It’s been a while since I’ve written about Stanislaw Burzynski, the Houston cancer doctor who inexplicably has been permitted to continue to administer an unproven cancer treatment to children with deadly brain cancers for nearly 37 years now. Beginning in 1977, when he left Baylor College of Medicine and opened up the Burzynski Clinic, Burzynski has administered a cancer therapy that he calls antineoplastons to patients. After nearly four decades and several dozen phase II clinical trials started, he never published a completed phase II trial. The only evidence he’s published consists mainly of cell culture studies, case reports, and couple of preliminary reports of his phase II clinical trials. Of course, Burzynski’s lawyer, Richard Jaffe, even dismissively admitted that these clinical trials are designed solely to allow Burzynski to keep giving antineoplastons.
So Burzynski operated from the late 1990s until summer 2012, charging exorbitant “case management” fees to enroll patients in his clinical trials, working with a credulous filmmaker who wanted to make a movie about him—twice—and flouting regulations designed to protect human subjects involved in clinical trials. Meanwhile, he branched out to “personalized gene-targeted cancer therapy,” which he promoted through Suzanne Somers; to AminoCare, which is basically antineoplastons sold as an antiaging nostrum (or, as Burzynski puts it, a “genetic solution to aging“); and to selling an orphan drug as a “prodrug” for antineoplastons.
So what happened in summer 2012? As far as I have been able to ascertain, there was a treatment-related death of a child, which led the FDA to issue a partial clinical hold on the Burzynski Clinic that prevented him from enrolling any new children on his clinical trials, although he could keep treating existing patients and enroll new adult patients. That partial clinical hold was extended to adults in January 2012, at which time the FDA arrived at the Burzynski Clinic to investigate. It was an event that was included at the tail end of Eric Merola’s second propaganda film about Stanislaw Burzynski and represented as, in essence, jackbooted fascists trying to keep the cure for cancer from The People. None of this stops credulous reporters from writing misleading articles with titles like Young mother with brain cancer given just a year to live BEATS the disease and gets married after having controversial treatment in the US, which is a story about Laura Hymas, a woman whose good fortune is most likely not due to Burzynski. Not long before that, there was another credulous article featuring another Burzynski patient, Hannah Bradley, as one of four patients treated for cancer with alternative therapies and are allegedly doing well. Again, Hannah Bradley’s good fortune is highly unlikely to be due to Burzynski’s nostrums.
All of this is why those of us who follow Burzynski have been waiting with the proverbial bated breath to find out what the FDA concluded. Just before the government shutdown the first shoe dropped, when the FDA released a warning letter to the Burzynski Research Institute. Then last week, the second shoe dropped, when the FDA released the original forms describing its findings regarding the inspection. The findings are, to put it mildly, damning in the extreme. In fact, now, more than ever, I wonder how on earth Burzynski has been allowed to continue to run clinical trials—or even practice—for so long. The findings include massive deficiencies in the Burzynski institutional review board (IRB), the committee responsible for making sure that regulations designed to protect human subjects in research are adhered to.
Stanislaw Burzynski versus human subjects protections: Human subjects protections lose
Before looking at the new FDA findings, let’s recap what is 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 has been trying for decades 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? Having Hazlewood serve on the BRI IRB 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. Again, one wonders how Burzynski supporters would react if pharmaceutical companies or even research institutes trying to commercialize a discovery made by their investigators allowed high ranking leadership sit on their IRBs.
Of course, I have discussed the problems with Burzynski’s IRB before, and these notes simply amplify and add detail to the problems that were already known. The first of the revelations that came out last week are basically the same as what I discussed back in March and again about a month ago.
Unfortunately that was not all. The second Form 483 posted to the FDA website answers a question that many of us interested in Burzynski have wondered about for a very long time.
There are two central mysteries about Stanislaw Burzynski that I would really, really like to see answered, and, hopefully, I will see them answered soon. The first is, of course: How has he gotten away with it for so many years? The second is: What are his real results? I’m not referring to the results Burzynski and his sycophants claim, but the real results? People like Paul Goldberg and others have been reporting for years that Burzynski’s results don’t seem to match his claims, with cancer experts who have seen some of his actual data reporting that Burzynski’s data “can never be useful to show true merit or lack of merit of his drug” because of an absence of rigorously reported results and independent verification” and “what we have here are bad trials that could never get past peer review of any clinical trials cooperative group.” Indeed, even back in the 1990s, serious adverse reactions were reported, mostly due to the hypernatremia. Now, thanks to these additional two FDA reports (here and here), we finally see a glimmering of light through the shroud of secrecy overlying the Burzynski Clinic.
Much of what is contained in these additional reports overlaps what I discussed before, but there is one kind of violation that does not. It’s a truly egregious violation that I find very difficult to comprehend, given how much it goes against every tenet of clinical research and clinical trials that I’ve been taught and learned over the years. It appears on this Form 483, where it’s discussed under “Observation 1,” and this other Form 483, where it’s discussed under “Observation 1″ and “Observation 2.” The brief versions are stated either as “Failure to monitor the progress of an investigation under your IND”; “an investigation was not conducted in accordance with the signed statement of investigator and investigational plan”; or “failure to prepare or maintain adequate case histories with respect to observations and data pertinent to the investigation.” What does this mean? Basically, it means that the BRI misclassified tumor responses to therapy and adverse reactions. Worse, records that would allow the validation of responses to therapy are missing.
Before I get more specific, let me just briefly review what I mean by tumor response, as it’s been a long time since I’ve discussed this. Whenever a drug is given to treat a tumor, the response is the degree of tumor shrinkage that occurs in response to the treatment. In general, there are four categories of results defined and reported in clinical trials of new chemotherapeutic agent:
- Complete response (CR): The tumors shrink away to the point that they are no longer detectable by physical examination, imaging studies (MRI, CT scan, etc.), or tumor markers. Obviously, this is the best possible result. This is further divided into a pathological complete response, which means that there are no detectable tumor cells in the resected tumor specimen. Obviously, when this happens, it is a very good thing and a very good prognostic sign. Sadly, it is not seen that often in clinical trials.
- Partial response (PR): This is usually defined to mean that the tumors shrink by more than 50% (or, in the case where tumor volume cannot be measured easily, tumor markers fall by more than 50%) in response to therapy but remain detectable. More recent definitions have at times loosened this criteria to include tumors that shrink by 30% or more. Whatever the specific criteria used, a certain degree of tumor shrinkage, or evidence of tumor regression, defined before the clinical trial, must be observed.
- Stable disease (SD): The tumors either shrink by less than the criteria for a PR or remain the same size. In some trials, this definition may be broadened to include tumors that increase in size slightly during therapy by less than, depending on the trial, 0-25%, although I’ve pesonally always been suspicious of calling any detectable growth above random variation in imaging measurements “stable.”
- Progressive disease (PD): Tumors increase in size on therapy and/or new metastatic tumors appear. This is obviously strong evidence that in that patient the therapy did not work.
How tumor response is measured varies according to the tumor. Most commonly RECIST criteria are used. For brain tumors, there are other criteria other than RECIST that are often used, such as the Macdonald criteria or its update, the RANO criteria. Other methods are being developed, as well. Obviously, there are pros and cons associated with each method. However, when you write a clinical trial, you have to pick one, stick with it, and use it appropriately to classify clinical trial subjects as either having CR, PR, SD, or PD. If these FDA reports are to be believed, Burzynski failed to do that. Worse, he either destroyed, or allowed to be destroyed, the original primary records used to make these determinations.
For example, the FDA notes that:
a. …For 18 of 27 (67%) of subjects, the investigator did not comply with the protocol requirements for assessing the efficacy endpoint of tumor response and recorded inaccurate assessments for tumor response in study records. For example:
- Study [REDACTED]: Subjects 005297 and 007197 were inaccurately classified as Complete Response (CR). Subjects 004721 and 008765 were inaccurately classified as Partial Response (PR). Subjects 005974, 011373, 012184, 012206, and 12252 were inaccurately classified as Stable Disease (SD).
- Study [REDACTED]: Subjects 06389, 11819, and 13660 were inaccurately classified as CR. Subjects 21428 and 23399 were inaccurately classified as PR.
- Study [REDACTED]: Subject 009990 was inaccurately classified as CR. Subject 004881 was inaccurately classified as PR.
- Study [REDACTED]: Subject 006239 was inaccurately classified as PR. Subject 004240 was inaccurately classified as SD.
b. You did not have a QA monitor properly monitor CRFs [case report forms] and subject records. The investigator destroyed critical subject case history records (target tumor measurement worksheets) or misplaced case history records (original subject CRFs) for all subjects.
Elsewhere, the FDA investigators note:
Your MRI tumor measurements initially recorded at baseline and on-treatment MRI studies for all study subjects were destroyed and are not available for FDA inspectional review.
The other Form 483 goes into a little more detail. Unfortunately, much of what I’d really, really like to know is redacted, specifically how each of these patients didn’t meet one or more of the criteria for the given response level to which Burzynski assigned them. Be that as it may, there’s plenty of damning information in these reports. For example, there are more examples of Burzynski’s failure to report adverse events (i.e., complications or bad things that happened to subjects being treated according to his protocols) in a timely fashion as required by the OHRP and the FDA. For example:
You failed to monitor as required by Section 16 of your Monitoriing Plan. The investigator did not report adverse events (AEs) experienced by study subjects, including 18 cases of hypernatremia.
Now let’s look at what I mean when I said that Burzynski misclassified AEs. AEs are graded according to a system known as the Common Terminology Criteria for Adverse Events (CTCAE). The CTCAE is nothing more than a list of AEs and SAEs (serious adverse events) commonly encountered in oncology. Each AE term is defined in the CTCAE and accompanied by a grading scale for severity. The AE terms are also organized by System Organ Classes definted by the Medical Dictionary for Regulatory Activities. The CTCAE is a long list, which can be downloaded as a Microsoft Excel spreadsheet, and it’s been updated several times. The most recent update is v.4.0, released in May 2009. Most of the AEs discussed by the FDA were from before that, so that CTCAE v.3.0 was being used to classify them. AE grades generally range from grade 1 (minor), grade 2 (moderate), grade 3 (severe), grade 4 (potentially life-threatening), to grade 5 (death).
Hypernatremia as I have discussed many times before, is a sodium concentration in the blood that is too high. If the hypernatremia is bad enough, it can be life-threatening. These reports document at least two subjects whose hypernatremia was graded a 2 when it should have been graded a 4. Of course, these two subjects pale in comparison to the number of patients whose hypernatremia either wasn’t reported or wasn’t reported for a long time. for example:
You failed to protect the rights, safety, and welfare of subjects under your care.
Forty-eight (48) subjects experienced 102 investigational overdoses between January 1, 2005 and February 22, 2013, according to the Weekly List of Hospitalizations/SAE [REDACTED] Overdose [redacted]/Catheter Infection report. Overdose incidents have been reported to you on a weekly basis during your Monday, Wednesday, and Friday staff meetings. There is no documentation to show that you have implemented corrective actions during this time period to ensure the safety and welfare of subjects.
This last sentence bears repeating: There is no documentation to show that you have implemented corrective actions during this time period to ensure the safety and welfare of subjects. So what we have here is a report finding that not only did Burzynski fail to report in a timely fashion a lot of SAEs, but that he tended to downplay the severity of the ones that he did report. Some AEs weren’t reported until as much as seven years later. Subjects also weren’t removed in a timely fashion for toxicity. For instance, one protocol stated that subjects would be removed after a third episode of Grade 3 or 4 toxicity or any single Grade 4 toxic effect that is “truly life-threatening or is not easily and rapidly reversible.” Of course, one wonders how the IRB could have approved such wording, as there is no distinction between “truly” life threatening and “life threatening” in the definition of Grade 4 toxicity. One patient had seven instances of Grade 3 or 4 toxicity but was not terminated from the trial until over a month after the seventh.
Other violations, although not as egregious, were nonetheless still quite bad. For instance, the informed consent didn’t include a statement of any additional costs to the subject that might result from the research. Several examples of patients who signed the informed consent days to weeks before they signed the billing agreement were presented. In addition, the Burzynski Clinic didn’t keep adequate records of its stocks of antineoplastons and could not account for how much was used by subjects. The number of bags of antineoplastons unaccounted for are truly staggering. One subject had 159 bags unaccounted for. Others ranged from one to 23 bags unaccounted for. Record keeping this sloppy would shut down nearly any clinical trial in and of itself.
The most serious violations of regulations designed to protect human subjects are clearly: (1) the BRI IRB’s misuse of the expedited approval process as an excuse to treat any patient Burzynski wanted to treat; (2) failure to keep original records to document baseline tumor measurements and tumor response; and (3) failure to report AEs and SAEs properly. However, there are a whole bunch of other lesser, but still serious, violations, so many that I find it hard to fathom.
I’ve said it before, and I’ll say it again, though: The central mystery behind Burzynski is how he’s gotten away with it for 37 years. Why does the FDA keep investigating him, finding serious violations, and giving him, in essence, a slap on the wrist? Since 2000, he’s been investigated multiple times, and he’s received FDA warnings for his violation of human subjects regulations. True, this is the first time since the 1990s that the FDA has taken substantive action against him, issuing a partial clinical hold that appears unlikely to be lifted any time soon, if ever. Still, I’m worried. If Burzynski comes up with a response that satisfies the FDA, he could conceivably have his same old bogus trials resurrected yet again. Why doesn’t the FDA shut down any clinical trials done BRI and Burzynski Clinic permanently? Why doesn’t it at least shut down the BRI IRB, which would have the effect of shutting down the Burzynski Clinic because no reputable IRB would ever approve the clinical trials that Burzynski proposes? To get its scientifically dubious clinical trials approved, Burzynski needs an IRB run by an old crony of his from Baylor (Carleton Hazelwood) who just so happens to be the chairman of the board of BRI, a massive conflict of interest. Any other IRB with so many repeated violations and such a massively obvious conflict of interest would be shut down. Any other research institute with so many violations of FDA regulations would not be allowed to do clinical trials of any kind.
That the Burzynski Clinic and Burzynski Research Institute still exist and still treat patients continues boggles the mind.