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The illusions of “right to try” laws

There is nothing like a touching anecdote to spur a politician into action. And those who want to try investigational drugs outside the FDA’s clinical trial process have touching anecdotes in spades. If I, or a loved one, had a terminal cancer, I’d probably be right there with them, telling my story and hoping to get my hands on an investigational drug, no matter how slim the chance for improvement it offered. But a less emotion-driven analysis of so-called “Right to Try” bills currently before several state legislatures reveals some sobering truths about the false promises behind these bills, promises which in some cases appear to be driven more by political ideology than genuine concern for patients.

“Right to Try” bills are pending before four state legislatures: Colorado, Louisiana, Arizona and Missouri. We’ll get to the details of these in a bit. Legislators in other states have expressed an interest in filing similar bills. On February 26th, a Missouri legislative committee “heard emotional debate from supporters of a bill that would allow makers of investigational drugs, biological products or devices to make them available to eligible terminal patients.” Among those testifying were the parents of a young girl with a brain tumor and the father, a physician, of a patient with metastatic colon cancer. These stories are hard to hear and make it hard to say no.

The Right to Try bill has been christened with another catchy name (Warning! Link to credulous media report!) – the Dallas Buyer’s Club bill after the terrific movie which just won Matthew McConaughey and Jared Leto Academy Awards for best actor and best supporting actor, and deservedly so. It depicts a macho, homophobic, HIV-infected cowboy (McConaughey) who saves the day battling the evil, bureaucratic FDA and the medical establishment. He skirts the law to bring life-saving drugs to AIDS patients at a time when AIDS was pretty much a death sentence. The plot even includes a delicensed American doctor who supplies the unapproved drugs from his Mexican clinic. And dietary supplements, of course. (You’d be tempted to suspect Stanislaw Burzynski, Hulda Clark and a naturopath co-authored the script.) But no matter its merits as a movie, it is just that, a movie. It is based on a true story but its interpretation of events has been called into question. (Orac also deconstructs the factual inaccuracies on Respectful Insolence today.) Nevertheless, it is a public relations boon to the Right to Try promoters, although, considering their decidedly right-leaning political inclinations, there has to be a certain amount of squeamishness in associating their cause with a movie featuring raunchy, sexually-explicit scenes, lots and lots of cussing, and a colorfully dressed trans-gender person (Leto) as its most sympathetic character.

Attempts to liberalize FDA’s expanded access

The genesis of these bills can be traced to another young cancer victim, 21-year-old Abigail Burroughs, who died of the disease in 2001. Abigail herself led a lobbying and media campaign to urge greater access to investigational drugs after one was recommended by her oncologist. After her death, her father formed the Abigail Alliance for Better Access to Developmental Drugs because they considered the FDA’s expanded access policy insufficient.

To help us better understand what the Alliance wanted, here’s a brief explanation from the FDA of how the extremely complicated process for a new drug approval works:

The first step for a company seeking approval to sell a new drug is to perform laboratory and animal tests to learn how the drug works and if it will be safe enough to be tested in humans. The company submits an Investigational New Drug Application (IND) for FDA’s review prior to testing in humans. The company performs a series of clinical trials in humans in three phases, which FDA monitors, to test if the drug is effective and safe. Next, the company sends its data from all these tests to FDA’s Center for Drug Evaluation and Research (CDER) in a New Drug Application (NDA). A team of CDER physicians, statisticians, toxicologists, pharmacologists, chemists and other scientists review the data and proposed labeling. If this review establishes that a drug’s benefits outweigh its known risks for its proposed use, the drug is approved for sale.

(New biologics and medical devices are regulated by the FDA in a somewhat different manner, but from now on we are going to focus on drugs because that appears to be the main target of the Alliance and other advocacy groups.)

In 2003, the Abigail Alliance and the Washington Legal Foundation filed a Citizen’s Petition with the FDA requesting that the Agency amend its IND regulations “to grant Initial Approval for promising drugs, biologics, and devices intended to treat life-threatening diseases with unmet needs,” and to seek “regulatory changes to permit expanded availability of developmental lifesaving drugs following phase 1 clinical trials and at all subsequent stages of the trial and review process.”

A Phase I Clinical Trial, which typically involves only a few patients, is designed to assess toxicity and dosing but does not establish either the safety or efficacy of a drug. While the trial may incidentally show some evidence of efficacy, that initial evidence is not always borne out in later phases. As our good friend Orac explained:

Phase I clinical trials represent the very first time a promising new substance is ever given to humans. The intent is not really therapeutic. Rather, it is to gather toxicity data and to determine the optimal dose. Basically, what is done is something called a dose escalation, where increasing doses are tried until toxicity is observed. The usual patients enrolled in these trials when done for cancer drugs have advanced disease that is incurable with present modalities. One reason for this is that in many cases it would be unethical to try such drugs out in patients who could expect to have a chance at long-term survival using conventional treatments, and that healthy volunteers would be unlikely to be willing to undergo the risk of toxicity from these very powerful drugs. Another reason is that sometimes we can see anti-tumor activity even in a phase I trial. However, it is not expected that antitumor activity will be observed, and not observing activity would not preclude moving on to a larger, randomized Phase II trial, in which the drug is tested against specific tumors.

The FDA denied the Petition and the Alliance sued the FDA in federal court claiming that terminally ill patients had a constitutional right to access as-yet-unapproved drugs. The U.S. District Court disagreed and the Alliance lost the case, but that decision was overturned by the U.S. Court of Appeals for the District of Columbia Circuit. A three-judge panel of the Court held that where there are no other FDA-approved treatment options, a terminally ill patient has a constitutionally-protected “fundamental right” to access investigational drugs This decision became the subject of some debate among legal scholars, especially on the right end of the political spectrum. They were torn between their distaste for federal regulation they regard as limiting personal freedoms and their distaste for courts finding constitutional rights not specifically enumerated in the Constitution itself, which is exactly what the Court of Appeals had done.

The FDA then requested a rehearing en banc, that is, before the full Court of Appeals. Here, the FDA was joined in seeking a reversal of the decision by several medical organizations, including the American Society of Clinical Oncologists. The Court’s en banc decision was 8-2 against the Alliance, a decisive victory for the FDA. The Alliance filed a petition for certiorari asking the U.S. Supreme Court to hear the case but the Supreme Court denied the petition. That does not mean the Supreme Court might not decide the issue in a future case, but for now the Court of Appeals decision stands.

Meanwhile, over in the U.S. Congress, Sen. Sam Brownback introduced Alliance-supported legislation allowing expanded access to investigational drugs not already available under the FDA’s rules, but it didn’t go anywhere. (It contained some disturbing provisions gutting placebo controls in clinical trials.) Later, Rep. Diane Watson introduced the Compassionate Access Act of 2010, but the bill never made it past the House Subcommittee on Health.

There are a number of good reasons to disagree with the position taken by the Alliance in its suit against the FDA and the two bills it supported, and we will get to some of the reasons to oppose expanded access in a minute. But before we move on to the Right to Try bills, I want to note the extent of access to investigational drugs at issue up to this point. The first Court of Appeals decision held that where there are no other treatment options, terminally ill patients have a fundamental right to access investigational drugs. And both Congressional bills retained some FDA oversight of the expanded access process.

A more radical approach

Enter the Goldwater Institute, an extremely conservative think tank which, beyond lambasting the Affordable Care Act, doesn’t seem to have any real interest in healthcare policy. The Institute is named for, and was founded “with the blessing of,” the late U.S. Sen. (and unsuccessful presidential candidate) Barry Goldwater. The Institute’s model statute, on which the current state “Right to Try” bills are based, doesn’t just liberalize FDA requirements for access to investigational drugs. It completely removes FDA from the picture. The model statute conveniently comes complete with pre-packaged legislative findings so a legislature doesn’t have to bother with making an independent determination of the wisdom of the Right to Try bill.

Here are the main provisions, with a few comments (more of those later):

  • The drug must have successfully completed Phase I clinical trials and still be involved in the clinical trial process. As we know, Phase I is designed to assess toxicity and dosing but not safety or effectiveness. And any evidence of either safety or effectiveness which appears at this point may not hold up in later phases of the process.
  • To access the drug, the patient must have a “terminal illness,” defined broadly as “an advanced stage of a disease with an unfavorable prognosis and no known cure.”
  • The patient, in consultation with “a physician” (no matter the physician’s lack of expertise in treating cancer or other terminal illnesses, or, for that matter, never having a previous relationship with the patient at all) has “considered” (not tried, “considered”) all other FDA-approved treatment options. There is no mention of how the drug is to be administered, how the dose is to be calibrated, or what follow-up must be provided.
  • The patient has a prescription “or recommendation” for the drug and has given informed consent (or it has been given for him if he is a minor or mentally incapacitated).
  • All of the above must be documented by the physician. Just “documented;” no medical rationale for the decision needed.
  • The drug’s manufacturer can, but is not required to, make the drug available (although it can do so without an actual prescription) and can choose whether or not to charge the patient. “Drug manufacturer” is not defined; clinical trials do not necessarily involve a “manufacturer.”
  • Insurance companies can, but don’t have to, cover the cost of the drug itself. Other costs of treatment with the drug are not addressed.
  • The state medical board is prohibited from taking action against the physician “solely based on a medical professional’s recommendation, prescription or treatment with a the investigational drug.” “Solely based on” is not further defined.
  • Any “official, employee, or agent of the State” who blocks access, or even attempts to block access, is guilty of a class-one misdemeanor punishable by up to 6 months in jail and a $2,500 fine.

In other words, extremely powerful drugs with no evidence of safety or efficacy would be removed from FDA jurisdiction once the cursory requirements of this legislation have been met. Disciplinary action against a physician would be thwarted, and perhaps denied altogether, possibly even in cases where the physician fell far below the standard of care. Yet physicians and manufacturers would remain subject to liability for injuries even if they comply with the act. No matter how devastating the effects of an unapproved drug might be, or how reasonable their actions might be, any state employee or official who takes action to block access could wind up in jail for 6 months and paying a $2,500 fine.

What could possibly go wrong? A lot, that’s what. Physicians with less-than-pristine intent could set up practices specializing in filling out the paperwork necessary for patient access. And what if, after careful evaluation, an ethical, competent physician has to refuse a patient’s desperate pleas to facilitate access? Patients could be deterred from participating in clinical trials, lured by the false “get-well-quick” promises of an unapproved and costly drug. And patients in the last months of their lives could be diverted from palliative care and a meaningful opportunity to spend time with loved ones by an experimental drug with terrible side effects that, in fact, kills rather than cures them. One could even envision a scenario where a patient who pushes aside other options in favor of an investigational drug ends up thereby disqualifying himself from a later clinical trial offering a real hope of improvement. What if child welfare authorities try to intervene in favor of a terminally ill child who is about to be treated with a horribly inappropriate drug? Will they go to jail?

The proposed statutory language is based on a Goldwater Institute “Policy Report,” with the superficially appealing title, “Everyone Deserves the Right to Try: Empowering the Terminally Ill to Take Control of Their Treatment.” It contains a number of dubious claims about expanded access, among them:

  • Expansion of FDA authority in the 1960′s to require that a drug demonstrate efficacy was “drastic” and “unwarranted.”
  • Polls purportedly showing medical specialists think the drug process is too slow, a broad assertion that says nothing about whether they would halt all FDA supervision for particular patients once a drug passed Phase I trials.
  • “The major emphasis of Phase I testing is safety” and drugs that have passed Phase I have “passed basic safety testing.” This is a half-truth that could leave the uninformed with the impression that the FDA has decided at this early stage that a drug is actually safe.
  • The report speaks of patients “battling an immediate life-threatening illness” who “lack other treatment options.” Yet neither of these situations is required before their legislation would allow access to investigational drugs. The report also makes the hyperbolic claim that the FDA’s regulations “impair health” or “cause death.”
  • Drugs that have cleared Phase I are continually referred to as “potentially life-saving,” an assertion partially refuted by their own statistics. They note that 30% of drugs make it from Phase Two (which tests efficacy) to Phase Three. And that is for any drug demonstrating efficacy for any purpose, not just those designed to treat terminal illnesses.
  • The report claims that “risk to an individual patient outside the clinical trial is no greater than the risk the FDA is permitting patients inside the trial to take.” Likewise, the report claims that informed consent will be an adequate protection because it is the same informed consent used in the clinical trials. Hardly. Clinical trial participants are carefully chosen based on certain eligibility requirements, and are closely monitored. If at any time it becomes apparent that further testing (for a particular participant or for all of them) is inappropriate, the FDA can pull the plug. An Institutional Review Board must sign off on the informed consent. None of these safety measures apply to patients allowed access by this legislation. There’s not even a requirement that administration of the drug be supervised or that the patient be followed at all.

There are other insufficiencies in the “Policy Report,” but we’ll leave it at that.  In fact, the whole idea is so poorly thought out and so ill-considered  the science-based community is really piling it on this week, with SBM’s own cancer expert weighing in, as well as our pal Orac.

We’ve already touched on some of the legal complications-in-waiting that might appear if the Goldwater Institute’s bill is passed. Indeed, the enthusiasts backing Right to Try bills in their states have had to clean up some of the more obvious drafting oversights. All states tightened the definition of terminal illness. Arizona excludes primary care physicians from the definition of physician. Missouri excluded controlled substances and Colorado added some protection against liability for manufacturers.

Political theater at taxpayer expense

But I’ve saved the biggest legal complication for last. Right to Try laws, as proposed here, are either wholly unconstitutional or at least unconstitutional in the majority of possible applications. That is because the FDA has exclusive jurisdiction over the regulation of drugs via Congress’s constitutional authority to regulate interstate commerce and state laws that impinge on that exclusivity are pre-empted. Federal drug laws regulate not only the approval process for new drugs, but also the misbranding and adulteration of drugs, both of which could come into play with the provision of an unapproved drug to a patient. It might be possible to envision a scenario where a manufacturer could have an operation that is so devoid of any interstate commerce it would fall outside the FDA’s jurisdiction. That would be extremely difficult to do although, according to David Gorksi, that is exactly what Stanislaw Burzynski did early in his career, before he started the (never completed) FDA approval process.

But here’s another hurdle: the drug must have passed a Phase I Clinical trial and still be involved in the clinical trial process. Colorado specifies that this must be an FDA-approved clinical trial; the other versions do not. However, they strongly imply that we are talking about an FDA drug approval process here by reference to the drug’s not yet having received the agency’s approval. Once the FDA-drug approval process is underway, the manufacturer is by definition under FDA jurisdiction. (Is there even such a thing as a non-FDA drug-approval, clinical trial process?) The FDA is certain to take a dim view of a manufacturer with a drug still in clinical trials going off and distributing that same drug to patients outside the trial process.

Could the FDA expanded access program use some more expanding? Perhaps. Could the FDA drug approval process as a whole be improved? Most definitely, and the place to start is adequate funding by Congress. But all the Right to Try legislation does is engender false hopes that access to “potentially life-saving drugs” is just around the corner. Of course, the Goldwater Institute won’t be paying for the ensuing litigation over the constitutionality of state right to try laws. That burden will fall doubly on the taxpayers, as both state and federal resources will be consumed. But it can benefit nicely from the political theater that allows it to pose as a champion of state rights and individual freedom defending a bill it most certainly knows cannot survive constitutional scrutiny.

Posted in: Cancer, Clinical Trials, Legal, Politics and Regulation, Science and Medicine

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88 thoughts on “The illusions of “right to try” laws

  1. Yodel lady says:

    Excellent post! Thank you for looking into this.

    I’m a cancer patient. Legislation like this freaks me out. It doesn’t serve me – it uses me. A phase I trial doesn’t do anything to warrant letting just any yahoo prescribe a drug, nor does it establish any drug as “potentially lifesaving.” These bills show that the people drafting the bills know nothing about what cancer really is.

  2. Lawrence says:

    Damn, looks like a law specifically designed to allow Burzynski to keep operating…..

  3. Lawrence says:

    @Yodel – exactly right. All it does is validate crank theories…..

  4. windriven says:

    It is easy to agree that the proposed law is deeply flawed. But I struggle with the notion that the federal government should be able to prohibit any sane adult from ingesting, inhaling, or injecting whatever they wish with the notable exception of antibiotics because of the well-understood problem of resistance.

    That is not to say that the government does not have a legitimate interest in the potential consequences. It is legal for adults to consume alcohol. It is illegal for adults under the influence of alcohol from operating automobiles, boats, airplanes, etc.

    It is not people using antineoplastons that disturbs me, it is Burzynski’s touting it as a cure for … anything. It is one thing to say that X is an interesting compound that may have D, E, and/or F actions but we are early in testing and it is definitely not ready for prime time but you may purchase it at cost on a compassionate use basis. It is quite another to say that antineoplastons can cure glioma and you should come to my clinic for treatment.

    People dying of sometimes horrific diseases (are there fatal diseases that are not horrific?) are vanishingly unlikely to stumble serendipitously on an investigational drug that will cure their disease – or even dramatically slow its progress. But these people and their families are often desperate in their search for something to save the day. Driving that search underground or to the gray areas where cockroaches and scumbags like Burzynski thrive simply makes their search more expensive and LESS likely to be informed by science.

    Is that really the goal?

    1. goodnightirene says:

      Not all patients/families are as desperate as the ones we read about here and who are represented by the subject legislative attempts. Many people accept their terminal diagnoses and make peace with the situation in a number of ways. Desperation is not the only response, and I see no reason to pander to some kind of “right to pursue” any course of treatment when the process is completely uninformed. It’s rather like climate change denial–I don’t “believe” in it, so it doesn’t exist. In the case of untested drugs–I know nothing about this, but I can’t accept that I am mortal and won’t live to be 105, so I have a right to anything I can rummage up on the internet.

      1. windriven says:

        “Not all patients/families are as desperate as the ones we read about here and who are represented by the subject legislative attempts.”

        That is true. And no one is suggesting that anyone be forced to try experimental therapies. Further, some are desperate – or this conversation would never have arisen.

        ” I see no reason to pander to some kind of “right to pursue” ”
        So then you see it as your right to tell others what they can and cannot do? Can you tell them which god to believe in – or to believe in none at all?

        To continue with your climate change example, people are free to believe whatever they’d like about climate change. The government cannot effectively control what they believe. It can however, legitimately act to constrain people from engaging in activities that exacerbate the problem, for instance, by controlling fossil fuel consumption.

        Me? I’m ready to go quietly into that good night when my time comes. I’m in no hurry. But I’m not one to pull out all the stops.

        1. steney01 says:

          “So then you see it as your right to tell others what they can and cannot do?”

          I have a strong affinity for protecting someone’s right to do as they please…and if we’re weighing the right to inquire about using an unproven drug, then I support it. But when you’re talking about the right to ACCESS an unproven drug, well, I don’t think anyone has that right. If you can make it yourself in your basement, then by all means you should use it, but there’s no right to access a drug made by a pharmaceutical company.
          I say let the patients inquire, make sure appropriate FDA safeguards are in place (and that the process is reasonably streamlined) and go from there.

          1. windriven says:

            steney01, we aren’t very far apart. I certainly wouldn’t argue that any pharmaceutical or device company be compelled to make an investigational product available. And the very high likelihood is that many – perhaps most – would not. If my company made pharmaceuticals I would never agree to use of the product outside of clinical trials. There are too many opportunities for uncontrolled use leading to bad publicity that could potentially kill a valuable product before it ever made it to market. My concern is limited to where the federal government can compel with force of law.

    2. qetzal says:

      Windriven,

      I’m sympathetic to your points, but:

      I don’t think it’s actually illegal for patients to take these unapproved drugs. It’s just illegal for manufacturers to provide (market) them.

      As for driving desperate patients underground, I think that’s unavoidable – unless we eliminate drug approval entirely. And that wouldn’t help the terminally ill anyway. The sad fact is that most drugs being tested for terminal conditions will fail. They won’t work. And even the ones that do will almost all have incremental benefits.

      I’d be more sympathetic to the Right to Try claims if I thought there really were lots of drugs in development that could really make a difference. Unfortunately there aren’t. And, in the very rare cases where an unapproved drug truly looks like it might be a stand-out (e.g. Gleevec), the existing processes have been pretty good and getting it to patients quickly. They could be better, no doubt, but pushing these Right to Try laws is not the way to make things better, IMO.

      1. windriven says:

        Quetzal-
        You a make an interesting point about the legality of pursuing as opposed to selling investigational drugs. I need to look into this more to be sure that I understand precisely how the law is framed.

        “As for driving desperate patients underground, I think that’s unavoidable – unless we eliminate drug approval entirely.”

        I part ways with you here though. The underground presumes a willing seller and a willing buyer with an authority separating them. In most realistic situations involving pharmaceutical research I would expect a willing buyer and an unwilling seller. There is no issue there and no law required beyond the limitation that investigational drugs for compassionate use must be provided free or at cost. This would have the immediate effect of clipping the wings of characters like Burzynski.

        1. qetzal says:

          My point is that even if you greatly expand compassionate use, some people still won’t be able to access what they want (or think they want), if for no other reason that the drug developer may choose not to make their drug available under those circumstances. And even the patients who do gain access will often not be helped by an investigational drug. So those patients will still end up desperate for anything that might help, and will still tend to go “underground” to people promising miracle cures.

          Greater access to compassionate use is for sure not going to clip Burzynski’s wings. He’s willing to promise miracles; legitimate drug companies won’t. As long as Burzynski is allowed to continue being dshonest, desperate patients will continue believing him.

    3. Rokujolady says:

      It would be fine to let everyone put anything they please into their body if it doesn’t hurt the community…in the perfect world where people were willing to take responsibility for the decision and be at peace with the decisions of their loved ones. People want freedom to do whatever they want but it’s never their fault when things go south because they or their loved ones took a big gamble without understanding the odds…no one wants to admit it’s their fault when a loved one suffers. Cue the lawsuits.
      It’s rather cold and paternalistic to think of it this way, but that’s one reason it’s absolutely necessary to try to mitigate risk as much as possible before a product gets to the consumer.

    4. mousethatroared says:

      windriven “It is easy to agree that the proposed law is deeply flawed. But I struggle with the notion that the federal government should be able to prohibit any sane adult from ingesting, inhaling, or injecting whatever they wish with the notable exception of antibiotics because of the well-understood problem of resistance.”

      In my mind, this is a reasonable struggle. On one hand, we have an argument that I think is similar to the right to die arguments. While many people think it is best to live as long as possible with reasonable treatment, other would rather cut short their life and experience less suffer. Still others would prefer to gamble on a long shot, it seems. Some similar questions arise. Are the people making these decisions currently mentally competent to make the decision (or are their decisions skewed by the disease process or stress). Are the patients’ decisions going to be unreasonably impacted by pressure from society or loved ones (are patients going to try unproven treatment because they feel an obligation to try every option for a loved one who is not prepared to let go.) These are concerns, but I don’t think they completely supersede a patient’s right to approach their terminal illness as they wish. But, I also don’t think that companies or individual doctors should have a legal obligation to provide patients with the means to meet those wishes.

      On the other hand, windriven, the idea that you represent is in essence a libertarian argument. ie Society does not have the right to infringe upon your individual right unless that decision infringes upon others. But, in this case, I think that we are, as individuals, are indebted to “society” as represented by our governmental controls that have enable each of us to live in a time that has remarkable health (as compared to what it would be like without the controls of the FDA and other government interventions) If you were born without a serious teratogenic birth defect, have benefitted from clinal trials in medicine or have a loved one who has or have just lived in a society with access to effective cures for many disease, then you are somewhat indept to that system. I think that society does have some right to uphold that system which has benefited us all and require us to change our behavior in spite of our preferences.

      The question is to what degree ? One may say the the process that MadisonMD outlines down thread is reasonable. It may be reasonable to attempt to expediate that process. But, in my mind, these compromises should arise out of balancing respect for individual rights and citizens obligation to follow laws that benefit society and not out of a desire to protect a citizen from themselves, based on an preconcieved image of the kind of death they should want or the kind of risks they should be willing to take.

      Okay, that’s all, There’s a lot of caveats that I didn’t include and I’m not going to proof read, cause I gotta get some stuff done, but this was preying on my mind and I wanted to get rid of it.

  5. Liz says:

    The link to the Missouri legislation does not work. Has the Legislation been sidelined?

    1. Jann Bellamy says:

      The correct link is:

      http://www.missourinet.com/2014/02/26/parents-testify-in-favor-of-legislation-to-allow-investigational-drugs-to-terminal-patients/

      I will fix it in the post as soon as I can. Thanks for bringing this to my attention.

  6. steney01 says:

    Instead implementing “right to try” laws, streamlining the FDA’s existing expanded/compassionate use regulations seems like a reasonable response if the majority of physicians who deal with terminal patients believe that they are overly restrictive.
    However, I’ve seen the point repeated a couple times that these laws may “drastically decrease enrollment in clinical trials”. That seems like hyperbole and there’s never any evidence presented to support the claim. And it’s not as if some evidence couldn’t be gathered. Did the introduction of expanded use laws have an effect on clinical trial enrollment? How many people are likely eligible to pursue treatment under one of these right to try laws? How many of them are also eligible for clinical trials?

    1. Jann Bellamy says:

      I don’t know about “drastically reduce” but it would present a temptation not to enroll for some patients, in this manner: Drug A is recruiting participants for a Phase II clinical trial. Patient is eligible but foregoes trial and gets the drug directly under a “right to try” law because if he enrolls in the trial he may be get a placebo but if he gets the drug directly he knows what he is getting.

      As I understand it, few eligible patients enroll in clinical trials, one reason being they are often conducted at academic medical centers and the like that are too far away from where the patient lives. I don’t know what the reasons are.

      1. steney01 says:

        I think that’s a valuable clarification and a line of reasoning worth expanding upon…
        “Comis et al. demonstrated that the primary problem with accrual of patients in clinical trials is not attitudes but rather the result of unavailability of an appropriate clinical trial and disqualification due to protocols.”
        Comis, R.L, Miller, J.D., Aldige, C.R., Krebs, L., Stoval, E. (2003). Public attitudes toward participation in cancer clinical trials. Journal of Clinical Oncology, 21, (5), 830-835.

        So if you’re a terminally ill patient that isn’t eligible for any existing clinical trials (if your physician has even investigated the options to begin with, which is also a problem), I agree that that person may be interested in pursuing a drug through a “right to try” law instead. However, this population of patients isn’t eligible for clinical trials anyways, so we can’t justify the “decreasing enrollment in clinical trials” claim.
        Other reasons that patients don’t enroll in clinical trials? They “don’t want to be a guinea pig”, because of “fear of the unknown” and “concerns about cost”. Well, those concerns all remain with accessing drugs through a “right to try” law. These concerns may even be more significant in that case, since there’s little oversight of your treatment once you get the drug and no reimbursement for follow up treatment.
        So all I’m saying is it’s not a given that clinical trial enrollment will be adversely affected. It seems that the process of enrolling in clinical trials is doing a pretty good job of adversely affecting itself already.

        I think the emphasis needs to be on increased funding for new clinical trials, on improving patient’s and physician’s awareness of, and access to, existing trials and on allaying some of the concerns patient’s have about clinical trials in general. But then again, these are all very difficult outcomes to achieve.

        1. MHO says:

          So if you’re a terminally ill patient that isn’t eligible for any existing clinical trials . . . . However, this population of patients isn’t eligible for clinical trials anyways, so we can’t justify the “decreasing enrollment in clinical trials” claim.

          Couple thoughts, I think the term terminally ill isn’t clear here, or in the proposed law. I have friends who have late stage cancer and for whom no approved therapies have worked to keep their disease stable or in remission. These people have a terminal illness and yet they are eligible for clinical trials and do participate.

          next, if a patient has an illness that is terminal, currently his/her “best shot” is to enroll in a phase one trial. Its a huge gamble, but if one is a gambler, that’s where you can go.
          But if this law passes, who would ever volunteer for the phase one trials? The gamblers would prefer the odds on the drugs that have completed phase ones: less (perceived) risk than on a phase one, less regulatory interference.

    2. ChrisL says:

      The Wikipedia entry regarding high dose chemotherapy/bone marrow transplant (HDC/BMT) for metastatic breast cancer touches on the impact on enrolment in the section “Funding mechanisms and litigation”: http://en.wikipedia.org/wiki/High-dose_chemotherapy_and_bone_marrow_transplant

      “Right to try” in that situation lead to delayed accrual to the definitive randomized trials comparing (HDC/BMT) to conventional dose chemotherapy, at least in North America.

      Not really covered in the Wikipedia entry is the impact that off protocol HDC/BMT for metastatic breast cancer had on health care resource allocation. A great deal of time, effort and money was put into developing HDC/BMT programs for solid tumours, the demand for which evaporated after the ASCO Annual Meeting in 1999.

      1. MadisonMD says:

        ChrisL: This is an outstanding example of a problem that occurs when treatments are accepted and publicly demanded before efficacy is established. Not only was it costly to expand use of high-dose chemotherapy beyond clinical trials, not only did it delay definitive answers as to its utility, but it also took quality time away from people with incurable disease without actual benefit. It also killed about 4% of the people who had the treatment.

        1. windriven says:

          @Madison

          “it also took quality time away from people with incurable disease without actual benefit.”

          It took – or they willingly gave? I would argue that the dice were theirs to roll.

          1. Jann Bellamy says:

            Perhaps I’ve misunderstood your several comments, but here’s my response:
            Once a company puts its drug into the FDA approval pipeline, it must follow the rules. What I hear you saying is that the company should be able to give away its drugs before the process is complete whenever it thinks it is appropriate – in other words, break the rules it agreed to follow. If we are going to allow that, why have a drug approval process in the first place? Should the company be allowed to break any of the rules it doesn’t agree with or just this one? And if you think individuals should be free to seek out and take drugs that have cleared only Phase I trials, as long as they have the facts, then why not push it back even further, to access after only animal studies, or even after in vitro studies? I fully agree that the FDA’s expanded access policy might be liberalized and the drug approval process streamlined. But I don’t agree that we can start cannibalizing the process based on what an individual company thinks of the rules or an individual patient thinks is best for himself. To me, this is an area where the great public benefit (for the companies, doctors and patients) derived from a unified system trumps any individual’s claim to personal benefit

            1. windriven says:

              “Once a company puts its drug into the FDA approval pipeline, it must follow the rules.”

              I’m far less interested in “the rules” than I am in the philosophical and ethical elements of this debate. I won’t insult you with a litany of former rules and laws – some of them quite recent – that reflect rather poorly on those who wrote them and more poorly still on those who followed them like drones.

              My interest in this is the ability of terminal patients having the ability to purchase investigational drugs if the company is willing to sell them – without government interference except where specific, demonstrable threat to others would result, for instance, antibiotic resistance.

              I have come at this from the perspective of assuming sane adults having agency and freedom to determine what actions are in their best interests (even when they are certainly wrong) without government interference unless those actions pose a clear and specific risk to others. Explicit is the demand that the pharmaceutical company be a willing seller and moreover be willing to sell the investigational drug at cost or provide it free.

              ” To me, this is an area where the great public benefit (for the companies, doctors and patients) derived from a unified system trumps any individual’s claim to personal benefit”

              On that we will agree to disagree.

        2. MadisonMD says:

          It took – or they willingly gave? I would argue that the dice were theirs to roll.

          They gave and it took–both. The premise was based on wishful thinking among cancer doctors, poor quality data, and downright fraud(Audit here). So patients–and many doctors– were rolling dice with inaccurate information blown out of proportion by the press.

          If you would argue it was their dice to roll, then why not support Burzynski’s latest antics?

          1. Andrey Pavlov says:

            I am still novice in this sort of thing but I would argue that we have an onus to take an extra step to help protect people. The hardcore (or perhaps caricatured?) libertarian stance of “do absolutely anything you want so long as you are an adult and can pay for it yourself” is something I do not agree with. Paternalism and autonomy are not discrete entities but (hypothetical) extremes on a continuum. Saying that it is their dice to roll ignores the fact that were they educated in the relevant sciences and data they would be much, much less likely to roll those dice.

            If a subset of people genuinely believed that the bullet in a game of Russian roulette could not hurt them, despite the well established fact that bullets to the head kill, we would not be so blasé about saying they should just roll the dice and who cares. If they demonstrated that they absolutely knew the consequences then we would be forced to remand them to their own autonomy.

            The same goes with this sort of question, though it is not so obviously plain to see as a bullet to the head. It is also muddied by unclear thinking because of the condition they are in. It is a delicate place to tread and we must always and in all circumstances be checking ourselves and each other to make sure we aren’t unreasonably restricting individual autonomy, but in cases like these it is (IMHO) arguable that a smidge of paternalism is in order. If I, knowing what I do, would not even consider taking a risk on such a drug procured through this type of “Right to Try” legislation I feel there is an onus to ensure people who do not have my education do not get duped into a false sense of understanding and try these drugs anyways.

            One solution would be to make it even more onerous to obtain the right to try exemption, but one place I do agree with the Libertarians is that more onerous government and regulations is something to be avoided if at all possible. Since there are other reasons outside individual protection plus an existing mechanism for compassionate use individual exemptions, that seems to obviate the entirety of the proposed legislation to me.

            1. windriven says:

              “Paternalism and autonomy are not discrete entities but (hypothetical) extremes on a continuum.

              Indeed. And I would argue that deciding where public policy should fall on that continuum should sin to the side of individual freedom unless and until that freedom impinges on that of another or poses a substantial public threat.

              “Saying that it is their dice to roll ignores the fact that were they educated in the relevant sciences and data they would be much, much less likely to roll those dice.”

              So, someone with more education than you in the liberal arts should be able to choose and enforce your reading list because, if you were so educated, you would recognize (insert your favorite author here) to be a charlatan and a hack unworthy of the paper her tripe is printed on?

              This is a slippery slope. Public policy should be made on solid principles that recognize individual agency and freedom of action. To do otherwise is little different from those who would vote to prohibit homosexual unions and limit abortion.

              1. Andrey Pavlov says:

                I would argue that deciding where public policy should fall on that continuum should sin to the side of individual freedom unless and until that freedom impinges on that of another or poses a substantial public threat.

                Agreed. But I would add emphasis on “substantial” and carefully explore what that means in each case. Because that is integral to answering your hypothetical:

                So, someone with more education than you in the liberal arts should be able to choose and enforce your reading list because, if you were so educated, you would recognize (insert your favorite author here) to be a charlatan and a hack unworthy of the paper her tripe is printed on?

                Not quite. Because I would argue that the potential harm from reading said tripe is minimal and thus could not warrant any sort of public policy. Plus, it would directly abut other freedoms not mentioned in my comment but I agree with fundamentally – namely freedom of expression. The necessary corollary to a person curtailing my reading list would be curtailing the author’s freedom of expression.

                It wasn’t a good analogy, but I do get your point and I agree with you. It is a slippery slope because I could argue that spreading the ideas of Ayn Rand would be very harmful to society and therefore it is in the best interest of society to censor her work (and where have we seen that sort of thing before, hmm?) Of course the counter to that would be that on the balance more harm is done by censorship than by allowing terrible ideas to be accessible.

                The point being is that, as I said, it tricky territory. But when we can scientifically quantify the risks and benefits (at least to a first approximation) then I think we can agree on reasonable public policy (which I agree should be as least restrictive as possible). We don’t have a problem with it when it is requiring the use of seatbelts because that is an obvious and quantifiable risk:benefit. Obviously certain topics are trickier than others. I think in this case, specifically on topic to the post, it isn’t quite as clear cut as that but certainly clear enough to warrant public policy making.

          2. windriven says:

            @Madison

            “then why not support Burzynski’s latest antics?”

            Because I have explicitly noted that compassionate use exceptions would have to be either free or at cost of manufacture. This would sharply curtail willing sellers and it would exclude profit-driven quacks and cranks like Burzynski.

            1. MadisonMD says:

              Loophole: Burzynski doesn’t charge for the drug. He only charges a “management fee.” And remember ROY? He sells baking soda–cheap as dirt– and still makes a killing (pun intended).

              Recall, windriven, that there is already a legal avenue towards compassionate use. It requires FDA and IRB oversight, willingness of the pharmaceutical company to provide drug, and acquiescence of a licensed physician. My colleagues and I have done this before– it is a lot of work– but it is possible. What do you find wrong with the currently legal process?

              1. windriven says:

                “What do you find wrong with the currently legal process?”

                Perhaps nothing, Madison. My area of expertise is devices not pharmaceuticals. So I have been approaching this more theoretically than actually.

                ” It requires FDA and IRB oversight, willingness of the pharmaceutical company to provide drug, and acquiescence of a licensed physician.”

                If this is in fact doable, that touches all my bases other than not selling the investigational drug at a profit. I am not sure why FDA needs a place in the equation as the IRB would seem the most competent authority.

              2. MadisonMD says:

                I am not sure why FDA needs a place in the equation as the IRB would seem the most competent authority.

                Effectively, any drug under investigation has an IND filed at the FDA by a sponsor. That sponsor is required to collect all serious adverse events from anyone taking the drug (hospitalization, death, or another serious toxicity) and report to the FDA and any investigator involved in distributing the drug on a clinical trial or under compassionate use.

                So, the institutional investigator and the IRB is responsible for conduct of the study at the institution, proper safety monitoring for the patient receiving the drug, and timely reporting of serious adverse events to the sponsor. The sponsor is responsible for collecting and reacting to potentially dangerous adverse events that will affect other patients anywhere in the world. The FDA is the sheriff making sure the sponsor is collecting and reporting adverse events accurately and in a timely manner so that other patients anywhere in the world are not exposed to the drug without consideration of potential new toxicity just reported. Also, the FDA will want to ensure that the additional safety data is reported in the new drug application (NDA) if one is ultimately filed.

                It would be very bad if an unexpected toxicity was missed because such data were not collected for patients receiving drug under compassionate use.

              3. MadisonMD says:

                … and the FDA has the power to pull the plug on the IND against the will of a vested sponsor when adverse safety signal merits this step…. as it did to Burzynski. It needs the tox data from patients on compassionate use to make an informed decision about this.

            2. windriven says:

              Laura S. is dying of metastatic pancreatic cancer. She reads about a new drug that might show promise in treating her condition. She lobbies for compassionate use, finds a willing physician, gets her Congressman to badger FDA into agreeing, begs and wheedles and gets the drug company to give her the drug. It all comes together on August 19 but unfortunately Laura S died on August 12 leaving her family bitter and exhausted.

              Laura S. is dying of metastatic pancreatic cancer. She reads about a new drug … yadda, yadda … which she promptly receives under a new expedited compassionate use plan. Laura S. dies on August 12 leaving her family grieving but secure in the illusion that they’ve done all they could.

              I can appreciate all of the issues you mention including tracking side effects – but those are addressed with protocols and recordkeeping. For Laura S. and her family pharmaceutical science has delivered a comforting illusion. That is not what pharmaceutical science is for but it can be a useful nonetheless.

              We have front line medical schools and world renowned medical centers pitching acupuncture and chiropractic and all manner of useless crap – with impunity. We have the federal government – the same federal government that FDA is an arm of – spending $100 million a year at NCCAM trying to prove that exactly 1,412 angels can dance on the head of a number 2 pin. And yet we’re going to cluck that the tees aren’t crossed and the eyes dotted on an investigational drug for compassionate use? Am I alone in finding that pretty effed up?

              1. Andrey Pavlov says:

                And yet we’re going to cluck that the tees aren’t crossed and the eyes dotted on an investigational drug for compassionate use? Am I alone in finding that pretty effed up?

                The reasonable position is to be against both of them. By (correctly) claiming that something is “worse” than this does not make this OK.

  7. John R says:

    I struggle to see what incentive a major drug company would have to release these drugs outside of clinical trials. We are talking about giving drug candidates that the companies have spent millions of dollars on to worst case patients. This would likely result in poor outcomes no matter how good the drug. I would think that the companies would be afraid that data could be used against the drug come approval time.

    1. windriven says:

      “I struggle to see what incentive a major drug company would have to release these drugs outside of clinical trials.”

      Precisely. Compassionate use should be a rare exception. I can envision a company well along in trials with a drug likely to have substantial benefit to a specific patient agreeing to compassionate use. But the bias would be strongly against it – as it should be.

  8. LindaRosaRN says:

    Jann Bellamy wrote: “And what if, after careful evaluation, an ethical, competent physician has to refuse a patient’s desperate pleas to facilitate access?”

    Well, let’s hope this physician doesn’t work for a state-owned hospital, because then he/she could be threatened by the patient with a criminal charge for obstructing access.

    This is just the analysis I hope legislators presented with this bill get a chance to read.

  9. Harriet Hall says:

    Is there any provision in these bills requiring compilation of data from patients given drugs outside clinical trials? We might learn something about how promising the drug is and at least about side effects. If Burzynski had been required to provide the FDA with detailed reports on every patient he treated, he would have been out of business a long time ago.

    I see the issue as similar to other laws designed to protect the public. For instance seat belt laws. On rare occasions, seat belts may contribute to a fatality, but in the overwhelming majority of cases they save lives. And we are all impacted when our tax dollars are used to treat accident victims and complications from untested drugs. And our insurance premiums go up. And we are all impacted when our friends and relatives suffer unnecessarily. “No man is an island.”

    The FDA is an easy target for criticism. It is not without its flaws, and sometimes it is slower than other countries to approve a useful drug, but overall they have done a pretty good job. Remember, for every Gleevec there is a Thalidomide.

    1. Jann Bellamy says:

      No, there is no mechanism for collecting statistics. These bills would completely remove the drug from all regulatory control once the physician fills out the necessary paperwork and the manufacturer hands over the drug. There’s not even a requirement that the drug be given in any particular dose, or that it be administered in any particular manner(the patient could self-administer the drug for that matter), or that the patient be followed at all.

    2. David Gorski says:

      Is there any provision in these bills requiring compilation of data from patients given drugs outside clinical trials?

      Nope. None that I am aware of.

    3. Peter H Proctor, PhD,MD says:

      In some ways, thalidomide is a bad example. Its efficacy was not the issue. The drug worked fine.

      Rather, the problem was a specific toxicity– teratogenesis. This was not recognized in the preclinical work because Grunenthal used only rodents for teratogenic screening, and like alcohol, the fetus is only thalidomide sensitive at certain developmental stages. An important lesson long since learned. But, one which has detrimentally affected a separate area, drug efficacy, ever since.

      Interestingly, the potential anticancer effects of thalidomide were recognized at the time. IIRC, the reason Merrill pushed for approval even after Gruenethal took the drug off-market. Remember, about the only effective anticancer drugs in the early ’60′s were methotrexate and a couple of alkylating agents.

      But because of the fuss and Kefauver’s political pandering, the drug took another three decades to enter clinical use. These days, docs don’t give thalidomide to pregnant women. Just like Accutane, arguably even more teratogenic.

      Review: “Thalidomide: The Tragedy of Birth Defects and the Effective Treatment of Disease” http://toxsci.oxfordjournals.org/content/122/1/1.full

      Interestingly, teratogenicity seems related to generation of reactive oxygen species and “redox-signaling”, my area of research…

  10. WilliamLawrenceUtridge says:

    For me, the “evil FDA/good caring doctor in Mexico/greedy doctor running clinical trials” angles basically ruined the movie – and that’s not even getting into the factual inaccuracies. Woodroof actually sold drugs that were antiretrovirals that were more toxic than AZT. Peptide P didn’t do anything for AIDS. He was himself a bisexual and had had numerous sexual encounters with men. And the way the gay community was relegated to passive victims is also distasteful. It’s like watching a movie about poor savages being saved by the white man’s Jesus.

  11. Crankyepi says:

    “The [Goldwater Institute Policy] report claims that ‘risk to an individual patient outside the clinical trial is no greater than the risk the FDA is permitting patients inside the trial to take.’” In order for that to be true, the patient would need to meet all inclusion and exclusion criteria for “the trial” (which trial to be chosen for the comparison?) and follow all safety and follow-up procedures. Also, use the same dose, route and schedule of the investigational drug found in the protocol, etc. So, the patient might as well enroll in the trial. Except that they would have to qualify for the trial. Even if he or she got placebo, risk would be no greater.

    Only 1 in 6 investigational drugs makes it to market (http://www.eoncology.eu/site/wp-content/uploads/2013/01/clinical-trials-success-rates.pdf). True, a small percentage of the time this is due to business reasons rather than therapeutic failure. But “Right to Try” is not a good thing at all, and Yodel Lady is right on the money.

  12. This is a good article! Not a good idea.

    It is amazing how ideology, money and influence trumps what is good for a society community.

    In a free society people are free to do what they wish as long as they do not harm another. In this case if the drug or person harms then a recourse should be in place.

  13. Lawrence says:

    Unfortunately, I assume the stipulation would be that if someone took the drug & it killed them, they / their families would have no recourse – since they would assume sole responsibility (since the drug was officially “not approved.”)

    Somebody like Count Stan would love this type of law.

    1. David Gorski says:

      Yeah, it makes me wonder if any of Stan’s minions is behind the push for these sorts of laws, although it certainly could be just that the same people who are for these sorts of laws are also prone to support Stan.

  14. David Gorski says:

    As an FYI for our readers, here are some other articles criticizing the history and facts as presented in Dallas Buyers Club:

    The movie distorts the facts about AZT, for instance, to make Woodroof seem heroic for his murderous advice to others not to take it. It’s true that there were HIV deniers and AZT deniers in our midst who were pushing vitamins and herbs, even regular gusts of ozone up the butt, and clearly AZT had serious toxicities at the dosage tested. It was also clear that AZT worked. Unflagging pressure from Marty and ACT UP and so many others led to expedited approval, before an optimal dose could be established. And why not, since the course of HIV without treatment had already been demonstrated thousands of times?

    http://www.huffingtonpost.com/patrick-mulcahey/dallas-buyers-club_b_4262093.html

    Woodroof also sued the FDA for not allowing him in the initial trial of AZT, a drug he publicly campaigned against: “Look at AZT (one of the few government-approved AIDS treatments). I don’t know if I wouldn’t prefer giving a shot at eating Comet cleanser. I’m serious. That stuff will eat you up.”

    http://entertainment.time.com/2013/11/08/the-true-story-of-dallas-buyers-club/

    In the film, Dallas Mercy Hospital is having a randomized controlled trial to test AZT’s effectiveness. Unable to be sure he’s getting the drug rather than a placebo in the trial, Woodroof bribes a hospital employee to supply him with AZT, to which he reacts very badly. Throughout the rest of the movie, he and other characters denounce the drug as “toxic,” and Woodroof recommends that customers of the buyers club dispose of what AZT they have and never take it again. At one point, a news broadcast is heard which emphasizes that AZT was the most expensive drug ever produced at that point. One could be forgiven for coming away with the sense that the medical community was poisoning HIV/AIDS patients with the drug, and keeping them from other, safer, therapies.

    The trouble is that AZT is actually a very effective therapy against HIV/AIDS. “People who were consistently using AZT prolonged life for one year,” says Jonathan Engel, a medical historian at Baruch College and author of “The Epidemic: A History of AIDS.” That may not sound like a lot, but at a time when the disease had a mortality rate of 100 percent, anything that delayed death was valuable.

    This is not to say that Woodruff and others were imagining things. The dosages at which the drug was prescribed really were too high, but that was because of worries that a lower dose wouldn’t be enough to meaningfully slow the virus.

    Peter Staley, a longtime HIV/AIDS activist and co-founder of the Treatment Action Group who informally consulted on “Dallas Buyers Club,” notes that though later studies showed that half the original dose worked just as well, researchers didn’t know this in the early days of the epidemic, and they only figured it out by comparing a lower dose to the original dose and finding the two had same rate of deaths. “They basically had to guess at a dose to use and decided to ‘hit hard.’” Staley says. “It was not some government conspiracy that picked a high dose of AZT; it was a fear that hitting the virus too lightly wouldn’t do the trick.”

    And:

    At Staley’s insistence, the film ends with a title-card noting that AZT went on to save millions of lives as part of HAART. But for the other two hours of the film’s running time, the drug is spoken about in overwhelmingly negative terms.

    http://www.washingtonpost.com/blogs/wonkblog/wp/2013/12/10/what-dallas-buyers-club-got-wrong-about-the-aids-crisis/

  15. Xplodyncow says:

    Health literacy is a significant problem in the United States. If all patients were to be granted the “right” to access investigational medicines outside clinical trials, could informed consent really be informed consent? (And has anyone ever seen informed consent forms [ICFs]? They’re filled with medical- and legal-ese. Ugh.)

    1. MHO says:

      One of the proponents today explained that the informed consent would be the same exact one that is used for the patients in the clinical trial.
      But as has been said, it wouldn’t be, because the person going outside the trial could have co-founding factors that were never studied.

      1. David Gorski says:

        Also, clinical trials have very strict monitoring and follow up requirements. Would patients getting investigational agents outside of clinical trials have to be monitored as they would be for a clinical trial? I doubt it. That would make the risk of adverse events higher than in a clinical trial.

  16. PMoran says:

    It seems to be assumed by some that the drugs in question will definitely not be of benefit those seeking them. Yet there must be some reason why a company would be investing huge sums in it, even if only from theory, along with results in animal studies.

    That will be enough for some desperate people to want to try it, and while there is a chance of benefit to them at their own expense and risk I find it difficult to be too obstructive.

    I doubt if phase ll trials of a cancer treatment would involve placebos. They would be more likely to consist of case series wherein each patient acted as their own control. There are many reasons why some patients might not qualify for inclusion, including geography. Is it fair to deny to them a few month’s trial of something that may yet turn out to be a useful treatment? Ideally, as Harriet implies, any such use should be constructed so as to contribute to knowledge concerning safety and efficacy

    If phase ll trials did suggest benefit it would be vastly more difficult to ethically restrict access to the drug. I agree that the establishment of secure scientific knowledge and the economic security of those developing the drug should not be put at risk.

    1. mho says:

      Phase 2′s in cancer trials are populated with patients who have only been pre-treated with one or two different drugs. The end-stage patients are likely to have been treated with multiple protocols and many drugs.

      Could I say, the prior probability of benefit is very different for one than for the other?

    2. MadisonMD says:

      @Peter
      Many phase II oncology trials are randomized now. There is no placebo arm– it is usually standard arm versus standard + investigational drug X. The randomized design plays a crucial role in developing or validating the biomarker used to select patients most likely to benefit; the biomarker-based selection of patients is used in phase III.

      I know expanding access seems harmless… but there are many unintended consequences. Our current system allows off label use of approved drugs (within limits), investigational use of unapproved drugs on trial, and compassionate use access to unapproved drugs, with appropriate regulatory review and all under the purview of a treating physician. It is rare that a new unapproved drug is so promising that it is the best choice… but when that occurs, use compassionate use. To this oncologist, the current system seems the least of all evils.

      1. David Gorski says:

        Exactly. Plans like the “Dallas Buyers Club”-inspired “right to try” bills will likely harm far more cancer patients than they might help.

    3. David Gorski says:

      I doubt if phase ll trials of a cancer treatment would involve placebos. They would be more likely to consist of case series wherein each patient acted as their own control.

      No, not really. Most phase II trials are randomized these days, and often do involve placebos. Usually, it’s:

      1. Standard of care + investigational drug
      2. Standard of care + placebo

      You’re correct that it’s rare to see a placebo-only arm in cancer clinical trials, but it’s very common to see placebos in a schema like the simple one I listed above.

      1. Andrey Pavlov says:

        Dr. Gorski, it is also my understanding that in certain cases (I seem to recall it for skin cancers and cancers that have no good treatment options) that a crossover design is also used. That way there can truly be a placebo arm, but clinical equipoise is maintained because the existing standard of care offers so little benefit and the crossover allows both groups to potentially experience some benefit of the investigational drug.

        1. David Gorski says:

          Some trials are designed that way.

  17. Bob says:

    When the bill went up in front of committee in Missouri, patients of Stanislaw Burzynski spoke on behalf of the bill. I can’t see patients benefiting from this. Only quacktitioners.

  18. Musa Mayer says:

    Plus ça change, plus c’est la même chose….

    http://jco.ascopubs.org/content/21/20/3881.full

  19. Bill says:

    You certainly bring up some valid concerns, but neglect to consider the fact, that not all of these “drugs,” or therapies, show toxic side effects. There are some very promising approaches currently in the pipeline, dare I say game changers, that have shown little or no negative side-effects, yet they will have to undergo the same lengthly process as well known, and established toxins.
    Drugs that have already been through the lengthily FDA screening for one use, are required to repeat the torturously long process, when an alternate benefit is discovered.
    There should undoubtedly be a fast-track FDA approval process, especially when a drug, or treatment has already been through the ringer, and shown to have little, to no toxicity issues.
    I understand your concerns, but when you mention risk vs benefit… Certain death is certainly a significant risk, and currently only the wealthy can afford to take that risk, by going to other countries where the lure of money supersedes most testing requirements.

  20. Tom says:

    Jann’s a much smarter, more brilliant person than I will ever be. Just like the people who run the FDA. But my mother died of multiple myeloma about a year before the release of Gleevec, a drug which would likely have extended her healthy life a few years at least.

    She was very much dying in that year. Not much hope. A lot of pain and suffering. Might she have risked everything and tried Gleevec had she been able to? Hell yeah. Even though the super geniuses like Jann would prefer she not have that option. (For her own good, of course.) Well, fortunately for my mother, the super brilliant people kept her safe and sound from Gleevec and she got to die much faster and suffer a great deal and the most utterly important truth was maintained: We did not let the FDA get one molecule less power than they had the year before. They’re super genius people and dumb morons like my Mom and me need them to guide us, explain to us and decide for us. Thank you!

    I cannot thank the FDA enough and I cannot apologize enough either for the idea that my mother should have been able to have the Right to Try. Who knows. My mother might have lived long enough to oppose the ACA, something that would have been ever more nefarious than trying some drug out without the Nannies We Must Worship giving approval.

    Jann’s article shows me that I must follow, not question and worship my superiors. How can we ever doubt, when they do it all out of love for the little folk?

    I adore the FDA again and praise anyone who helps them keep things on course!

    KUDOS!!!

    Tom

    1. MadisonMD says:

      @Tom,
      What makes you think Gleevac is effective for Multiple Myeloma? It targets a kinase that is genetically activated in Chronic Myelogenous Leukemia (CML). It was approved by the FDA unusually early in the clinical trial process– after the phase I trials demonstrated both safety and high efficacy (uncontrolled, but clearly unusual effects given expected disease progression). You like to approve a drug before a phase I trial? Without any human testing? I don’t think this right-to-try law would even allow it.

      Gleevac is not used for myeloma. It doesn’t really make sense to try it for myeloma, yet it has actually been tested in a phase II trial–demonstrating lack of efficacy.

  21. Peter H Proctor, PhD,MD says:

    I’ll repeat what I have said before. Even though it meets all the criteria in the bill and has regulatory approval for ALS, cancer docs don’t use Riluzole, Dr. Gorski’s drug. off-label. This is the case even though the potential toxicity seems pretty low and its anticancer effects were recognized over a decade ago.

    Some even think such use constitutes quackery. If this is the case with a drug docs can use, it is unlikely this bill will have much effect.

    As for Bryzinski– I have stayed out of this. However, a fellow medical toxicologist and mentor was involved in the first TMB action against him. One issue is that he does get the occasional (if rare) save. From a modern prospective, arguably, his treatment works against some rare cancer genotype. But this has kept him in business.

    BTW, any ad hominems will be responded to by an extensive recounting of my credentials. We don’t want that, do we?

  22. MadisonMD says:

    BTW, any ad hominems will be responded to by an extensive recounting of my credentials. We don’t want that, do we?

    Hi Peter. Do you mean credentials that are ancient or recent? Your 1970′s credentials are sort of cool. Your recent ones– approx last 25 years– less so.

    Anyway, I’m wondering what made you switch careers in the 1980′s? I could understand the difficulty of academics. Care to enlighten?

    1. Peter H Proctor, PhD, MD says:

      Didn’t drop out. Just started patenting my discoveries. The money is much better and intellectual property claims are legally enforceable.

      E.g.,

      “Nitrone, Nitroso, and Nitroxide Spintraps and Spin Labels and Their Hydroxylamines. ” United States 20120115905, Filed November 17, 2010

      Abstract: “Nitrone, nitroso, and nitroxide spintraps and spin labels and their reduction products are claimed for the prevention and treatment of fibrocystic disease of breast, premenstrual dysphoric syndrome and associated symptomology, prevention and treatment of migraine headache, cyclic vomiting syndrome, rectal hemorrhoids, trigeminal neuralgia, peripheral vascular disease, influenza, peridontitis and gingivitis, herpes zoster, herpes simplex, and post-herpetic neuralgia.”

      The fibrocystic disease–dense breast part is now issuing. Makes those breasts crystal clear. You can imagine the significance, if only for diagnosis. The rest is serial “divisions in part”. Plus a recent flurry of significant new and unexpected indications that I cannot talk about.

      However, when I can quickly resolve an issue in the scientific literature, I sometimes do so. E.g., Why the second wing of the NXY-059 for stroke trial failed, costing AstraZeneca several $billion in NAV. And so forth. All practical stuff, but with basic science important.

  23. MadisonMD says:

    Interesting, but patents aren’t subject to peer review– explaining why you are going off the scientific rails a bit. Also, advertising is subject to hyperbole and even dishonesty that doesn’t befit a true scientist.

    The fibrocystic disease–dense breast part is now issuing. Makes those breasts crystal clear. You can imagine the significance, if only for diagnosis.

    Yes, this, for example. You would do well to have peer review. Do you have any evidence to support your assertions?

  24. Peter H Proctor, PhD, MD says:

    Trolling, trolling, trolling…..

    1. MadisonMD says:

      Ha, yes! Asking for evidence on SBM is trolling. Wow. Sorry you found that request offensive Peter. I’ll ignore you now.

    2. simba says:

      Do you ever get the feeling people use the word ‘troll’ like ‘communist’: a get-out-of-jail-free card that means “I don’t have to engage with your ideas.”

      Even trolls are usually engaged with on skeptical websites, because people want to provide the evidence both for the troll themselves and for the lurker reading.

  25. TedH5 says:

    In 2010, after experiencing weakness in my legs and hands, I found myself at Emory University Hospital sitting across from one of the foremost neurologists in the world. My wife and I sat in disbelief as our world was turned upside down. The doctor explained to us that I had ALS, or Lou Gehrig’s disease. The chilling words — “There is no known cause, and no known cure” — continue to reverberate through my head.

    I was 38. I was facing a future without hope, until I had a chance to exercise my “right to try,” thanks to Emory University and their partnership with Neuralstem Inc.

    A groundbreaking safety study was taking place at Emory involving the injection of neural stem cells directly into the grey matter of ALS patients’ spinal cords. I was told it was only to prove it was safe, that it was very risky, and that it most likely wouldn’t help me. I gave my informed consent to participate.

    Then the most unexpected thing happened. It helped.

    Weeks after invasive surgery, I put down my cane and regained strength throughout my body. Empirical data showed that while I was not cured, they could document me regaining strength. You can only imagine the depth of my family’s joy and happiness, all because we had the “right to try.”

    The Goldwater Institute has crafted “Right to Try” legislation that four states are in the midst of passing and eight others are considering. “Right to Try” allows a patient access to investigational medications that have passed basic safety tests without interference by the government when certain conditions are met:

    1.) Patient has been diagnosed with a terminal disease;

    2.) Patient has considered all available treatment options;

    3.) Patient’s doctor has recommended the investigational drug, device or biological product represents the patient’s best chance at survival;

    4.) Patients or their guardians have provided informed consent;

    5.) The sponsoring company chooses to make the investigational drug available to patients outside the clinical trial.

    I am making it my personal mission to introduce “Right to Try” to the Georgia General Assembly as part of next year’s legislative session. Everyone deserves hope and the opportunity to “try.” Can anything be more inhumane than forcing people to endure a fatal plane crash because the onboard parachutes weren’t approved by a federal agency?

    This scenario plays out in medicine daily. I appreciate that the FDA is the gold standard in drug safety; however, if you or a loved one were facing mortality, would you be willing to settle for a silver standard?

    The research and results of the safety and potential efficacy of this research has gone global. A small glimmer of hope, a commodity previously nonexistent in the ALS community, has been ignited. I regularly receive emails requesting help from people throughout the world.

    The desperation is not unique. According to the Goldwater Institute, “More than 500,000 Americans died last year of cancer alone, and thousands more of other terminal illness. Promising treatments exist that could save their lives, but it takes a decade and a billion dollars for a drug to reach full FDA approval. Only 3 percent of the sickest Americans qualify for clinical trials, and the FDA protocol for approving drugs has not changed in 50 years.”

    Through my advocacy efforts, I have learned that only an average of 27 new drugs are approved by the FDA on an annual basis. They could be for acne, arthritis or anemia. Typically, very few of them are for diseases that have no cure, such as ALS or virulent forms of cancer. This leads sufferers to risky and potentially fraudulent “treatments” that may cost tens to hundreds of thousands of dollars..

    If you believe as I do, that patients in Georgia deserve the right to try, then please reach out to state legislators and tell them to introduce and pass “Right to Try” legislation next session. Trying will not be enough. That right should be reserved for people dying without hope.

  26. Chris Kloss says:

    I would prefer a more positive paper that nurtured and amended the legislation to make it work in accordance with the worthy concept. But it is far easier to criticize than it is to build and create.

    The claim that it is inadequate to have completion of Phase 1 trials as a take-off point for right-to-try permission is an example. A more positive person would recommend how to fix this, not just state it is inadequate. (This paper must have been written by a lawyer. They are always negative)

    The paper seems to favor a level of governmental control that would render the proposed legislation largely impotent. Such a level of control is unwarranted. It is an attempt to perpetuate the FDA bureaucracy at the expense of the inherent right of an individual to fight for their own life.

    I believe that terminally ill individuals should be free to make their own decisions on doctors, procedures, and drugs without the sometimes unintelligible rules, forms and procedures that seem to attend most legislation (Lawyers again).

    The mass of useless forms , etc. cause us expense , time, and governmental overhead and show that our well-intended governing bodies seem to forget that the citizenry is not the servant of the government.

    The political bias of the author is clear. His points would be clearer if the paper was more succinct. It appears that he was paid by the volume of words produced.

    1. Harriet Hall says:

      “It appears that he was paid by the volume of words produced.”

      An unwarranted and false assumption. No one is paid for writing here.

      1. David Gorski says:

        One notes that Mr. Kloss seems unable to provide an evidence- and science-based refutation of anything I wrote. All he can apparently come up with is a rant about government control. Of course, that’s all most proponents have. Right to try laws are based on a fantasy that there are thousands of patients who are dying unnecessarily because they don’t have access to experimental drugs. There is no compelling evidence to support this assumption, and in reality the chances for harming patients with such a policy are far greater than the minuscule chance that a patient will be helped.

      2. Someone is definitely benefiting financially from the confusion it generates.

        Here I go again!
        Yall are attempting to conquer the SBM community and crack the codes, but everyone is focused on technology and ignoring a few truths; nature and humanity. Human nature, deceptions, the business and marketing of medicine, ignorance, lack of options, the biology and physics of the unknown, human variability etc. all must be addressed.

        Key definitions and logical points are misunderstood, corrupted esp related to pain, where is it and how to effectively treat it. Knowing how-to possibly treat pain in the old school manner takes trials and errors which is why my opinions are shunned and are not counted. I’m not the only person who practice in this manner, so leaving out this data will lead to gaps in logic which will result in poor outcomes.

        Ingraham, Quintner, Wolfe, Mckay et al are partly incorrect which is contributing to a major error. To maintain their renowned status, they have blocked my dialogue in an attempt to win. This is an example of the distorted dialogue:
        http://www.fmperplex.com/2013/02/14/travell-simons-and-cargo-cult-science/

        Well, we will all lose to big business in the end.

        1. WilliamLawrenceUtridge says:

          Human nature, deceptions, the business and marketing of medicine, ignorance, lack of options, the biology and physics of the unknown, human variability etc. all must be addressed.

          What, you mean with things like clinical trial registries, ethical review committees, calls for open access to journals and raw data, science education, ongoing criticisms of the influence of pharmaceutical firms in the research, approval and advertising of drugs? There are efforts to address the issues you raise (efforts you seem to be unaware of), but the real bee in your bonnet is that we are applying these same standards to you – we are asking for good evidence, well-controlled studies, and restrictions on the disbursement of public funds and the ability of quacks to make claims on the basis of shoddy evidence. The very things you see as large issues also exist in your much smaller world, but you don’t seem to recognize them.

          If your interventions to treat pain are effective – why not publish? Why not study them? Why not try to help someone beyond the small circle of the patients who pay you for your treatments?

          Also, how has anyone “blocked your dialogue”? What, because everyone here doesn’t see you as a brilliant genius? All the skeptics want is good evidence, not old books and claims that your experience is sufficient to change the practice of medicine throughout the world. If what you do works – test it and publish. Don’t bitch and moan on the internet about how your genius isn’t taken seriously by all the Big Pharma reps. The reality is, you are not a genius, and you completely fail to understand how deceptive your experience can be.

  27. David Gorski says:

    I would prefer a more positive paper that nurtured and amended the legislation to make it work in accordance with the worthy concept. But it is far easier to criticize than it is to build and create.

    And why on earth would Jann do that if she views the concept as irredeemably a bad idea, as I do?

    http://www.sciencebasedmedicine.org/right-to-try-laws-and-dallas-buyers-club-great-movie-terrible-public-policy/

    http://www.sciencebasedmedicine.org/the-compassionate-freedom-of-choice-act-ill-advised-right-to-try-goes-federal/

    “Right to try” laws are bad medicine, bad science, and terrible public policy. There is no fixing them, and, given how fatally flawed they are in their very concept, there is definitely no reason to “nurture” and “amend” such laws to make them work because they won’t work. They can’t work. The FDA controls drug development, and state “right to try laws” are nothing more than feel-good measures that give the illusion of hope to desperate patients.

  28. Ben says:

    In future writings, please spare me the political angle. am busy and wanted to understand the issues, not wade through your emotional disrespect for conservative groups.

    1. David Gorski says:

      It is impossible to avoid delving into some politics when discussing these matters. If you don’t like it, no one is obligating you to read. As for “emotional disrespect,” I really don’t see that in Jann’s writing.

      Try these instead:

      http://www.sciencebasedmedicine.org/right-to-try-laws-and-dallas-buyers-club-great-movie-terrible-public-policy/

      http://www.sciencebasedmedicine.org/the-compassionate-freedom-of-choice-act-ill-advised-right-to-try-goes-federal/

      1. Ben says:

        Thank you, I read both, and they argue well.

        Still, a change in incentive for the FDA to be less conservative might be in order, as suggested in my other post, which addresses a tradeoff that likely is postponing the availability of drugs in a non-optimal way.

        Perhaps another class of approval, with cautions aplenty? I hear the objection about undermining clinical trials.

        Perhaps more pressure to approve, along with a probationary period for new drugs so that patients are aware of the greater risk? The Right To Try movement might in this way have a beneficial effect.

        1. David Gorski says:

          There already is such a mechanism. It’s called fast track approval. The problem is, once a drug gets that provisional fast track approval, it’s almost never removed. The only example I can think of in the last decade is the removal of approval of Avastin for breast cancer a couple of years ago when a larger randomized clinical trial showed no survival benefit. Avastin had been approved based on a couple of phase II trials with the requirement that Genentech do a larger trial. Those results were basically negative; so the FDA pulled its approval. That caused a lot of political pushback from advocacy groups, who accused the FDA of letting breast cancer patients die.

    2. Windriven says:

      @Ben

      As a recovering conservative libertarian I’d like to ask you to step back a few paces and look at the human condition in the US dispassionately and in context of the sweep of history. Austrian economics has much to recommend it- at least theoretically, but many reasons to question it as well. If the society that you want to bequeath to future generations is to be measured only by GDP, you might just carry on. That is not the society I want. I expected conservative economics to lift people from poverty and to pave the way for a freer and better society. Instead what I see is a playing field increasingly biased in favor of rentiers. Poverty may now carry cell phones and big screen TVs but it is the draping of bangles and baubles on a wretch. Pockets of the nation and fractions of the populace have execrable educational and employment opportunities, crappy public transportation, ineffective public safety, poor health care opportunities, and are trapped in an increasingly intractable underclass.

      It doesn’t have to be this way. Some more liberal systems in Europe have done an imperfect but far better job than have we.

      In any event political choices have consequences that ripple through health care, education, agriculture, and crime. Talking about these issues without talking about the politics that drive them is feckless masturbation.

  29. Ben says:

    A recent article in National Review doesn’t add much to the conversation, but a commenter said something interesting:

    “Milton Friedman had a very good insight as to why the FDA stonewalls new drugs. Basically the consequences of a false positive (e.g. Thalidomide) are a lot more obvious than the consequences of a false negative (i.e. delaying potentially life-saving drugs), even though they are no worse. The public will be outraged if the FDA approved a drug that then kills or makes sick a lot of people. They will almost never be outraged if the FDA blocks a drug that would save many more lives. So as a matter of protecting their reputation, the FDA is overly cautious and errs on the side of too many false negatives.

    Really, like so much bad economic thinking, it comes down to what Bastiat wrote: people have a hard time seeing what is unseen.

    http://www.nationalreview.com/article/377907/right-try-amity-shlaes

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