The drip, drip, drip, drip of FDA findings against Stanislaw Burzynski continues

The central mystery of Stanislaw Burzynski is how he keeps managing, no matter what is thrown at him by state and federal medical authorities, to keep on treating patients with deadly cancers. He’s like the Energizer Bunny; he just keeps going and going and going and going. Or maybe he’s like the game Whac-A-Mole™, where, as soon as one strategy seems on the verge of shutting him down he pops up elsewhere with another angle.

Burzynski, as regular readers know, is the Houston doctor (I refuse to call him a cancer doctor, because he has no formal training in oncology or even board certification in internal medicine) who for the last 36 years has been treating patients with compounds to which he refers as “antineoplastons” (ANPs) Back in the mid-1970s, he claimed to have discovered these compounds in the blood and urine and that they are the body’s natural defenses against cancer, inhibiting cancer growth. Thirty-six years later, and more than 15 years after starting six dozen clinical trials for the express purpose of bypassing a judge’s order that he could not administer ANPs to anyone who was not on an FDA-approved clinical trial. Indeed, it was a blatant ploy, as Burzynski’s lawyer, Richard Jaffe, acknowledged, referring to one of his clinical trials as a “joke” and the others as a way to make sure there was a constant supply of new cancer patients to the Burzynski Clinic. A decade and a half later, Burzynski has only completed one of those clinical trials and has not published the results of a single one. Most recently, he was presenting some clinical results at the Society of Neuro-Oncology meeting a couple of weeks ago, but he still hasn’t published a complete clinical trial. I rather suspect he never will.

Last month, Liz Szabo published an expose of the Burzynski Clinic for USA TODAY that detailed his many abuses of science, patients, and clinical trials. It was astounding. Not only did he misclassify tumor responses, fail to report adverse events properly, fail to provide proper informed consent, and charge enormous sums of money to patients on clinical trials as “case management” fees. She also described why all those anecdotes and testimonials provided by patients of Burzynski’s patients are not valid evidence that Burzynski’s treatments work. Even so, despite the negative publicity, Burzynski has still managed to line up more patients to try to pressure the FDA to grant compassionate use exemption for ANPs. The stories made me think that maybe we should rename Burzynski Dracula, given how much he sounds like Dracula and seemingly his clinic and its ANPs can’t be killed.

Maybe two more stakes will take care of it. A few hours ago, the FDA issued two more warning letters to the Burzynski Research Institute and Stanislaw Burzynski, as documented in USA TODAY last night:

In letters to Burzynski and his research institute posted online Wednesday, the FDA says that Burzynski inflated success rates for experimental drugs that he calls antineoplastons. The FDA also says Burzynski failed to report side effects and to prevent patients from repeatedly overdosing.

But when the FDA asked to see the child’s medical files, Burzynski sent the agency records that were different than those stored in his office, giving the appearance that the records had been altered, according to the warning.

D’oh! This part is worth quoting in full:

You have failed to maintain and retain accurate case histories as required in all cases of expanded access. Specifically, you failed to maintain and retain accurate case histories for Patient 022387, whom you treated under a Single Patient Protocol (individual patient expanded access), also referred to as a Special Protocol Exception, to Protocol BT-10.

In response to a (b)(6), FDA’s Division of Oncology Products 2 (DOP 2) requested that the sponsor, Burzynski Research Institute (BRI), provide DOP 2 with copies of the records for Patient 022387.

On (b)(6), BRI provided DOP 2 with copies of the following records for Patient 022387:

• Case Report Form titled “Physical Exam – Baseline,” for physical examination conducted on (b)(6)
• Case Report Form titled “Baseline Visit – Prior Cancer Treatment History”
• Case Report Form titled “Baseline Visit – Pathology History”
• Case Report Form titled “Adverse Events”

The records BRI submitted to FDA on (b)(6), were not in the files that you provided regarding Patient 022387 during the inspection. However, during the inspection, you provided other Case Report Forms for this patient, with the same titles and for the same visit date as noted above, but containing information that differed from that which BRI submitted to FDA. Notable differences are contained in the following tables.

(b)(6)

(b)(6)

(b)(6)

We recognize that the Form FDA 483 issued to you does not include this as an observation and, therefore, your written response did not address this issue.

Please explain why the Case Report Forms at your site for Patient 022387 differed from the Case Report Forms that Burzynski Research Institute submitted to FDA’s Division of Oncology Products 2.

Failure to maintain and retain accurate case histories raises concerns about subject safety and data integrity, as well as concerns about the adequacy of safeguards in place at your site to protect patients being treated under expanded access.

Yes, you read that right. The FDA investigators who visited the Burzynski Clinic and Burzynski Research Institute from January to March 2013 looked at the medical records of a child who suffered an adverse event. Then the FDA’s Division of Oncology Products asked for copies of the patient’s records. The copies provided to the DOP 2 didn’t match the copies that the investigators looked at. Is that suspicious? Hell, yes! Does it raise suspicions that the Burzynski Clinic tampered with patient records? Hell, yes, it does! Is there potentially an innocent explanation? Possibly, but this is Burzynski we’re talking about. It’s not as though he deserves the benefit of the doubt. In fact, he most certainly does not. Still not convinced. Then consider this. The patient in question here is Josia Cotto, the child who died of massive hypernatremia (elevated serum sodium levels) caused by antineoplaston treatment. Yes, the different sets of records were maintained on a child with a terminal brain tumor whose life was cut even shorter because Burzynski’s treatment killed him.

Much of the rest of the two letters addressed the FDA’s finding that the responses of the Burzynski Clinic to the original two warning letters from this year were inadequate. As I predicted when I discussed the Burzynski Clinic’s response to those clinics in detail, the FDA wasn’t buying what Burzynski was selling when it came to his excuses for his numerous violations of FDA regulations and regulations designed to protect the safety and rights of subjects participating in clinical trials. Truly, as I said, hilarity ensued. Unfortunately for Burzynski the FDA didn’t find his explanations funny at all.

As you might recall, Burzynski tried to justify his misclassification of responses to therapy by playing fast and loose with the guidelines for classifying responses as either complete responses (CR), partial responses (PR), stable disease (SD), or progressive disease (PD). A lot of what Burzynski tried to argue was that because the guidelines for determining response in brain tumors changed a few years ago in order to incorporate observations of whether the patient is on steroids while under treatment, and more importantly, whether that dose of steroids was stable, increasing, or decreasing, rather than looking only at pure tumor size on imaging studies. The FDA wouldn’t have any of it, and rightly so. For example:

We note that the examples cited above are consistent with two previously treated subjects from Protocol BT-10 and Protocol BT-22 (which had the same criteria as Protocol BT-10 regarding classification of Stable Disease). For Subject 005974 in Protocol BT-10, the Tumor Measurements CRF indicates, based on MRIs taken on January 12, 1999, and April 6, 1999, that the subject had less than 50% change in tumor size compared to baseline, and that this state was maintained for a minimum of 12 weeks. However, the Steroids Report CRF shows that the subject was not on either a stable or decreasing dose of corticosteroids. Therefore, the subject did not meet the criteria for Stable Disease.

And:

Your responses noted in the preceding paragraphs are inadequate. The protocols required specific consideration of corticosteroid use. In addition, the definition of “a patient off corticosteroids” that you stated you followed, was not included in any of the protocols listed above.

We acknowledge that the use of corticosteroids to maintain physiologic levels may be appropriate, despite protocol wording requiring that subjects be off corticosteroids completely for a Complete Response. However, for all of the subjects listed above as having been classified as a Complete Response despite being on corticosteroids, their corticosteroid doses were well beyond those needed to maintain physiologic levels. Specifically, these subjects were on doses of Decadron (dexamethasone, a corticosteroid) that ranged from 4 mg/day to 16 mg/day, while the physiologic-replacement equivalent of Decadron is in the range of 0.25 mg/day to 0.75 mg/day.

Any physicians out there will know that a dose of 16 mg/day of decadron is a fairly hefty dose. In fact, 16 mg/d is a typical dose for cerebral edema, otherwise known as brain swelling, which is the very reason why patients with brain tumors get steroids in the first place, to reduce swelling in response to the tumor. Usually, the dose is 10 mg as a first dose and then 4 mg every six hours until the cerebral edema subsides, usually within 24 hours, after which the dose is usually tapered over 2-4 days. For a patient to be on 16 mg/d of Decadron implies either the treatment of acute cerebral edema or a whopping chronic dose far above physiologic replacement levels. So, either the patients in question were undergoing treatment for acute cerebral edema or Burzynski had these patients on huge regular doses of steroids. This basically blows Burzynski’s tap dancing around the issue of his misclassifying various responses by claiming that patients were on stable or decreasing doses of steroids out of the water.

As for the rest of the FDA findings, in these two new FDA warning letters, it’s hard not to note that perhaps the most common phrases used are all variations of “Your written response noted above is not adequate.” This is understandable, of course, because, as I described last time, Burzynski’s explanations just weren’t convincing to anyone who knows anything about how clinical trials should be run. For example, the FDA noted that Burzynski did not provide adequate informed consent because the informed consent forms didn’t contain a statement regarding additional costs that patients might incur from participating in the research, other than vague generalities. More importantly, patients were only presented with a billing agreement after they had already consented to participate in Burzynski’s clinical trials. This is exactly backwards; the patients should know what expenses they might incur up front, before they sign anything related to the clinical trial.

Worse, even though the FDA didn’t mention it in these letters, it is generally the practice that patients shouldn’t have to pay for expenses incurred because of a clinical trial. Normal medical expenses related to standard-of-care treatment of their condition can be billed to third party payers, just like any other medical expense, but charges related only to the clinical trial (i.e., charges that the patient would not have otherwise incurred if he or she weren’t on the clinical trial) should be paid by the entity funding the clinical trial.

I could go on, but the specifics are laid out pretty clearly in the FDA letters. You don’t have to have a deep understanding of how clinical trials work to be able to understand why what Burzynski did was wrong and how it violated rules designed to protect patients who participate in clinical trials. The question you probably have (I know I do) is: What’s next? What can the FDA do at this point.

One thing that the FDA can do it’s already done. That’s to put a partial clinical hold on the research protocol in question or the institution carrying out the protocol. This is usually done to protect human life when regular investigative channels would be too slow. Indeed, this is exactly what the FDA nearly a year and a half ago in the wake of the death of a child, Josia Cotto, of hypernatremia (elevated sodium) due to ANPs. It put a partial clinical hold on ANPs, such that no new pediatric patients could be enrolled in Burzynski’s clinical trials, although existing patients could continue to receive the drug. This partial clinical hold was then extended to adults early this year. The FDA can even bring criminal prosecution, but that is rare. However, if there’s anyone who deserves an FDA criminal prosecution, it’s Stanislaw Burzynski.

Given how unresponsive Burzynski has been and how he hasn’t adequately moved to correct the violations noted by the FDA, the most obvious next thing the FDA can do is to move to disqualify Burzynski from conducting any more studies regulated by the FDA. It can also terminate an investigator’s IND (investigational new drug) application. Why the FDA hasn’t done either of these things yet with ANPs, I still can’t understand, but it hasn’t. We can only hope that this latest round of investigation and findings is the cattle prod that’s needed to get the FDA to act, but after 16 years or so I’m not holding my breath. Certainly, Burzynski qualifies as having “repeatedly or deliberately violated FDA regulations,” which could justify such an administrative action. He’s also arguably “deliberately submitted to FDA or to the sponsor false information in any required report.” Indeed, here are the grounds for revoking an IND:

(i) Human subjects would be exposed to an unreasonable and significant risk of illness or unjury.

(ii) The IND does not contain sufficient information required under 312.23 to assess the safety to subjects of the clinical investigations.

(iii) The methods, facilities, and controls used for the manufacturing, processing, and packing of the investigational drug are inadequate to establish and maintain appropriate standards of identity, strength, quality, and purity as needed for subject safety.

(iv) The clinical investigations are being conducted in a manner substantially different than that described in the protocols submitted in the IND.

(v) The drug is being promoted or distributed for commercial purposes not justified by the requirements of the investigation or permitted by 312.7.

(vi) The IND, or any amendment or report to the IND, contains an untrue statement of a material fact or omits material information required by this part.

(vii) The sponsor fails promptly to investigate and inform the Food and Drug Administration and all investigators of serious and unexpected adverse experiences in accordance with 312.32 or fails to make any other report required under this part.

(viii) The sponsor fails to submit an accurate annual report of the investigations in accordance with 312.33.

(ix) The sponsor fails to comply with any other applicable requirement of this part, part 50, or part 56.

(x) The IND has remained on inactive status for 5 years or more.

(xi) The sponsor fails to delay a proposed investigation under the IND or to suspend an ongoing investigation that has been placed on clinical hold under 312.42(b)(4).

Burzynski has arguably met several of the above conditions, specifically i, iv, v, vi, and vii. Yet his IND still stands. It would be one thing if these were the first violations. Federal regulations for FDA approval, the conduct of clinical trials, and human subjects protection can be complex, and even the best can sometimes stumble. Burzynski, however, is not the best, and this is far from the first time that he’s been found in violation of FDA regulations. In particular, he’s been dinged time and time again for a sloppily run institutional review board, as well as deficiencies reporting adverse events. FDA investigations and findings of violations are not a new thing for the Burzynski Research Institute. He’s had numerous warning letters since 2000. Yet, his IND for ANPs and his clinical trials continue to stand.

The issue that continues to haunt me is: How? Why? How does Burzynski continue to get away with it. As much as I’d like to think that these two new warning letters and the FDA’s resounding rejection of Burzynski’s lame excuses for his actions will finally—finally!—spell the end of the Burzynski saga, or at least of the saga of how he subverted and abused the clinical trials process, given that I fully expect Burzynski to bolt the country once his ANP operation is finally shut down once and for all, I’m under no illusion that they are. The FDA has been a paper tiger, guilty of gross dereliction of duty. Ever since powerful legislators like Joe Barton harassed the FDA for trying to do its job and shut Burzynski down in the 1990s, the FDA seems to have been once bitten, twice shy, failing utterly in its duty. I sincerely hope that this is indeed the beginning of the end of the FDA’s fear of Burzynski and his allies and, even more importantly, the beginning of the end of Burzynski’s abuse of clinical trials to enrich himself.