The FDA’s Guidance on Conduct of Clinical Trials of Medical Products during the COVID-19 Public Health Emergency, last updated on June 3, contains non-binding recommendations for industry, investigators, and institutional review boards. The recommendations are intended to assure participant safety, maintain good clinical practice, and lessen risks to trial integrity. Examples of challenges research now faces include “quarantines, site closures, travel limitations,” infected site personnel or subjects, and supply-chain interruptions. The Appendix to the Guidance offers answers to 23 common questions ranging from, “Submitting changes to IND and IDE protocol,” “Capturing data on protocol and process deviations,” and “Alternative monitoring approaches” to “Remote performance and clinician-reported outcomes” and “Challenges and temporary waivers for eCTDs.”
The Regulatory Affairs Professionals Society took a world-wide look at regulation in the time of COVID-19 in a June 15 article. They note that the “pandemic has disrupted clinical trials globally and has resulted in a 65% worldwide decrease in new patient enrollment year-over-year during March 2020.” Discussing the CTAP, “which combines elements of multiple existing review pathways,” the website Agency IQ is cited to the effect that of the 50-plus available regulatory pathways, 22 are “most likely” to be used under the program.
International and Public-Private Cooperation and Coordination
The Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) consortium of NIH, FDA, CDC, HHS, the European Medicines Agency (EMA), and “16 biopharma companies…represents an unprecedented collaborative framework between industry and regulators to support and prioritize the global development of therapeutics and vaccine for COVID-19.” Along with others, EMA is stressing that evaluation of whether a protocol amendment is “substantial” should not be determined by sponsors and that “While study visits may be converted to phone or video visits, a transition to remote source data verification (SDV) will be considered to be a substantial amendment.”
And if re-consent is needed, it may be given by phone or videocalls with a confirming e-mail. The Medicines and Healthcare products Regulatory Agency (MHRA) opines that substituting a phone call for an in-person visit is not “a serious breach of protocol.” MHRA and FDA have both stressed that the reasons for protocol deviations (PDs) be documented. In India, the CDSCO is freezing research approvals excepting COVID-19 trials, while the ICMR guidelines allow text or email consent and virtual ethics committee meetings.
FDA Under Pressure: Rapid Development and Politicization?
A June 10 piece re-published by the nonprofit Boston broadcaster WGBH examines whether pressure for COVID-19 drugs could be leading to lower standards at the FDA. The article is by Dr. Leigh Turner, who is a professor at the University of Minnesota whose work focuses on bioethics, pharmaceutical care, and public health. He notes that the combined illness, death, and social and economic semi-crises caused by COVID-19 make our efforts to combat the virus especially urgent. Given the recent withdrawal of the EUA for HCQ, the question of integrity at FDA is especially important.
In this new context, “standards appear to be dropping at a time when rigorous regulatory review and robust oversight are crucial.” An example is the FDA’s EUA for chloroquine phosphate and hydroxychloroquine despite known safety concerns and paltry evidence that they work. Key problems include political and otherwise inappropriate pressure to allow EUAs and “an overwhelming surge of clinical trials,” potentially overwhelming the FDA’s “capacity to carefully scrutinize them” prior to use by the public. Turner compares the eight-year average for drugs to go from “initial authorization of clinical trials to FDA approval” to the 24-hour turnaround for clinical study protocols now touted as common by the FDA. The agency set up the Coronavirus Treatment Acceleration Program (CTAP) to expedite review processes and cut bureaucratic red tape. But the FDA has kept CTAP opaque as to the who, what, and why of its decision-making process. Specific concerns include recent approval of a stem cell product for COVID-19 investigation despite the absence of a control group. Other problems are small sample sizes, overlap with other studies, and “poor study design.” WGBN also argues that President Trump’s “boosterism” for certain drugs undermines FDA’s independence.
Politico Points out Problems with Rushed Vaccine EUAs
Along those lines, a June 15 article from the liberal-leaning Politico offers a detailed look at how White House pressure for a vaccine may be a problem. While President Trump has “promised that there will be a coronavirus vaccine before the year is out,” experts are worried that an EUA may be granted for a vaccine before we know that it works. If that happens, there may be millions of doses available outside the trial setting, making recruitment for ongoing trials harder and possibly pushing aside other, maybe better, candidates. Politico cites Ezekiel Emanuel, “chair of the department of medical ethics and health policy at University of Pennsylvania and health adviser to Democratic presidential candidate Joe Biden,” from a recent a New York Times opinion piece: Emanuel is worried that the Trump administration may authorize a vaccine as an “October Surprise” to help win reelection.
More on the October Vaccine Surprise
Notably, Jeffries equities analyst Jared Holtz recently commented in an interview, “We believe the FDA will likely approve at least one vaccine prior to the November election.” He continued, “Perhaps multiple vaccines could get the go-ahead at some point early in the fourth quarter and quell fears of a second wave of COVID-19.” In Operation Warp Speed, President Trump declared a vaccine would be approved by January 2021.
Another Point of View
On the other hand, COVID-19 has completely turned the U.S. upside down and hence, efforts to aggressively drive progress could be just as easily considered rational and reasonable given the circumstances. Already, societies and their economies around the world are subjected to unprecedented pressures that would trigger an aggressive response in any governing body. So the pressures to approve; to progress; and to expedite all make sense, and given the context and circumstances, could be considered rational responses. However, patient health must represent the primary objective regardless, and hence any associated risks, emergency, or expedited programs must be thoroughly and systematically understood and disclosed. This requires informed and educated healthcare consumers.