You might have noticed that I was very pleased last Friday, very pleased indeed. Given the normal subject matter of this blog, in which we face a seemingly-unrelenting infiltration of pseudoscience and quackery into even the most hallowed halls of academic medicine, against which we seem to be fighting a mostly losing battle, having an opportunity to see such an excellent deconstruction of bad science and bad medicine in a large mainstream news outlet like USA TODAY is rare and gratifying. As you might recall, USA TODAY reporter Liz Szabo capped off a months-long investigation of Dr. Stanislaw Burzynski and his Burzynski Clinic with an excellent (and surprisingly long and detailed) report, complete with sidebars explaining why cancer experts don’t think that Burzysnki’s anecdotes are compelling evidence that his treatment, antineoplastons, has significant anticancer activity and a human interest story about patients whom Burzynski took to the cleaners. Most of this, of course, is no news to SBM readers, as I’ve been writing about Dr. Burzynski on a fairly regular basis for over two years now. It’s just amazing to see it all boiled down into three articles and ten short videos in the way that Szabo and USA TODAY did, to be read by millions, instead of the thousands who read this blog. Szabo also found out who the child was who died of hypernatremia due to antineoplastons in June 2012, a death that precipitated the partial clinical hold on Burzynski’s bogus clinical trials, about which both Liz Szabo and I have quoted Burzynski’s own lawyer, Richard Jaffe, from his memoir, first about Burzynski’s “wastebasket” trial, CAN-1:
As far as clinical trials go, it was a joke…it was all an artifice, a vehicle we and the FDA created to legally give the patients Burzynski’s treatment. The FDA wanted all of Burzynski’s patients to be on an IND, so that’s what we did.
And Jaffe’s characterization of the six dozen phase II clinical trials that Burzynski submitted in the late 1990s was this:
A cancer clinic cannot survive on existing patients. It needs a constant flow of new patients. So in addition to getting the CAN-1 trial approved, we had to make sure Burzynski could treat new patients. Mindful that he would likely only get one chance to get them approved, Burzynski personally put together seventy-two protocols to treat every type of cancer the clinic had treated and everything Burzynski wanted to treat in the future…Miracle of miracles, all of Burzynski’s patients were now on FDA-approved clinical trials, and he would be able to treat almost any patient he would want to treat!
I’m just repeating those quotes again, because they can’t be emphasized enough. Quite frankly, if I were Burzynski, I’d fire Jaffe for having published such statements in his book. But that’s just me. In the meantime, let’s take a look at the counterattack and why Burzynski’s excuses regarding the deficiencies found in the FDA reports do not ring true.
The Burzynski shills strike back
My original plan for today had been to look into the story in a bit more detail than I had time for on Friday, in particular addressing the Burzynski Clinic’s response to the original FDA report in more depth and looking at some historical context. I figured that the Burzynski Clinic would strike back at some point, but it hasn’t yet, not really. Instead, it’s unleashed its resident propagandist and attack chihuahua Eric Merola, the man who wrote and directed two “documentaries” about Burzynski that were such propaganda about the “great man” that they’d make Leni Riefenstahl blush. Merola rapidly posted on his own website an open letter to Liz Szabo and then turned around and went full Godwin on her at his movie’s website. His responses are remarkable for their intensity; so I’ll briefly deal with them before I get into the “meat” of this post. His first response, which made the rounds within a few hours after Szabo’s story appeared, was his open letter/e-mail to Szabo. His second response appeared on the website for his movies and was entitled “Dear Burzynski Movie Subscribers“.
Both responses contain the same sorts of tropes, misinformation, and pseudoscience that we’ve come to expect from Merola: USA TODAY is biased and in the pocket of big pharma. It was a “hit piece.” Burzynski is far ahead of his time and will be vindicated (i.e., the Galileo gambit). It’s not just Burzynski, but the Japanese, who have “proven” that antineoplaston’s work. I’ve deconstructed these, and many more, of Merola’s nonsense over the last two years. What actually surprised me was the viciousness of the counterattack. For example, in his letter to Liz Szabo, he actually hopes that her child will get cancer, so that Burzynski supporters can gloat about it and Szabo will have to apologize to her children for her “perfidy” (in Merola’s eyes, at least):
Burzynski has found a life-saving cure for many cancers. You have just aided in helping to destroy that. I feel for you if your children get diagnosed with a pediatric brain tumor. You can look them in the eye and tell them “I’m sorry, I helped destroy the only thing that could have helped you.”
Such a nice guy. He denies that he hopes Szabo’s children will develop brain cancer, but then gloats gleefully over the possibility that she would have to face them after having—again in his mind—”helped to destroy the only thing that could have helped” them. In the dictionary, under the definition of “despicable,” there should be a picture of Eric Merola. Then, just when I thought Merola couldn’t go any lower, he does, this time in his longer response on his movie website:
Trying to “debunk” USA TODAY’s diatribe on Nov. 15, 2013 would be like someone living in Nazi Germany trying to debunk the writings of Joseph Goebbels, or an African American trying to explain to his slave master that he too is also a human being with rights and emotions, or the parents of an American soldier trying to explain to members of the Westboro Church how disrespectful it is to hold up signs that read “God Hates Fags” during their child’s funeral.
This type of unbridled hate and bigotry goes far too deep for any rational human discourse.
Obviously, to Merola asking Burzynski to follow normal rules regulating medical ethics and human subject protections in clinical trials is exactly like murdering millions of people, carrying out horrible medical experimentation, making untold numbers of Africans slaves, and harassing the grieving families of soldiers killed in battle. My first thought on reading this is that it’s rare to see an article in which someone “goes Godwin” so quickly and so despicably. It’s only the third sentence, fer cryin’ out loud! Didn’t anyone ever teach Merola that you need to build up to that sort of climax?
It’s also one reason that I don’t have any compunction about comparing Merola to Leni Riefenstahl. Of course, the big difference between Leni Riefenstahl, unfortunately, is that she had talent, and Eric Merola does not. Just watch his movies—if you can stand the robotic narration, the choppy editing, and the cheesy graphics—if you don’t believe me. However, the intensity of the images used by Merola do demonstrate the intensity of the hate he bears for critics of his hero Stanislaw Burzynski. To Merola, we are Nazis, slave owners, and bigoted religious fanatics. This explains quite well why he decided to attack us so viciously and clownishly in his most recent movie. At the time, I described it as almost Monty Pythonesque, except that Monty Python were brilliant and produced such effects on purpose. Merola is a hack and is only funny by accident because he has no filters that tell him when he’s going way over the top. To him, we are infidels. We do not share his belief, but, even worse, we have the temerity to criticize his god, or, to mix metaphors shamelessly, to point out that his emperor has no clothes.
Since I’ve dealt with so many of the tropes included in Merola’s not-so-little rant, I hardly see the need to repeat myself. However, as a cancer surgeon, I find one of Merola’s lies to be as despicable, or perhaps more so, than his Nazi/slavery/Westboro Baptist Church comparisons. In essence, he denies the toxicity of antineoplastons in terms I’ve never seen anyone try to downplay before:
ANP… is toxic?
This was perhaps the most stunningly malicious use of emotion to manipulate the reader in any of the propaganda pieces against ANP in history. Never mind that tens of thousands of people die from complications from approved and properly prescribed pharmaceutical drugs per year—being one of the leading causes of death in the USA. Never mind that the average Stage IV cancer patient dies from complications due to chemotherapy and radiation before the disease has a chance to kill the patient. USA TODAY will have you believe that “sleeping in excess” a little bit while under ANP is a dangerous and toxic side effect of the therapy.
Never mind that not one single cancer patient in the history of ANP’s existence has ever died from the therapy.
Tell that to the parents of Josia Cotto. Josia, as readers of Liz Szabo’s report will know, was the six year old boy with an inoperable brain tumor who died of hypernatremia (elevated sodium levels in the blood) as a result of Burzynski’s therapy. As I pointed out last Friday and Szabo reported in her story, before his death Josia’s serum sodium was measured at 205 mEq/L, way above the normal range of 136-145 mEq/L and well into the lethal range. As I pointed out then, I’ve never seen a sodium level anywhere near that high. During my residency, the highest I recall ever seeing was maybe around 180 mEq/L. As for Merola’s swipe about “sleeping in excess” as a toxicity, it’s rare for someone (but not Merola) to reveal such ignorance in a single sentence. Lethargy and somnolence can be symptoms of hypernatremia, and are often followed soon after by seizures. They can also be symptoms of the tumor progressing. Absolutely they are adverse events. Truly, Merola’s ignorance of what is and isn’t considered and adverse event and why it’s important to report all adverse events in clinical trials approaches black hole-levels, from which no scientific knowledge can escape.
Of course, none of this is new information. A Cancer Letter article from 1998 pointed out that investigators had observed “severe toxicity” in 33% of patients that necessitated stopping treatment. One of those patients experienced—yes—somnolence before developing seizures. I also note that one of Burzynski’s most famous patients, Hannah Bradley, who with her partner Pete Cohen proclaims herself cured of her brain cancer, thanks to Burzynski, suffered some pretty serious toxicities from antineoplastons herself, including high fevers to 103.9° F, shaking chills, and severe rashes. Pete even documented how badly Hannah reacted to antineoplastons in his YouTube documentary “Hannah’s Anecdote”.
The rest of Merola’s rant reads like a greatest hits compilation from cancer quacks. The system is corrupt. Oncologists know chemotherapy doesn’t work and only administer it to make money. The FDA is fascist. You get the picture. That’s the wingnut counteroffensive against Liz Szabo’s article. Now let’s see how Burzynski, knowing that Szabo’s story would be published soon, tried to pre-empt the FDA findings that I described in detail last week.
Burzynski tries to defend himself
Before I discuss why Burzynski’s explanations don’t excuse his activities, I can’t help but point out that I find it rather curious that the FDA released the two Form 483′s describing what its investigators found at the Burzynski Clinic during their investigations from January to March 2013. To be honest, as I mentioned before, the biggest disappointment that I had over Szabo’s excellent reporting is that she apparently couldn’t get to the bottom of why the FDA has let Burzynski continue to run his dubious clinical trials for so long, despite multiple investigations over the preceding decade that had found deficiencies in his operation, particularly in how his institutional review board (IRB) works. (An IRB is a required committee that each institution doing human subjects research must have to approve and monitor human subjects research and ensure that it meets Office for Human Research Protections (OHRP) requirements.) Given that the USA TODAY story makes the FDA look very, very bad indeed—and more than justifiably so—it strikes me as more than a tad coincidental that the FDA finally released these preliminary reports a mere week before Szabo’s story was published, eight months after its investigation concluded. It’s almost as though the FDA were trying to cover its exposed posterior. One can only hope that Szabo’s story lights a fire under that same posterior to actually do something more about Burzynski, such as making the clinical hold permanent and banning him from ever doing any further clinical trials.
Be that as it may, let’s recap what the FDA found, summarized by yours truly. The findings came in two reports. The first set consisted of the first Form 483 and a warning letter issued by the FDA in late September:
- The IRB failed to follow FDA regulations regarding expedited review procedures [21 CFR 56.110(b)].
- The IRB approved research without determining that the following criteria were met: risks to subjects were minimized [21 CFR 56.111(a)(1)]; 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 [21 CFR 56.111(a)(2)].
- The IRB failed to determine at the time of initial review that studies involving children are in compliance with 21 CFR part 50, subpart D, Additional Safeguards for Children in Clinical Investigations [21 CFR 56.109(h)]. This is a repeat violation from our 2010 inspection.
- The IRB failed to prepare, maintain, and follow written procedures and maintain adequate documentation governing the functions and operations of the IRB [21 CFR 56.108(a), 21 CFR 56.108(b), and 21 CFR 56.115(a)(6)].
As I discussed before, this is a massive failure of the Burzynski Research Institute (BRI) IRB. It is, in essence, the abuse of a process designed to allow minor changes to clinical trial protocols to be approved by an IRB without a full meeting of the IRB for a purpose for which the expedited approval process was never intended: to approve single-patient protocols, which are, in essence compassionate-use exemptions that allow patients who normally wouldn’t meet the inclusion criteria of the trial to receive the experimental therapy. Such protocols require full meetings of the IRB to discuss. Of course, such abuses are not surprising, given that the BRI IRB is run by an old crony of Burzynski’s from his Baylor days, Charlton F. Hazlewood. There’s very little in the way of a response that Burzynski could make to these allegations and be convincing. OHRP rules on single-patient protocols are not unclear:
A “single patient use” allows a physician to obtain access to an investigational drug for the treatment of a single patient. Usually, the patient is in a desperate situation and unresponsive to other therapies, or in a situation where no approved or generally recognized treatment is available. Further, there is usually little evidence that the proposed therapy is useful, but may be plausible on theoretical grounds or anecdotes of success. Access to investigational drugs for use by a single, identified patient may be gained either through the sponsor under a treatment protocol, or through the FDA, by first obtaining the drug from the sponsor, and then submitting a treatment IND to the FDA requesting authorization to use the investigational drug for treatment use [21 CFR 312.35].
There are situations when it is allowed to do single-patient protocols without getting IRB approval first, but they are very uncommon:
First, the FDA human subjects regulations allow for a test article to be used in emergency situations without prior IRB approval provided that the emergency use is reported to the IRB within five working days; subsequent use of the test article must be reviewed by the IRB [21 CFR 56.104]. An emergency is defined as a life-threatening situation in which no standard acceptable treatment is available and in which there is not sufficient time to obtain IRB approval [21 CFR 56.102(d)]. [See Guidebook Chapter 2, Section B, "Food and Drug Administration Regulations and Policies."]
In other words, IRB approval is required before single-patient use of investigational agents. This presentation confirms that. Indeed, it is listed as an impediment to single-patient protocols because of the time and expense of convening a full IRB meeting for a single patient. Expedited review, the very same process that the BRI IRB used to approve single patient protocols, is listed as a potential solution to the difficulties in getting single-patient protocols approved. Of course, that means that currently the expedited review process is not permitted as a method for an IRB to approve a single-patient protocol. Oddly enough, there’s not much in the Burzynski Clinic response about single-patient protocols.
The second set came from the second Form 483, which listed these deficiencies:
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.
There were several others, so many that I could do a series of posts about them, but these two stand out to me most of all:
- 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.
- You failed to monitor as required by Section 16 of your Monitoring Plan. The investigator did not report adverse events (AEs) experienced by study subjects, including 18 cases of hypernatremia.
Let’s deal with what I view to be the worst of the worst, namely Burzynski’s apparent inability to accurately assess whether a patient is experiencing a complete response (CR) to therapy, a partial response (PR), stable disease (SD), or progressive disease (PD), terms that are fairly self-evident but that I defined in depth last time around. So how did Burzynski dance around the issue? He did it in a number of ways, because there were a number of reasons why individual patients were thought to have been misclassified. For example, the FDA notes:
Subject 23643 : The study protocol required the subject to be off chemotherapy for at least 4 weeks. The cbemotherapy on 7-17-12 and began treatment with the investigational product, one day later, on 7-18-12.
And indeed, the protocol did require:
At least eight weeks must have elapsed since the last dose of radiation therapy and at least four weeks must have elapsed since the last dose of chemotherapy (six weeks for nitrosoureas) or immunotherapy.
Since the full effectiveness of initial therapy (including radiation therapy) may not be seen until a few months after the initial therapy is completed, it is very difficult to analyze the effectiveness of initial therapy before the patient has completed treatment and follow-up. Because of this treatment decisions are usually not made on the base of radiological studies performed earlier than four weeks following completion of radiation therapy.
The only exception is:
However, patients with clear evidence of disease progression during the initial therapy may be enrolled less than (8) eight weeks following the last dose of radiation therapy, less than 4 weeks after surgery or the last dose of chemotherapy, if the investigator has determined that it is safe to administer antineoplastons to such patients.
I mentioned, but did not explain, the phenomenon of “pseudoprogression,” because I was impressed with how well Szabo had explained it in her story. Pseudoprogression can confound treatment decisions regarding second line therapy after initial treatment, being basically a phenomenon in which late effects of radiation therapy can produce enhancing lesions that look to all the world on MRI like tumor recurrence. There was a nice review of this topic a few years ago that describes the phenomenon thusly:
Now that concurrent TMZ and radiotherapy are used as standard therapy, the postradiotherapy radiological assessment is made earlier than before, when radiotherapy was given alone. However, it can be difficult to interpret the radiological image obtained, as any changes observed may be due to treatment-related pseudoprogression rather than true disease progression. In their recent study of 51 patients treated with radiotherapy and concomitant TMZ, Chamberlain et al.20 reported seven (14%) cases of early necrosis without signs of tumor recurrence; 26 patients had a radiological diagnosis of early disease progression and, of these, 15 underwent re-resection, with 7 (47%) of the 15 having a surgical diagnosis of radionecrosis. These data open a dual scenario: the possibility of a higher incidence of early radionecrosis and the risk of mistaking the latter for disease progression. In a series of 32 glioma patients, de Wit et al.21 observed that the first postradiotherapy MRI showed progressive enhancement in nine cases; in three of these nine cases, MR images showed improvement or stabilization for 6 months without additional treatment being given.
In patients under treatment for brain tumors, worsening of the preexisting neurological focal deficits, suggesting tumor progression or recurrence, can be accompanied by a neuroradiological image of edema and contrast-enhancing lesion within the tumor bed. However, this radiological pattern is not necessarily associated with any clinical deterioration. These alterations, described in 1979 by Hoffman et al.3 in a group of patients treated with radiotherapy and carmustine (BCNU) at an interval of 8 weeks, were investigated with serial CT or MRI scans. Within 18 weeks following radiotherapy, 49% of patients had a deterioration that strongly suggested tumor progression. In 28% of the cases, however, spontaneous improvement occurred without a change in therapy. Following this pattern, which is indistinguishable from that of tumor recurrence, improvement usually occurs within a few weeks or months, with a thorough neuroradiological follow-up showing that these signs regress within 4–8 weeks. The timing of these clinical features, known as “early delayed reactions” following radiotherapy,4 seems to correspond to the turnover time of myelin.
As a reminder, I will also quote the USA TODAY article again, because it is the most succinct explanation of pseudoprogression I have ever seen:
Many of Burzynski’s patients are terminally ill and have had one or more previous types of conventional cancer care — surgery, radiation or chemotherapy — before they see him.
But these therapies may have delayed benefits, taking weeks or months to shrink a tumor. So patients treated by Burzynski may credit him for their progress, just because he was the last doctor to treat them, says Peter Adamson, chair of the Children’s Oncology Group, an NCI-supported research network that conducts clinical trials in pediatric cancer.
Conventional cancer treatment can also cause tumors to swell temporarily, due to inflammation. A patient who isn’t familiar with this phenomenon may assume her tumor is growing. When that swelling subsides, patients may assume it’s because of Burzynski, Adamson says. In reality, the tumor was just returning to its previous size.
To avoid such confusions, researchers typically require patients to wait before starting a new treatment, Adamson says.
In other words, in a small but not inconsequential number of cases (perhaps as much as 28%), apparent tumor progression really isn’t. That’s why it’s called pseudoprogression, and is defined as the delayed but still-early effects of therapy mimicking tumor recurrence on MRI scans. In other words, therapy of brain tumors can result in the enhancement seen on MRI associated with the tumor increasing in size due to increased blood flow due to inflammation. The same phenomenon is very likely true for many Burzynski patients who are presented as “success stories.” They show pseudoprogression, and, as pseudoprogression does, the “enlarging cancer” decreases in size after the patient is put on antineoplastons. However, the decrease has nothing to do with the therapy. That’s why in Burzynski’s case well-conducted clinical trials are absolutely essential, as well as why clinical trials require patients to be off therapy from 4-8 weeks to avoid the confounding effects of pesudoprogression. Of course, the number of patients exhibiting pseudoprogression who don’t ultimately develop a real recurrence that kills them is much, much smaller, but not so small that it can’t explain many of Burzynski’s testimonials. In fact, I bet pseudoprogression in patients who were lucky enough to be cured or have had their tumors shrunk enough that it takes a long time to recur probably explains the majority of Burzynski’s brain cancer testimonials.
Another big issue that the FDA noted was that some of the patients whose tumor responses to antineoplastons had been overestimated by Burzynski were still on steroids. Steroids are often administered to brain cancer patients to lessen the edema (swelling) that frequently occurs around tumors. Given that the skull is a fixed volume, any swelling can result in increased intracranial pressure, which can damage the remaining brain. The problem here is that if Burzynski’s patients were on steroids, it could make the tumors appear smaller than they really are. Burzynski started out his excuse with some obfuscation that the guidelines for determining CRs have changed twice over the last several years. Well, yes, that’s true. As referenced by Burzynski, the Macdonald criteria for response assessment were changed in 2010 to incorporate changes in steroid doses as part of the definition of responses. For a response to be assessed as a CR or PR, the patient now has to be on stable or decreasing steroid doses. Burzynski tries to justify some of the patients this way:
Our definition of a “patient off corticosteroids” is one who continues on the lowest dosage necessary for neurologic stability and is maintained at their level of comfort and function. This is ordinarily determined by decreasing the close until signs increase or become apparent and then increasing the dose until they subside. If deterioration is secondary to tumor growth or treatment–induced effects, the glucocorticoids dose may have to be increased to keep the patient comfortable. Hence, “off corticosteroids” in order to interpret response to treatment is defined as a patient that may either be off steroids or be receiving a stable steroid dose to maintain neurologic and physiologic stability.
Since the beginning of Phase ii study program under IND 43,742, the criteria used for assessing response to therapy in malignant brain tumors have changed twice. The most recent recommendations of the Response Assessment from the Neuro-Oncology Working Group became active in April, 2010. According to these recommendations, it has been accepted that complete and partial responses can be determined when the patient is on physiologic replacement doses of corticosteroids.
All of which is true, but irrelevant. Response criteria can’t be changed mid-stream in a clinical trial without actually altering the clinical trial. If the standard methodology of measuring tumor response changed, then if an investigator wants to use those changes he has to submit an amendment to his protocol to his IRB and the FDA and get it approved. Clearly, Burzynski didn’t do that, and according to his protocol the patient had to be off steroids. So the FDA called him on it.
Some of Burzysnki’s other excuses are ludicrous in the extreme, and I’ll deal with some of them briefly. For example, for one patient, Burzynski writes:
Patient 004240: An assessment of SD was determined based on the size of the enhancing lesion and does not reflect the overall increase of tumor size due to formation of a Cyst. The change in the overall size of the brainstem lesion on studies between 2/21′/96 and 5/22/96 is due to an increase (4/10/96) and collapse (5/22/96) of the cystic component of the lesion.
No, you don’t get to estimate tumor volumes that way, particularly back in 1996. It rather reminds me of the way Burzynski has played fast and loose calling responses when tumors get larger based on seeing increasing size of “cysts,” the way he did with Amelia Saunders.
For another patient, he seems to want to have it both ways:
Patient 005974: The enhancing portion of the tumor increased 30%, which met the criteria of SD using previously used criteria. Since we are amending the protocol, this patient will be reclassified as PD.
In other words, when I the old criteria don’t make me declare a patient as having PD, I use them. When they would force me not to call a CR or PR but the new criteria will, I use the new criteria. Again, you can’t flip back and forth between new and old criteria, picking whichever set of criteria gives you the better results. You have to pick one and stick with it for every subject on the trial. It’s acceptable to change to the updated criteria, but if as a principal investigator you choose to do that then you need to go back and reassess response for every single subject on your trial from day one using the new criteria.
I could go on and on, but even I get tired after a while. However, I can’t finish without looking at one claim that Burzynski made as an excuse that almost cost me a keyboard as I was drinking coffee as I read it. Perhaps the most damning finding of the FDA was the Burzynski Clinic’s failure to keep original scans and records on some patients. Here is the Burzynski Clinic’s excuse:
ICH E6, section 1.51, also defines source data as “All information in original records and ‘certified’ copies of original records or clinical findings, observations, or other activities in a clinical trial necessary for the reconstruction and evaluation of the trial.”
The clinic notes contained copied source data of tumor measurements that had been verified, dated and signed, which from our interpretation would constitute being a “certified copy” of the data. We judged that the data of tumor measurements were accurate and could be audited back to the source document.
A5 for the issue of misplaced case history records original subject CRFS, we maintain that these original CRFs were populated with data that was derived from the patient case files and would not be considered original source data. The source data are the patient files. Back in the year 2000, BRI regulatory and clinical staff determined that the “original were considered inadequate and required redesigning in that they had a number of missing fields. As was done for the “original new CRFS were again generated from the source data in the case history records and not derived from the original CRFs. These “new are available for review. We retained a total of 132 of the “‘original which have been located in our archives. However, we do not plan to use these, based on the aforementioned reasons as well as not being source documents. The remaining ‘original which were not signed off on as true and accurate copies of source data were destroyed for the reason of being incomplete.
No, “certified” does not mean “copied onto new forms or into new computer database fields because we redesigned our forms.” Certified copies tend to be copies of medical records from other institutions used in the conduct of clinical trials; i.e., certified medical records such as any patient can request from a health care provider, as in photocopies of clinical records, copies of scans, or CDs or DVDs containing radiology tests. For a clinical trial, there is no excuse for destroying original documents from your own clinic used for a clinical trial. None. Ever. At least not without FDA and IRB approval before doing so. The reasons are obvious. It destroys the very paper trail that is critical to the trustworthy conduct of a clinical trial. Destroying such records indicates either gross incompetence or an investigator trying to hide something. This suspicion becomes particularly pertinent given that many of the original MRI scans of Burzynski patients appear to be missing, making it impossible for the FDA to do repeat measurements, in order to determine whether Burzynski’s response assessments were correct.
There are multiple other examples of dubious claims in Burzynski’s response, but I’ve mostly covered them in my original post on the FDA revelations. These include the hypernatremia cases that Eric Merola basically denied, which Burzynski tried to brush off due to changes in the Common Terminology Criteria for Adverse Events (CTCAE) over the years. In essence, he claimed that hypernatremia wasn’t listed on the earlier version of CTCAE; so he made up “clinical severity” criteria, which didn’t agree with the CTCAE. Now, the CTCAE has been around since 1983, although it was called the Common Toxicity Criteria until v.3 in 2003. Each version has added more criteria. Before 2003, Burzynski might have had a point; I can’t find whether CTC v.1 (1983 to 1996) or CTC v.2 (1996 to 2003) listed hypernatremia, but any time after 2003, he’s undoubtedly full of bovine feces, as CTCAE v.3.0 does list hypernatremia, as does CTCAE v.4.0.
Isn’t this enough?
I’ve written time and time again about what I call the central mysteries of the Burzynski saga. The first mystery is why the Texas Medical Board hasn’t been able to shut him down, despite over 30 years of trying. That’s the easier mystery to explain. The Texas Medical Board is a paper tiger, intentionally weak to protect doctors’ business interests. The second central mystery is why the FDA has let Burzynski get away with so many violations with respect to clinical trials. We know why he was allowed to register those clinical trials in the first place. Political pressure on the FDA from U.S. Representative Joe Barton and other woo-loving heavy hitters in the 1990s saw to him being able to register 72 phase 2 clinical trials, but what’s allowed those trials to remain registered, and why on earth did the FDA ever approve Burzynski’s one and only phase 3 clinical trial back in 2009, a trial that never accrued a single patient before closing?
The great thing about the USA TODAY story is that it is likely to be the most widely-read detailed story about Burzynski ever published, given how large the circulation of USA TODAY is, and it was a front-page story. As good as it was, it doesn’t have all the answers. The first step is shutting Burzynski down, but that’s not enough. We need to know what’s wrong with the FDA that allowed Burzynski (mostly) free rein for so many years, and we need to fix it.