):15-24.
2. Chong MF, Fielding BA and Frayn KN. Mechanisms for the acute effect of fructose on postprandial lipemia. Am. J. Clin. Nutr. 2007 Jun;85(6):1511-20.
3. Li P, et al. A high-fructose diet impairs Akt and PKCzeta phosphorylation and GLUT4 translocation in rat skeletal muscle. Horm. Metab. Res. 2008 Aug;40(8):528-32.
4. Kebede M, et al. Fructose-1,6-bisphosphatase overexpression in pancreatic beta-cells results in reduced insulin secretion: a new mechanism for fat-induced impairment of beta-cell function. Diabetes. 2008 Jul;57(7):1887-95.
5. Mellor KM, et al. Elevated dietary sugar and the heart: experimental models and myocardial remodeling. Can. J. Physiol. Pharmacol. 2010 May;88(5):525-40.
6. U.S. Department of Agriculture, Agricultural Research Service. 2009. USDA National Nutrient Database for Standard Reference, Release 22. Nutrient Data Laboratory Home Page, http://www.ars.usda.gov/ba/bhnrc/ndl.  accessed 29 July 2010
7. Alexander R.J. Maltodextrins: production, properties and applications. In: Starch Hydrolysis Products; Worldwide Technology, Production, and Applications (F.W. Schenck and R.E. Hebeda, eds.) 1992, pp.233-276. VCH Publishers, New York.
8. Schiffman SS et al. Synergism among Ternary Mixtures of Fourteen Sweeteners. Chem. Senses. April 2000; 25(2):131-140 
9. Hanover LM, White JS. Manufacturing, composition and applications of fructose. Am. J. Clin. Nutr. Nov. 1993; 58(5): 724S-732S
10. Davis EA. Functionality of sugars: physicochemical interactions in foods. Am. J. Clin. Nutr. 1995; 62(1):170S-177S
11. Shallenberger RS. Intrinsic chemistry of fructose. Pure & Appl. Chem. 1978; 50(11-12):1409-1420
12. Marshall RO, Kooi ER, Moffett GM. Enzymatic conversion of D-glucose to D-fructose. Science 5 April 1957; 125(3249):648-649.
13. The Colibree Company, Inc. website. accessed 23 July 2010. http://agavesyrup.net/product.html
14. Monsivais P et al. Sugars and satiety: does the type of sweetener make a difference? Am. J. Clin. Nutr. 2007; 86(1):116-123 
15. Stanhope, KL et al. Twenty-four-hour endocrine and metabolic profiles following consumption of high-fructose corn syrup-, sucrose-, fructose-, and glucose-sweetened beverages with meals. Am. J. Clin. Nutr. 2008 May; 87(5):1194-1203.

One of the pillars of science has traditionally been the peer review system. In this system, scientists submit their results to journals for publication in the form of manuscripts. Editors send these manuscripts out to other scientists to review them and decide if the science is sound, if the methods appropriate, and if the conclusions are justified by the data presented. This step of the process is very important, because if editors don’t choose reviewers with the appropriate expertise, then serious errors in review may occur. Also, if editors choose reviewers with biases so strong that they can’t be fair, then science that challenges such reviewers’ biases may never see print in their journals. The same thing can occur to grant applications. In the NIH, for instance, the scientists running study sections must be even more careful in choosing scientists to be on their study sections and review grant applications, not to mention picking which scientists review which grants. Biases in reviewing papers are one thing; biases in reviewing grant applications can result in the denial of funding to worthy projects in favor of projects less worthy that happen to correspond to the biases of the reviewers.

I’ve discussed peer review from time to time, although perhaps not as often as I should. My view tends to be that, to paraphrase Winston Churchill’s invocation of a famous quote about democracy, peer review is the worst way to weed out bad science and promote good science, except for all the others that have been tried. One thing’s for sure, if there’s a sine qua non of an anti-science crank, it’s that he will attack peer review relentlessly, as HIV/AIDS denialist Dean Esmay did. Indeed, in the case of Medical Hypotheses, the lack of peer review let the cranks run free to the point where even Elsevier couldn’t ignore it any more. One thing’s for sure. Peer review may have a lot of defects and blindnesses, but lack of peer review is even worse. It’s no wonder why cranks of all stripes loved Medical Hypotheses.

None of this means that the current system of peer review is sacrosanct or that it can’t be improved. In the 25 years or so I’ve been doing science, particularly in the 20 years since I began graduate school, I’ve periodically heard lamentations asking, “Is peer review broken?” or demanding that the peer review system be radically altered or even abolished. Usually they occur every two or three years, circle around scientific circles for a while, and then fade away, like the odor of a particularly stinky fart. It looks as though it’s time yet again, as a rather amusingly titled article in a recent issue of The Scientist, I Hate Your Paper: Many say the peer review system is broken. Here’s how some journals are trying to fix it:

Twenty years ago, David Kaplan of the Case Western Reserve University had a manuscript rejected, and with it came what he calls a “ridiculous” comment. “The comment was essentially that I should do an x-ray crystallography of the molecule before my study could be published,” he recalls, but the study was not about structure. The x-ray crystallography results, therefore, “had nothing to do with that,” he says. To him, the reviewer was making a completely unreasonable request to find an excuse to reject the paper.

Kaplan says these sorts of manuscript criticisms are a major problem with the current peer review system, particularly as it’s employed by higher-impact journals. Theoretically, peer review should “help [authors] make their manuscript better,” he says, but in reality, the cutthroat attitude that pervades the system results in ludicrous rejections for personal reasons—if the reviewer feels that the paper threatens his or her own research or contradicts his or her beliefs, for example—or simply for convenience, since top journals get too many submissions and it’s easier to just reject a paper than spend the time to improve it. Regardless of the motivation, the result is the same, and it’s a “problem,” Kaplan says, “that can very quickly become censorship.”

I daresay pretty much every scientist has submitted a paper (probably several) papers, only to have outrageously unreasonable reviewer comments returned to them similar to those Kaplan described above. I myself have experienced this phenomenon on multiple occasions. Most recently, it took me multiple submissions to four different journals to get a manuscript published. It took nearly a year and a half and more hours of writing and rewriting and doing more experiments than I can remember. But “censorship”? I’m half tempted ot respond to Dr. Kaplan: Censorship. You keep using that word. I do not think it means what you think it means. In fact, I just did.

No, incompetent or biased peer review is not “censorship.” It’s incompetent or biased peer review, and it’s a problem that needs to be dealt with wherever and whenever possible. As for “rejecting papers for convenience,” perhaps Dr. Kaplan could tell us what a journal editor should do when he or she gets so many submissions that it’s only possible to publish 10 oe 20% of them. Peer reviewers aren’t paid; with the proliferation of journals the appetite of the scientific literature for peer reviewers is insatiable. Moreover, reviewing manuscripts is hard work. That’s why higher impact journals not infrequently use a triage system, where the editor does a brief review of submitted manuscripts in order to determine whether it is appropriate for the journal or has any glaring deficiencies and then decides whether to send them out for peer review.

I have the same problem with another complaint in the article, that of Keith Yamamoto:

“It’s become adversarial,” agrees molecular biologist Keith Yamamoto of the University of California, San Francisco, who co-chaired the National Institutes of Health 2008 working group to revamp peer review at the agency. With the competition for shrinking funds and the ever-pervasive “publish or perish” mindset of science, “peer review has slipped into a situation in which reviewers seem to take the attitude that they are police, and if they find [a flaw in the paper], they can reject it from publication.”

He says that as though that were a bad thing. There is no inherent right to publish in the scientific literature, and papers with major flaws should be rejected. How major or numerous the flaws have to be to trigger rejection comes down to the policies of each peer reviewed journal. Don’t get me wrong. I’m not all Pollyannaish, thinking that our current peer review system is the best of all possible worlds. Improvement in the system can only be good for science, if true improvement it is, and there are some good suggestions for improving peer review in the article.

Perhaps the most pernicious problem in peer review is the problem of reviewers with a bias or an axe to grind. To attack this problem, some journals are trying to eliminate anonymous peer review. The idea is that, if everything is completely open and transparent, with the peer reviews being “part of the record,” so to speak. I can see the appeal of this change. A reviewer is less likely to “be a dick” if he or she knows that the review will be in the public record, for all to see, or at least that the manuscript authors know who the peer reviewers are. Personally, I have a problem with this, mainly because I think the downside of getting rid of reviewer anonymity outweigh the potential good side. For example, I rather suspect that a lot of reviewers would be reluctant to be too hard on the manuscripts submitted by big names in their field if they knew their names would be on the review. You don’t want to piss off the big Kahunas in your field. These are the people who organize conferences, invite outside speakers, and sit on study sections. In general, it’s not a good idea to get on their bad side, particularly if you’re still young and struggling to make a name for yourself in the field. For example, I’m a breast surgeon, and I know I would be reluctant to apply even deserved respectful insolence to a paper by, for example Monica Morrow or Armando Guliano (two very big names in the field) if I knew they knew who was reviewing their papers and even if the paper I was reviewing was obviously crap.

Personally, I like the idea expressed here:

Frontiers journals are trying to find a balance by maintaining reviewer anonymity throughout the review process, allowing reviewers to freely voice dissenting opinions, but once the paper is accepted for publication, their names are revealed and published with the article. “[It] adds another layer of quality control,” says cardiovascular physiologist George Billman of The Ohio State University, who serves on the editorial board of Frontiers in Physiology. “Personally, I’d be reluctant to sign off on anything that I did not feel was scientifically sound.”

As would I.

Another idea I’ve proposed before in debates about peer review is to go for full anonymity. In other words, reviewers are anonymous to the authors of manuscripts, and–here’s the change–the authors are anonymous to the reviewers. One advantage to such an approach is that it would tend to alleviate any effect of personal dislikes or even animosity, and it would “take the glow” off of big names submitting papers, hopefully making it less likely that reviewers would give a weak paper a pass because it came from a big name lab. On the other hand, in small fields, everyone knows what everyone else is doing; so anonymizing the manuscript authors would often not hide the identity of the authors.

The last two problems with peer review discussed by this paper are highly intertwined:

• Peer review is too slow, affecting public health, grants, and credit for ideas
• Too many papers to review

The first of the two problems above is largely a function of the last. As I pointed out above, the appetite of journals for peer reviewers is insatiable, and peer reviewers are not paid. They’re expected to do it out of the goodness of their hearts, because it’s service back to the community of science. True, peer review activity counts when it comes time to be considered for promotion and tenure, but it’s a lot of work for very little reward, not to mention articles like the one under discussion, in which seemingly no one can get it right. Oddly enough, there was one suggestion that I didn’t see anywhere in this article, and that’s to pay reviewers for their hard work. Apparently the financial model of journal publishing won’t support it.

Be that as it may, one solution to this proposed is to go to a model like that of PLoS ONE:

An alternative way to limit the influence of personal biases in peer review is to limit the power of the reviewers to reject a manuscript. “There are certain questions that are best asked before publication, and [then there are] questions that are best asked after publication,” says Binfield. At PLoS ONE, for example, the review process is void of any “subjective questions about impact or scope,” he says. “We’re literally using the peer review process to determine if the work is scientifically sound.” So, as long as the paper is judged to be “rigorous and properly reported,” Binfield says, the journal will accept it, regardless of its potential impact on the field, giving the journal a striking acceptance rate of about 70 percent.

“The peer review that matters is the peer review that happens after publication when the world decides [if] this is something that’s important,” says Smith. “It’s letting the market decide—the market of ideas.”

This approach has also proven successful, with PLoS ONE receiving their first ISI impact factor this June—an impressive 4.4, putting it in the top 25 percent of the Biology category. And with a 6-fold growth in publication volume since 2007, Binfield estimates that “in 2010, we will be the largest journal in the world.” Since its inception in December 2006, the online journal has received more than 12 million clicks and nearly 21,000 citations, according to ISI.

I realize that my experience is anecdotal, but among the worst reviewer experiences I ever had was submitting a manuscript to PLoS ONE. In my case, at least, the reviewers were every bit as brutal as any I have ever experienced, which I found odd, because after PLoS rejected my manuscript, I turned it around and reformatted with minor revisions for a different journal. I even got it accepted after one round of revisions to a “traditional” journal with an impact factor significantly higher than that of PLoS ONE. Maybe my experience was anomalous, but I don’t accept the argument that PLoS ONE represents the savior of anything or even that much of an improvement over traditional publication methods.

More intriguing is the concept of letting authors take their peer review with them when they resubmit their manuscript to a different journal after rejection. When I first heard of this concept, I was quite skeptical. After all, if your paper was rejected, chances are that the reviews probably weren’t that positive or that they were, at best, lukewarm. Personally, I can say unequivocally that after I’ve had a paper rejected from a journal, the last thing I want is to show the next journal to which I submit my manuscript the crappy reviews that I got the first time around. I want a fresh start; that’s why I resubmit the manuscript in the first place! Peer reviews from the journal that rejected my manuscript are not baggage I want to keep attached to the new manucript as I submit it to another journal.

In the end, peer review is the mainstay of scientific publishing. While it has a great deal of difficulty detecting fraud, it can usually detect gross methodological flaws in the science being reported, which is about all that can be expected. Post publication evaluation of such results by fellow scientists, after all, is what ultimately decides what science endures and what science ends up being forgotten. No one claims that the current system is perfect or even that it doesn’t have a lot of problems, some of them serious. However, the cries that “peer review is broken” strike me as a perennial complaint without that much substance. As scientists, we can and should do whatever is feasible to shore up the peer review process, and we shouldn’t be afraid of trying out new models of peer review, such as some of the models described in this article. Just don’t throw the baby out with the bathwater. Peer review may have significant problems, but it works surprisingly well, given its ad hoc nature, and it’s incumbent upon those who would overthrow it or radically alter it to show that the systems that vie to replace it would result in better science being published.

He was unvaccinated, but that was because of his age.  He was part of the population that is fully dependent on herd immunity for protection, and that is exquisitely prone to a life-threatening course once infected.  This is a topic we’ve covered ad nauseum, and I’m not inclined to go into greater depth in this post.  Suffice it to say his death is a failure at every level; we, both as medical professionals and as a society at large need to do a better job of protecting our children from preventable diseases.

Different approaches are required if we hope to improve our rates of vaccination.  Though we devote a great deal of time and effort on this blog addressing the various issues surrounding vaccination, none of us are so deluded (believe it or not) as to think that our posts will be persuasive to all of our readers, much less the general public.  In fact, I’d broaden that statement further, and say that the medical community in general is delusional if we think we can resolve the public health threat posed by the undercurrent of distrust in the vaccination program on our own.  No number of studies, consensus statements, or ad campaigns by the CDC, WHO, AAP, AAFP, etc (not to mention countless blog posts) will be sufficient to maintain the public trust in the vaccination program.  We need public support as well.

I’m not saying the work done by the medical community has been a wasted effort, far from it.  The vaccination program (along with the rest of modern medicine) must continue to be held to the highest possible scientific standard, we must perpetually re-examine our practice and recommendations, and we need to improve the communication between the public and medical communities.  These projects are absolutely essential.  However, the fact remains that no matter how strong the science may be, how large and uniform the expert consensus, how eloquent the argument, people are far more likely to be swayed by the opinion of a trusted friend, the actions of their peers, or the words of a celebrity, and we are fools to ignore that fact.*  Sometimes, different approaches are required.

Here is one example of a different approach: this Sunday, Penn & Teller’s “Bullshit” closed out their season by addressing the anti-vaccination movement.  Orac provided a review of the episode on Respectful Insolence, and I don’t have much to add to his analysis.  The show is characteristically blunt in their opinion, heavily slanted toward entertainment rather than informational content, and doesn’t shy from ad-hominems… in other words, you won’t find a transcript on SBM any time soon.  On the other hand, most of their arguments were sound, well grounded in science, and they didn’t even consider creating a false-balance.

I am certain Penn & Teller’s finale will do nothing to sway hardcore anti-vaccinationists, and its style is likely to turn off some others, but nevertheless the show has its place.  There is a fraction of the population for whom a blunt statement of fact and righteous anger (and Penn can provide both in spades) is exactly the type of presentation they need to see.

Here’s another example, and one that, while less flashy than Penn & Teller’s effort, is likely to have a broader appeal and greater impact in the long run.  In Atlanta, Georgia this September is a rather sizable (~40,000 people) convention called Dragon*Con.  Our skeptic friends at Skepchick.org and the newly formed “Women Thinking Free Foundation” are launching their their “Hug Me! I’m Vaccinated” education campaign at Dragon*Con, and have organized a local pertussis vaccination clinic during the event.  In coordination with the local health officials, they are providing free TDaP vaccinations for any Dragon*Con participant, as well as information and educational materials.**

I love this type of project.  As a public outreach effort Skepchick and Women Thinking Free Foundation are doing everything right by:

• Choosing to address an issue, pertussis, that is currently in the public eye
• Finding a venue with people from all over the nation (and world), thus reaching multiple communities with their message
• Coordinating with the local public health service to provide accurate information and safe services
• Targeting a population, primarily young adults, that represent a primary reservoir of pertussis and that have or will soon have children requiring vaccination
• Going out to the people to provide cost-free vaccines, thus eliminating the barriers that finances, a lack of access to health care, or even sheer apathy may present
• Providing a positive example as both parents and peers, and in doing so filling a gap in public communication the medical community can never fill on its own

That last point is perhaps the most important, and the easiest to emulate.  It doesn’t take access to a TV show or a Herculean effort to coordinate a vaccine drive to make a difference.  It doesn’t even require a confrontation.  You have more influence over the people in your life than any public health official or blog will ever have.  Just speak up, let people know you got your kids vaccinated today, let them know you got vaccinated!

As we strive to improve the quality of care and communication from the medical community, seeing concerned citizens stand up to make a difference in whatever way they can, no matter how large or small their sphere of influence, gives me hope.  Hope that maybe, just maybe, this might have been the last child I’ll ever fail to save from pertussis.

* I can see some accusing me of hypocrisy here for advocating the use of celebrity and personal anecdotes to provide support for vaccination.  It’s been said before, but let me be clear: Jenny McCarthy (as an example) is not wrong because she’s a celebrity, or a mother, because she’s not medically educated, or because she’s providing her own personal anecdotal experience.  She’s wrong because the basis for her arguments and anecdotes begins and ends at her celebrity/motherhood status instead of with facts and evidence; she is wrong because she misrepresents the state of objective reality.

** If you feel inclined to help, the Women Thinking Free Foundation is accepting donations on their website linked above to offset the cost of this and future outreach and educational projects.

Avandia, or rosiglitazone, is one of a new class of anti-diabetes drugs approved for marketing by the FDA in 1999. It, and its competitor, Actos (pioglitazone), are thiazolidinediones (TZD’s), a class of drugs that act to decrease insulin resistance. A third TZD, troglitazone, was withdrawn after studies showed a 1:20,000 incidence of hepatitis and potential liver failure.

Avandia was a clear market success, with sales peaking at $2.5B in 2006, the year prior to the first research “shot across the bow” regarding patient safety.

Among scientists, the mid-July review capped a rising level of concern. Among the public, a tide of safety concern had been rising for several years, flowing from the scientific community into the legal and political arena.

The story is a paradigm of how science and public opinion interact to determine the fate of a medical treatment where there is little dissent over effectiveness, but little agreement over safety.

Setting the Stage for the Review Process

The FDA charges Advisory Panels with evaluating therapeutic agents and devices on the scientific evidence, driven by concerns over two criteria: effectiveness and safety. The panel’s safety assessment must look at risk (side effects, adverse reactions, and dosage limits) in the context of expected benefit.

But with marketing approval by the FDA, questions of risk may still remain. Most companies will try to anticipate safety concerns that arise during the pre-marketing development of the drug. Research protocols are altered to include new findings….but you can’t check for everything. When the FDA judges that the unanswered questions are not of sufficient concern to postpone approval to market the drug, they will direct “post-marketing” studies to fill in the blanks.

Most of the hoopla from these panels comes from disagreements about safety. Drugs and devices that are clearly ineffective never make it to an initial panel hearing. Even if the agent is only slightly or partially effective, this measure is considered met.

Panels do not carry out comparisons between drugs that address the same health benefit to find the best one. With healthcare reform, a closer look at which agents do a better job will become more common, a process known as “comparative effectiveness.” But FDA panels are not charged with that. They compare drugs, yes, but mainly in pursuit of safety and effectiveness, not whether it’s the best.

A vote is taken. The results of the vote constitute the recommendation of the panel to the FDA, who makes the final decision.

Last week, when all was said and done, the panel recommended continued approval for Avandia, but with stronger restrictions on its use, and additional warnings about risk….I think. The voting process–a multiple choice method–left some lay observers in doubt.

From the public’s point of view, these decisions can seem arbitrary, or influenced by outside interests: patient safety advocacy groups or the pharmaceutical industry. Journalistic interpretations of FDA action make no attempt to assess data, so it’s not surprising that many in the country think that science is a process of dueling research studies, a fight to see who can amass the most—and loudest–supporting authority.

But the process is not like that.

The Science Of the Review

The 2-day meeting illustrated the complexity and limitations of determinations of safety. Oral agents in the treatment of diabetes have had a checkered history. Most have significant warnings and precautions, and well-defined–if rare–serious adverse reactions. The issue with Avandia is whether the drug is a significant risk of heart attacks (MI) and other heart disease, and if so, of enough risk that it should be withdrawn.

Two questions needed answering: does Avandia add to the heart risk of diabetes, and if so, is it at odds with that of similar approved oral agents for diabetes?

The advisory committee of the Division of Metabolism and Endocrinology Products had previously met in 2007 to consider just these issues. A signal study combining data from 42 clinical trials had been published demonstrating an odds-ratio of 1.4 (CI: 1.1-1.8, p=0.02) for “non-serious and serious myocardial ischemia.” Back then the committee thought the study was strong enough to be concerning, but there was too much variation in (1) the length of the studies (mostly short), (2) what other medicines the patients might have been taking, and (3) other characteristics of the patient populations. When the committee tried to eliminate this variation (by analyzing sub-sets of the data to control for variation) the odds ratio for ischemia fell to 1.0 (no increased risk) or less.

An even bigger blow came when Avandia was compared to placebo versus Avandia compared to other anti-diabetic agents: the increased risk was present ONLY in the placebo studies. Maybe ALL the anti-diabetic drugs examined were similarly risky.

There were 3 longer term studies available (DREAM, ADOPT, and, preliminarily, RECORD) that showed higher event rates for MI with Avandia, but lower mortality than controls. Not very helpful.

The Office of New Drugs (OND) thought Avandia should be “thumbs up” with warnings, the Office of Surveillance and Epidemiology (OSE) thought it should be “thumbs down.” The findings were submitted to the Oversight Board, which went with OND. Ultimately, not everybody agreed, but the 2007 data was inconclusive, the WARNINGS and PRECAUTIONS label was updated, post-marketing studies were directed (including RECORD, which was ongoing), and Avandia was retained.

Then Why Did They Meet Again In 2010?

Science is an iterative process. You keep going back to look at issues with new variables, under different conditions, and in the light of new data. Particularly if there are continuing reports of adverse events.

Specifically, there was new data comparing Avandia to Actos, and updated information on heart risk. The controversy had also spilled over into the public arena, including lawsuits, and a Senate special report.

Patients, Public Opinion, and Politics Enter the Process

Over 13K lawsuits have been filed against Avandia, claiming harm due to the drug. Potential awards from those suits total between $1 and $6B. Patients clearly noticed there was dissension in the scientific community over safety. This is always a spur to litigation. In the Vioxx case, lawsuits exploded similarly. By May of 2010, the company GlaxoSmithKline (GSK) had agreed to settle 700 Avandia suits for a total of $60M.

Constituent complaints had pushed the Senate Finance Committee to conduct a two-year investigation. The report, released in February of this year, alleged the company (GSK) was aware of the possible cardiac risks years before such evidence became public. It also charged that the company intimidated physicians, focused on strategies to minimize findings that Avandia may increase cardiovascular (CV) risk, and sought ways to downplay findings that the rival drug Actos was safer.

Politics, trolling trial lawyers, and public opinion were sniping at the ‘07 review, and pressing for a new FDA review. The Director of OSE, who had argued in 07 to withdraw the drug, sent a memo in Oct of ’09 up the chain urging reconsideration:

“The benefits of rosiglitazone do not outweigh its risks. I recommend granting the Citizen Petition’s request that FDA remove rosiglitazone from the market.”

The FDA decided to re-open the question of Avandia’s safety; directives were issued to gather data for a hearing in July.

The Science In 2010

Background material alone for the 2010 Advisory Panel meeting was 765 pages long. Sessions from both days were Live-Blogged for internet viewers (a large number of whom were traders attempting to anticipate stock prices).

New data included completion of the third long-term study (RECORD), comparing Avandia to older anti-diabetic drugs. The data showed that Avandia was no more risky than the others with regard to cardiovascular death. The manufacturer argued that this supported removing the (CV) warning from the label. The study, conducted by the manufacturer, was criticized on several grounds by the Division of Cardiovascular and Renal Products, (DCRP) with allegations of “mishandling” of cases (recording errors, record changes, improper adjudication of endpoints).

An FDA cardiology consultant from OND (recall that office had recommended in ‘07 to keep Avandia) reviewed the DCRP allegations, and while admitting some limitations, argued in just as much detail that the DCRP erred by re-defining the study’s endpoints (post-study) to include more CV events. Admitting there was “ascertainment bias” in RECORD, he pointed out that even if you corrected for the alleged bias, the odds ratio was still not statistically significant for increased MI risk. The ratios were as follows:

Further he subjected the original 2007 study to withering criticism, concluding that (1) the studies included were so small and short-term that slight changes in the data could have had big impact on the odds ratios, (2) they weren’t adjudicated, (3) they weren’t originally designed to look at CV risk, and (4) they didn’t define the signal event of MI.

The lead investigator for the 2007 study admitted the weaknesses, but insisted that even so, after 10 years GSK should have stepped up to better studies (according to the Live Blogging record) The result was to make the original study look like more smoke than fire…if still a concern.

In sum, there were unfavorable trends for MI in both analyses but neither was statistically significant. The cardiologist then added a hammer blow that when you lumped MI in with all-cause mortality, risk disappeared: In his words,

“results on the primary endpoint (time to first cardiovascular death or cardiovascular hospitalization) are not entirely conclusive. Conversely, the findings on all-cause mortality seem readily interpretable and important in RECORD, and they favor rosiglitazone.“

It was déjà vu all over again. With this analysis, the consultant had undermined the original signal 2007 study and minimized criticism of the long-term study. The panel then shifted its attention to the TZD alternative, Actos: would it be a safer alternative? In the minds of some, this would be sufficient argument for withdrawing Avandia.

One panel member asked, in effect, “Are we creating a precedent by comparing drugs in this way?” The answer given was, “Yes, but not in such a way that implies one drug is better than another.” This answer puzzled some observers, but having treatment choices available is a strong argument for preserving alternative agents for those patients who might benefit from one drug but not the other. This bordered on exceeding the FDA’s authority. As I said earlier, they do not do “comparative effectiveness”. They focus on an individual drug’s efficacy, bounded by safety.

The data comparing Avandia and Actos, when presented, were confusing and complex. The observational studies varied so widely in design that the statistician could come to no firm conclusion. By contrast the meta-analysis by OSE (the thumbs down people) concluded

Comparisons of rosiglitazone with pioglitazone consistently show a clinically meaningful increased risk of adverse cardiovascular outcomes, especially acute myocardial infarction, with rosiglitazone.

But what about the argument over alternatives? Does a suspected increased risk (note they said “clinically meaningful” increase rather than “statistically significant”) warrant removing an alternative? If so, what do patients who can’t take Actos do?

In summary, all the studies had biases and limitations. But, despite all the lack of certainty, there’s a clear warning: the heart risk may be there, underneath it all.

The Vote and It’s…Result

The vote was set up as follows. Each member would vote for one option:

1. Allow continued marketing and revise the current label to remove the boxed warning and other warnings regarding an increased risk of ischemic CV events, or
2. Allow continued marketing and make no changes to the current label, or
3. Allow continued marketing and revise the current label to add additional warnings
4. Allow continued marketing, revise the current label to add additional warnings, and add additional restrictions on use)
5. Withdrawal from the U.S. market

The results were:

1. 0
2. 3
3. 7
4. 10
5. 12

That a plurality voted to withdraw, but the majority wanted to allow continued marketing in some form was a head-scratcher to some. But clearly, had the choices been withdraw or not withdraw, the results would have been to “not” withdraw (By comparison the vote in 2007 was 22 to 1 to continue marketing Avandia). Nobody wanted to allow the manufacturer to remove the warning label regarding CV risk (as GSK requested). Clearly, the weight of opinion from the scientific community was shifting, in parallel with public opinion.

Historically, the FDA decision-makers rarely dissent from panel recommendations.

The Public Aftermath

Law firms were quick off the mark (same day) to inform clients and the general public that the recommendation to allow Avandia to continue didn’t preclude them from suing based on the company’s alleged malfeasance in hiding unfavorable data on Avandia. The manufacturer was also quick to issue a press release with the voting results, re-iterating its position that with suitable precautions, Avandia does not increase CV risk. The media produced a flurry of articles, that all seemed to say slightly different things. Their descriptions of the result were: Avandia “dead,” “can stay,” “a zombie,” “kept,” “revealed mixed opinions,” “restricted.” All over the map.

Sales of Avandia have been dropping since 2007. Given public awareness of the controversy, why would a patient prefer it?

Ominously, the week after the panel meeting the FDA ordered a halt to enrolling patients in a GSK study (TIDE) that would directly compare Avandia to Actos, citing the need to come to grips with Avandia’s safety before deciding on further research.

There’s already more data than usual. The panel’s review did not achieve closure. No one knows whether longer term studies will confirm the claim of risk. My guess: Avandia is on the way out. The momentum of the science, and public opinion, is in the direction of withdrawing the drug. Withdrawal will probably occur before the science is settled. But, no matter what happens to the drug, the legal actions will go on for years.

Vioxx was withdrawn in 2004. The most recent Vioxx law suit against Merck occurred in March of 2010.

About the Author

James Dougherty, MD, MPH, Brig Gen USAF (ret), is a Fellow of the American College of Preventive Medicine. His 35 years in medicine have been split evenly between clinical practice, from F-16 flight surgeon to consultant to the AF Surgeon General, and medical management, from regional health care planner to CEO of a medical center. He developed the first backpack-based surgical team for Special Operations, defended the anthrax vaccine in testimony before Congress, and rebuilt a medical center destroyed by Hurricane Katrina. He was briefly an instructor in philosophy at the University of Md. He has a continuing interest in (1) data-driven decision making in medicine and public health policy, and (2) medical ethics.

During January 1– June 30, 2010, a total of 1,337 cases were reported, a 418% increase from the 258 cases reported during the same period in 2009. All cases either met the Council of State and Territorial Epidemiologists definitions for confirmed or probable pertussis or had an acute cough illness and Bordetella pertussis–specific nucleic acid detected by polymerase chain reaction from nasopharyngeal specimens.

In addition, if the trends continue through the end of this year, which they are likely to do, this will be the highest incidence of pertussis in almost 50 years. These numbers are not in question, but there is some discussion about what, exactly, is causing it.

The tempting conclusion is that pertussis is making its way back into the population due largely to vaccine refusal and anti-vaccine propaganda. However, there is yet no data to support that conclusion. It may or may not be the case – we will know once a more thorough analysis is done of the individual cases of pertussis. And in any case, there are many factors at work.

First, pertussis has a natural tendency to cycle every 5 years or so, and this year is the peak of the cycle. This is certainly a significant part of the increase this year, regardless of other contributors.

In addition, the lack of vaccine-induced immunity is also playing a role, but not necessarily from vaccine refusal. Pertussis is a very contagious illness, partly because people are often contagious with it for days or weeks prior to knowing they have it, or that their cough is not just a common cold. Prior to vaccination pertussis was a significant cause of childhood death, causing about 8,000 deaths a year in the US alone. After the wide availability of vaccination against pertussis there has been on average about 10 deaths per year.

The current vaccine is an acellular pertussis vaccine (part of the DTaP injection, which included diphtheria and tetanus). The aP vaccine is a toxoid vaccine – it contains inactivated toxin proteins which are themselves harmless. It is therefore  a very safe vaccine with few side effects. Prior to 1996 the whole-cell pertussis vaccine was used – this was similar but still contained entire bacteria (although inactivated) and had a higher incidence of side effects. The DTaP vaccine is actually less effective than the older DTP vaccine, but a little bit of efficacy was traded for increased safety.

The childhood vaccine schedule requires 5 injections between 2 months and 6 years of age. Young infants are therefore most susceptible to pertussis because they have not yet had time to get vaccinated and develop immunity. Immunity does last for years, but wanes in teenagers and older adults. Therefore periodic boosters (with a vaccine called Tdap) are recommended to maintain lifelong immunity. Incidentally, immunity from the vaccine is not much different than immunity from the illness itself:

A review of the published data on duration of immunity reveals estimates that infection-acquired immunity against pertussis disease wanes after 4-20 years and protective immunity after vaccination wanes after 4-12 years.

The factors, therefore, that are contributing to the fact that the current epidemic is likely to be the biggest in 50 years are – the natural cycle of pertussis, a lower degree of immunity from the current DTaP vaccine vs the older DTP vaccine, and waning immunity in older children and adults with low rates of booster shots to maintain immunity.

Two other factors are currently under investigation. One is the rate of undocumented aliens in California that may not have been vaccinated. The CDC reports:

Incidence among Hispanic infants (49.8 cases per 100,000) was higher than among other racial/ethnic populations. Five deaths were reported, all in previously healthy Hispanic infants aged <2 months at disease onset; none had received any pertussis-containing vaccines.

So early indications are that the Hispanic population is disproportionately getting pertussis. But the burning question is – are there pockets of low vaccination rates among vaccine-refusers, lacking herd immunity, that are also contributing to the epidemic? A recent New York Times article by Tara Parker-Pope argues that vaccine refusal is likely not a contributor because there is no association between county-wide vaccine rates and pertussis incidence. However, this argument is not valid. Counties are a mostly arbitrary political boundary, not a meaningful population or social boundary. There are small pockets of low immunization rates in communities that have been centers of vaccine-preventable diseases in the past, and it is still possible (even probable) that pertussis is having an easier time spreading through these populations as well.

Further – we are on the cusp of a new school year. Once children go back to school, the pertussis epidemic may get into full swing. There are schools that, because of their culture and policies, have very low vaccination rates. We will have to see what happens with pertussis in these schools once the classroom doors open.

Conclusion

What we can say at this point for certain is that 2010 is an epidemic year for pertussis, and this cycle will be the worst in half a century. We know that vaccination with DTaP is safe and effective, but requires booster shots as adults, and that not enough people are getting this booster shot. This epidemic is still nothing compared to the pre-vaccine era of pertussis, but it highlights the ongoing need for vaccination and herd immunity against contagious and deadly diseases like pertussis.

Whether vaccine refusal is playing a significant role has neither been confirmed or rejected by current information, but eventually this data will be available. And unlike the anti-vaccine crowd, we will base our conclusions on the evidence, not rhetorical expediency.

I have been reviewing John Brinkley’s goat gland scam for a presentation on medical frauds. In an era before the isolation of the hormone testosterone, Brinkley transplanted goat testes into human scrotums in an attempt to treat impotence and aging. We are more sophisticated today … but not much. Longevity clinics and individual practitioners are offering testosterone to men as a general pick-me-up and anti-aging treatment. Their practice is not supported by the scientific evidence.

Men’s testosterone levels drop as they age. According to a review article in the New England Journal of Medicine

the decrease in testosterone in men occurs moderately and gradually over a period of several decades. The serum total testosterone concentration decreases from a mean of about 600 ng per deciliter (20.8 nmol per liter) at 30 years of age to a mean of about 400 ng per deciliter (13.9 nmol per liter) at 80 years, although the range is wide at all ages. In one study, approximately 20 percent of men older than 60 years of age had total serum testosterone concentrations that were below the normal range for young men.
An essential but still unanswered question is whether this decrease in the testosterone concentration is physiologic, perhaps conveying a benefit, or pathologic, causing harm.

Other things happen as men age, and a simplistic, hopeful approach is to blame many of the consequences of aging on decreased testosterone levels and to use replacement therapy to bring the levels back to those of healthy youth. That approach is not science-based. Science only supports raising testosterone levels in patients who have specific problems attributable to abnormally low levels.

A recent article in JournalWatch reviewed the subject with reference to three new studies.

A July 2010 article in the NEJM by Wu et al. found that the only symptoms that correlate to low testosterone levels are poor morning erection, low sexual desire, and erectile dysfunction. Other psychological and physical symptoms correlated poorly with low testosterone levels. Total testosterone levels were sufficient for diagnosis; free testosterone levels did not add to diagnostic accuracy.

An article in the Journal of Clinical Endocrinology and Metabolism by Krasnoff et al.  found that total testosterone was not associated with mobility limitation, subjective health, or any physical performance measures, whereas free testosterone was associated with subjective health and some (but not all) physical performance measures. Low baseline free testosterone levels were associated with subsequent decline in mobility but not in subjective health. JournalWatch editor Dr. Alan Brett comments that this study

shows correlations between free testosterone and some measures of physical performance; however, findings were mixed, and significant associations in observational studies do not necessarily indicate cause-and-effect.

A third study by Basaria et al. published in the New England Journal of Medicine  studied older men with limitations of mobility to see if testosterone supplementation would improve mobility by increasing muscle mass and strength. This trial was stopped early because of a higher rate of cardiovascular events in the testosterone group compared to the placebo group.

The JournalWatch editor comments:

These studies — considered alongside other recent studies in which testosterone supplementation did not yield impressive results in frail older men or in healthy older men — argue against indiscriminate use of testosterone as an “anti-aging” drug. This conclusion is supported by a new practice guideline from the Endocrine Society.

Testosterone is not harmless. The Mayo Clinic website lists several adverse effects of testosterone: sleep apnea, elevated red blood cell count, heart disease, acne, benign prostatic hypertrophy, breast enlargement, reduced sperm production, and shrinkage of testicles. Mentioning a risk of testicular shrinkage in the infomercials would put quite a dent in sales, I imagine.

Meanwhile, Suzanne Somers recommends testosterone for everyone: both men and women. On the Oprah website, readers provide testimonials:

Just ask my husband who take [sic] testosterone daily thanks to Suzanne’s books.

The unsupported opinions of celebrities and longevity opportunists versus the evidence of science-based medicine: take your pick.

This Saturday, August 21, I’ll be giving a talk co-sponsored by Chicago Skeptics, Women Thinking Free Foundation, and the Center For Inquiry-Chicago at the Black Rock Pub & Kitchen. My talk will be on a topic near and dear to my heart (or a topic that fills me with alarm–the two are not mutually exclusive), mainly the infiltration of pseudoscience into medicine. I’ll be sure to touch on a number of issues, and you can be sure I’ll have something to say about the recent acupuncture review that appeared in the New England Journal of Medicine and perhaps a bit about the sort of pseudoscience that’s being practiced at some of our largest and most respected cancer centers. Afterwards, you–yes, you!–can ask me about anything you want if you show up. Anything, including vaccines, skepticism, and even Bill Maher!

If you live in Chicago and want to harass me (not the way Age of Autism harasses me), head on over to the Chicago Skeptics event page and click on the link to RSVP!

ADDENDUM: Holy crap! Someone just informed me that Chicago Comic Con will be in Chicago the same weekend as me. Even worse, William Shatner will be there on Saturday, which is when I’m giving my talk. How on earth can I possibly compete with the Shat?

Today, I want to riff a bit on one aspect of this phenomenon. As a cancer surgeon, I’ve dedicated myself to treating patients with cancer and then subspecialized even further, dedicating myself to the surgical treatment of breast cancer. Consequently, the interface of so-called “complementary and alternative medicine” (CAM) in the treatment of cancer both interests and appalls me. The reason for my horror at the application of CAM to cancer patients, as you might expect, is that cancer is a disease that is highly feared and can be highly deadly, depending upon the specific kind of cancer. Cancer patients deserve nothing less than the best science-based evidence that we have to offer, free of pseudoscience. Yet in even the most highly respected cancer centers, such as M.D. Anderson Cancer Center and Memorial Sloan-Kettering Cancer Center, there are departments or divisions of what is increasingly called “integrative oncology.” The claim behind “integrative oncology” is that it is “integrating the best of science-based and ‘alternative’ medicine,” but in reality all too often it is “integrating” quackery with science-based medicine. I have yet to hear an explanation of how “integrating” pseudoscience or nonscience into science-based oncology benefits cancer patients, but, then, that’s probably just the nasty old reductionist in me. Let’s find out.

“Integrative oncology”

I was reminded by the level of “progress” in integrating woo into oncology last week when the July 25 issue of HemeOnc Today showed up. Right there on the front page I saw a story Integrative oncology combines conventional, CAM therapies, with a subtitle reading “This growing medical discipline incorporates methods such as yoga, acupuncture and stress management.” And so it does. But I worry that that’s just the beginning:

The National Center for Complementary and Alternative Medicine defines integrative medicine as treatment that combines conventional medicine with complementary and alternative therapies that have been reported to be safe and effective after being studied in patients.

Lorenzo Cohen, MD, PhD, of M.D. Anderson Cancer Center is conducting a phase 3 trial of the effects of yoga on women with breast cancer.

“Integrative medicine is a philosophy based on treating patients by focusing on the whole person and using both conventional and complementary therapies in a multidisciplinary care fashion,” Lorenzo Cohen, MD, PhD, director and professor of the Integrative Medicine Program at The University of Texas M.D. Anderson Cancer Center, told HemOnc Today.

“It is similar to complementary medicine, but one key difference is that there is an open communication between practitioners of the different traditions,” he said.

“Between the traditions”? Note the clever use of language that Kimball Atwood is so fond of pointing out. Note how Dr. Cohen equates “conventional” and “alternative” therapies (the latter of which he calls “complementary”) as though they had equal validity and equal efficacy. It’s just two different traditions! What’s the problem with bringing them together, and integrating one into the other? It’s the best of both worlds, right?

Also notice another thing. I’ve referred to certain aspects of CAM, sometimes called “integrative medicine” (IM) and, in this case called “integrative oncology” (IO), as a “Trojan horse” to bring woo into medical schools and academic medical centers. Most — but not all — academic medical centers do not use hard core quackery like homeopathy, although many appear to be using a modality just as bad, reiki, which happens to be Dr. Mehmet Oz’s favorite modality. In any case, whenever you see discussions of “integrative medicine” and in particular “integrative oncology,” chances are, the modalities discussed generally include yoga, various dietary modalities, exercise, and, quite frequently, acupuncture. Sometimes, they include various herbal remedies. In other words, “integrative oncology” rebrands modalities that have no reason not to be counted as part of science-based medicine as “alternative” or “integrative” and points to them as having some promise. They then lump together pseudoscience like reiki and acupuncture with the rebranded modalities, such as herbal therapies. This story demonstrates exactly what I mean in this passage:

According to Cohen, integrative medicine includes a plethora of therapies and methods but can be most easily classified into five categories: biologically based therapies, mind/body medicine, manipulative body-based practices, energy medicine and whole medical systems.

Biologically based therapies include ingestibles such as herbs and supplements, megadoses of vitamins or specialized diets. Mind/body medicine consists of techniques that typically help with stress management. These techniques include meditation, yoga, guided imagery and other forms of relaxation, according to Cohen. Manipulative body-based practices include therapies such as massage, medical acupuncture and chiropractic work.

The most controversial area of integrative medicine, according to Cohen, is energy medicine, which includes techniques such as healing touch, Reiki, a Japanese form of energy healing, or the use of magnets for healing. Healing touch techniques such as Reiki and Qigong, an ancient Chinese healing therapy, are based on the theory that human beings are energetic bodies and certain individuals with specific training can emit energy into another person for therapeutic purpose.

I realize that HemeOnc Today isn’t the NEJM, but on the other hand, given how the NEJM recently fell for the pseudoscience that is acupuncture, maybe they aren’t so different after all. In any case, this entire article is the sort of credulous treatment that drives me crazy, particularly the last paragraph quoted above. Energy medicine isn’t just “controversial”: it’s quackery, pure and simple, and Dr. Cohen should know that. The best that can be said about so-called “energy medicine” is that it is religion, not science, or that the various modalities that fall under the rubric of “energy medicine” are based on a prescientific understanding of how the human body works and how diseases attack it. Some of them are not even “ancient.” Reiki, for instance, only dates back to 1922. It was invented by a man named Mikao Usui, who wanted to find out how Jesus healed the sick. His answer, reiki, is no more than faith healing; the only difference between it and what Benny Hinn does is that reiki is based on Eastern mysticism instead of Christian faith. None of this discussion of “energetic bodies” and the claims that practitioners can either channel some form of “universal energy” or manipulate the flow of human “life energy” for therapeutic intent belongs in science-based medicine, at least until someone can characterize the claimed energy and actually show that these practitioners can actually do anything other than wave their hands over patients.

Cohen also speaks of “whole medical systems.” In other words he refers to ancient medical systems, such as traditional Chinese medicine and Ayurvedic medicine, characterizing them as having “their own methods and techniques for diagnosing patients, prescribing treatments and following patients over time.” That much is certainly true, but none of these techniques were based on science, either. They were based on much the same thoughts that early “Western” medicine was based on. After all, when you come right down to it, “balancing” or “adjusting” the flow of qi is not that different than the idea that the four humors must be balanced or that disease comes from “contamination” due to miasmas. As Ben Kavoussi has pointed out, there isn’t that much difference between the concepts used to justify blood letting as a treatment for disease. Yet, somehow “integrative medicine” and CAM love modalities based on Eastern mysticism. Where’s the love for black bile, yellow bile, phlegm, and blood, which make just as much sense, from a science-based standpoint as the concept of qi? In fact, they make more sense, because they, at least, exist and can be observed.

The Trojan horse

Time and time again, when I observe integrative oncology programs, I notice that many of them heavily emphasize modalities like diet and exercise. Indeed, in the HemeOnc Today article, the various advocates and “experts” in integrative oncology emphasized time and time modalities like yoga:

Karen Mustian, PhD, MPH, assistant professor of radiation oncology and preventive medicine at the University of Rochester Medical Center, discussed the findings of a yoga study at the 2010 ASCO Annual Meeting, held in Chicago in June.

Researchers enrolled 410 survivors of non-metastatic disease who participated in the Yoga for Cancer Survivors program. Survivors reported suffering from moderate or severe sleep disruption 2 months to 24 months after completing adjuvant therapy.

The participants were assigned to breathing exercises, 18 gentle Hatha and restorative yoga postures and meditation for 4 weeks with twice-weekly sessions.
Patients practicing yoga had greater improved sleep quality (22% vs. 12%), decreased incidence of clinically impaired sleep (31% vs. 16%) and less daytime sleepiness (29% vs. 5%) compared with those who did not practice yoga.

Adding to these findings, a study of the effects of yoga on women with breast cancer is also in the works. In April, Cohen received a $4.5 million grant to conduct a phase 3 trial in women with breast cancer to determine the improvement in physical function and quality of life during and after radiation treatment.

The results of the study presented at ASCO described above are, of course, utterly unsurprising. Would anyone expect that gentle exercise and meditation would harm quality of life and sleep quality? My guess is that substituting gentle exercise and prayer or non-yoga meditation would likely produce the same result. But yoga is “Eastern,” so it’s automatically way more cool than “Western” exercises. In any case, I bet I could save the NIH $4.5 million by predicting the results of Dr. Cohen’s study. Yes, yoga very likely will be found to improve physical functioning and quality of life, because, by and large, it is relatively gentle, low-impact flexibility exercise. In fact, in women who have undergone axillary dissection (removal of the lymph nodes under their arms), I would predict that yoga probably will decrease the incidence of impaired range of motion. The reason I make this latter prediction is because I already prescribe gentle stretching exercises to women who have undergone axillary surgery because it does decrease the incidence of impairments in range of motion. In fact, I would go so far as to predict that virtually any low impact exercise, be it yoga, Tai Chi, or simply low impact “Western” forms of exercise, such as walking and stretching, would produce the same results.

Oddly enough, I have been unaware of any investigators being awarded $4.5 million to study whether walking preceded by some gentle “limbering up” has all these effects in cancer patients. Why is that? This is the sort of stuff that is well-within the purview of science-based medicine, leading me to ask: Since when did exercise become “alternative” or “integrative”? Dr. Cohen’s study compares yoga versus “stretching/relaxation” (which is what I thought much of yoga was; so I’m not sure what the difference is) versus a wait list control group. So my being unaware of such a study is at an end, because apparently that’s just what Dr. Cohen will study. But does anyone think that the NIH would have funded such a study if it were about exercise and relaxation rather than yoga? My prediction for the outcome: the first two groups will both do better than the control group in terms of the outcome measures. I also wonder why on earth it will take $4.5 million and five years to answer this question. In any case, given the copious science already demonstrating that low impact exercise results in better quality of life outcomes for cancer patients, I would question the value, the “bang for the buck,” of spending $4.5 million in order to study an “alternative” or “complementary” therapy that is nothing more than a fancy form of stretching exercises and relaxation, the former of which is already known to be of benefit in cancer patients undergoing chemotherapy, surgery, and radiation. Surely such a study could be done for $1 million? Heck, for $4.5 million, I could start up a multi-investigator P01 with teams of investigators doing heavy duty basic science.

I know, I know. Sour apples. I really am in the wrong business.

The HemeOnc Today article, as credulous as it is, though, is merely an indication of just how far the concept of “integrative oncology” has gone. To appreciate just how far it has gone, I thought I’d peruse the websites of what are commonly accepted as two of the most respected institutions devoted to cancer in the United States, if not the world.

“Integrative oncology” invades and metastasizes

“Inspired” by the HemeOnc Today article, I decided to peruse the “integrative oncology” website of one of the two premier cancer centers in the country, that of the M.D. Anderson Cancer Center, as well as to take a peak at what the National Cancer Institute website says about various “alternative,” “complementary,” or “integrative” modalities. What many readers may not know is that the NCI has an Office of Cancer Complementary and Alternative Medicine (OCCAM, perhaps the most unfortunate acronym ever, given what it stands for). Moreover, OCCAM has a budget that is of approximately the same magnitude as that of the National Center for Complementary and Alternative Medicine (NCCAM), in the range of $121 million a year. Thus, OCCAM is potentially as large a force in studying and promoting CAM as NCCAM has ever been.

Let’s start with M.D. Anderson first. On its website, it has a webpage called Complementary/Integrative Medicine Education Resources (CIMER). On the CIMER webpage, perhaps the most telling and useful “resource” is a page on therapies. On this page are links to several review articles authored by CIMER staff and physicians in the Integrative Medicine Program of the M.D. Anderson Cancer Center.

Whenever I take a look at a cancer center’s website, I go straight for the most hard core quackery to see what it says about it. Usually, I go straight for homeopathy. If a website concludes anything other than that homeopathy is pure quackery and that there is not a single molecule of active substance in most true hemopathic remedies (the dilution and succussion process having diluted it to nothing), then I know I’m dealing with quackademic medicine. Here’s an excerpt from what the great M.D. Anderson says about homeopathy:

The practice of homeopathy is based on its “law of similars” which proposes that “like cures like”. That is, a substance that causes specific symptoms in a healthy person is believed to ultimately relieve those same symptoms in a sick person. A few homeopathic physicians treat cancer by prescribing minute doses of tumors and carcinogenic substances.

The intent of homeopathic medicine is to help the body begin the healing process. Rather than focusing on a specific diagnosis, prescriptions are tailored to an entire set of symptoms and may vary between individuals with the same disease.

Significant reduction of some side effects of cancer treatments has been reported in two randomized controlled trials justifying further research with larger trials.

Current research includes a National Cancer Institute (NCI) clinical trial of a homeopathic substance for chemotherapy induced mucositis in children.

So far, not so good. The passage above is completely credulous, without the least bit of skepticism about the very basis of homeopathy. It reports homeopathy as a homeopath would report it, which makes me wonder if it was written by a homeopath. Particularly disturbing is the “detailed scientific review” of homeopathy. I’ll give the author credit because he at least mentions Avogadro’s number, but then credulously parrots the typical homeopath claim that water has “memory.” The article also cites primarily articles from that journal of pure woo, whose editorial standards I’ve lambasted here and elsewhere time and time again, the Journal of Alternative and Complementary Medicine, as well as homeopathy journals, such as the British Homeopathic Journal. It is beyond the scope of this post to explain why such journals are generally not good sources (perhaps I’ll do a post on that someday), but they aren’t. The only “real” journal article I saw was the infamous TRAUMEEL S study from 2001 looking at whether homeopathic TRAUMEEL S can alleviate stomatitis in children undergoing treatment for lymphoma and leukemia. (I shudder at the unethical nature of testing magic water in a clinical trial with children as the subjects.) In any case, this study reported a positive effect; however, one might also note this from the study itself:

TRAUMEEL S® is a homeopathic-complex remedy that has been sold over the counter in pharmacies in Germany, Austria, and Switzerland for over 50 years. It contains extracts from the following plants and minerals, all of them highly diluted (10⁻¹–10⁻⁹ of the stem solution): Arnica montana, Calendula officinalis, Achillea millefolium, Matricaria chamomilla, Symphytum officinale, Atropa belladonna, Aconitum napellus, Bellis perennis, Hypericum perforatum, chinacea angustifolia, Echinacea purpurea, Hamamelis virginica, Mercurius solubilis, and Hepar sulfuris. Information from the manufacturer indicates that TRAUMEEL S is used normally to treat trauma, inflammation, and degenerative processes.

In other words, this is an herbal remedy in which there is still ingredient, given that even a 10^-9 dilution is not enough to dilute away what’s in there. Why it’s even called homeopathic, I have a hard time figuring out, given that there are many herbs and minerals in there, with no rationale of “like curing like” obvious for them all. If TRAUMEEL S “works,” it’s not any sort of validation of homeopathy; all it shows is that maybe some of the herbs or minerals in the concoction have a beneficial effect. One also notes that this is a small study (N=30, 15 per group) and that the distribution of disease in the two groups was very different and that this study has never been replicated. Both Edzard Ernst and the Cochrane Reviews note this study but conclude that there is no evidence that homepathy is any better than placebo for cancer side effects.

But apparently not M.D. Anderson. M.D. Anderson appears to believe in magic. If you don’t believe me, just take a look at its review on reiki, including the “scientific evidence” for its efficacy in cancer patients, or its review on healing touch, which is more or less reiki shorn of explicit Eastern mysticism. Particularly nauseating is this introduction to “energy therapy” methods, which divides the very concept of energy itself into “Western” and “Eastern” notions of energy. (Silly me, I thought that energy was energy, and it was defined scientifically.) The author then postulates the “blending” of “Eastern” and “Western” concepts of energy thusly:

Modern physics has shown that light can exist as two interchangeable forms: a particle (form and structure) and a wave (movement and vibration). The rest of nature can also be experienced in the form of a particle and a wave. For example, water in the ocean is both particles of water and movement of coastal currents, thermal layers and tides. As in the ocean, the human body contains and is affected by energy that can be blocked, flow freely or vary in frequency. Various forms have been postulated:

• An all-pervasive background frequency without form that extends beyond the limits of the body structure
• Vertical energy flows that serve as conduits to external energy
• Additional currents of energy with identifiable paths and patterns

The extent to which a background field extends beyond a person reportedly varies with each individual. Some people have said that they are sensitive to these fields – seeing or hearing these projections. Heat emanating from a body is one form of energy and one expression of that person’s energy field⁸.

Notice that no evidence is presented showing that these claims are valid.

The introduction concludes:

Contemporary energy therapies are only recent manifestations of a larger and more ancient body of energetic and spiritual concepts that are beyond the scope of these reviews of a few contemporary energetic healing practices. MD Anderson recognizes that physical healing is only part of the cancer treatment process and also offers spiritual support through many different programs such as the Chaplaincy Services — representing a wide range of faiths and spiritual beliefs — and the Place … of wellness — where people touched by cancer can enhance their quality of life with activities that help to heal the mind, body and spirit.

Remember, this is the website of the M.D. Anderson Cancer Center, which is widely viewed to be one of the top two or three cancer centers in the United States, if not the world, and its Integrative Medicine Program appears to be based on magic more than anything else. Quackademic medicine, indeed.

Unfortunately, the NCI’s OCCAM website isn’t all that much better. Because I spent longer than anticipated going through the M.D. Anderson website, I’ll wrap it up fairly quickly. OCCAM has some fairly disturbing pages itself. For instance, its Categories of CAM Therapies is a simple list of CAM therapies with little discussion at all other than defining what they are in the way any woo-meister would be happy with. OCCAM is superior to M.D. Anderson’s CAM pages in that it does from time to time throw in passages like this:

Biofield therapies are intended to affect energy fields that purportedly surround and penetrate the human body. The existence of such fields has not yet been scientifically proven.

If there is no good science to show that these fields even exist, then why study trying to manipulate them? I never understood putting the cart before the horse like that. There’s a lot of that sort of stuff going on in the list of CAM therapies referenced by OCCAM, although a lot of the articles are in fact NCCAM articles. One article on a CAM therapy that is hosted by the NCI and apparently was written by NCI staff is entitled Questions and answers about acupuncture. Depressingly, it begins with a credulous discussion of qi and meridians that is credulous and full of magic. It also contains statements like:

Scientific studies on the use of acupuncture to treat cancer and side effects of cancer began only recently. Laboratory and animal studies suggest that acupuncture can reduce vomiting caused by chemotherapy and may help the immune system be stronger during chemotherapy. Animal studies support the use of electroacupuncture to relieve cancer pain.

And:

Human studies on the effect of acupuncture on the immune system of cancer patients showed that it improved immune system response.

One wonders just how critically the studies to which this article refers were evaluated. Certainly, the lists mix “electroacupuncture” (which is not acupuncture at all — as Mark says, where were those batteries in ancient China to hook up to the acupuncture needles?) with acupuncture studies. One wonders if this is another case of accepting the authors’ misinterpretation of their own results, as I discussed for one such study a couple of months ago. As for the effects of acupuncture on the immune system, the physician’s version of the review points out that all these studies were conducted in China, and, unfortunately, it’s well known that acupuncture studies from China tend to be overwhelmingly positive, in marked contrast to acupuncture studies from other countries, leading some writers of meta-analyses to question how to handle these studies. In any case, it would appear that the NCI, although its material on its website is not as credulous as that of M.D. Anderson, is not exactly a bastion of science when it comes to some “alternative” medical modalities.

Indeed, let me tell you a brief anecdote. Two years ago, at the AACR Meeting, I visited the NCI booth on the convention floor because I knew there was going to be a representative from OCCAM there. My confidence in the scientific rigor of the entire OCCAM enterprise was not boosted by the conversation I had there. In brief, after a brief (and neutral) conversation about what OCCAM does, I gently challenged the OCCAM representative regarding alternative medicine by pointing out that there really isn’t that much evidence for much of it and asking him if he could point me in the right direction. In particular, I asked him why one would think that a mixture of herbal medicines would do better than pharmaceuticals. He then began to pontificate about “royal herbs” and couldn’t provide a good rationale why anyone should conclude that impure mixtures of compounds would be more effective or reliable than pharmaceuticals. When he started going on about “emperor” herbs, “minister” herbs, and “assistant” herbs, I couldn’t take it anymore and looked for an opportunity to politely excuse myself.

“Integrative oncology”: The quackademic oncology that’s here to stay?

I first became aware of the phenomenon of quackademic medicine several years ago. Before then, I was blissfully ignorant. Over the last several years, in particular the last couple of years, I’ve become increasingly alarmed at just how much pseudoscience is finding its way into medical academia in general and into oncology in particular in the form of “integrative” oncology. When the websites of what have in the past been a bastion of science-based oncology, M.D. Anderson Cancer Center and the NCI, become infiltrated with this sort of pseudoscience, I become alarmed. But it’s far, far worse than that. I only picked two websites. There are many more out there, thanks to promoters of woo like the Bravewell Collaborative and others. I only picked on M.D. Anderson and the NCI because of their reputation for being much better than this, a reputation they are endangering by their embrace of woo. Cancer patients, as I say frequently, are among the most vulnerable of patients. Many of them are facing a very unpleasant death without treatment; seeing that they receive the most effective medicines and treatments we have, free of quackery, is a moral imperative, and I fear that we will soon be failing our patients. We now even have a Society of Integrative Oncology promoting the “integration” of pseudoscience into oncology.

The Trojan horse of herbals, diet, and exercise in the form of yoga may have breeched the walls of academia, bringing with it pseudoscience like acupuncture, reiki, and even homeopathy, but still I see reason for hope. Val Jones once coined the term “shruggie” for health care professionals who have seen the infiltration of pseudoscience into medicine and in essence shrug their shoulders, dismissing it as not being important or as not being their business if people choose quackery instead of science-based medicine. However, as the infiltration of pseudoscience reached a critical mass, it started to alarm even some of the shruggies. There has been pushback. We here at SBM like to think that we have been a significant part of that reaction, but we also know that there are many others, such as Edzard Ernst, Ben Goldacre, and Simon Singh. Even though a disturbing number of skeptics seem to have a blind spot when it comes to quackery, the broader skeptical movement appears to be taking more and more notice. I only hope that it’s not too late. When an admired and esteemed institution like M.D. Anderson goes woo, we have an uphill battle to reverse that.

There was a time when I believed my betters. Then the Annals of Internal Medicine had their absolutely ghastly series on SCAMS, the publication of which was partly responsible for interest in the topic. Since that series of articles, I have doubt whenever I read an Annals article. When a previously respected journal panders completely to woo, they lose all respectability. Sure, the editors that were responsible for that travesty are long gone, but the taint remains. I tell my kids that once a trust has been violated, it is difficult to get it back. The Annals has permanently lost my trust, I am afraid.

But we will always have Paris. I mean the NEJM. The NEJM is the premier medical journal. Just because an article is published in the NEJM doesn’t mean it’s right; the results of clinical trials are always being superseded by new information. But the article has supposedly been rigorously peer reviewed. Its like Harvard and… Oops, Bad example. Harvard, as we have seen, has feet of clay, and so, evidently, does the The New England Journal of Medicine.

Goodness, gracious, great balls of fire, the editors of the NEJM have fallen into the depths of nonsense with this one.

Let’s go through it, shall we.

First up, the authors:

Brian M. Berman, M.D., Helene H. Langevin, M.D., Claudia M. Witt, M.D., M.B.A., and Ronald Dubner, D.D.S., Ph.D.

From the Center for Integrative Medicine, University of Maryland School of Medicine (B.M.B.), and the University of Maryland Dental School (R.D.) — both in Baltimore; the Department of Neurology and the Program in Integrative Health, University of Vermont College of Medicine, Burlington (H.H.L.); and the Institute for Social Medicine, Epidemiology, and Health Economics, Charité University Medical Center, Berlin (C.M.W.).

You always want acknowledged experts in a field to write your review. If you want a review of Lyme disease, you ask a Lyme expert (The Connecticut Attorney General not withstanding), and if you want a review of heart attacks, you ask a cardiologist.

So in that spirit, if you want a review of prescientific magic, you want someone well-versed in the practice of prescientific magic. Fortunately, these authors seem well qualified. Dr. Berman founded the Center for Integrative Medicine at University of Maryland and has a long history of research into acupuncture. The center has on its staff a reflexologist/reiki master. Really. And the center offers:

Physician Consultations, Acupuncture, Nutrition, Massage, Homeopathy, Mindfulness-based Stress Reduction, Shiatsu, Reflexology, Yoga, Qi Gong, Tai Chi, Osteopathic Manipulation.

The University of Maryland proudly offer both acupuncture and reiki to their trauma patients.

Reiki is a Japanese technique of relaxation that works similarly to acupuncture, in that you are releasing and moving energy,” explains Donna Audia, R.N., a nurse on Shock Trauma’s pain management team and a certified Reiki master. “By using Reiki with trauma patients, we are not only helping them to relax, we’re also making them active participants in their own healing, and that can be very empowering.

Reaction from trauma patients has been positive, with most requesting follow-up treatments. In fact, many family members ask to be a part of the Reiki session. A group of volunteers trained in Reiki now visits Shock Trauma regularly. The University of Maryland Medical Center is the only facility in the country offering Reiki to trauma patients, although it has also been used to treat people with cancer and other illnesses.

Seriously. Your body has been shattered in a car accident and your health care providers think they can improve your condition by moving and releasing your energy by waving their hands over you.

If, god forbid, you have trauma in Maryland, get transferred. Fast.

Dr. Berman has published extensively on acupuncture and Dr. Witt has published multiple articles on homeopathy, including one using homeopathy for low back pain.

So two of the authors are well grounded in magical thinking: who better to write a NEJM review on acupuncture? They found a Dumbledore, a Gandalf, to write the article, which explains the content as the editors of the NEJM were evidently hit with the confundus charm. As I think about it, that is not the best metaphor, since in the fantasy world, magic is real, but in the real world, magic is fantasy, as well as a review article in the NEJM.

The authors start with a case of chronic low back pain with mild degenerative disease but no anatomical or physiologic reason for the pain. The vignette ends with:

The patient wonders whether acupuncture would be beneficial and asks for a referral to a licensed acupuncturist.

Nope. Simple enough. Acupuncture is nonsense. Oh wait. There’s more.

They review the epidemiology, physiology and anatomy of chronic low back pain and note that the understanding of the disease is a long way from satisfactory and conclude with:

In addition, psychological and behavioral factors, including fear of movement, appear to play an important role in patients with chronic low back pain. Such patients have been shown to have altered brain-activation patterns at subcortical and cortical sites associated with emotion and postural control. Studies comparing psychosocial variables with anatomical findings have shown the former to have greater predictive value than the latter.

In other words, with low back pain there is a big psychological overlay. It is the psychological overlay of pain that makes it difficult to determine the effectiveness of a therapy meant to decrease the pain. When treating a condition in medicine, most interventions attempt to alter the underlying pathophysiology: block a receptor with a drug, alter anatomy with a procedure as examples. If the intervention has no effect on the underlying pathophysiology, then there is little reason to expect benefit beyond a placebo effect, which is almost no effect.

Then they jump into acupuncture.

Acupuncture is a therapeutic intervention…

It is an intervention, yes, but therapeutic? Therapeutic means relating to healing of disease. So they are front loading the language, saying at the beginning that acupuncture is effective rather than proving the case. I would have used ‘useless magical’ instead of ‘therapeutic,’ but that’s me.

Although a number of different techniques or schools of acupuncture practice have arisen, the approach used in traditional Chinese medicine appears to be the most widely practiced in the United States.

Why? Is Chinese acupuncture better? Or is popularity the criteria we use for determining appropriate medical care? There is Chinese and Japanese and tongue and foot and ear and the German head acupuncture. Is there any justification offered for using one over the other? Which is the correct style? As I have said before, it is a trick question, like asking which is the real astrology: European, Indian or Mayan. It makes no difference.

Then they delve into real nonsense.

Traditional Chinese medicine espouses an ancient physiological system (not based on Western scientific empiricism) in which health is seen as the result of harmony among bodily functions and between body and nature. Internal disharmony is believed to cause blockage of the body’s vital energy, known as qi, which flows along 12 primary and 8 secondary meridians. Blockage of qi is thought to be manifested as tenderness on palpation. The insertion of acupuncture needles at specific points along the meridians is supposed to restore the proper flow of qi.

I hate to point out that the physiologic system I use, based on so-called “Western scientific empiricism,” is also based on anatomy, chemistry, biochemistry, histology etc. All based on physical structures that can be isolated and examined.

Meridians and qi blockage is based on what? Nothing. Meridians and qi do not exist. Here is the NEJM offering up, complete with a picture, the idea of meridians and qi as if they are a meaningful construct. Next up in the NEJM will be:

Traditional European medicine espouses an ancient physiological system (not based on Western scientific empiricism) in which health is seen as the result of harmony among bodily functions and between body and nature. Internal disharmony is believed to cause blockage of the body’s vital energy, known as humors: black bile, yellow bile, phlegm, and blood which flows in the body. Blockage of humors is thought to be manifested as illness. Bleeding and purging is supposed to restore the proper flow of balance of humors.

If anyone sees a conceptual difference between the two paragraphs, let the editors of the NEJM know after they accept my review on therapeutic bleeding. Being published in the NEJM is the medical equivalent of being on the cover of the Rolling Stone, and I think I have my opportunity.

Efforts have been made to characterize the effects of acupuncture in terms of the established principles of medical physiology on which Western medicine is based.

Why? Isn’t an ancient physiological system enough upon which to base a therapeutic intervention?

These efforts remain inconclusive, for several reasons. First, the majority of studies have been conducted in animals, and it is difficult to relate findings from such studies to effects in humans. Second, acupuncture has been shown to activate peripheral-nerve fibers of all sizes, rendering a systematic study of responses complex. Third, the acupuncture experience is dominated by a strong psychosocial context, including expectations, beliefs, and the therapeutic milieu.

And fourth, having no basis in reality, acupuncture can’t work any more than homeopathy or reiki. It is tooth fairy science, published in the NEJM.

Then they delve into the physiology of acupuncture and the basic science studies. Fine. You stick people with needles, you will get a variety of physiologic responses, both locally and in the brain. The question is whether these effects are specific to acupuncture or nonspecific results of poking people with a sharp object. Like all acupuncture apologists, they lack a certain precision in what they consider acupuncture, and offer electroacupuncture as evidence.

In the rat, electroacupuncture has been shown to induce pituitary secretion of adrenocorticotropic hormone and cortisol, leading to systemic antiinflammatory effects.

Ah yes, electroacupuncture. I remember when they discovered those ancient Chinese Duracell’s and alligator clips that allowed the Chinese to shock their patients.

I quote from the electroacupuncture article, referenced above:

While the EA frequency was held constant, intensity was adjusted slowly over the period of approximately 2 min to the designated level of 3 mA, which is the maximum EA current intensity that a conscious animal can tolerate. Mild muscle twitching was observed… For sham treatment control, acupuncture needles were inserted bilaterally into GB30 without electrical stimulation or manual needle manipulation.

And when shocked, the rabbits released ACTH and cortisol, as any animal would if electrocuted. Release of ACTH and cortisol is part of the response to stress. I can just see the poor rat, “placed under an inverted clear plastic chamber” for observation saying,” don’t tase me bro, don’t tase me bro.” Wait. It’s not a taser. It’s a projectile electroacupuncture remote deliver system, and if I use it on you, you are going to release some cortisol and ACTH as well, bro.

Did the NEJM editors look at the references? They seriously need some new reviewers.

But I will grant them that sticking needles in people has physiologic effects and shocking a rat makes it squirt cortisol.

However, acupuncture is about putting needles in specific sites. In the animal models and human studies they attempt to needle specific sites that correlate with treating a disease. Most acupuncture studies use the traditional sites associated with whatever illness they are not really treating; acupuncture is about putting the needle just so.

The basic science concerns, as I read it, the effects of needling people. If you are going to recommend acupuncture, and they will, then you need to justify the use of needles in specific sites by people trained in acupuncture, and the literature doesn’t support that. It doesn’t matter where you put the needles, or even if you use needles at all, as we have mentioned, since twirling a toothpick has better effects on knee pain than needling. And I will ask again: whose style of acupuncture are you going to use? Ear, tongue, foot, Japanese or German or Chinese?

Then they move on to the clinical trials and my gaster is flabbered.

… real acupuncture treatments were no more effective than sham acupuncture treatments. There was nevertheless evidence that both real acupuncture and sham acupuncture were more effective than no treatment and that acupuncture can be a useful supplement to other forms of conventional therapy for low back pain.

Lets take a trip back in time.

There was procedure for the treatment of angina where they ligated the internal mammary artery. The theory was that by tying off the artery the back-pressure forced blood down the coronary arteries and relieved cardiac pain.

Angina improved and there are about 40 plus papers in the 50s and 60s on the benefit of the procedure as well as the underlying physiology of the procedure. Mammary artery ligation ‘worked’ and was popular in the early 60s. Until the procedure was compared to a sham operation. That’s right. They opened people up and did nothing.

The result?

The combined results of two RCTs comparing an earlier surgical procedure for angina — bilateral internal mammary artery ligation (BIMAL) — to a sham surgery clearly show that patients “experienced significant subjective improvement,” with both BIMAL (67% substantial improvement) and the sham procedure (82% substantial improvement). [see Moerman, Meaning, Medicine and the “Placebo Effect”, 2002]

So how would you interpret the study? If a procedure is equal sham, then I would say the procedure does not work. In the case of sham surgery, no underlying change occurred in the blood supply to the ischemic heart. This study is perhaps the classic clinical trial that demonstrates the difficulty in assessing the results of an intervention for pain. Patients had significant improvement in their angina. Much better than doing nothing (although these studies did not have a ‘usual care’ wing), 2/3 of angina patients do not get significant improvement on their own.

And guess what? Open heart surgery “has been shown to induce pituitary secretion of adrenocorticotropic hormone and cortisol, leading to systemic antiinflammatory effects.” Surgery releases endogenous opioids and I bet it actives both peripheral and central pain fibers.

Hmmmm. Looks like we have a justification for going back to treating angina with internal mammary artery ligation.

The authors of the review justify the recommendation on the two studies that demonstrate the equivalence of sham acupuncture and real acupuncture in treating low back pain, the same number of studies for mammary artery ligation.

Now being an article on back pain, they did not include the article that showed knee pain treated with sham acupuncture (in this case twirling tooth picks on the skin) is superior to real acupuncture. It matters not where the needles are placed or even if needles are used.

So far the authors provide no historical scientific plausibility, non-specific modern pathophysiology, a bit of gratuitous rabbit torture, and two clinical trials that demonstrate no efficacy of acupuncture over placebo. Their level of justification reaches that of mammary artery ligation. I start to wonder if the NEJM editors actually read the review before publishing it. The authors then move on to clinical use.

(Acupuncture) not been established to be superior to sham acupuncture for the relief of symptoms of low back pain [translation: it doesn’t work]. As a result, it is not often regarded as the first choice of therapy [translation: clinicians do not like to use ineffective therapy].

However, since extensive clinical trials [er, since when did two become extensive? Are the authors even reading the manuscript?] have suggested that acupuncture may be more effective than usual care, it is not unreasonable to consider acupuncture before [you mean as first line therapy? when it doesn’t work?] or together with conventional treatments, such as physical therapy, pain medication, and exercise [adding nothing to something does not increase the net effect].

That is some interesting sentence structure, worthy of Animal Farm: even though acupuncture doesn’t work, and isn’t first line therapy for pain, it should be used for first line therapy. Although the qualifiers ‘not been established,’ ’suggested’, ‘may be,’ and ‘not unreasonable’ muddy the water with their density.

Acupuncture is a regulated discipline, and patients should be referred only to practitioners who are licensed by the state in which they practice.

Why? It’s like Duck’s Breath Mystery Theatre’s Dr. Science. A license to practice ineffective nonsense still results in ineffective nonsense.

In the traditional practice of acupuncture, needle insertion itself may be accompanied by a variety of ancillary procedures, including palpation of the radial artery and other areas of the body, examination of the tongue, and recommendation of herbal medications. All of these steps are based on the application of principles of traditional Chinese medicine, as opposed to Western physiological and medical concepts. To what extent such procedures may contribute to the psychological milieu of acupuncture is unknown, and only a few studies have examined the context in which acupuncture treatment is delivered.

Note, it is not that radial artery palpation and tongue examination increase the diagnostic accuracy, it is to contribute to the psychological milieu. Like a psychic talking to your dead parent, it is important to make the environment conducive to fooling the patient into believing that an actual effect is occurring.

Take the pulse. In TCM they are not looking for tachycardia, but imaginary diseases based on imaginary diagnosis. An example:

Each pulse position can reflect different phenomena in different situations. For example, in a state of health, the left middle pulse (Liver) will be relatively soft and smooth, neither superficial nor deep. Therefore, we can say the liver and gall bladder energies are balanced or that the Yin and Yang within the Liver/Gall Bladder sphere are balanced. If a patient is experiencing migraine headaches and her pulse feels wiry (harder or tighter than normal) and more superficial and pounding, then we may diagnose this as Excessive Liver Fire (Yang) Rising (up the Gall Bladder channel to the head). The pulse reflects the rising energy.”

Or tongue examination, which is another example of prescientific nonsense where the body is represented on the tongue.

The editors of the NEJM seem to think this is reasonable, worthy of unqualified discussion. Of course, there is no reference to demonstrate that these additions increase diagnostic or therapeutic accuracy.

The practitioner may further stimulate the needle with electrical current (electroacupuncture), moxibustion (burning the herb artemisia vulgaris at the end of the acupuncture needle), or heat.

Why? No data given that this nonsense increases efficacy. I keep telling myself this is the NEJM, adding their imprimatur to the respectability of burning a plant on top a needle stuck in the skin to ease chronic pain. Then they note that patients need multiple treatments, a minimum of 12, with boosters, and they need to come in to prophylactically keep their spine aligned — no wait, the last is what chiropractors do. It seems, at 65 to 125 dollars a pop, that acupuncturists have recognized the financial wisdom of D.D. Palmer’s descendants. The NEJM is suggesting that people pay around 1200 bucks for what is, at best, a placebo.

The authors go on to the adverse effects. “8.6% reported at least one adverse event, and 2.2% reported one that required treatment.” Pretty impressive complication rate for an expensive, ineffective therapy! They do not mention that in the acupuncture/toothpick for knee pain study, toothpicks had the same effect as acupuncture and zero side effects, nor do they mention the well-reported cases of infection from sloppy aseptic technique.

I will ask you. If you have two procedures of equal efficacy and one has zero side effects, are you not ethically bound to suggest the procedure with no complications? If you are going to suggest acupuncture, ethically you have to offer sham acupuncture with twirled toothpicks, especially when what you offer is no better than a placebo effect.

Then, in the areas of uncertainty section of the review, they note that the effects of acupuncture are mostly explained by elaborate placebo effects. Benefit from acupuncture is

mostly attributable to contextual and psychosocial factors, such as patients’ beliefs and expectations, attention from the acupuncturist, and highly focused, spatially directed attention on the part of the patient. These studies also seem to indicate that needles do not need to stimulate the traditionally identified acupuncture points or actually penetrate the skin to produce the anticipated effect.

It does nothing, and you do not need to do acupuncture to get the effect. Acupuncture has complications and ethically can one recommend and charge for an elaborate placebo? I do not think so. Not the authors.

The patient in the vignette has chronic back pain that has not responded to a number of medical treatments.

So instead, we will go with the unethical, expensive, useless placebo.

He has specifically requested a referral for acupuncture, and we would suggest a course of 10 to 12 treatments over a period of 8 weeks from a licensed acupuncturist or a physician trained in medical acupuncture.

Can you believe this? From the NEJM! Such total tripe. I rely on the NEJM to provide reviews of relevant medical topics as, outside of ID and quackery, I do not have the time to read the primary literature. If this is the best NEJM can do on a topic upon which I have some background, then I suppose I cannot trust them in the future. As I tell my kids, you can judge a person by the company they keep.

The NEJM has lost some of its credibility. I doubt they will ever get it back.

One of the finest examples of these failures was just published in the journal Homeopathy.  Leaving aside for the moment the absurdity of a journal devoted to magic, let’s see what they did here.

Leptospirosis, a systemic disease caused by bacteria of the genus Leptospira, is probably the most common zoonotic (spread by non-human animals) disease on the planet.  It can cause anything from a mild flu-like illness to liver failure and death.  It is spread in water contaminated by urine from infected animals.  An outbreak occurred during my internship year among triathletes swimming in a lake in Illinois, but occupational exposures are more common.  There are no widely-available vaccines for disease prevention.

Given the common and sometimes serious nature of the disease, especially in developing countries, there is a need for effective prevention of leptospirosis.  One proposed solution, published this month in Homeopathy, is “Large-scale application of highly-diluted bacteria for Leptospirosis epidemic control.”

Methods

The authors conducted what they called an “epidemiologic cohort study”.  For the study, the designated a large area of eastern Cuba the “test” population (”intervention region (IR)”), and the rest of Cuba the “control” population.  These were assumed to be distinct geographic regions.

In the intervention region, local outbreaks were treated with vaccination and antibiotic prophylaxis which, according to the study, reached about 3% of the population, but they do not indicate whether this is 3% if the total population or a targeted, at-risk population.  The entire population of the intervention region was also targeted to receive a homeopathic  (i.e., inert*) preparation especially designed and “potentised” (i.e., shaken up) to prevent leptospirosis, as per homeopathic beliefs.

The authors state that the study complied with ethics requirements of the authoritarian regime who runs the country and presumably profits from the manufacture of the product being tested.

Data

The authors report that the control region had fewer natural disasters (and presumably were at lower risk for lepto) than the intervention region.  During one such emergency in the IR, the potion was widely used.  A drop in reports of the disease were noted afterward.

The statistical analysis section of the paper is quite long, but fails to address fundamental problems.  There was, in effect, no control group.  There was an opportunity to apply this alleged therapy on one group and placebo (chuckle) on another and compare rates of disease in each group.  This wasn’t done.  The entire population in question was treated, and rates of disease recorded.  The authors note that leptospirosis is occurs in cycles, and there is no reason to think that the drop in disease seen after the application of homeoprophylaxis is due to the intervention rather than to the natural course of the endemic.  Given that the intervention is supposed to be prophylactic rather than therapeutic, the authors’ conclusions are even more suspect.  Finally, the did end up comparing rates in the intervention region and the rest of the country, but these regions were defined as being geographically distinct, with different geography and differing rates of natural disaster.

This study has nothing to do with natural disasters.  Blame for the disaster here rests completely with the authors.  They conducted a study of questionable ethics and questionable methodology, and came up with questionable conclusions.  Most important, however, was the lack of a plausible hypothesis from the start.  There is no reason to think that ultra-diluted potions containing nary a molecule of “medicine” should affect anything.  Given this lack of plausibility, statistically significant findings should be examined with suspicion, and other explanations for any such findings should be sought aggressively.  The authors do not discuss possible alternative explanations, exacerbating the travesty that is their work.

References

Bracho, G., Varela, E., Fernández, R., Ordaz, B., Marzoa, N., Menéndez, J., García, L., Gilling, E., Leyva, R., & Rufín, R. (2010). Large-scale application of highly-diluted bacteria for Leptospirosis epidemic control Homeopathy, 99 (3), 156-166 DOI: 10.1016/j.homp.2010.05.009
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*From the paper:

From the mother tinctures, 1/100 serial dilutions wereprepared using homeopathic pharmaco-technical methods(Korvsakovian dilutions). Between each dilution step, thesolution was succussed 100 times using an automatic dynamizerup to 200C (200 1:100 dilutions) and 10 MC(104 1:100 dilutions).

The claims have captured the attention of MS patients, many of whom have a progressive course that is only partially treated by currently available medications. There are centers popping up, many abroad (such as India), providing the “liberation procedure” and anecdotes of miraculous cures and spreading over the internet. There is even a Facebook page dedicated to CCSVI, and you can read the anecdotes for yourself. Many profess dramatic improvement immediately following the procedure, which seems unlikely even if Zamboni’s hypothesis is correct.

Zamboni is also getting attention from neurologists and MS specialists, who remain skeptical because Zamboni’s claims run contrary to years of research and thousands of studies pointing to the current model of MS as an autoimmune disease.

There are at least two stories to follow here. The first is the scientific story – the questions being proposed are answerable with scientific research, and they will be answered. MS remains a serious illness that is inadequately treated (not to downplay the important advances we have made, but we certainly are far from an adequate cure for MS). The potential of a new treatment deserves serious research attention, and CCSVI is getting it. It will probably take another ten years for the research to play itself out adequately for there to be a confident consensus on CCSVI, but eventually we will have a scientific answer.

The other story is the the reaction of the public and the MS community. This has been mixed, but already there are conspiracy theories that the neurology community, the MS society, and Big Pharma (of course) are fighting against CCSVI as part of a misguided turf war. (See the comments to my previous posts on this topic at NeuroLogica for some examples.) Anecdotes are being used to argue against published scientific evidence, and negative studies are being dismissed. If CCSVI is eventually found to be a scientific dead end, I have to wonder if it will survive as just another fringe “alternative” treatment, like Laetrile, psychomotor patterning, and other discarded ideas in medicine.

The Scientific Story

So far there is not much of a scientific story to tell. A PubMed search on CCSVI yields a total of 19 publications (a pittance), indicating how new this concept is. I suspect this number will grow into the hundreds at least before this story plays itself out. If CCSVI is proven to be legitimate then this number will grow into the thousands over the next few decades. If it is disproved, publications will trickle off.

Most of the current research is published by Zamboni’s team. He is building an impressive list of studies, exploring various aspects of CCSVI and MS, but evidence that derives entirely from a single research team is always suspect. The role of bias in research is well documented, and further most new ideas in medicine turn out ultimately to be wrong. Therefore skepticism is the proper approach to bold new claims being supported by a lone research team. Replication will be necessary for the broader scientific community to take CCSVI seriously.

The core claim made by Zamboni is that most patients with MS display 2 or more out of 5 criteria on studies of venous anatomy (using ultrasound or venography) of venous insufficiency. While control patients (healthy subjects or those with other neurological disorders) display 1 or no criteria, and never 2 or more. All other claims (benefit from angioplasty, matching patterns of venous insufficiency with types of MS) derive from this core claim.

I found four independent replications in the literature, three very recently published. The first is by Al-Omari MH, Rousan LA, who found:

“According to the described criteria, 92% of the MS patients showed abnormal findings and 84% of them showed evidence of CCSVI, however; only 24% of controls showed abnormal findings, but none of them showed evidence of CCSVI (OR=7.25, 95% CI 2.92-18.01, P<0.0001).”

These are similar numbers to Zamboni, although the 84% is a little less. This study used only ultrasound, which is a non-invasive technique and therefore good for screening, but the results are very operator dependent. There is no indication in the study that the patients were assessed in a blinded fashion.

The next study by Florian Doepp et al used the following methods:

We performed an extended extra- and transcranial color-coded sonography study including analysis of extracranial venous blood volume flow (BVF), cross-sectional areas, IJV flow analysis during valsalva manoever (VM) as well as ‘CCSVI’ criteria. 56 MS patients and 20 controls were studied.

They found no subjects met the Zamboni critieria for CCSVI – a completely negative replication.

The second was performed by Krogias at al, who found:

The authors conclude that the „chronic cerebrospinal venous insufficiency (CCSVI)“ cannot represent the exclusive pathogenetic factor in the pathogenesis of MS. In our cohort, only 20% of the patients fulfilled the required neurosonological features of CCSVI. So far, the pathogenetic relevance of these findings remains speculative. Thus, based on the current scientific position we cannot justify invasive „therapeutic“ approaches, especially if they are performed outside of clinical trials.

The third study is a Swedish study by SundstrÃm et al (“Venous and cerebrospinal fluid flow in multiple sclerosis – a case-control study.” Peter SundstrÃm, Anders WÃ¥hlin, Khalid Ambarki, Richard Birgander, Anders Eklund and Jan Malm. Annals of Neurology) – not yet available online. This study used MRI scanning to assess blood flow in the internal jugular vein in 21 MS patients and 20 controls, and found no difference.

Conclusion

One of four replications found results similar to Zamboni. A second found only 20% of MS patients met Zamboni’s criteria, while two others found that no patients with MS did. Four studies is not a lot – and is not even close to ending this controversy from a scientific point of view. But these early results are not promising and will tend to deepen skepticism within the neurological community.

Clearly there is a need for more research so that both patients and professionals can feel comfortable that CCSVI has been given a thorough investigation and we can say with confidence what role, if any, it plays in MS. The results, also, do not have to be black and white. While it seems unlikely that Zamboni has discovered the sole and ultimate cause of MS in most or all patients, it is possible he has found a significant consequence of MS. Chronic inflammation may result in venous insufficiency in some patients. This venous insufficiency may further play a role in worsening the clinical course in a subset of those patients, who may benefit from treatment. So CCSVI may ultimately play a minor but important role in the management of MS.

Or it may all turn out to be a figment of Zamboni’s imagination, spawned by the sincere hope of finding a cure for MS. Time and research will tell.

My open plea to the MS community, especially those who are going down the rabbit hole of conspiracy theories, is to keep this discussion about the scientific evidence. This is not the place for cheap conspiracy theories. I fear my plea will fall on deaf ears, but it never hurts to ask.