Opinion | Taking the Fight to the Virus, Step 2:  Do you Want Treatment?

There have been over 5,000,000 COVID-19 cases in the United States, yet there remains a problem finding clinical trial participants to try all the compounds medical experts wish to study as well as fill clinical trials’ “control arms.”  Doctors involved in these trials are ethically conflicted; torn between serving the needs of the study vs. the needs of the patient and frustrated when not permitted to exercise their own best clinical judgment.  Their greatest ethical dilemma is whether continuing to administer a placebo to large numbers of sick individuals who desire to be treated can be justified.

What if we were to put SARS-COV-2 infected patients, not the needs of the studies, at the center?  Every time a person is called and informed they have COVID-19 they could be asked a simple question: Do you want treatment?  Then they could self-select:

  • A.  Yes, and I’d like to choose a drug for myself.
  • B.  Yes, and I’d like a doctor to select a drug for me.
  • C.  I’m interested in participating in a clinical trial.
  • D.  No, I’ll isolate and ride this out without treatment.

If A, would you like to immediately begin taking one of the agents below?

  • apixaban
  • camostat mesylate
  • colchicine
  • defibrotide
  • EIDD-2801
  • EIDD-2801/merimepodib (investigational antiviral cocktail)
  • enoxaparin
  • favipiravir
  • favipiravir/umifenovir (antiviral cocktail per Glenmark Pharmaceuticals)
  • HeberFERON (interferon cocktail)
  • Ivermectin
  • leronlimab (subcutaneous injection)
  • peginterferon lambda (subcutaneous injection)
  • quercetin/melatonin (with vitamins and zinc per Dr. Paul Marik)
  • REGN-COV2 (antibody cocktail per Regeneron Pharmaceuticals)
  • rivaroxaban

Will you consent to blood tests and vital signs monitoring, and that your data (without identifying information beyond demographics) be shared with researchers?

  • Yes  (medication will be provided free of charge)
  • No  (you and your prescription benefit plan will be responsible for the cost of the medication)

Excellent progress is being made toward a COVID-19 vaccine, but we still face an autumn and possibly a winter through which it is unlikely that such a vaccine will be widely available.  During that time people are going to contract COVID-19.  Treatment of an antiviral nature is more likely to succeed if it is begun in the early phase of the disease.  While there is no proven COVID-19 therapy appropriate to outpatient treatment, there are strong candidates.  We’ve faced this scenario before, with AIDS.  With COVID, though, we must act fast, at scale, if our actions are to be effective.  Our protocols for “compassionate use” are much too slow and individual.

Today the people who are tasked with calling those with positive COVID test results, including contract tracers, have little to offer infected patients, so like the boys in the 1995 Ira Sher short story “The Man in The Well", we do nothing but isolate the sufferer.  The time has come to put the power to choose in patients’ hands.  The way to do that is to replace double blind, placebo controlled phase 3 trials with a national comparative study of the most promising drug candidates.

Which drugs get in or are removed should be decided by a team of doctors.  While that’s not far from what is usually done for each drug by panels appointed by the FDA, it should be a more public and transparent process in this case.  What I am proposing is that drugs that have been deemed successful in phase 2 trials (whether for COVID treatment or for another condition) or are already COVID approved drugs in other countries be eligible for consideration by the keepers of what I’ll call the “equipoise gate,” who are empowered to allow a drug to take its place on the comparative study questionnaire.  An affirmative decision by the committee would result in the issuance of an Emergency Use Authorization.

The comparative study would be conducted more like a phase 4 study than a phase 3.  Those who elect NOT to undertake treatment, but who ARE willing to have tests done and disclose the results, serve as the control arm.  That data should probably be used only to the degree matched pairs can be identified on the basis of health & demographic data; the main point of the study is to compare treatments against each other.

This would be a study of a somewhat different nature than is the standard practice of FDA.  While that agency is equipped to be the gatekeeper, there is another agency of government that is best positioned to execute a study of this nature, the Agency for Healthcare Research and Quality (AHRQ).  In this video <same as above>, AHRQ Director Gopal Khanna explains his agency’s mission.  AHRQ is a logical point of contact for state health departments working to implement an ambitious study, and upload data.

The list of drugs I’ve offered can be used as a starting point for further research and consideration.  Like everything in this editorial, it represents the opinion of the author.  There is a story behind each, and for each a reason I included it, but a final list should be compiled by a committee of doctors.  Many of the drugs you’ve heard of are for hospital use; those listed above can be taken pre-hospitalization.

The now recinded emergency use authorization for chloroquine and hydroxychloroquine was advanced by politicians.  This time, we need evaluation by experts.  My reasons for leaving out hydroxychloroquine, chloroquine, and azithromycin are several.  There are still a few credible physicians who would like to try low-dose hydroxychloroquine with zinc, though.  To them I say:

  • Show me a successful phase 2 trial against any virus (malaria is a parasite, not a virus).
  • Does it belong on a list for people who have tested positive, or is it most likely to succeed beforehand, as prophylaxis?
  • Does it meet equipoise where another antiparasitic, ivermectin, is already being considered?

Who should sit on the “equipoise gate” committee overseeing the study?  There is already a doctor tasked with therapeutics development by the Trump Administration: Janet Woodcock, director of FDA’s Center for Drug Evaluation and Research and therapeutics development manager for Operation Warp Speed.  FDA has a website with a breakdown of what they’re looking at: https://www.fda.gov/drugs/coronavirus-covid-19-drugs/coronavirus-treatment-acceleration-program-ctap.  Two Los Angeles doctors I’ve come to know, Binh Ngo and Marc Rendell, have been analyzing where we stand on COVID-19 therapeutic trials with an international group of researchers, and will be publishing that analysis shortly.  In an excellent Stat News article dated July 6, authors Matthew Herper and Erin Riglin quote physicians currently outside government, including a former FDA director.  A letter from Drs. Richard Malley and Marc Lipsitch of Harvard to the New York Times published May 22 helped focus attention on early stage, outpatient treatments.  There are many doctors I could list who I’ve written about, quoted or interviewed, whose participation would give me confidence, but I see no need to stack the deck.  What’s needed is a process that will get COVID treatment into the field and into the hands of patients and doctors who want to try them, quickly, efficiently, and in a manner that will allow us to learn lessons not yet foreseen.

One other thought concerning FDA: if they want to protect the public, they need to act where there IS evidence to pull PPI type acid reducers from the market (as they did with another stomach drug, ranitidine) or at a minimum designate them schedule IV controlled substances, returning them to limited prescription-only availability for the duration of this pandemic and publicizing the reason for it.  If they don’t do that soon, America’s trial lawyers will exact a price.