In a recent article in the WSJ, Dr. Scott Gottlieb, former head of FDA, described the landscape of potential treatments and preventative measures currently under development. The subtitle of the article was “Antivirals and antibody therapies are showing promise. The FDA needs to pick up its pace.” The article was advocating for moving the clinical trials and regulatory review forward even more quickly. In fact, he states, “it is worth doing whatever it takes to move such a drug to market.”
This is a laudable goal, within limits.
The role of the FDA is to protect the public health. This includes ensuring that all medicines are proven to be safe and effective before being made commercially available to patients. The regulation of medicines has been evolving for over 100 years. Almost all these regulations were created in response to a threat to public safety: Diethylene glycol poisoning, thalidomide babies, the emergence of AIDS. In addition, events like the holocaust led to the development of codes of ethical principles and regulations that protect the rights of individuals participating in clinical experiments.
COVID-19 is just the latest stress that will further shape the regulations.
So yes, there may be some red tape to cut and some focus brought to bear. However, completely upending regulatory or ethical principles or ignoring these lessons of the past is NOT the way to find what we need.
In fact, the regulatory system may not be the issue at all.
Crossing the Scientific Vacuum
The science that needs to be done to understand how the SARS-Cov-2 virus spreads and causes the disease COVID-19 is a huge hurdle. There is so much we do not know. Finding an intervention that frees us from this pandemic is even more challenging.
It is absolutely essential that we do not pick the winner in the fight against SARS-Cov-2 prematurely. We need to take many shots on goal. History shows that many great ideas will fail and that we need to keep trying.
Dr. Gottlieb described three approaches to attacking the virus responsible for COVID-19: vaccines, antivirals, and antibody-based drugs or biologics.
The long game – vaccines
Dr. Gottlieb only mentioned vaccines for prevention of infection with a short note that this will not be available this year. This is true but needs some context. We need to understand why it takes so long.
It takes 12-18 months to develop a vaccine because of the science required to show that it works. First, we need to assume we have a vaccine in hand (we don’t.) That experimental vaccine would then need to be shown to work in animal models, meaning that administering it would trigger the production of antibodies against the virus.
Antibodies are like smart missiles that only attack the very specific virus. Antibodies are one layer of the immune system uses to attack intruders like viruses. If the vaccine does not generate an antibody response, it won’t work, and we go back to square one.
If it does produce the antibody response in small animals (mice), it may need to be tested in larger mammals (mini-pigs, dogs) and maybe even non-human primates before moving into people.
Once we find a vaccine that does produce this antibody response, small safety studies will be done in people to rule out any immediate and glaring safety problems. Part of these studies will be to measure the production of SAR-Cov-2-specific antibodies in humans.
If successful, the sponsor (the ones funding the research) may decide to do a viral challenge study – a study in which people who have received the vaccine or a placebo are intentionally exposed to the virus and followed under extremely controlled conditions. This type of study would give us a very good indication of the potential for the vaccine to work in a relatively short period of time (a couple months). If it doesn’t work, we go back to square one.
As we have seen, this virus can be brutal, so a viral-challenge study would need to be done in a tightly controlled in-patient setting equipped to handle the worst. You can imagine the ethical dilemma of running such a study for a virus for which we have no proven effective rescue treatment.
Finally, when we are more confident that the vaccine is effective, we can launch a field trial. This clinical study would involve enrolling thousands of people to receive either the vaccine or placebo and be followed for an extended period to see whether the vaccine prevents people from getting the virus at a population level.
Proof is Evasive but Necessary
There are several challenges to completing such a vaccine study. Proving prevention is a difficult venture. How do you know that someone who doesn’t get sick would have gotten sick without the vaccine?
First, we do not know enough about the virus to predict what will happen in the future. There is a belief that it is seasonal and is likely to subside in the summer and return in the fall. That means we could not possibly run such a study until the new season, presumably in October or later.
Second, we do not know how long the season really lasts or if there will be another season. How long should people be followed? Will this year’s vaccine be effective next year?
Third, if we continue or return to physical distancing, then we may confound the experiment. On the other hand, if we let people go back to normal and the vaccine is ineffective, we could have a second pandemic.
None of these decisions or experiments are easy. There is serious risk involved. But an effective vaccine is our best hope for long-term control of this virus.
We need this work to continue.
Hope in the Current Treatment Pipeline
The second option that Dr. Gottlieb discusses are antiviral medications to treat the disease after someone is infected. There is great promise for remdesivir from Gilead Sciences. There have been anecdotes about this drug having some promising signs of efficacy against SARS-Cov-2. The advantage of looking at this one drug are that it has undergone significant work (years) to understand the safety profile and risks. Unfortunately, Gilead was unable to gain FDA approval for the initial use of this product, Ebola virus. It is still an unapproved, experimental compound.
As Dr. Anthony Fauci has repeatedly told us, promising signs do not equal proof.
Proof comes in the form of carefully controlled studies that demonstrate a real effect, a predictable response. The problem with treating widely based on anecdotes is that there are hundreds of examples of compounds people thought were going to work that failed. This creates a risk of treating people with something that may not work.
The sponsor, Gilead, has already had to curtail the supply of remdesivir for compassionate use, pre-approval access due to manufacturing capacity constraints. Here is a real opportunity for focus and acceleration. Moving into clinical studies of remdesivir in patients confirmed to have SARS-Cov-2 as quickly as possible will help us better understand whether this drug will work and will teach us a lot about the course of the disease. We need this work to continue.
But remdesivir is not the only antiviral being worked on. Several biopharmaceutical companies have begun looking at their libraries of experimental compounds looking for new approaches. It is critical that these other approaches continue to be studied. We need to have alternatives in the pipeline if remdesivir fails. We also need alternatives for those patients for whom remdesivir does not work or who do not tolerate it well. We must have a multi-pronged approach.
We need this work to continue.
The Antibody Strategy
The third option that Dr. Gottlieb discusses are antibodies. First, he gives basis of the theory of using antibodies in plasma from recovered patients. While this can be effective, it is not scalable. There just isn’t enough plasma for everyone who needs it. However, recombinant technology allows scientists to produce synthetic antibodies that may work.
Second, he talks about several antibody-based products that are likely to go into clinical trials this summer (Regeneron, Vir Biotechnology, Adaptive Biotech (Amgen), and Lilly). These are most likely small Phase 1 studies in healthy people to understand the doses needed and begin to understand the safety profile of these treatments.
As mentioned before, if the virus subsides it will be difficult to enroll a clinical study in patients, people with the disease, in the summer.
This will probably force companies to start their studies in the Southern Hemisphere (Australia, South Africa, South America) which brings its own logistical challenges. The first studies in patients (Phase 2) will be relatively small-scale just to test the theory. These will be followed by larger studies to confirm the efficacy and look for safety problems. Note that these larger trials could provide treatment for significant numbers of people, people willing to take the risk they get placebo.
Antibodies to Antibodies
Dr. Gottlieb states, “the drugs can move quickly because much of the science and the safety is already understood.” Even if he is correct, “much of the science” is not “all of the science.”
The real challenge with antibody products will come in manufacturing consistently at the needed scale, testing for the stability of the product in various conditions, understanding the impact of freezing and thawing (maybe repeatedly), and other practical matters. Stability studies tell us about the shelf-life of a product. If you want it to last 6 months, you need to show that the product does not change for at least six months of storage. If it needs to stay frozen, supply chains need to have adequate equipment. To keep it frozen.
Another challenge is the human body’s reaction to antibody-based drugs. Many promising biologic products have shown to be insufficiently effective because humans produce antibodies against them. This could be very important if COVID does become a seasonal disease.
As you can see, there is significant scientific study that needs to be completed before we have a permanent answer to the COVID-19 pandemic. No treatment and no vaccine have been proven to be effective yet.
FDA’s Pace is not the Big Issue
So, I begin to question the premise of the subtitle for Dr. Gottlieb’s article. Recall, the subtitle ended with “The FDA needs to step up its pace.” The FDA is not the issue here, at least not yet. The FDA does not do this science, they oversee and regulate it.
They protect public health by only allowing the use of drugs and biologics that have been proven to be safe and effective. But this oversight work requires many people, many highly educated people. The FDA needs to be adequately staffed to absorb this huge wave of new work. It would be short-sighted to simply redeploy existing medical reviewers and manufacturing experts to COVID-19 applications. Why? Because the work they were doing on treatments, cures, and prevention of other diseases will suffer. This work needs to continue.
Dr. Gottlieb suggests that the FDA could work faster if they began “to evaluate the data as it is read out from clinical trials, instead of waiting until the trial concludes.” This may be miswritten. I believe it would be more correct to say, “evaluate the data with the drug developers as they put together their applications for marketing approval.”
No one should be reviewing the efficacy data before the trial is completed. Doing so would compromise the trial data and likely call any approval into doubt. Nearly a century of developing anti-infective drugs has shown that these studies are vulnerable to bias, intentional or unintentional. Huge amounts of effort are put into protecting the “blind” so that the results of the trial can be considered free from such bias.
“Being a big fan” of a drug does not make it safe and effective. In fact, being a fan calls into question the veracity of the data and the conclusions. Companies have been fined many billions of dollars for making such ungrounded claims. It is against the law. Breaking the blind weakens the ability of a study to provide a reliable answer.
The profit motive and the public health stakes are too high. If we remove or weaken the requirement for proving medicines are safe and effective, we open the public up to the same dangerous risks that brought about the Food, Drug, and Cosmetic Act in the first place.
We Need This Work to Continue
In conclusion, I agree that we need to accelerate the development of drugs and vaccines to fight COVID-19. We need to be realistic about what can and cannot be accelerated. Lowering standards for safety, quality, and scientific rigor is not the answer.
Similarly, the way that the FDA reviews applications and regulates the industry should not be the target today. However, as more innovative solutions come forward, there is a real risk that the FDA will become a bottleneck. We have the opportunity to beef up the FDA ahead of the wave of new products to be processed.
And there is one more consideration. COVID-19 is not the only disease that is impacting lives. Three months ago, there was a thriving Research and Development industry investing around $100 Billion searching for treatments and cures for those other diseases. Those patients are still waiting.
We need to invest in them too.