There is an extraordinary amount of public interest in the development of drugs, biologics and vaccines for COVID-19. But just as companies are trying to generate evidence about the safety or efficacy of their products, that same public interest threatens to hurt their ability to collect it—and may even trigger scrutiny by regulators.
By Aaron Badida, JD
Executive IQ Brief
- How Things Work Now: Although the FDA generally doesn’t regulate when and how clinical trial results can be reported, the careful release of that data is important. Premature release of partial study results could introduce bias into the study, such as by causing different behaviors by clinical staff or enrolled patients. These confounding factors could cause the FDA to consider trial data to be invalid or unreliable, causing it to reject a company’s application for approval or requiring further study. As a result, most companies carefully restrict access to interim data, and only release study results once all data has been collected and analyzed.
- What’s New: The market for drug and vaccine development for COVID-19 is extraordinarily crowded. Some reports estimate that more than 200 drugs and vaccines are in the running, with nearly 20 in clinical trials. Already, some trial data about study results is being leaked, causing concerns about the integrity of ongoing clinical studies. The leaks are also resulting in attention from regulators, including the Securities and Exchange Commission (SEC).
- What’s Next: This is unlikely to be the last time decontextualized results of an early trial phase leak to the public. COVID-19 has put immense pressure on the government and industry, while the public desperately awaits the development of an effective treatment or cure. Trial sponsors need to stay vigilant and selective about the administration of clinical trials to ensure that data—even in the aggregate—is reported responsibly and in the proper settings with sufficient context that accurately depicts efficacy. They will also need to anticipate the potential for data to leak and have plans in place to communicate the context of that data to the public, and to understand the potential effects the leak might have on ongoing studies.
Before initiating a clinical trial, drug sponsors are required to submit the protocols they intend to follow as part of their Investigational New Drug (IND) application to the FDA. Typically, these protocols lay out the study’s design, including randomization, appropriate controls, and study participation.
A study’s protocol is intended to ensure that data generated are valid, or mitigate the impact of bias or confounding variables. The FDA’s requirements for study protocols are outlined at 21 CFR 312, which defines the critical phases and guiding principles that are required for study design and data generation. The regulations require that the study must be well-controlled, scientifically valid and closely monitored in order for the data to be considered reliable evidence on which to base agency approval.
The FDA administers the Bioresearch Monitoring Program, better known as BIMO. Under this program, the FDA inspects and investigates clinical trial sites to ensure compliance with protocols and that data is being collected in a reliable way. The agency reports that more than 1,000 inspections are carried out annually under this program.
The vast majority of major pharmaceutical companies are publicly traded firms. That means the regulations that ensure good science are often operating in conjunction and alongside the regulations that oversee fair trading and valuation.
In order not to fall afoul of these regulations when announcing new drugs in development or another activity that represent an investment opportunity (or return on investment), drug developers often utilize “forward-looking statements.” This language, defined in the Private Securities Litigation Reform Act of 1995 (“Securities Act”) at 15 U.S.C. § 78u–5(i)(1), are statements about economic or financial performance projections, including the “assumptions underlying them” that accompany company press releases. The law further requires these statements to be accompanied by “cautionary statements” so as not to unethically induce investment in the company.
Although the FDA requirements for dissemination of information from clinical trials generally don’t specifically govern when and how results can be reported, the careful release of that data is important. Premature release of partial study results could introduce bias into the study results, such as by causing different behaviors by clinical staff or enrolled patients. These confounding factors could cause the FDA to consider trial data to be invalid or unreliable, causing it to reject a company’s application for approval or requiring further study.
As a result, most companies carefully restrict access to interim data, and only release study results once all data has been collected and analyzed.
Even the tightest clinical protocol is subject to misinterpretation, as good data collection does not always translate into responsible data reporting. Therefore, clinical protocols typically have multiple endpoints to determine safety and efficacy, all of which are processed with validated statistical analytical methods and controls.
Similarly, the Securities and Exchange Commission (SEC), the government entity that oversees the publicly traded markets, seeks to ensure that financial projections and investments aren’t affected by unsubstantiated claims. Because the standards for data generation and validation in clinical trials is so high, and requires such tightly controlled data, drug approval carries significant weight for public investors.
As a policy, the Securities Act and other laws seek to strike a balance between free speech and ensuring that information that can affect investment decision is accurate. Ensuring the security of data generated during testing of a drug is one way to protect consumers from noncontextualized, and potentially misleading, efficacy data that could impact financial decisions.
The market for drug and vaccine development for COVID-19 is extraordinarily crowded. Some reports estimate that more than 200 drugs and vaccines are currently in development, with nearly 20 in clinical trials. The first-to-market product will have a significant advantage over other later products, including in public discourse.
Gilead Sciences’ remdesivir may be an instructive case for what drug companies can expect from regulators in the financial and clinical trial sectors. Because the drug was already in advanced testing for another indication before COVID-19 emerged, the drug and company are relatively far along in the development and production process compared to other companies and drug candidates. The company also has a long history of successful drug development for other viral conditions, including HIV and Hepatitis C.
On April 16, 2020, the healthcare media company STAT reported on a video of a Clinical Site Director at the University of Chicago outlining the drug’s apparent efficacy in patients enrolled at the clinical study site. In that video, the individual makes several claims that could, without context, indicate evidence of the drug’s efficacy—including a statement that only two of the 125 study enrollees had died from COVID-19. By the next day, Gilead’s stock value jumped approximately 10 percent, leading Representative Lloyd Doggett (D-TX-35) to call for an SEC inquiry into the situation.
Gilead quickly released a statement, maintaining that the “totality of the data [needs] to be analyzed in order to draw any conclusions from the trial. Anecdotal reports, while encouraging, do not provide the statistical power necessary to determine the safety and efficacy profile of remdesivir as a treatment for COVID-19.”
“Gilead had nothing to do with the information sourced by STAT from an internal recording out of the University of Chicago hospital,” company spokesperson Chris Ridley said in a statement to CNN.
Given the enormous public interest in potential treatments for COVID-19, the leak of trial-related information that is normally closely held is unlikely to be a one-off occurrence.
As a larger number of clinical staff, institutional review board staff, data monitoring committee staff and others work from home, it could be especially difficult to prevent those staff from surreptitiously recording meetings or copying key findings.
Companies will need to consider several key implications.
First, the leak of that data could have a major impact on their ability to successfully complete a trial. The leak of positive data might skew attempts to randomize the data, or could lead to investigators at other sites becoming biased toward how they report results. Negative interim results could also skew a trial, causing additional patients to not consent to treatment or doctors not to enroll their patients.
These concerns could harm not only the clinical trial, but also the chances of a drug obtaining a favorable review decision from the FDA.
They might also trigger reviews by the SEC. Public perception about the efficacy of a drug could have major implications for a company, both positive and negative. The early release of interim data could be considered forward-looking statements under the purview of the Securities Act.
It seems likely that pressure on both companies and regulators will increase in the coming months. Many of the drug candidates now in early-stage testing for COVID-19 will be entering Phase II or III studies by the end of the year, and there will be considerably more public scrutiny of those products by that time.
It’s also just as likely that public health officials themselves may be to blame for accidental leaks. For example, the World Health Organization (WHO) accidentally leaked information about the performance of remdesivir in a trial in China, STAT reported.
This is unlikely to be the last time decontextualized results of an early phase trial for COVID-19 products makes headlines and impact the stock market. The pandemic has put immense pressure on the government and industry, while the public desperately awaits for science to deliver a solution. Trial sponsors will need to stay vigilant about the potential for data to leak and what it could mean for their long-term prospects.