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Proposed Changes to FDA Regulation Present a Dilemma

The Food and Drug Administration (FDA) is proposing a very interesting loosening of their regulations of pharmaceutical company marketing. The pros and cons of the proposed changes present an interesting dilemma, with legitimate points on both sides.

When the FDA approves a drug it is approved for a very specific medical indication. I have long thought that FDA approved indications for drugs were too narrow and restricting. For example, most anti-seizure medications are initially approved not for seizures but only for certain types of seizures – for example for adjunctive therapy (meaning it is meant to be added to another drug rather than used alone) for focal onset seizures (and not against primary generalized seizures – or ones that begin all over the brain at once).

Once approved physicians are free to use drugs as they see fit. If evidence shows that a new seizure medication is effective as first line treatment, then it is ethical good medicine to use it that way, even if it is not FDA approved for that use (this is called off-label use). FDA approved is not equivalent to science-based.

While physicians are free to follow the evidence and their clinical judgment, pharmaceutical sales representatives can only talk about the FDA approved indication for the drugs that they promote. They can only provide information (FDA approved information) for on-label uses. They are not supposed to even talk about off-label uses for their drugs.

If a pharmaceutical company wants to market a drug for an off-label use they must apply to the FDA and provide sufficient evidence to earn a separate indication for their drug.

The change being proposed now would allow drug companies to provide to physicians published studies about their drugs, even if they discuss off-label uses. This new policy is called the “Good Reprint Practice.” To balance this loosening of restrictions the FDA says, “This guidance also safeguards against off-label promotion.” They add further reassurance that articles will be restricted to those that are peer-reviewed, published by editorial boards, and not published in journals or supplements funded by the drug makers.

Now here’s the dilemma. Proponents of this new proposed change to the FDA imposed restrictions argue that companies are gagged from promoting uses for their drugs even when they are solidly evidence-based and life-saving. For example, a New York Times article on this issue reports that:

“The consequence of rapid disclosure of these benefits could be measured in lives,” said Dr. Scott Gottlieb, a former F.D.A. deputy commissioner.

Of course, physicians can get access to this information without the help of pharmaceutical companies. But considering the overwhelming amount of new scientific medical information published each year, any method of disseminating quality scientific information to physicians is useful.

Critics of the proposed changes also have a very legitimate point to make. Again, quoting the NYT article:

Representative Henry Waxman, Democrat of California, said the proposed rule “caters to the industry’s desire to market their products without adequate testing or review.”

But more to the point, if pharmaceutical companies can promote off-label uses for their drugs by providing published articles then that removes their incentive to fund and conduct sufficient studies to gain FDA approval. In general companies pay for expensive clinical trials of their products only to the extent that they are required to by regulation. Therefore the new regulations could mean less pharmaceutical company funded clinical research.

I don’t think there is a clear resolution to this controversy, because either choice is a trade-off. Restricting dissemination of legitimate scientific information about life-saving uses of drugs and medical devices will cost lives. But allowing companies to provide published studies on off-label uses will decrease their incentive to pay for further research.

I always find it ironic, however, that when people are discussing FDA regulation of drugs there is almost a universal failure to apply the same arguments to supplements, for which there is even less regulation. For example, by allowing supplement makers to sell their products with health claims (under DSHEA) without the need to provide any evidence or pass any FDA review process, there is absolutely no incentive for the supplement industry to conduct meaningful clinical research.

The dilemma between the protection of regulation and oversight vs the freedom to disseminate information and make claims without restriction exists throughout health care – it is not unique to drugs and medical devices. At the moment, in the US, this conflict is resolved very far to the regulation end of the spectrum for drugs and to the freedom end of the spectrum for supplements (even though supplements are often used as drugs). There is nothing in between. FDA approval is all or nothing – either you meet a very high bar of evidence or none is required.
Perhaps the solution is to provide different levels of FDA oversight. There should be a mechanism for the FDA to have expert panels review existing published evidence and then to approve those claims that are sufficiently science-based – without necessarily requiring millions of dollars worth of new research.

Such a review process could be applied to supplements – replacing the anything goes rules of the current regulations under DSHEA. Such a process could also be used for off-label uses of approved drugs.

It seems that that binary aspect of FDA approval is no longer adequate to deal with the complex world of health products. It has lead to our current situation of irrational regulations and unnecessary trade-offs.  My counter-proposal for the FDA is to institute mechanisms for one or more levels of science-based FDA review to handle the full spectrum of commercial health claims that are being made to the public. Until then we will be stuck with inadequate regulation and an unresolvable dilemma.

Posted in: Pharmaceuticals, Politics and Regulation

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29 thoughts on “Proposed Changes to FDA Regulation Present a Dilemma

  1. qetzal says:

    Alternatively, respected medical bodies could perform such a review function, perhaps with FDA’s advance blessing.

    For example, ASCO could review published papers on off-label use of approved cancer drugs, and decide which papers met their standards. Those standards could include both intrinsic quality as well as consistency with other knowledge in the field. (The latter would address the concerns this blog has raised regarding EBM versus SBM.) FDA could stipulate in advance that any oncology paper approved by ASCO could be distributed by pharma to physicians.

    That would avoid burdening FDA with a whole new raft of reviewing responsibilities, and let the experts in each specialty make the judgements.

  2. apteryx says:

    Technically, supplements cannot claim to diagnose, prevent, treat, mitigate, or cure any disease, no matter how much scientific evidence there may be that they can do so. They are allowed to make “structure-function claims” only if there is evidence to support those claims. FDA cannot pre-approve the claims, but can go after unsupportable false claims (so if they are failing to do so, it is not because they lack the legal power). Structure-function claims are often backed by scientific evidence that primarily supports disease claims. For example, a supplement containing EGb 761 ginkgo extract may say “helps enhance normal memory,” whereas in fact there is enormous evidence that it slows the progression of senility and improves cognitive function in the senile, but none at all that it will improve the memory of normal people. As has been repeatedly noted, the structure-function claims therefore serve as hints to the more accurate health claims that may not be spoken by the manufacturer. That’s a flaw in the system.

    It is not reasonable to expect every manufacturer of supplements to spend fortunes on clinical trials. Firstly, most of them, like most small food manufacturers, simply do not have that kind of money. Secondly, even if a company had $200 million or so to spend proving that its elderberry product, say, shortened the duration of colds, they would then neither have marketing exclusivity for the species as a whole (nor should they), nor would they even be able to proclaim on the package that their specific product relieved colds. That would be – horrors! – a disease claim. They would still be stuck with a mushy structure-function claim (“helps maintain a healthy immune system”), and all the extra supporting evidence they had generated would be used by free-riding competitors to support their structure-function claims as well. If there is no potential gain to equal the expense involved, this would be fiscally suicidal, or at best for a larger company, would violate their fiduciary duty to their shareholders.

    While the anti-supplement lobby argues that expensive manufacturer-funded studies should precede mere legal sale of a traditional product, they also tend to reject any and all positive results from supplement studies funded by a manufacturer, on the grounds that such funding may create bias (and it certainly may, although we do not reject all studies of Big Pharma products on the same ground). Dr. Novella wants the “supplement industry” to conduct “meaningful clinical research,” but the chances that most folks on this board will acknowledge the results as meaningful are pretty slim. Would you be willing to create positive incentives for research, such as allowing disease claims to be made on supplements when supporting evidence has been generated? If not, research requirements, like the new drug-like GMPs, would serve no purpose except to put manufacturers out of business and deprive consumers of choice.

  3. Joe says:

    Apteryx bleats the standard quack refrain “We cannot afford to prove our stuff is safe and effective, so we should just be allowed to proceed as if it is.” AS IF …

    When it was abundantly clear that ephedra was killing people, the manufacturers spent a lot of money settling wrongful-death cases rather than withdraw (or study) it. After the FDA banned it, the industry spent more $ on legal fees to challenge the ban.

    Money is not the problem, the real problem is that good research has yet to find compelling evidence in favor of dietary supplements. In fact, high-quality studies invalidate claims for supplements. So, it is counterproductive for merchants to conduct such studies. They would rather continue making money AS IF.

    The fiduciary responsibility to shareholders should be trumped by concern for customers. The DSHEA is a triumph of charlatans over consumer advocates.

  4. Harriet Hall says:

    What bothers me about supplements is

    (1) that they are marketed under the fiction that they are not intended to treat disease, but people are obviously taking them for that purpose.
    (2) the public falsely believes that they must have been proven safe and effective before marketing.
    (3) the public falsely assumes they have been subjected to the same kind of quality control as prescription drugs.
    (4) Few people seem to read or understand the FDA disclaimer statements.
    (5) The FTC can’t keep up with prosecuting the lies supplement manufacturers print, and the public assumes what they read has been “allowed” by the government so it must be true.

    I think the DSHEA should be repealed, but if it continues in force, I think we need a strong public education campaign so consumers will better understand what they are and aren’t getting.

    Supplement marketing need not be deceptive. It seems to me a company could build a reputation and make a lot of money by offering accurate information and quality-tested products. Consumers are willing to pay more for quality, and they’re willing to pay for information, as the success of Consumer Reports shows.

  5. durvit says:

    Apteryx wrote:

    While the anti-supplement lobby argues that expensive manufacturer-funded studies should precede mere legal sale of a traditional product, they also tend to reject any and all positive results from supplement studies funded by a manufacturer, on the grounds that such funding may create bias.

    I hope that I would pay some attention to the quality of the study, although there are very similar concerns about research support and the potential bias of findings discussed in these papers: Does Industry Sponsorship Undermine the Integrity of Nutrition Research/ and Relationship Between Funding Source and Conclusion Among Nutrition-Related Science Articles .

    I’ve had a number of people quote the Landmark Study at me but there seem to be some real concerns about the quality of the study.
    Harriet Hall wrote:

    Consumers are willing to pay more for quality, and they’re willing to pay for information, as the success of Consumer Reports shows.

    In the UK, the Consumers’ Association Health Which? was independent but closed down after 16 years because it could not be supported by its subscriber base. Of course, with the NHS, we have different expectations about healthcare and possibly about paying for healthcare information.

    People do pay surprising amounts for supplements, but, in the UK, you would not really have any way of knowing if they dissolve, use bioavailable ingredients, etc. etc. I’ve known people spend around 400 pounds per month – so around 750-800 US dollars. It is unfortunate that they can’t be sure of what they are getting for that level of investment.

  6. apteryx says:

    Joe – Your instant resort to ad hominem attacks suggests that you have little fact-based argument to offer, so I will not bother to debate with you. I have already hashed over with others the question of whether only negative studies of botanicals can be considered “high-quality,” given the fact that many studies have been positive.

    Dr. Hall – To address your points:

    1. People indeed do use botanicals to treat disease, as they have been doing for tens of millennia. A large percentage of the world’s people use plant-based medicine because it is the only medicine they can afford; in the West, most users do it because it alleviates their suffering. I see no problem with that.

    2. These are not novel compounds that were just invented yesterday; they have a history of continuous human use dating to long before the FDA gained its current regulatory power. It makes no more sense to suddenly prohibit existing medicinal plants in use, absent evidence of harm, than it would to prohibit all food plants not important in American agribusiness. You might promise that those minority foods could be allowed back on the market after “extensive safety testing,” but who would shell out for those tests, for a product no longer even on the market? The botanicals that have been tested for efficacy have been tested not because they are the most potent, but because they are presently popular among consumers in the nation whose scientists are doing the testing. Absent continued human use, these plants will never be tested at all.

    3. Quality control has been a problem in segments of this industry, as in the drug and food industries. FDA’s new GMPs for supplements are equal to or more stringent than their drug GMPs (in contravention of DSHEA). They will admittedly put at least some small manufacturers out of business, and on the face of it ban herbalists from making their own individual remedies. If these GMPs are enforced, there should be no more concerns about supplement purity and quality than about drug purity and quality.

    4. The average regular consumer of botanicals, in the West, is of above average education. Since sellers are forbidden to provide information on uses of their products, users of botanicals must either locate experts to consult or must educate themselves. I think that most such people are smart enough to be taught what a disclaimer means, if they do not already know.

    5. There are scam products being marketed with outrageous lies – almost entirely on the Internet, not by reputable manufacturers. Swindlers will always exist, and should be prosecuted. As far as I can tell, the FTC is not “unable to keep up”; they aren’t even trying. If they would make an example out of a few people, it would be good for the whole market. The friendliest explanation I can offer for their failure to do so is that the Bush administration is so hostile to regulation and consumer protection that they will let corporations do pretty much whatever they want.

    Finally, you are quite right that consumers will pay more for quality and information. I think that is why the best-selling botanicals are generally those with scientific evidence behind their use (with the exception of occasional fads like Hoodia). As you suggest, there are a number of American supplement companies, as well as European phytopharmaceutical manufacturers, that have built reputations and are making money by offering rigorously controlled product quality. Personally, I think that trend can be taken too far. If you are using ginkgo to treat Alzheimer’s, you want EGb 761 (or some equally well standardized and clinically tested extract). If you are using chamomile tea for an upset stomach, you do not need a super-standardized product; that will just mean that the product is much more expensive than it needs to be.

  7. Egaeus says:

    Nobody mentioned the fact that a study on the efficacy of Sambucol, to use apteryx’s example, would not cost $200 million. Elderberry extract is GRAS, therefore it’s safety is not in question, just effectiveness. How much will it cost to innoculate 300 people with a typical cold virus, treat 100 with Sambucol, 100 with a placebo, and 100 with nothing? “Nutritional supplements” are a multi-billion dollar industry; surely they can afford a few double-blind studies with more than a dozen people. Judging from it’s disappearance from the shelves here in Tallahassee, the sales here alone could probably pay for it. It’s not a matter of cost, it’s a matter of incentive. They have none, which makes finding the few things that work among all the snake oil nearly impossible for consumers.

    That being said, my MD recommended Sambucol for a cold, and it worked, and has worked for one documented illness and 2 suspected illnesses (persistent sore throat after being around sick people) since. I keep an unopened bottle just in case the local store runs out again, and I’m ready to do my own long-term data collection.

    Yet for something that seems to work so well, I’d surprisingly never heard of it before, but it seems that the whole world has heard of Airborne thanks to the lack of requirement for proof of efficacy and powerful woo marketing. Are reasonable scientific studies too much to ask?

  8. apteryx says:

    I was not, in fact, referring to Sambucol, but to a random example; there are other elderberry products on the market, plus those you could make in your own kitchen if you chose. Sambucol has not sold out at your local store. It has been recalled by the American distributor because they discovered that the manufacturer (an Israeli company whose name slips my mind) had included “undisclosed preservatives and flavors,” i.e., had padded it with non-elderberry fruits. Oops. Everyone still seems to agree that the product works, even if the manufacturer is not so good as we thought. With flu season heating up in my area, I want to try the outrageously expensive Blockade lozenges, which reportedly have some science behind them, but they are (really) sold out at my local store.

    I have personally worked with people who were spending over $10K per patient for a trial of a botanical, all costs considered; the lowest estimates I have heard are $2500 to $3000 per patient. Your proposed 300-person trial – with one arm seeming superfluous to me, as a “no treatment” arm is almost never seen in drug studies – would probably cost a couple million dollars, even more if extra safety testing was added because GRAS status is not enough to satisfy some where botanicals are involved. Then, you would have to have this replicated and re-replicated, because if you get results with 100 people per arm, suddenly that too will be a small study and not conclusive; add more millions.

    That is also not counting the cost of spending a year jumping through Institutional Review Board hoops before each study (many IRBs hate botanicals), or the effort required to get through an Investigational New Drug application. If you are looking at “disease endpoints” such as days sniffling, you must first have FDA permission to do research on this “new drug,” and may have to not only demonstrate safety to their finicky satisfaction, but prove you can standardize the product virtually perfectly. Oh, yes, that’s another point. Legally, if a botanical has been the subject of an IND application before it has been sold as a dietary supplement, it can NEVER be sold as a supplement, but would have to go through the almost impossible process of botanical drug approval. (Or, if appropriate, it could be sold as a conventional food – no kidding.) Thus, if you were rich enough to do disease-endpoint studies on a new botanical before you marketed it, the moment you filed the IND requesting permission to do the study, you would automatically be barred from ever marketing it – whereas if you had only done safety testing to jump through the “new dietary ingredient” hoop in DSHEA, you could market and then test at your leisure.

  9. Joe says:

    Apteryx doesn’t want to “debate” me (the horror, the horror). Says I don’t have facts. What about the facts about the lethal supplement (ephedra) that I cited? What about the fact that no dietary supplement has passed high-quality safety/efficacy testing? It is you who lacks facts; otherwise you might be able to argue.

    Apteryx wrote “Thus, if you were rich enough to do disease-endpoint studies on a new botanical before you marketed it, the moment you filed the IND requesting permission to do the study, you would automatically be barred from ever marketing it – whereas if you had only done safety testing to jump through the “new dietary ingredient” hoop in DSHEA, you could market and then test at your leisure.” How about explaining why this is a bad idea … Unless, you want to make millions selling junk. As your continued article said, you should be able to sell the stuff AS IF; how stupid can you be?

  10. qetzal says:

    apteryx,

    I agree with many of your points that the current regulatory systems may actually inhibit clinical testing of supplements for disease indications. And I can also vouch for your figures on the per-patient costs of a typical clinical trial. (Although a year for IRB approval is pretty excessive, in my experience.)

    I am, however, curious about a couple of things.

    First, what makes you say the new GMPs for supplements are more stringent than drug GMPs? I know the drug GMPs reasonably well. So far, I’ve only skimmed the supplement GMPs, but they look pretty comparable.

    Second, do you think the standards for quality, manufacturing controls, and efficacy data for supplements should be lower than for drugs? If so, why?

  11. Apteryx, “While the anti-supplement lobby argues that…”

    Apteryx, I consider myself a very proud member of the “anti-supplement lobby”. My interest in supplements is very personal and somehow I think yours is too. You can find out all about me by clicking on my profile which will bring you to my webpage or just go directly from here: http://rosemaryjacobs.com

    Now who are you? Is my suspicion correct? Do you also have a personal interest in supplements?

    Joe’s statements about ephedra are accurate although just the tip of the iceberg. So I have to assume that when you responded, “Joe – Your instant resort to ad hominem attacks suggests that you have little fact-based argument to offer, so I will not bother to debate with you,” that you thought that by calling him names you would distract readers from the fact that you weren’t giving them any way to verify that what Joe said is inaccurate as you claim. If there is an honest supplement manufacturer and if he followed the ephedra debacle, he would have been ashamed and stood up to the industry he belonged to, but I haven’t heard of any supplement manufacturer doing that. Have you?

    Judging from your previous post where you said, “There are scam products being marketed with outrageous lies – almost entirely on the Internet, not by reputable manufacturers. Swindlers will always exist, and should be prosecuted. As far as I can tell, the FTC is not “unable to keep up”; they aren’t even trying,” I am going to guess that you will classify silver supplements in the scam category. If so, then why is it that the supplement industry protects the silver scammers and gives them a home in their thorny nest?

    When the FDA published a proposed rule for silver supplements in the Federal Register (docket # 96N-0144) and requested comments, the supplement trade group, the Council for Irresponsible Nutrition, CNR, sent a letter stating, “In any further publication or communication on this topic, FDA should explicityly state that this rulemaking does not apply to dietary supplements.” Why do you think they wanted to protect the silver scammers and their right to sell dangerous, useless snake oil? Do you think their reason was based on science or on finance?

    Please don’t tell me the good little scientists at CNR just weren’t aware of the scam that early in the game because I personally had already sat in a small room with members of the President’s Committee On Dietary Supplement Labels which included several supplement industry leaders, one of whom was Annette Dickinson, Ph.D, CNR’s Director of Scientific & Regulatory Affairs, and told them all about the scam. I even had a pile of documentation which included promotional material and the articles that the promotional material referenced which showed that the claims were fraudulent and I know very well that the industry saw it all.

    Your remark about the FTC is flippant. I filed a complaint about silver quacks with that agency years ago. I found out how to do that by speaking with aides to one of my senators who put me in touch with a real live person at the FTC. When I told her on the phone that the salesmen were using quacks from the early 1900s as references, quacks they were pretending were contemporary scientists, she laughed and said, “They all do that.” I’m not sure of the # now without checking files, but I think she said that the FTC had 35 employees to deal with fraud in the entire US. And don’t blame Bush. Clinton was in the White House then.

    And don’t tell me that there isn’t big money for small companies in supplements because I know of a few that made large sums in a short time. I also have a press release saying that Clifton Mining Company bought a controlling interest in ASAP, a Utah silver supplement company. Clifton said it was a “perfect fit”. It multiplied “silver values at least 50 fold”, not 50%, 50 fold! That’s some markup! Just think how much the mining companies could make if silver actually offered benefits and didn’t turn humans into smurfs!

    If you regulate every industry in town but one, you don’t have to be a rocket scientist to know where the crooks will flock. The supplement industry is for all practical purposes unregulated and it is full of crooks and naive innocent people who believe salesmen’s claims without ever even realizing the need to verify them independently.

    Rosemary Jacobs
    Proud Member of the Anti-Supplement Lobby
    Believer In Full Disclosure

  12. Harriet Hall says:

    I don’t have any problem with people taking supplements for medical reasons; what I object to is the two-faced fiction the DSHEA promotes. “You can take this medicine as long as we all pretend it isn’t medicine.”

    The fiction that supplements are “food” means consumers are not provided full disclosure about the products. I would like consumers of supplements to have access to the kind of information I can get from the Natural Medicines Comprehensive Database (which requires subscription). At the very least, the products might carry a warning when they are known to interact with other medications.

    When I get a prescription medication, it comes with an information sheet telling me more than I need to know. When I buy a bottle of over-the-counter Tylenol, it warns me not to take it with other products containing acetaminophen, and it lists all the inactive ingredients so I can make sure I’m not allergic to them. I was given a Chinese remedy called Lemonin that contained acetaminophen under the British name paracetamol, that contained no warnings, and that did not list the inactive ingredients at all. The person who was handing it out had no idea paracetamol was the same as Tylenol.

  13. Grayson says:

    This is incredibly random, but where has Pec been recently? I had grown accustomed to seeing him be shot down by remarkably educated and well informed people on a daily basis. It was a daily affirmation of sorts, for me, proving that the forces of logic and reason can, given a chance, win over the forces of CAM and woo-woo.

  14. I don’t believe that the forces of logic and reason alone will ever beat the great scientists in the supplement industry’s marketing departments when it comes to protecting the mass market from useless and dangerous products.

    This is not a intellectual game. It is about life and death, wellness and chronic disease. Like it or not we all learn through our senses and our experiences even Skeptics, scientists and academic MDs. Like it or not, the best antidote for an anticdote is an anticdote. When people tell me that a supplement known to be dangerous can’t possibly be because they have taken it for years and not been injured, I respond, “My mother smoked heavily for 65 years and never had lung cancer. Do you think that means that Camels are safe or that my mother was a very lucky lady?” (That anecdote is an illustration which hopefully gets intelligent consumers to realize that N=1 means nothing.)

    I have spoken with many very frustrated and worried public health officials who say that DSHEA will be on the books till there is a major disaster. They say that historically it has always taken such an event to motivate the public to change such a horrible law.

    Many years ago I corresponded with a pharmacognosist who held a high position with the FDA who contacted me after seeing my posts on the Health Fraud list. He was expecting such a disaster and hoped that no one he loved would be injured or killed. Then guess what, he was gone from FDA. I was told that he’d taken a job with a supplement company. Maybe he thinks he has a better chance of keeping dangerous supplements off the market there than at the FDA? I don’t have a clue.

  15. One point – supplements (broadly defined in DSHEA as almost anything) are not banned from making disease claims. Rather – if disease claims are made for a product then they are subject to regulation as a drug. The FDA, in effect, defines “drug” as something for which a disease claim is made, and “supplement” as something for which non-disease (so-called structure/function) health claims are made. So it is NOT true that if an herb did prove efficacy for a disease that it could not be marketed for it – it would just need FDA approval as if it were a drug.

  16. Egaeus says:

    You misinterpreted my statement, apteryx. I don’t think that GRAS food-derived products should have to go through the same safety testing as artificial chemicals, as their safety has been demonstrated continuously. Of course, extracts from plants known to contain small amounts of toxins would have to be shown not to contain significant amounts of that toxin, such as the mild cyanide toxicity of raw elderberries.

    I do, however, think that if they are being promoted as having health benefits, even the broad structure-function claims, should be backed up with multiple solid studies, and no more “These statements have not been evaluated by the FDA…” disclaimers. If you can’t show that your product does something, then you shouldn’t be able to market it as doing anything.

  17. apteryx says:

    qetzal – The supplement GMPs require that testing for identity, compositiion, etc. be done both at the beginning and at the end of the manufacturing process, if suitable tests exist (not if they are affordable, but if they exist – and the manufacturer must be prepared to prove that they don’t). You get your raw materials in – echinacea extract, let’s say. You generate chemical fingerprints. Yep, it’s echinacea. Great. You mix up your product. Now you must do another set of tests to prove again that it’s echinacea in the bottle. What, was there any chance that it was going to magically change species in the mixer? If the drug maker must only do one set of chromatographic tests per batch, while the supplement maker must do two, then more costly requirements are being demanded of the latter.

    This contravenes DSHEA, which told the FDA to produce foodlike GMPs. (Food manufacturers do not have to do so many tests. As another example: If a lot of thyme, say, is divided up and sold to 100 supplement manufacturers, each of the latter must independently reprove its identity, without relying on certificates of analysis. But if it is sent to Campbell’s to put in soup, they can just accept the supplier’s certificate of analysis.) I do think that supplements should be less expensively regulated. How can we say that a product must be expensively controlled to maximize efficacy, when official policy says that it is not to be considered efficacious for any disease? There is also a broader therapeutic dose range for surviving botanicals than for most drugs; tincture of echinacea is more comparable to prune juice, which will alleviate constipation to some degree even if it is less potent than average and will not kill you if it’s more potent than average, than to Tylenol, which might kill you if it’s not carefully standardized.

    Rosemary – I’m sympathetic to the harm you’ve experienced from suffering argyrism. Silver supplements are not by my definition traditional medicine but weird quackery from the era of heavy-metal allopathy, and I’ve never had anything good to say about them. I certainly wish FTC would make an example of the people who market them with false claims to innocent folks like you. They have the legal authority to do so.

    I hope your suffering will not lead you to believe that anyone who disagrees with your new opinion is a bad person. I did not “call Joe names”; mentioning a person’s ad hominem attacks is not an ad hominem attack. (You can find the phrase in your dictionary.) In fact, while some people in the industry (and some herbalists) legitimately disagreed with the FDA’s assessment of ephedra risk, many who did not use ephedra in their products supported or did not oppose the FDA ban. As for your “suspicions” that “somehow” I have a “personal interest” — to forestall you from stooping to ad hominem attacks, I will tell you exactly what my interest is. My family and I are satisfied users of botanicals, and I’ve seen them used by people in other countries who can afford only traditional medicine. I am pretty familiar with the scientific literature supporting the uses of, primarily, popular European herbs, which convinces me that our ancestors’ accumulated medical knowledge, though limited and imperfect, was not the less-than-zero some would suggest. However, I do not work in the supplement industry, however broadly defined, nor have any investment in it.

    Steven Novella – It doesn’t make sense to say “supplements are not banned from making disease claims” when the making of a disease claim instantly moves the product from the supplement category to the drug category — thereby making it an illegal, unapproved, “misbranded” drug to be confiscated on the spot. As you note, it has recently become legally possible to pursue drug approval for botanicals, but approval is still almost impossible to achieve in practice. At least one company has run itself into the ground trying, with the result that others still think they are better off selling efficacious botanicals as supplements and counting on consumers to learn about their utility by word of mouth.

  18. apteryx says:

    Egaeus – YOU maybe don’t think that GRAS products should be expensively safety-tested before the real research even starts, but not everyone agrees with you. Look at the people who have tried to claim pregnant women shouldn’t use ginger. Elderberry sometimes contains significant cyanide in the foliage, but I’m not aware of any serious toxicity problems with the ripe fruit. These are food plants. My assumption is, if you can sit and eat the stuff with a spoon, one capsule of it isn’t going to kill anyone.

    Structure-function claims certainly are legally required to have scientific backing, and certainly ought to have. But if they were to be preapproved by a government agency, we need an agency more liberal in its attitude than the FDA. A “solid” study can’t mean one with negative results, and the amount of research required to support a claim can’t cost more than anyone could hope to recover selling the plant.

  19. David Gorski says:

    This is incredibly random, but where has Pec been recently

    Sadly for Steve Novella, he appears to have infested Steve’s personal blog.

  20. qetzal says:

    apteryx,

    If the drug maker must only do one set of chromatographic tests per batch, while the supplement maker must do two, then more costly requirements are being demanded of the latter.

    In fact, the same rules do apply to drugs. You have to test the API and all other critical ingredients before making the batch, then you have to test the final product to prove that it’s what it should be. That includes not just purity & related quality tests, but also identity tests. In fact, of all the required tests, FDA treats identity tests at the beginning and end of manufacture as among the most important. This largely to avoid mix-ups, which do sometimes happen, and can have devastating consequences if not caught.

    One can argue whether such testing is generally necessary, but in this instance at least, the supplement GMPs are not more stringent. (Whether DSHEA mandates they should be less stringent is beyond my knowledge.)

    I do think that supplements should be less expensively regulated. How can we say that a product must be expensively controlled to maximize efficacy, when official policy says that it is not to be considered efficacious for any disease?

    Fair enough, but should supplements be able to make efficacy claims, in your opinion? And if so, should they then be subject to regulatory controls similar to drugs? Let’s ignore for the moment whether current drug GMPs are appropriate. I’m interested in whether you think supplements should be able to make claims like drugs, but still be held to a lower regulatory standard.

    That’s what I was trying to get at originally. Sorry for being unclear (& thanks for the considered replies above).

  21. apteryx says:

    Perhaps I am misinformed about the drug GMPs. It had been my understanding that identity testing for a single synthesized molecule was only actually required at the end of the process, which is when its identity is relevant to the consumer (though of course nobody would go to the expense of processing a batch of chemical without checking the identity of the starting material). But botanicals are not generally being subjected to chemical alterations; they’re ground up or extracted, blended, and put in the bottle or capsule. This is more comparable to what happens to plants — often the very same plants — in food processing. When you fill the can of soup, juice, or hot sauce, you do not have to spend hundreds of dollars per batch proving that the species you put into the vat came out of it as well.

    I think that the Germans are doing fine with a system whereby botanicals are allowed to make health claims that are supported by significant human use data and a reasonable amount of scientific evidence. Germany does have stringent quality control regulations, but these have not been written to prevent phytomedicines from being marketed (and often prescribed and covered by insurance). Likewise, Canada allows traditional medicines to make qualified health claims as such (at least for diseases that the regulators deem appropriate for patient-directed treatment), and people have not been dying like flies from “dangerous supplements” up there. If the medical profession admitted that tomatoes might prevent prostate cancer, I would not take that as evidence that only standardized tomatoes should be sold, nor that tomatoes should be prescription-only. One of the advantages of traditional medicine is its lower cost; a botanical should not have regulations heaped on it that are more appropriate to a toxic drug, if the result will be that the botanical costs more than a drug but is not covered by insurance. Consumers want product quality, not regulations that deprive them of access to products.

  22. Apteryx wrote: “It doesn’t make sense to say “supplements are not banned from making disease claims” when the making of a disease claim instantly moves the product from the supplement category to the drug category — thereby making it an illegal, unapproved, “misbranded” drug to be confiscated on the spot. As you note, it has recently become legally possible to pursue drug approval for botanicals, but approval is still almost impossible to achieve in practice. At least one company has run itself into the ground trying, with the result that others still think they are better off selling efficacious botanicals as supplements and counting on consumers to learn about their utility by word of mouth.”

    Regarding the first point – we are down to semantic. Disease claims require FDA approval as if it were a drug – but anything can get this approval if they meet the requirements. The point is – it is not based upon substance but the claims made for them.

    Also – isn’t this the point of my original blog post? We need to get away from this all-or-none system, because it leaves us with mostly no regulation of a broad spectrum of agents. There are lots of studies of herbs and supplements, but the FDA has nor process for reviewing them, and no bar for health claims except a full drug approval. If some evidence were required for all health claims then some of the billions of dollars from the supplement industry would go toward even more research. The system now is an incentive against research.

    This is bad unless you ASSUME that many herbs and supplement have health benefits. I don’t. When they do get studies they tend to have little or no benefits, and hidden risks emerge. By having no regulation I think we are doing more harm than good.

  23. apteryx says:

    I want incentives for research BECAUSE I assume that many historically used botanicals have health benefits. When they do get studies they often do show benefits, in animal and lab studies as well as human trials, and although a few significant “hidden risks” have turned up, this is not true for the large majority of plants studied. Sorry, don’t have time to write more on the matter now – but it seems to me you are not too familiar with the literature.

  24. qetzal says:

    apteryx,

    Thanks for the response. My issue with quality testing of supplements and phytomedicines is this. If the supplement has enough pharmacologic activity to treat a disease, the way a conventional drug would, why should we be less concerned about its quality, potency, purity, etc., than we should with a drug?

    Is it the mere fact that it’s a supplement or a botanical? That seems illogical to me. Is it because the supplement has significant human use data and a reasonable amount of scientific evidence, as you say? If so, then shouldn’t a comparable drug be held to a similarly relaxed standard?

    I don’t buy the argument about expense (and neither does FDA, typically). One should not be exempted from meeting agreed safety and efficacy standards simply because they cost money. We don’t let pharma sell things without controlled clinical trials, simply because they may cost $10-15K/patient. There needs to be a better justification than that to hold supplements to a lower standard. (Of course, some would say it’s justified because most supplements don’t actually do much. But in that case, such supplements shouldn’t be allowed to make efficacy claims.)

    Also, re your comment:

    It had been my understanding that identity testing for a single synthesized molecule was only actually required at the end of the process….

    Most emphatically not. For an approved drug product, the manufacturer must at minimum perform a visual inspection and an identity test on every batch of active pharmaceutical ingredient before using it to make the final product. I believe the same holds true for any other ingredients that are considered ‘critical,’ even if they’re not ‘actives.’

    Moreover, to accept an API based on appearance and ID as the only in-house tests, the manufacturer needs a certificate of analysis from the supplier, AND the manufacturer must have qualified the supplier’s processes and test methods. Qualification is intended to show that the supplier’s methods are reliable, i.e. that the manufacturer can trust them. Qualification typically requires that the manufacturer perform full testing on several API lots from the supplier (appearance, ID, overall purity, specific impurities, potency, etc.) to prove that the supplier’s test data are reliable. It also typically requires an on-site inspection of the supplier’s facilities, and a review of their documentation and quality assurance procedures. Finally, even with a qualified supplier, the manufacturer is expected to perform full testing on occasional lots of the API (I think at least once annually).

    That’s for an approved drug. Requirements are relaxed somewhat for drugs in the early stages of development, simply because the necessary methods are often still in development as well.

  25. Apteryx, either you are ignoring the points I have tried to make or I wasn’t very clear. You said, “silver supplements are not by my definition traditional medicine but weird quackery.”

    Let me try again. The discussion was about dietary supplements, and by legal definition silver supplements are classified as “dietary supplements” in the US, a term also used for them in other English speaking countries. People who call themselves “alt. med. practitioners” sell silver supplements all over the world and claim that silver is an “alt. remedy”. Silver is also sold as a dietary supplement in health food stores right along with the botanicals.

    The supplement industry has tried hard to make sure that silver supplements can continue to be legally sold in the US as “dietary supplements” in spite of the fact that the industry knows they are useless and dangerous while at the same time that very same industry claims that the public must have free access to whatever anyone wants to make in his garage, call a dietary supplement and sell to the public because they insist that supplements offer great health benefits. Because of this, I have a very low opinion of the supplement industry.

    Now if you jump to the conclusion that I want silver supplements banned, you will be incorrect. What I want is truth in advertising. I want silver supplements to be required to carry warnings about argyria and statements to the effect that scientists who have studied them conclude that they are useless. I want similar factual disclosures on all supplements. But I assure you that that is not what the dietary supplement industry wants which is another reason why I have a very low opinion of the industry.

    I want people who commit fraud in advertising prosecuted and given penalties that will serve as deterents and I’m tired of hearing you say that the FTC has the authority to prosecute and that you wish it would while you continue to ignore the fact that it lacks the resources to do so especially under DSHEA which of course is exactly how the supplement industry wants it and another reason for my low opinion of that industry.

    You said, “I hope your suffering will not lead you to believe that anyone who disagrees with your new opinion is a bad person.” That statement coupled with your failure to address my very real concerns about supplements and the supplement industry leads me to wonder if you are trying to marginalize me so that people will be distracted from the facts I’m presenting about a very dirty industry.

    You said, “mentioning a person’s ad hominem attacks is not an ad hominem attack. (You can find the phrase in your dictionary.)”

    If I thought you were an MD, I’d tell you that sounds quite arrogant to me which I guess shows I have a double standard, one for MDs and one for everyone else, at least when it comes to courtesy. I am not anywhere near as well educated as the majority of the people on this list. Neither do I have their facility with language. However, I could very easily engage in a logical debate with you if I chose. My major was philosophy. But I have no intention of debating, which in the supplement industry is extensively used as a marketing tool, a way to draw attention to the products, give the public the impression that “the experts disagree” and distract attention from the fact that supplement promoters aren’t presenting any evidence to substantiate their claims.

  26. Harriet Hall says:

    Just for grins, I once went through the Natural Medicines Comprehensive Database and tabulated all the listed natural medicines (1384 pages of them) by safety and efficacy ratings.

    Likely safe 38%
    Possibly safe 25%
    Possibly unsafe 6%
    Likely unsafe 8%
    Unsafe 4%
    Insufficient information 21%

    Effective 5%
    Lilkely effective 6%
    Possibly effective 26%
    Possibly ineffective 2%
    Ineffective <1%
    Insufficient information 60%

    That sounds better than it really is. Almost all the natural medicines rated effective and safe are vitamins, minerals, and products also available as prescription or over-the-counter meds approved by the FDA.

    When you consider that only a small percentage of promising new drugs make it through the testing process and are marketed, what are the odds that a natural medicine picked at random from this database will turn out to be safe and effective when adequately tested? Then, what are the odds that a purified active ingredient might be safer and more effective than the original product (as with aspirin and digitalis)?

    Add that to the many reports of contaminated products and content not corresponding to labeling, and it seems to me that taking one of these inadequately tested products is risky. Some of us are more willing to take risks, but don’t you think at least consumers should at least have access to the best available information?

  27. Add to that the fact that scientists have scoured the jungles extensively searching for botanical drugs that worked. They found very few which did and then had to improve on them.

    “The Fever Trail, In Search Of The Cure For Malaria” by Mark Honigsbaum, Farrar, Straus & Giroux, 2001 illustrates the very real difficulties encountered when trying to introduce a botanical that is an effective drug into the practice of medicine.

  28. apteryx says:

    Harriet – I assume that you were using the newer 2006 edition of the NMCD, and that you counted the most positive rating for each product. The NMCD is an excellent compilation, which I highly recommend, although it is not complete; the ratings are quite conservative. The stated criterion for a “likely effective” rating is “Reputable references generally agree that the product is effective… based on two or more randomized, controlled, clinical trials involving several hundred to several thousand patients… and published in established, refereed journals.” The criterion for “possibly effective” is “Reputable references suggest that the product might work… based on one or more clinical trials…” This is open to introduction of bias, and no amount of human use data has any relevance in this system, which they say “curtails perpetuation of myths and age-old beliefs.”

    Efficacy ratings thus tend to be conservative, as almost no trials of botanicals can afford to include several hundreds or thousands of patients. Cranberry for UTI prevention and hawthorn for CHF, both of which just got favorable Cochrane reviews, and ginkgo for dementia and memory impairment are rated as “possibly effective.” “Possibly effective” therefore really means that there is some pretty decent evidence. (Notably, they rate glucosamine “likely effective” for knee osteoarthritis.) If there have not been human RCTs (as will be the case for most plants not popular in Europe, where most good research has been done), a product will fall into the “insufficient information” category. Your count has 60% in that category; of the remaining 40% that have enjoyed human studies, apparently 37% had positive study results, and only 3% were found to be possibly ineffective or ineffective, meaning that of products studied in RCTs, *90%* had positive results for at least one use. Presumably, the “best” products – those with the most animal and in vitro studies and human experience data or popularity – are more likely to receive the very limited research dollars, so the remaining 60% might have lower efficacy rates. Still, this indicates that people are buying the “best” products for the very rational reason that the products are helping them.

    Then there is the safety question. Their “likely safe” and “possibly safe” ratings largely parallel the effectiveness ratings. To be just “possibly safe,” “reputable references” must agree on the fact, and there must be “sufficiently rigorous human studies reporting no serious adverse effects.” (Again, human experience doesn’t count.) “Possibly unsafe” means “There is some evidence [what kind??] suggesting that use of the product might be unsafe,” and “likely unsafe” means “Reputable references or reliable literature report that the product can be harmful, based on human studies or reliable case reports of significant adverse effects.” This is a conservative standard both for “safe” ratings, which require expensive research to have been done, and for “unsafe” ratings,” which may be based on human experience, anecdotes, or speculation. Where some “unsafe” ratings are concerned, an even more conservative standard may have been followed, as I note below. The highest rating given to honey is “Possibly safe…when used topically”; no rating for food use is given, except “Possibly unsafe” for children due to infant botulism. Pumpkin seed, another FOOD, is rated “possibly safe.” Your numbers for safety total 102%; taking your numbers that 81% were rated, and 63% were found to be likely or possibly safe versus 18% at least possibly unsafe, this indicates that we can feel good about the safety of at least 78% of studied products. The potentially unsafe remainder include things like hydrazine and Lorenzo’s oil which are not typically sitting on the shelf at your local Whole Foods. Since FDA has the power to ban products that can be proven to be dangerous in ordinary use, and since regulation or fear of litigation has largely removed the botanicals with narrow safe dose ranges from the market, the products remaining tend to be pretty safe.

    (A huge number of botanicals, including GRAS food plants, are listed as “likely unsafe” in pregnancy – and lactation! – based on three books that list them as possibly inducing or affecting menstruation, with no citation whatsoever of any anecdote of harm in humans. Food plants in this category include peppermint, flaxseed oil, and thyme. The books cited did not get these concerns from scientific evidence, which largely does not exist, but from compiling those “age-old beliefs” that the NMCD team elsewhere sneers at. Garlic is said to be “possibly unsafe” in pregnancy even though there are no published anecdotes of adverse effects, and a human study in pregnant women showing no adverse effects. Thus, the authors really did not live up to their own guidelines, making their protestations of a total lack of bias seem doubtful.)

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