Will public pressure impair drug quality?
By Jill Bederoff
The world is on hold. Never before has there been such a yearning for the pharmaceutical industry to come to the rescue. This has put both scientists and regulatory agencies under enormous pressure to quickly produce a treatment of a vaccine against the dreaded Coronavirus. But this means that there is a risk that quality will suffer.
In a recent article in the scientific journal Science, the scientists Alex John London of the Carnegie Mellon University in the USA and Jonathan Kimmelman of the McGill University in Canada warn against fast-tracked research in the wake of the pandemic.
“Crises are no excuse for lowering scientific standards”, the scientists argue.
In the article, they highlight the intrinsic conflict at present between the expectations from society for quick results, and scientific research, which is a careful, systematic and slow process by nature.
The scientists have noted that there has been a large number of applications for new clinical studies for treatments of or vaccines against COVID-19, and are seeing certain potential problems with the quality requirements.
“Early phase studies have been launched before completion of investigations that would normally be required to warrant further development of the intervention, and treatment trials have used research strategies that are easy to implement but unlikely to yield unbiased effect estimates. Numerous trials investigating similar hypotheses risk duplication of effort, and droves of research papers have been rushed to preprint servers, essentially outsourcing peer review to practicing physicians and journalists.”
To some extent, the FDA’s actions have added to their concerns. In early March, the U.S. Food and Drug Administration approved antibody tests for COVID-19 without having validated their reliability, which raised many eyebrows. After the shortcomings of the tests had become obvious, and the storm of criticism against the agency had grown, the FDA announced that companies that sell antibody tests will need to submit data within 10 days or the product will be banned.
The pressure on the FDA is not becoming any lower by the U.S. President, Donald Trump, speaking publicly in favour of the malaria medicine hydroxychloroquine as a miracle drug, and revealing to a shocked press corps that he has been taking the medicine himself for a few weeks as a preventative measure.
The FDA, which by the end of April gave hydroxychloroquine a so-called EUA, emergency use authorisation, recently felt compelled to publicly warn against non-hospital treatments or in a clinical study against the backdrop of the risks of heart side effects.
The main question for regulators is how much evidence on safety and efficacy they will need to have to approve early, and how much greater uncertainty in this pandemic situation we are prepared to accept, compared with a non-pandemic situation, Thomas Lönngren, Strategic Advisor for NDA Group and former Executive Director at EMA, reasons.
“Getting this right will be crucial. Such assessment must be based not only on strict criteria on safety and efficacy but also epidemiologic considerations on how to best manage the pandemic.”
Most of the therapeutics in development are repurposing of old drugs or drugs in clinical development for other indications.
“For these drugs there is already pre-clinical and, in some cases, clinical data available that could be extrapolated and used for treatment of COVID-19. From a regulatory point of view, conditional approvals based on strong phase 2 data could be an option followed by confirmatory phase 3 studies and post authorisation safety and effective studies”, Thomas Lönngren says.
Christoph Varenhorst, Country Medical Director for Pfizer Sweden, argues that the concern for impaired quality of clinical research or reduced official requirements in the wake of the corona crisis should be taken seriously, but still plays down the risks.
“We can feel safe about public agencies’ assessments and the process being well-regulated, and to us, patient safety always has the highest priority”,Christoph Varenhorst, Country Medical Director for Pfizer Sweden
Neither Dag Larsson, Senior Policy Advisor at the Swedish Association of the Pharmaceutical Industry (Läkemedelsindustriföreningen, LIF), has noticed any signals that there is reason for such concern
“There are high expectations from society, and it’s important to be observant that there won’t be any shifts. But we need to believe that our authorities will be consistent in their interpretations of the evidence that is being presented for a formal approval of a new medicine or vaccine.”
On the other hand, there is a risk of a shift concerning the use for new indications of medicines that have already been approved, so-called off label use, Dag Larsson argues.
“One thing is how the Medical Products Agency or the EMA values and interprets the evidence, but then, healthcare experts could interpret it differently. With hydroxychloroquine, for example, you don’t need to go through a regulatory agency to decide whether it’s a good medicine or not, since there is such a thing as the so-called right of prescription for use beyond approved indications. We don’t have the same rigorous system for handling evidence there”.
“There’s a risk here”, he repeats, “that you have access to an existing product from a poorly designed clinical study with half-baked results and take it to clinical use for a new indication”.
He also mentions other accessible routes to using medicines that have not yet been approved. One such thing is the emergency access licence that the Swedish Medical Products Agency (Läkemedelsverket) has recently issued for remdesivir, and compassionate use, which means that treatment is allowed outside of a clinical study during the regulatory process.
Christoph Varenhorst emphasises that, considering the serious emergency situation that the world is in right now due to COVID-19, it is important that development proceeds fast. It has occurred to him that the collaboration to find possible solutions and remove all unnecessary lead times between academies, agencies and companies has reached a completely new level during the crisis.
“The collaboration has contributed to enabling the process around the development of new therapies to become more efficient. Accessibility to the agencies for advice and support, but also reprioritisation, goes above and beyond what is normal”.
Examples of that include the agencies’ quick assessment of changes to clinical trials such as home deliveries of medicines for studies, or monitoring them remotely, but also the fact that a company such as Pfizer is making the tools that are being developed accessible to all through an open-source platform in real time.
“Since we don’t have all knowledge about the virus, many people are working to develop call-based analyses, viral screening, serologic analyses and translational models to test potential treatments and vaccines. By sharing not only our success but also our failures, we can help avoiding double work and speed up processes”, Christoph Varenhorst says.