Regulatory discoherence: The case of remdesivir; WTO TRIPS Waiver informals
Originally published December 3rd, 2020 on Geneva Health Files
The story of Gilead’s drug remdesivir, one of the earliest candidates of repurposed medicines that showed promise for the treatment of COVID-19, should hopefully have lessons for regulatory authorities the world over.
In reporting this story with my colleagues in the cross-border investigations team working on this project, we spoke to a number of experts from different parts of the world, in trying to understand how regulatory processes work. And what approvals from regulatory authorities mean for governments, for clinicians, for people and for companies.
THE REGULATORY RELAY RACE FOR REMDESIVIR
Remdesivir, a drug first developed to treat Ebola, was already sought after for use in clinical trials in China and elsewhere, as early as January and February 2020.
In March 2020, when WHO announced the Solidarity Therapeutics Trial, remdesivir was of the existing drugs that was included in the clinical trial.
Over the summer remdesivir, along with dexamethasone, emerged as possible candidates for therapeutics in the treatment of COVID-19.
The U.S. National Institute of Allergy and Infectious Diseases’ (NIAID) ACTT-1 trial showed the drug was superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection. This was the basis of conditional approvals including from the European Medicines Agency (EMA).
Some countries including the U.S., went ahead with issuing Emergency Use Authorization of the drug as early as May 1, 2020. In the following months, remdesivir became the first drug in some countries, approved for the treatment of COVID-19.
An Expression of Interest was invited in July 2020 by WHO. WHO reasoned that Remdesivir was seen to be promising according to trials being carried out earlier in the year. When companies want medicines to be prequalified and procured internationally, they submit their products for WHO assessment. If WHO finds them to meet international standards they are included in the prequalified or Emergency Use Listing. Essentially it is a quality assurance service WHO provides to international suppliers and which countries can use as a reference.
Over the summer, a number of countries including the EU and others signed agreements with Gilead to procure the drug. The company also signed voluntary licensing deals with generic manufacturers in Asia to supply to specific countries.
WHO listed remdesivir as prequalified on October 15, 2020, based on the conditional approval given by EMA.
What is important to note is that WHO’s prequalification team, approved its listing for remdesivir — the same day that the interim Solidarity trial results were published.
On October 15 2020, WHO’s massive Solidarity trial which is examining the effect of drugs including remdesivir had found, in its interim results, that the drug appeared to have little or no effect on mortality or the duration of hospital stay among hospitalized patients of COVID-19. Solidarity trials are one of the largest international randomized trials for COVID-19 treatments, that have enrolled nearly 12,000 patients in 500 hospital sites in over 30 countries, according to WHO.
The whole prequalification process actually, ended the same day that the results were published, a WHO spokesperson clarified. The PQ team listed Remdesivir even before the results were published. WHO has said that its PQ process and the solidarity trial team efforts are separate processes and should not be pulled in together. This is to avoid conflicts of interest, a WHO spokesperson explained.
The role of WHO’s prequalification system is to assess the quality, the safety concerns, but not efficacy in the sense that — is this clinically viable, a WHO spokesperson explained.
(We have struggled to understand why the PQ team at WHO did not refer to results of the Solidarity trial.)
Dr Barbara Mintzes, Associate Professor, The University of Sydney Charles Perkins Centre and School of Pharmacy, who has also worked on the link between clinical trial evidence on drug effectiveness and drug-financing decisions, said, “One of the key rationales for WHO prequalification scheme of specific products is to ensure adequate manufacturing quality, because of the problem of counterfeit products in many parts of the world. It has an important role in access to essential medicines by allowing national governments to know which low-cost generic products have good product quality. However, this makes sense for medicines that have an important role in treatment. The risk of course is that this may be interpreted to mean that WHO carried out its own research and has found remdesivir to be effective, not just that, WHO found that Gilead has adequate manufacturing standards.”
Finally, more than a month later, WHO suspended remdesivir from its prequalification listing. This was a result of WHO issuing a conditional recommendation against the use of remdesivir in hospitalized patients, regardless of disease severity. (November 20, 2020).
Despite, the emerging evidence from WHO’s Solidarity trial, the FDA, a week later on October 22, 2020 gave an approval for the use of remdesivir.
Some regulatory authorities have not yet taking into account the interim results of the Solidarity trial. It is also not clear, if they will consider WHO’s recent guidance advising against the use of the drug.
It is understood that as recently as last week (November 25), at least one country has gone ahead and eased regulatory processes around the use of remdesivir. (Watch out for our story on this.)
While regulators including the EMA have said that they will review the final results from the Solidarity trial, and review their approvals, it is not clear how and if this will have an impact on agreements already signed with Gilead for the procurement of this drug.
At a recent press conference, WHO top officials said that the trial is continuing with the remdesivir arm till the sample size is reached. “We had an agreement with Gilead for a certain number of doses and we will continue to enrol till we complete that. When we have these clinical trials we work with different manufacturers we have an agreement to share the data, once the trial is completed and the data set is locked. It will take a few more weeks, because the trial is still on going, people are being randomised, but will be shared very soon,” Dr Soumya Swaminathan, WHO Chief Scientist said in response to a question raised by Geneva Health Files at the briefing.
THE NON-ALIGNMENT OF REGULATORY ACTORS
In the course of reporting this story, it appeared a number of regulators, cited each other’s regulatory approvals defending their decisions around remdesivir. Experts are of the view that there has been a kind of a domino effect between countries and between regulators. And this even extended to WHO.
Dr Mintzes at the University of Sydney, said, “Two problems are highlighted: the lack of transparency about decision making, especially with little effectiveness evidence available, and also the influence that one country’s decision for emergency use authorisation can have on other national decisions.”
Overall there seems to be political pressure operating on regulators that could have led to some regulators compromising scientific rigor even for emergency authorizations, some believe.
Brook K Baker, Professor of Law, Northeastern University, School of Law, who also represents civil society in both the diagnostics and therapeutics pillars of the ACT Accelerator, said, “in general we should require greater coherence between treatment guidelines, clinical advice and regulatory processes.”
This criss-crossing of regulatory decisions has repercussions on trust not only within the medical community, but also among patients.
“You are trying to build trust in clinicians who were trying to figure out what medicines to use, you are trying to build trust among patients who are trying to figure out which medicines are safe and effective. Then there’s a reversal in the decision in the use of that drug. People who are rationally thinking about medicines become concerned that the regulators don’t know what they’re doing. This is worse than just wasting public resources. Here we are concerned when patients and clinicians get fooled and then become skeptical,” Baker said.
What is also interesting to note that the therapeutics pillar of the ACT Accelerator had not recommended remdesivir within its treatment options. One expert said that in general ACT Accelerator is set up to focus on the acute phase of the pandemic. “So the thinking in the ACT Accelerator was if a drug was not useful in addressing mortality or severe disease, then there was not much support for it. Results of Remdesivir’s lack of effectiveness in addressing mortality became clear early on,” a source pointed out. To be sure, the ACT Accelerator is not a norms-setting body, but relies on WHO guidance.
The Therapeutics partnership had to analyse over 1,700 ongoing clinical trials to identify promising treatments that could be scaled up. “The pillar did not take a view on any specific treatments prior to this analysis or clinical trial results. The pillar is guided by the results of large, robust clinical trials,” a spokesperson for Unitaid on behalf of the ACT-A Therapeutics pillar said. For example, less than 20 days after dexamethasone was identified as an effective treatment by the RECOVERY trial, the Therapeutics Partnership secured 2.9 million treatment courses for low- and middle-income countries, the spokesperson added.
IMPLICATIONS FOR GILEAD
The story of regulatory approvals around remdesivir has been compared to the saga on countries stockpiling Tamiflu during the H1NI pandemic.
Experts such as Tahir Amin, among others have drawn this comparison with Roche’s TamiFlu. Amin said in a recent post, “At one point this year, early positive news about Gilead’s remdesivir, the first treatment to be approved for COVID-19, added approximately U.S $15.7 billion to the company’s market capitalisation. In the third quarter of 2020 alone, sales of remdesivir earned Gilead U.S $873 million. But in October, data from the largest scale remdesivir trial to date by the WHO showed the drug had no meaningful impact on survival. The WHO has now issued a conditional recommendation against the use of remdesivir in hospitalized patients, regardless of disease severity.”
It has already been reported how this non-alignment of regulatory decisions globally might have put the company in a stronger position, including while negotiating with countries for the procurement of this drug.
(In a statement on the interim Solidarity trial results, Gilead underscored its prequalification status [that was issued the same day as the results were published]: .. “Additionally, we are pleased that today WHO has prequalified remdesivir, which assures procurement agencies such as the United Nations that Veklury has met global standards of quality, safety and efficacy.”)
To be sure, the picture on remdesivir will not be absolutely clear till the Solidarity trials conclude. Jessica Burry, HIV/HCV Pharmacist, MSF Access Campaign said, “There are some studies showing potential benefit in some patient subgroups (ie, hypoxemic but not ventilated or critical)– so, in places where hospitals are over-flowing with patients, reducing hospital stay may be helpful. However, this needs to be balanced with the fact that it is an IV infusion, for 5 days of treatment, requires cold chain and comes with a high price tag from Gilead (or may just not be available at all). Countries and health care providers would need to consider these potential strains on a health care system for a drug with unclear clinical benefits and that is not recommended for use in COVID-19 per the WHO’s recent guidance update.”
LESSONS FOR THE FUTURE
So what are the immediate lessons for the future in the context of this pandemic? Mintzes at the University of Sydney said, “In the face of evolving evidence in an emergency situation, in which emergency authorisations might be carried out based on very limited evidence because of some indication of possible benefit, there needs to be preplanned regular review of the evidence and reconsideration of any decisions. And we need full public access to the evidence that is under review and regulators’ assessments of its strengths and weaknesses and the conclusions that can and can’t be drawn from it.”
Regulators, and the public will look up to WHO in the coming months as the vaccines frenzy reaches a crescendo. “WHO for example still hasn’t articulated a position on when it is going to allow an emergency use listing versus when it’s going to require full pre-qualification. With Remdesivir it seems they got something pre-qualified that they don’t want doctors to recommend,” Baker said.
This article is part of the series #BehindThePledge, a cross border investigation into the money trail of pandemic related medicines and vaccines. Journalismfund and IJ4EU awarded this project with grants. Ludovica Jona (Italy), Lise Barnéoud (France), Lucien Hordijk (The Netherlands), Hristio Boytchev (Germany) and Staffan Dahllöf (Denmark) contributed to the reporting of this story.
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