In response to the most serious global health threat in a century, the world’s biomedical establishment is unleashing an unprecedented response to the Covid-19 pandemic, rapidly increasing resources aimed at finding safe and effective treatments for the disease. But without careful attention to the pitfalls that can befall biomedical research and regulatory decision-making during a time of crisis, a lot can go wrong.

On March 28, the FDA provided emergency use authorization for hydroxychloroquine — a medicine approved for treating malaria — for people hospitalized with Covid-19. It also however, told health providers that the optimal dose and duration of treatment were unknown. The authorization did not identify any clinical study on which this approval was based, and while hydroxychloroquine may affect viral replication and might ultimately prove beneficial, its impact on health outcomes among patients with Covid-19 is currently unclear.

Against this potentially worrisome action, the scope of the search for a new treatment to mitigate or cure Covid-19 is breathtaking. One recent listing identified more than 70 candidate molecules, including 15 antivirals, potent suppressants of the human immune system, and high-risk oncology treatments already approved by the FDA to treat other conditions.

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The National Institutes of Health’s ClinicalTrials.gov lists more than 100 clinical investigations focused on Covid-19 from around the world, with sponsors that include medical centers, pharmaceutical companies, and national research institutes. In time, it is likely we will see direct-acting antivirals tailored to the most vulnerable molecular targets on the SARS-CoV-2 virus.

But this extraordinary effort is lacking international coordination, which may yield counterproductive competition among countries with biotechnology industries. The coronavirus does not respect national boundaries; neither can the development of new treatments, which are already being tested in more than 15 countries. As a first step, the biomedical community needs to insist on consistent use of central registries of clinical studies and on early sharing of complete details of both successful and failed studies, and not withhold important scientific evidence as proprietary information.

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Acting against this effort is a growing industry fueled by fear and panic. Medical history has taught us that when people get sick and scared they will take practically anything. For centuries, worthless and sometimes harmful treatments, ranging from arsenic to swamp root, have been promoted by everyone from charlatans to well-meaning clinicians.

In an emergency situation such as this one, attention will naturally turn to repurposing already available products, which makes good sense. But we need to let scientists do their jobs. In too many past cases, drugs have been widely used off-label or based on a positive response in a narrow laboratory or clinical measure only to have independent analysis later show that the treatments do more harm than good or target the wrong patient population. For example, a family of anti-arrhythmic drugs that was effective in stopping asymptomatic irregular heartbeats was subsequently found to increase the risk of cardiac arrest when given to heart attack survivors.

The biomedical establishment must speak with a clear voice about the need to adequately test new drug treatments for Covid-19 and to subject that evidence to independent evaluation by the FDA.

Other pitfalls await those too ready to embrace a new treatment. One is the power of the placebo effect. Among individuals participating in clinical trials, those unaware they are receiving an inactive placebo can show substantial improvement, sometimes equal to 80% of the apparent treatment effect of the active therapy. The placebo effect has been documented in clinical trials assessing health benefits that range from improvement in subjective psychiatric symptoms to objective laboratory results.

Who has not read media reports about an individual’s miraculous recovery at the hands of a caring physician trying an entirely new approach to treatment? Independent investigation of the case confirms the striking improvement was real. But it turns out to be a dramatic example of idiosyncratic recoveries that can be neither explained nor duplicated in other patients.

The coming flood of research from trials now or soon to be underway should lead us toward realistic and objective measures of the two fundamental properties of every therapeutic drug: benefit and harm.

A drug that shows “disease activity” against SARS-CoV-2 could prove too toxic to give to Covid-19 patients with worsening pneumonia. A claim that a drug reduces “viral load” could be valid, but its health benefits or harms could depend on when in the cycle of infection it is used. A drug intended for those with mild-to-moderate symptoms but who are otherwise healthy must be of low toxicity because it will be given to many patients who might have otherwise recovered on their own, while it may be more acceptable to offer drugs with more severe toxicities to patients at higher risk of death.

Another fundamental aspect of all drug testing is encouraging when it comes to Covid-19 research. As the first antibiotics for pneumonia taught us in the 1930s, a dramatically effective treatment for an acute illness can be convincingly demonstrated in a small number of patients observed over a few weeks’ time. The chances of discovering and documenting such a treatment grow if we also greatly increase the number of patients enrolled in clinical studies.

In the 1980s, during the HIV epidemic, patient advocacy groups not only helped shape the way clinical trials of the disease were conducted but served as a strong force for recruiting patients into trials of investigational drugs. A broad network of trial participants helped accelerate testing of drugs in the pipeline.

In the case of pediatric cancer, a collaborative professional network was established decades ago to ensure that all patients are enrolled in clinical trials at the time of initial diagnosis. These patients then get top-quality care and generate data to help future patients.

Supported by these forces, it is not surprising that both HIV and pediatric cancer have seen remarkable advances in care over the last 30 years.

It is a false choice to think that we can either have expeditious treatment options for SARS-CoV-2 or we can have rigorous testing of them. We can have both. Achieving that goal, however, will require avoiding missteps such as widely promoting unproven products so fearful people begin using them in inconsistent ways outside of the research enterprise. Instead, we will need international coordination of scientific goals, transparency of results, comprehensive participation in clinical research, and trials that evaluate meaningful outcomes. Doing that can ensure that any treatments that are developed do, in fact, benefit the patients who receive them.

G. Caleb Alexander, M.D., is a professor of epidemiology and medicine at the Johns Hopkins Bloomberg School of Public Health. Aaron S. Kesselheim, M.D., is a professor of medicine at Brigham and Women’s Hospital and Harvard Medical School. Thomas J. Moore is a lecturer at George Washington University Milken Institute School of Public Health.

  • Robert,

    I am so glad you mentioned EIDD-2801. The most important point is that unlike remdesivir which can only be currently administered intravenously, this one is “orally bioavailable”. Thus if it gets approved, it would be tremendously more convenient for the patients.

    Edward,

    Last time I checked, Fujifilm does not have a compassionate use program for Avigan. So how do you propose US to “use it”?

    • They are providing for free to 30 countries interested, and Eve if government pays for it it will be cheaper than all the UI claims and losses to economy

  • How about the drug made by Fujifilm Toyama Chemical, Avigan has shown to be very effective, what is stopping US from using it.

  • Any concept of the proportion of hospitalized COVID-19 patients who have been treated off label with hydroxychloroquine during the past two weeks within the Partners system?

  • With all due respect to the writers, I have several issues with this IMO inaccurate article:

    1. Evaluated by the FDA, whose jurisdiction is only in the US? What about EU or Japan or China?

    2. Competition is the norm for this industry. Ever heard of first mover advantage where the company to getting a brand new drug approved for an unmet disease would almost always reap the lion’s share of revenue with high profit margins. What’s so wrong with that?

    3. Off Label Use Concern. The sanctity of a professional and competent physician should always take precedence over bureaucratic barriers and obstacles. If a doctor treating very sick coronavirus patients, he or she should be allowed to do so without hampered nor influenced even by Fauci or Adams! One great example is Remeron which is a preferred anxiolytic and antidepressant with surprising and unintended but desirable side effects (appetite enhnancer and sleep aid). Any competent neurologist knows that but those specific indications were not specifically tested with clinical trials nor specifically approved as indications by the FDA. It is a pity since my mother who is often depressed, anxious, does not sleep well, and has poor appetite resulting in slight but steady weight loss, has been taking it for more than a year with amazing results. It is a great case study of “Real World Evidence” oft parrotted by the FDA for several years as sufficient rationale for approval but so far nothing more than this obstructionist bureaucracy headed currently by obstinate Stephen Hahn and not by much more progressive and reasonable predecessor Scott Gottolieb.

    4. Over the last 20 years, rapid and enthusiastic enrolment of AIDSents in the clinical trials of potentially new drugs was because of the stellar reputation and outstanding track record of Gilead as the foremost leader for this disease. Activist groups had very little role. In fact all they did with misplaced, acerbic, and abhorrent passion were mostly to protest the drugs price and challenge Gilead’s drugs’ patents!

    Responses welcome!

  • Please investigate what the effect of cannabis smoke administered with oxygen will be on Covid-19.

  • There is a plant / tree/ which is locally used for the treatment of a coughing donkeys traditionally.
    What about if this plant is tested for the treatment of Covid19?
    Thanks!!

  • Why no discussion of the combination therapy of chloroquine and Zithromax? Seems vastly more likely a combination therapy would have a chance at success given what was learned from HIV, no?

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