This essay explains some major issues involved in drug research and development as they relate to the COVID-19 pandemic. I have lectured on drug development at a medical school for almost 15 years and I want to contribute some basic information that may prove helpful for others.
Note that these are my own thoughts and not attributable to any organization or institution. I simply want to draw your attention to some basic facts. Facts matter because we cannot negotiate with a virus.
I will be as concise as possible to foster understanding and gloss over the finer points of the debates in this area. As events unfold, I will add to this discussion.
One of the most urgent challenges is to fight the temptation to recommend or approve pharmaceuticals and medical tests before they have undergone proper evaluations to ensure that they are safe and effective.
For medical tests, which are regulated as medical devices, that means that they are safe for humans to undergo and that they consistently provide accurate results. A test that provides too many false negative or false positives is not an effective test and can cause great patient harm.
A key point here is that the marketplace is not a good environment in which to test such products. People are injured or die from products that have not been properly vetted. So before products are allowed to compete in the marketplace, they must prove their worth first.
FDA is not inherently a political entity. It was established to ensure that biomedical product manufacturers marketed products that were safe for human use and were effective in treating, testing or assessing patients.
However, the products that FDA regulates are often highly politicized and that is where problems arise. Up until the COVID-19 pandemic, the most obvious examples of highly politicized products involved stem cells and birth control products. These products continue to be caught up in our culture wars.
Unlike the products fought over in the culture wars, the war against COVID-19 has been politicized over the issues of data and patience. There are powerful pressures to find COVID-19 treatments because they would lay a firm basis for reopening the economy. If we can treat the disease then it becomes more like other diseases that we suffer from now.
FDA is being drawn into the political arena as the Trump Administration wants to show progress in dealing with COVID-19. The pressure to act quickly builds with each passing day.
FDA’s primary job is to ensure that manufacturers do not make unjustified health claims about their products. At the same time, FDA is also acutely aware that unnecessary delays in allowing products into the market cause harm as well.
Consequently, the process through which FDA approves products for the market is more than a bureaucratic exercise. The way the agency approves a product is by requiring clinical trials for new products or for new health claims for existing products.
If a manufacturer wants to put a health claim on a product label or in its marketing material and sell it, the company first has to prove that claim to FDA’s satisfaction.
THE CLINICAL TRIAL STRUCTURE
The clinical trial structure is the way to prove that products are safe and effective to FDA.
FDA generally describes the clinical trial process in this way:
- PHASE I TRIALS: Researchers test a drug in a small group of human subjects for the first time. Researchers evaluate the treatment’s safety, determine a safe dosage range, and identify side effects.
- PHASE II TRIALS: The drug is given to a larger group of human subjects to test its effectiveness and to further evaluate its safety.
- PHASE III TRIALS: The drug is given to large groups of human subjects. Researchers confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect data that will allow the drug to be used safely.
- PHASE IV TRIALS: Post-marketing studies are conducted after FDA approves the product to obtain additional information including the risks, benefits, and best use.
Medical tests and diagnostics tools go through a similar regimen as drugs to evaluate safety and efficacy.
At this time in the pandemic, we are most concerned about Phase II and Phase III trials.
Existing products are also of intense interest because they have at least been proven to be relatively safe for human consumption. The important thing to remember, though, is that existing products are not necessarily safe for all patients. These products were designed and approved to treat people with specific conditions or symptoms and not for the general population.
News now has broken that a clinical trial demonstrated that remdesivir may curb the effects of COVID-19. That is indeed good news and a movement in the right direction. However, the results, while “clear cut,” are still tentative.
Nevertheless, FDA is expected to approve the product on an “emergency use” basis. But many experts say that the results are only preliminary.
And even if remdesivir proves to be an effective treatment, it is only one limited tool and will not be enough to start relaxing pandemic precautions, such as physical distancing and mask wearing in the near term.
The great fear is that this bit of good news will weaken the public’s patience with these precautions and prolong the pandemic by forcing policymakers to prematurely relax these safety and health protocols.
A significant controversy surrounds actions by President Trump in touting Hydroxychloroquine and Chloroquine as potential treatments for COVID-19. This was dangerous. These two products were designed and proven to treat lupus, rheumatoid arthritis and malaria. They were not proven to treat COVID-19.
Such actions present significant dangers because FDA does not regulate doctors. It only regulates biomedical product manufacturers. This is important, but it requires a little explanation.
Doctors are free to prescribe any drug or medical device based on their experience and knowledge (and their fears of malpractice suits). But often, they prescribe products at the insistence of their patients, which is one reason why drug companies spend so much money on direct-to-consumer advertising. And it is one reason why ill-considered statements from politicians are dangerous to public health.
When doctors prescribe drugs for purposes not included on the FDA-approved label, that use is called “off-label” use. This is not uncommon in the practice of healthcare, but it is still a gray area in the world of pharmaceutical R&D and sales.
In normal times, this kind of practice often raises concerns among consumer groups and some regulators. The worry is that drug companies may try to convince doctors to prescribe their products for conditions or symptoms not on the label. In other words, off-label use can be abused by enabling drug companies to avoid spending the time and money to conduct proper testing for the new use of the drug.
This can turn patients into de facto research subjects.
When the leader of the federal government recommends the off-label use of a product without any evidence of its effectiveness, it drives up the demand for that product. That was the case with Hydroxychloroquine and Chloroquine. Patients fearing COVID-19 demanded prescriptions for these products.
That meant that patients for whom Hydroxychloroquine and Chloroquine were designed were in danger of not having access to those drugs because of that demand for unproven uses for COVID-19.
The anxiety caused by the fear of a shortage was deep and real. Worse, it potentially made sufferers of lupus, rheumatoid arthritis and malaria even more vulnerable to COVID-19.
In other words, President Trump’s ill-advised trumpeting of Hydroxychloroquine and Chloroquine put patients with lupus, rheumatoid arthritis and malaria at risk by threatening their access to those drugs.
To put this into context:
- 1.5 million Americans have lupus.
- About 1.3 million Americans have rheumatoid arthritis.
- More than 225 million people around the world have malaria, but fortunately few Americans suffer from this disease.