[Ip-health] NYT: Does Remdesivir Actually Work Against Covid-19?

Reshma Ramachandran reshmagar at gmail.com
Tue Nov 17 04:51:18 PST 2020


Ravi Gupta and I wrote a piece today in The New York Times around the
approval of remdesivir, concerned that this is a crystallization of years
of assailing of FDA regulatory standards that will continue to leave our
patients with costly and poorly effective options. We point out the
proposed Cures 2.0 legislation, the next iteration of the 21st Century
Cures Act that seems to do more of the same in eroding evidentiary
standards.

Opinion <https://www.nytimes.com/section/opinion>
Does Remdesivir Actually Work Against Covid-19?

The evidence shows only that the drug might be effective. That once wasn’t
enough for F.D.A. approval.

By Ravi Gupta and Reshma Ramachandran

Dr. Gupta is an internal medicine physician at the University of
Pennsylvania. Dr. Ramachandran is a family medicine physician at Yale.


When the Food and Drug Administration approves a new treatment or vaccine,
as doctors we are assured that rigorous studies have proven it to be safe
and effective. But the F.D.A.’s haphazard issuance of emergency use
authorizations for Covid-19 treatments like hydroxychloroquine
<https://www.nytimes.com/2020/06/15/health/fda-hydroxychloroquine-malaria.html>
 and convalescent plasma
<https://www.nytimes.com/2020/08/24/health/fda-blood-plasma.html>, whose
potential benefits have not yet been backed up by data, has undermined this
trust.

Early in the pandemic, the agency awarded an emergency use authorization
for the antiviral drug remdesivir, based on evidence suggesting that it
<https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment>
*may*
<https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment>
be
effective
<https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment>.
Then last month, despite conflicting evidence
<https://www.nytimes.com/2020/10/29/health/covid-remdesivir-gilead.html?smid=tw-share>,
the F.D.A. prematurely granted its first full approval for Covid-19
treatment to remdesivir, now marketed as Veklury.

In early October, The New England Journal of Medicine published a report
<https://www.nejm.org/doi/full/10.1056/NEJMoa2007764> on the results of a
trial funded by the National Institutes of Health that found that
remdesivir decreased recovery time in Covid-19 patients who were
hospitalized with less severe illness, but did not curb mortality. Other
studies have shown no benefit, including the World Health Organization’s
Solidarity trial, released as a preprint
<https://www.medrxiv.org/content/10.1101/2020.10.15.20209817v1> on Oct. 15.

Based on these results, the European Society of Intensive Care Medicine is
now recommending that the drug not be routinely used in hospitalized
Covid-19 patients
<https://in.reuters.com/article/health-coronavirus-remdesivir-gilead/worlds-top-intensive-care-body-advises-against-remdesivir-for-sickest-covid-patients-idINKBN27T13K?source=news_body_link&utm_campaign=pharmalittle&utm_medium=email&_hsmi=99978590&_hsenc=p2ANqtz--uMcGhcuDSw-bo50cRUrcxJp2ymPs0YJqbQx0SedusCdqLdRfq8CNunS2zZ8q5RrDhe48cZhoBIoJSVOkCQrMOCrdl5BUNhOuf_lMuneh7bXelk4A&utm_content=99978590&utm_source=hs_email>
. Infectious disease experts
<https://blogs.jwatch.org/hiv-id-observations/index.php/does-remdesivir-actually-work/2020/10/18/>
have
stated that after examining all available evidence, we can reasonably
conclude only that remdesivir *may* work.


Some have argued that the approval of Veklury is justified even if it is
only mildly effective because there are no other proven therapies for
Covid-19. This fails to acknowledge, however, the proven effectiveness of
drugs like dexamethasone <https://doi.org/10.1056/NEJMoa2021436>, a cheap
and widely used steroid.

It also ignores years of assault on F.D.A. evidentiary standards,
accelerated by the passage in 2016 of the 21st-Century Cures Act
<http://doi.org/10.1001/jama.2016.20640>. This legislation, which sped up
the F.D.A.’s approval process, was based on unfounded claims that the
agency was too slow and hindered patients’ access to lifesaving drugs.

The F.D.A. is now increasingly approving new drugs based on weaker evidence
<https://doi.org/10.1001/jamanetworkopen.2020.3284>, relying on “surrogate
<https://doi.org/10.1038/nrd.2016.81>measures” like changes in tumor size
<https://doi.org/10.1016/j.eclinm.2020.100332> in lieu of more meaningful
clinical outcomes such as reduced mortality or hospitalizations. Recent
cancer drugs, for example, have been approved without evidence of improving
overall survival <https://doi.org/10.1001/jamainternmed.2020.1097>. Weaker
standards are a boon to pharmaceutical companies, but they can also depress
the development of truly innovative and effective treatments.

The F.D.A. has tried to offset its accelerated approval of Veklury by
asking its maker, Gilead, to complete 29 post-market studies to further
examine the drug’s effectiveness and safety. This is more than three
<https://bmcmedicine.biomedcentral.com/articles/10.1186/s12916-019-1344-3>
 to four <https://www.bmj.com/content/361/bmj.k2031> times the number
typically requested. It’s unclear, however, if these studies will ever be
done. One report found that, five to six years following approval, only
half of post-market studies
<https://www.nejm.org/doi/full/10.1056/NEJMp1705800> had been completed and
one-fifth hadn’t even been started.

Veklury’s approval could also have a chilling effect on the F.D.A.’s
ability to issue emergency use authorizations for other potentially
effective Covid-19 treatments, as the agency’s guidance requires
<https://www.fda.gov/regulatory-information/search-fda-guidance-documents/emergency-use-authorization-medical-products-and-related-authorities#_blank>
there
be “no adequate, approved and available alternative” for the disease. Just
last week, the F.D.A. granted an authorization to an antibody treatment
called bamlanivimab
<https://www.nytimes.com/2020/11/10/world/the-fda-grants-emergency-authorization-of-eli-lillys-antibody-treatment.html>,
for use in non-hospitalized patients with Covid-19 who are at the highest
risk of developing severe disease. This may have been possible only because
Veklury was approved specifically for hospitalized patients.


Veklury’s questionable effectiveness is even more problematic given the
drug’s price. A course costs $3,120 — a huge price tag, and one that
ignores the substantial public investment in the drug’s development.

Remdesivir predates this pandemic. It was first considered as a potential
treatment for Ebola
<https://journals.sagepub.com/doi/10.1177/1073110520958890>, and was
developed through a longstanding partnership between the U.S. Army and the
Centers for Disease Control and Prevention. It was repurposed for Covid-19
after multimillion-dollar trials sponsored by the N.I.H
<https://doi.org/10.1177/1073110520958890>. suggested it could work against
coronaviruses.

Despite Veklury’s questionable effectiveness, the F.D.A. has also awarded
Gilead a “priority review voucher” worth $75 to $100 million. This voucher can
be used by Gilead or sold to a different manufacturer to hasten review
<https://www.fda.gov/emergency-preparedness-and-response/mcm-legal-regulatory-and-policy-framework/21st-century-cures-act-mcm-related-cures-provisions#prv>
of
another drug application. This would perpetuate the entry of other
treatments that are hurriedly reviewed and, like remdesivir, may be of
uncertain benefit.

The dangers posed by the F.D.A.’s rush in approving Veklury are compounded
by the chaos of presumed political interference by the Trump
administration. But the weakening of F.D.A. standards will most likely
continue under the Biden administration. When he was vice president, Joe
Biden strongly endorsed
<https://obamawhitehouse.archives.gov/blog/2016/12/13/god-willing-bill-will-save-lives>
the
21st-Century Cures Act, and some in Congress are already pushing for its
next iteration, Cures 2.0.

If passed, it would further erode
<https://degette.house.gov/sites/degette.house.gov/files/Cures%202.0%20Concept%20Paper_0.pdf>
the
F.D.A.’s evidentiary standards. Among Cures 2.0 proposals is moving the
basis for approval away from randomized, controlled trials, long considered
the gold standard of evidence, and instead relying more on observational
evidence and surrogate measures.

It is hard to ask people to wait for the evidence when there’s a treatment
that could hold some promise, especially during a devastating pandemic. But
the hasty approval of expensive new treatments like remdesivir isn’t the
solution. Doctors like us must feel confident that the drugs approved by
the F.D.A. are worth prescribing to our patients.

Ravi Gupta (@rgupta729 <https://twitter.com/rgupta729>) is an internal
medicine physician and a fellow at the National Clinician Scholars Program
at the University of Pennsylvania. Reshma Ramachandran (@reshmagar
<https://twitter.com/reshmagar>) is a family medicine physician and a
fellow at the National Clinician Scholars Program at Yale University. They
are both members of the Doctors for America Drug Affordability Action Team.

-- 
*Reshma Ramacha**ndran, MD MPP *(@reshmagar <https://twitter.com/reshmagar>)
Veterans Affairs Scholar
National Clinician Scholars Program
Yale University School of Medicine
----
*The National Clinician Scholars Program*

A two-year fellowship advancing health and health care through scholarship
and action.

https://medicine.yale.edu/intmed/nationalcsp/


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