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Isn’t it time to take a fresh look at the FDA?

Of the various drug review divisions within the FDA, the Office of Hematology and Oncology Products is the fastest, most productive and most efficient. Its dismal performance in approving and monitoring  myeloproliferative neoplasm drugs is thus doubly disturbing. Hopefully this Report Card can help open a dialog on how we can assist the agency in its vital work of providing safe and effective drugs to  patients suffering from  MPNs.

Notes to report card:

Overall, the MPN FDA group* failed Effective Performance through unexplained lapses in safety monitoring (Sanofi’s federatinib), abrupt closure of a trial causing unnecessary harm to patients (CTI’s pacritinib) and failure to facilitate approval of MPN drugs demonstrated to be effective to a large subset of MPN patients.

The MPN FDA group failed Productivity tests. Although not responsible for drug research and development, only one new MPN drug was approved in the past five years and only two in the past 19 years. Two main drugs used for treatment of MPNs – hydroxyurea and interferon – still have to be prescribed by physicians off label despite decades of documented clinical use.

The most compelling productivity negative was the FDA’s failure to manage the end stages of clinical trial. The last two MPN drugs to reach Phase III, one in 2013 and one in 2016,  were terminated near the very end of their long and costly trial periods. Both Sponsors withdrew their New Drug Applications. Many believe the Sanofi drug was effective and with closer monitoring of thiamine levels could easily have been added to the bare MPN medicine chest. The pacritinib clinical hold is still shrouded in mystery.

The MPN FDA group failed to provide adequate Safety monitoring by permitting on-going use of a drug that resulted in death and injury to clinical trial patients despite data identifying Wernicke’s encephalopathy reported several months before the Sponsor terminated the trial. The FDA spokesman would not comment on whether the FDA was aware of the safety hazard and took no action or was not aware of the several Severe Adverse Effect incidents.  Either way, patient safety in this trial was compromised. FDA’s actions, in the pacritinib clinical trial, subjected MF patients, without public justification or prior consultation with on site physicians, to intense impacts of abrupt JAK inhibitor withdrawal.

This FDA response to the question of safety in MPN trials suggests a vigilance not readily apparent in the Sanofi fedratinib trial.

“To help protect the rights and welfare of research volunteers and verify the quality and integrity of data submitted for review, FDA staff meet with researchers and perform inspections of a wide variety of stakeholders involved with clinical research to include clinical trial study sites (domestic and international), sponsors, manufacturers, institutional review boards, and others as needed. …  In addition to the inspections conducted by the FDA, the FDA also monitors incoming safety reports during the conduct of a clinical investigation in order to identify trends or unique cases that might raise new concerns not appreciated during the original review of the protocol…..”

The MPN FDA group demonstrated equivocal Trustworthiness by refusing two Freedom of Information Act requests and providing inadequate communications fostering a lack of transparency and trust. FDA routinely communicates its reasons for terminating a trial by citing Trade Secrets and Privacy regulations and referring to Sponsor press releases that clarify nothing. Patient and media requests are routinely deflected by staffers.

There are times we need to pull away from the personal, medical aspect of our own MPNs and consider the regulatory forces that impact our health.

The absence of any new MPN drugs is one indication this is such a time. The abrupt back-to-back conclusion of two highly touted JAK inhibitors at the very end of their long clinical trial cycles is another.

The FDA is the primary regulatory US body charged with overseeing the effectiveness and safety of new medicines.

The FDA is not responsible for drug research and development but can facilitate, obstruct or end the drug approval process.  Where are all the promised new drugs? What is the FDA doing to help expedite the process. 

Where are all the missing reports of clinical trial outcomes? 

Fewer than 8% of commercial organizations, and only 29% of clinical trials led by US academic institutions, have published results within two years of study completion even though FDA regulations require such publication within 12 months of study completion. As a result there is unnecessary repetition of studies (requiring patient blood and suffering, wasted research time and money) and unshared results on toxicities and effectiveness. Shouldn’t the FDA be doing something to improve this record?  

When asked directly if the FDA had ever taken any action against any clinical trial Sponsor for not publishing trial results  as required by law, the FDA responded:

“Since passage of Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA), FDA has had certain implementation and compliance/enforcement responsibilities related to ClinicalTrials.gov. FDA continues to review records of “applicable clinical trials” and pursuing individual responsible parties, as appropriate, …. Without a final regulation to support full regulatory activities, full compliance/enforcement activities cannot be finalized. “

Can you translate that?   It seems to be an admission of sorts. The FDA has “certain implementation and compliance/enforcement responsibilities.” Still, nine years after passage of the law requiring publication of clinical trial data, the FDA’s hands are tied  by lack of “final regulation.”  What’s the hold-up? Who’s responsible for delaying a implementation of a vital piece of legislation for nearly a decade?  Who is the FDA pursuing?  Has anything at all been done to free up the data gleaned from our suffering through years of clinical trials?  Have other investigators seen any data to help avoid duplication, to learn from the past?  What has the FDA actually done under its compliance/enforcement responsibilities?

Given this kind of bureaucratic response, it’s not surprising that Sponsors of clinical trials simply ignore the requirement to report results.

Why is the FDA so close-mouthed and inaccessible to patients and hematologists? Why is there such a lack of transparency and inclusion at the agency?

• * So far as we know, there is no actual MPN  FDA group. A relatively large group of oncologists and staff headed by Dr. Richard Pazdur, director of the Office of Hematology and Oncology Products within the Center for Drug Evaluation and Research  has the ultimate responsibility to shepherd new oncology drugs through the clinical trial system, providing oversight and, when appropriate, approvals. And although his group is not charged with public communication of risk/benefits and sharing of results — as required by law — we trust his staff will take these concerns into account and forward this Report to the appropriate department.

The FDA is an agency of the Health and Human Services Department (HHS) which has published proposals to enhance transparency of clinical trial results.  The FDA’s failure to enforce timely reporting of Clinical Trial results — and actively resisting appeals to release such results — is inconsistent with those objectives.

• HHS values the public’s participation in clinical trials and the knowledge gained by their participation; considers it an obligation to support the maximal use of this knowledge for the greatest benefit to human health; and strongly supports sharing of clinical trial data in a manner that both protects participant privacy, and allows the broader scientific research community to validate and build upon initial clinical trial findings.

-ZS

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