Stanislaw Burzynski versus regulations protecting human research subjects, revisited

Here we go again.

Every time I think I can get away from this topic for a while, I get sucked back in. Indeed, it seems that hardly a week can go by when I don’t find myself pulled inexorably back to this horrible, horrible clinic and what I consider to be the abuses of science and clinical trials that go on there on a daily basis. Whether it be the patients who are offered false hope at the cost of tens or hundreds of thousands of dollars in the form of a chemotherapeutic drug known as antineoplastons that, contrary to what it is claimed, is not “non-toxic,” “natural,” or even particularly well-targeted gene-targeted cancer therapy, or other incompetence, the Burzynski Clinic is drawing me back below its event horizon again, like the irresistable black hole made up of supercompressed greed that I see it to be. If there was ever a target for skepticism and critical thinking where the consequences of letting a “brave maverick doctor” run roughshod over human subjects protections. How he has continued to get away with it for over 30 years is one of the great questions in drug regulation. Somehow, he does, year after year.

A while back, I discussed in depth what I referred to as Stanislaw Burzynski versus regulations protecting human subjects. Sadly, up until recently, when it came to a battle versus human subjects protections and Burzynski, Burzynski almost always won. Who knows? he might even win his latest kerfuffle with the FDA, which was recently on site at the Burzynski Clinic, resulting in an at least temporary shut down of antineoplaston usage and advertising. However, as Elton John’s song goes, I’ve seen that movie, too, and I have little faith that the FDA will do anything. Thirty years of impotence in the face of what Burzynski does will do that for me. On the other hand, Bob Blaskiewicz has obtained, through the Freedom of Information Act, the FDA Form 483 from at least part of the recent FDA visit to the Burzynski Clinic. It’s the most recently dated FDA report I’ve ever seen (dated February 7, 2013) and consists of the observational notes from the inspection that took place from January 22 to February 7, 2013. Given that it was apparently mentioned by attendees at the screening of the second installment of Eric Merola’s apparently never-ending hagiography of the Great Man on March 9 that the FDA was still at the Burzynski Clinic then, these notes can only be viewed as preliminary, but they are telling. They deal mainly with the Institutional Review Board (IRB) that oversees Burzynski’s clinical trials.

I’ve discussed the problems with Burzynski’s IRB before, and these notes simply amplify and add detail to the problems that were already known. These notes suggest how Burzynski uses his IRB to get around some of the restrictions that were placed on him using antineoplastons. As you might recall, the Common Rule demands that all clinical trials by investigators whose institutions receive federal funding or that are being done in order to win FDA approval for a drug or device must be overseen by an IRB, whose purpose is to protect the human subjects who take place in the trials. This is an absolutely essential purpose of the IRB, its key reason for existence. It is not there to evaluate the science, except to the extent that badly designed clinical trials based on bad science endanger human subjects. Its purpose is to make sure that the risks and benefits of clinical trials are reasonably balanced, make sure that patients entering clinical trials receive adequate informed consent, and to keep an eye on the trial as it is being carried out, evaluating adverse event reports and, if necessary, shutting the trial down if there are too many or if one group starts doing too poorly relative to the other.

First, let’s recap what has been known about Burzynski’s IRB. First, we know that the IRB is headed by Carlton F. Hazlewood, PhD, who just so happens to be on the board of directors of the Burzynski Research Institute. As I noted before, given that the Burzynski Clinic is trying to commercialize antineoplastons, this is a profound conflict of interest. I also ask you to think of it this way again: What would Burzynski’s defenders say if they found out that a sitting member of the board of directors of Merck, for example, was serving on the IRB that oversees Merck’s clinical trials? This is the same thing. True, it’s not quite as bad as having the principal investigator of a study chair the IRB overseeing his studies, as Mark Geier has done, but it’s pretty bad. This should not be done. Again, one wonders how Eric Merola, for instance, would react if pharmaceutical companies or even research institutes trying to commercialize a discovery made by their investigators could allow high ranking leadership sit on their IRBs. Apparently, however, to propagandists and apologists like Eric Merola, when Burzynski does it, it’s just ducky.

Before we move on to the new notes, lets look at the things the FDA dinged Burzynski for over the last ten years:

  • Enrollment of subjects into antineoplaston study protocols prior to the protocol-specified interval following prior chemotherapy and/or radiation therapy.
  • Failure to report all serious adverse events (SAEs) and adverse events (AEs) to the agency and/or IRB.
  • Failure to follow proper informed consent procedures.
  • Failure to maintain adequate drug accountability records.
  • Discrepancies between case report forms and source documents.
  • Failure to keep a copy of the study protocol and informed consent form.
  • Failure to receive and/or require progress reports from the principal investigator for the study.
  • Failure to receive and/or require a final report from the principal investigator for the study prior to removal from the IRB’s active list of studies.
  • Failure to assure that FDA approval was obtained by the principal investigator for the study prior to the treatment of a patient under a special exception.
  • Approval of special exceptions via expedited review.
  • The IRB approved research without determining that the following criteria were met: That risks to subjects were minimized and That risks to subjects were reasonable in relation to anticipated benefits, if any, to subjects, and the importance of the knowledge that may be expected to result.
  • The IRB Failed to prepare, maintain, and follow written procedures for conducting its initial and continuing review of research.
  • The IRB failed to ensure that informed consent would be sought from each prospective subject or the subject’s legally authorized representative.
  • The IRB failed to ensure that no member participated in the initial or continuing review of a project in which the member had a conflicting interest.
  • The IRB failed to conduct continuing reviews.

Reading the Form FDA 483 notes from the FDA’s latest visit is like a bad acid flashback of the letters sent to Burzynski over the last decade or so. Included in the notes are observations that:

  • “The IRB [Institutional Review Board] used an expedited review procedure for research which did not appear in an FDA list of categories eligible for expedited review, and which had not previously been approved by the IRB. Specifically, your IRB routinely provided expedited approvals for new subjects to enroll under Single Patient Protocols.”
  • “The IRB approved the conduct of research, but did not determine that the risks to subjects were reasonable in relation to the anticipated benefits (if any) to subjects, and to the importance of the knowledge that might be expected to result. Specifically, your IRB gave Expedited Approval for several Single Patient Protocols (SPP) without all the information necessary to determine that the risk to subjects are minimized.”
  • “The IRB did not determine at the time of initial review that a study was in compliance with 21 CFR Part 50 Subpart D, ‘Additional Safeguards for Children in Clinical Investigations.’ Specifically, an IRB that reviews and approves research involving children is required to make a finding that the study is in compliance with 21 CFR Part 50 Subpart D, ‘Additional Safeguards for Children in Clinical Investigations.’ Your IRB approved research involving children without documentation of the IRBs finding that the clinical investigation satisfied the criteria under Subpart D.”
  • “The IRB did not follow its written procedure for conducting its initial review of research. Specifically, the IRB is required to follow its written procedures for conducting initial and continuing review. Your IRB did not follow your written procedures for conducting initial and continuing review because these subjects received IRB approval via an expedited review procedure not described in your Standard Operating Procedures. If your IRB would have followed your own SOP for initial and continuing review, the following subjects would have received review and approval from the full board rather than an expedited review.” [2 adults and 3 pediatric patients are listed.]
  • “The IRB has no written procedures for ensuring prompt reporting to the IRB, appropriate institutional officials, and the FDA of any unanticipated problems involving risks to human subjects or others. Specifically, your current SOP-2012 v2-draft doc does not describe the requirements on Investigators on how unanticipated problems are reported to the IRB, Institutional Official, and the FDA, such as time intervals and the mode of reporting, or otherwise address how the prompt reporting of such instances will be ensured.”
  • “The IRB has no written procedures [in the SOP-2012 v2-draft doc] for ensuring prompt reporting to the IRB, appropriate institutional officials, and the FDA of any instance of serious or continuing noncompliance with theses [sic] regulations or the requirements or determinations of the IRB.”
  • “A list of IRB members has not been prepared and maintained, identifying members by name, earned degrees, representative capacity, and any employment or other relationship between each member and the institution.”

I mean, seriously. How long and how often can Burzynski get away with this sort of crap? The same deficiencies keep popping up again and again. Burzynski then assures the FDA, that, really and truly, this time the Burzynski Clinic will play nice and obey the regulations governing human subjects research. Lather, rinse, and repeat.

One violation in particular deserves a bit more discussion, as I’ve covered most of the others before in my previous posts on Dr. Burzynski versus the FDA. Burzynski’s apparent belief that the rules governing IRBs and overseeing clinical trials don’t apply to him because he is curing cancer seems to know no bounds.

In any case, I’m referring to Burzynski’s apparent abuse of the expedited approval process through his IRB. Quite reasonably, the Department of Health and Human Services through its= Office of Human Research Protections (OHRP) which oversees IRBs, do not require the same sort of approval process for every sort of human subjects research. For instance, in the case of human subjects research that involves pre-existing samples that have been de-identified can be exempted from full IRB review and oversight because, well, there are no human subjects to be endangered, even through linking of their identities to a specimen demonstrating a disease. Lots of research gets done this way, for example analyzing or staining pre-existing samples looking for a biomarker or a change in expression of a protein. I’ve done projects like this. This is Exemption 4, and there are several other exempt categories.

However, Burzynski doesn’t abuse the exemption process, which, let’s face it, would be very hard to abuse for the most part. What he appears to be abusing is the expedited approval process. The expedited review process generally involves approving things like minor revisions to research protocols and informed consent forms. “Expedited” generally means just that: Expedited. A full IRB review is not done, and a streamlined, faster process is used. Expedited approval can also be used for protocols that fall under categories that the HHS deems to be “minimal risk,” described thusly on the University of Kentucky website:

Expedited procedures can only be used to review a study if the only involvement of human subjects fits one or more of the categories specified in the federal regulations and if all of the procedures present no greater than “minimal risk.”

The IRB reviewer confirms that all of the research activities fit in one or more of the expedited categories. If the research includes activities that do not fit in the categories, the study is not eligible for expedited review even if the research involves “minimal risk.”

The Department of Health and Human Services defines minimal risk to mean “the probability and magnitude of harm or discomfort anticipated in the research are not greater in and of themselves than those ordinarily encountered in daily life or during the performance of routine physical or psychological examinations or tests” [45 CFR 46.102(2)(i)].

Investigators are asked to provide a risk assessment, but it is the IRB reviewer’s responsibility to determine whether the research meets the federal definition.

The IRB reviewer must consider two questions:

  • Is the probability of the harm or discomfort anticipated in the proposed research greater than that encountered ordinarily in daily life or during the performance of routine physical or psychological examinations or tests?
  • Is the magnitude of the harm or discomfort greater than that encountered ordinarily in the daily life or during the performance of routine physical or psychological examinations or tests?

If the answer is “yes” to either of these questions, then the research does not meet the definition of minimal risk.

A list of the types of research that can be approved through expedited review can be found on the OHRP website. These include things like blood draws, prospective collection of biological specimens by noninvasive means (one could collect urine specimens, for instance, under a protocol approved through the expedited review process), and research involving data that has already been collected. Here’s a hint: Approving “single patient protocols” for an investigational drug that is not FDA-approved does not fall into any of the categories for which expedited review is appropriate, particularly when so many of the patients involved are children and particularly when the drug being tested can cause severe hypernatremia. Basically, from my reading, Burzynski seems to be using the expedited review process to treat patients with antineoplastons who do not qualify for any of his numerous phase II trials, and he seems to have been getting away with it.

As a translational researcher who frequently works with clinical investigators, I just can’t figure out how Burzynski keeps getting away with it. Either the FDA is more impotent than I had thought, or he has some serious pull with some powerful people. If my university received even one report like this, it would be quite possible that all federal research funding to the university for biomedical research would be suspended until the university fixed the problems to the satisfaction of the federal government. Yet the FDA has found Burzynski to be deficient in numerous areas of human subjects protection not once but at least twice over the last decade and appears to be poised to find it to be deficient in many of the same areas yet again.

If there’s one thing I’ve learned over the years about Brave Maverick Doctors, it’s that they often come to believe that the rules don’t apply to them. They crave the respectability of science, of course, but they are too impatient or too arrogant to play by the rules of science. Unfortunately, that often includes the rules designed to protect human subjects in clinical trials. We’ve seen it before with Mark and David Geier, who formed their own IRB stacked with their cronies. We’ve now seen it with Stanislaw Burzynski, who formed his own IRB. In the world of these Brave Maverick Doctors, the IRB apparently exists not to protect human subjects, but is instead viewed as a formality to funnel patients into whatever they want to do to treat them.

In my recent post in which I discussed Burzynski: Cancer Is A Serious Business, Part 2 (or, as I like to call it: Burzynski II: Electric Boogaloo or Burzynski II: This Time It’s Peer-reviewed), I told you five things I learned from the movie, all of which was pretty much pure nonsense turned into a massive infomercial for the Burzynski Clinic. There was one thing, however, I didn’t tell you, and now seems like a perfect time to tell you.

According to our moles who attended the movie, in the Q&A session after the movie, there was considerable—shall we say?—venting (well, ranting, actually) at the FDA and the federal government, which were described in terms of “health tyranny” and religious dogma in which antineoplastons were represented as being a safe “natural” alternative to chemotherapy, radiation, and surgery that is “totally nontoxic.” Of course, as I’ve pointed out many times before, this is massively stupid, given that antineoplastons are chemotherapy. In the midst of this, apparently an audience member asked Mini-B (my name for Greg Burzynski, Stanislaw Burzynski’s son and heir apparent to the Burzynski cancer empire) said that they had thought about it and that “everyone has an opinion.” It was also revealed that Burzynski is working with other countries to make this a possibility and that some doctors in China is apparently interested in bringing antineoplastons to China. This also led to the obvious revelation that Merola has a seriously inflated view of Burzynski’s importance and the importance of the “health freedom” movement supporting him, which was represented as being bigger than Gandhi, Martin Luther King, and the Occupy Movement.

I’d like to conclude by making a prediction. I could be wrong, but if the FDA is not impotent this time (a big “if,” I admit), I could easily see Burzynski moving to San Diego, the better to open a branch of the Burzynski Clinic in Tijuana to take advantage of Mexico’s less—shall we say?—rigorous laws and human subjects protections. I could then see him using the Houston branch for his “personalized gene-targeted cancer therapy” (for dummies), which is easier to do in the U.S. because he can use his antineoplaston prodrug (as he calls it) sodium phenylbutyrate off-label, as he does now, and add it to his “everything but the kitchen sink” cocktail of targeted therapies based on simplistic interpretations of a commercial test, as he also does now. Meanwhile, in Tijuana, he could shed any pretense of trying to prove that his antineoplastons work against advanced cancer any better than conventional therapy, and just sell, sell, sell. In fact, I wonder why he hasn’t done this before. Maybe he really loves Houston.

In that case, I guess he could always dispatch Mini-B to San Diego.