Data Monitoring Committees in Clinical Trials: A Practical Perspective

Drs. Ellenberg, Fleming, and DeMets are individually and collectively to be congratulated for coauthoring a second edition of this must-read book about Data Monitoring Committees in Clinical Trials. I highly recommend this book and its new material. This book is essential for statisticians, clinicians, Pharma QA, clinical operations, data management, regulatory, senior management, CEO’s and many others to understand chartering, and operation of the Data and Safety Monitoring Board (DSMB). Likewise, potential DSMB members will benefit from understanding how the DSMB operates. The authors added new material to each chapter and one new chapter on legal issues was added. The authors reference international regulatory guidance’s, and cite the FDA (2006), WHO (2005), and EMA (July 2005) guidance regarding DMC’s.

This edition of the book came out right before the pandemic while clinical trials are underway for development of drugs, diagnostics, medical devices, and vaccines to treat or prevent COVID19. While there is nothing good to be said about the pandemic, there are many remarkable good things about how collaboration among for profit (pharma) and numerous not-for-profit/public United States Government and international agencies such as NIAID, NIH, DoD, BARDA, FDA, WHO, etc., contributed to remarkable speed in developing and evaluating vaccines and drugs for the Emergency Use Authorization (EUA) and WHO Emergency Use Listing (EUL).

Below I provide citations to recent (2020, 2021) news articles that vividly exemplify issues discussed in the book. The need for anonymity of DSMB members, and protection of DSMB members from undue influence, arguably may be best exemplified by the politicization of the mRNA vaccine effectiveness (unknown at the time), prior to the 2020 Presidential election. Prior to the November election, in a presumably very optimistic press release, the CEO Of Pfizer, Dr. Bourla, stated that he expected the vaccine to work extremely well (Reuters 2020; Thomas 2020). At the time of Dr. Bourla’s public statements, only the DSMB monitoring the trial would have known about effectiveness. Shortly after the press release, Dr. Bourla in an open letter (CNN 2020) to investors and the public and separate news media interviews with Pfizer senior executives confirmed that the efficacy was not yet known, and the trial would proceed according as planned. Dr. Bourla’s open letter clearly described the “event driven” timing of the interim. There was concern among some Governors about the possibility of release of results and approval of a vaccine before the election. In response, Governor Newsom (October 2020) in California established the Scientific Safety Review workgroup to review the submission if there was any question about the basis for vaccine approval. The results were released on November 8–9. Exactly what, if any, pressure the DSMB members felt in this situation may never be known.

I’ll coin a term for the second example of DSMB that may be called the “mega DSMB.” This is not specifically discussed in the book, but occasionally the media reported about this mega DSMB. The principles for DSMBs described in the book appear to “scale up” for the mega-DSMB during the Vaccine Phase III leading to emergency use authorization. A common DSMB was created under Operation Warp Speed, presumably for a more efficient review process for the several vaccine Phase III clinical trials that resulted in Emergency Use Authorization. The mega DSMB was for Phase III trials from Moderna, J&J, and CureVac. Pfizer did not use the shared DSMB. The committee Chair Dr. Whitely was appointed by Dr. Fauci. The University of Alabama, in a news release (Hansen 2021) identified Dr. Whitely as the “eminence grise” for the DSMB. Dr Whitely published a paper with coauthors that include Dr. Ellenberg (Joffe 2021). The paper described the very thorough work of the DSMB members to evaluate several Vaccine Phase III, conducted in parallel. There is at least one presumably hyperbolic print media description of the Mega DSMB as a “Secret Powerful Panel” (Pradhan 2020a,b). The article reports that the DSMB not entirely accurately “has the power to halt a clinical trial or fast-track it.” The DSMB makes recommendations to the sponsor and does not have the specific authority to halt a trial or fast-track it. Perhaps the journalist would appreciate a copy of the book.

The third instance, November 30, 2021, of an E-DSMB (External DSMB) is the Merck antiviral drug Molnupiravir for treatment of Covid. The briefing book prepared by Merck/Ridgeback for the November 30, 2021 Antimicrobial Advisory Committee Division (AMDAC) to FDA review of the anti-viral drug Molnupiravir clearly stated that DSMB recommendation was discussed with the FDA before the sponsor stopped the trial (Merck, investor news 2021).

I offer specific though minor suggestions should there be a future revision of the book. There should be consideration of DMC members and support staff, for example, administrative assistants, maintaining the secrecy of trial results. Presumably the sponsor Non-Disclosure Agreement (NDA) or sponsor contract with DSMB members specifically addresses this. Otherwise, a seemingly mundane list of essential office equipment/services such as secure paper shredding, secure USB drives and disposal of secure papers or “wiping” or disposal of computer hard drives and general cybersecurity. There is always a possibility of inadvertent disclosures or results, again possibly addressed as in the preceding. For example, in the Fortune 500 corporate pharmaceutical company where I once worked, the company would occasionally warn employees not to read confidential/proprietary materials on an airplane, train, or bus where the seatmate or person sitting behind could see the output. The sponsor NDA may alert to other inadvertent disclosures, such as having lunch or dinner with another DMC member while diners at nearby tables can overhear the discussion. Some publicly traded companies have a black-out period during the conduct of an interim where all employees are forbidden from trading stock and from sharing internal corporate news about DSMB activities while a DSMB review is underway or about to occur. In the United States, the Securities Exchange Commission (SEC) does investigate unusual stock trades that occur with public announcement of trial results such as a DSMB recommendation, or other sponsor announcements to investors. SEC may request information from sponsor employees about knowledge of a DSMB meeting or trial results.

I encourage readers to purchase this book. During the pandemic there are other reports of DSMB activities, which often are briefly described on sponsor investor news, and subsequently in the press. There are additional and interesting examples of DSMB activities during the pandemic which the interested reader may find by perusing the sponsor investor news and by general internet searches.

Chris Barker
Statistical Planning and Analysis Services, Inc.