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AIXIAL Review #7

COVID 19: An opportunity to dust off the hierarchy of evidence in therapeutics?

 

After more than a year of pandemic, research has invented and developed original vaccines in record time. However, despite the means put in place with such unprecedented speed as the pandemic itself, it is struggling to provide us with robust evidence of a curative antiviral therapy.

With urgency, the extensive research carried out in this area has mainly concerned old molecules in repositioning/repurposing, the advantage being that we already know a little about them. But it is clear that after a year, the results of the research are meager. Do not see in my comments any criticism, I would neither have the legitimacy nor the inclination to make them.

On the contrary, it is with admiration for the responsiveness displayed by certain researchers and institutions as well as for the intensity of the research carried out (see the COVID NMA Initiative[1]) that we can appreciate other ancillary results.

The cited examples below of those ancillary results are a testimony to their responsiveness and our admiration:

• The Solidarity clinical trial which, although negative, illustrates the possibility of rapid international cooperation in clinical research[2].• Technical innovations that have made it possible to facilitate and collect data (remote monitoring of patients, telemonitoring, etc.).

• The responsiveness of institutions which, in the name of national research priority, have facilitated and simplified research procedures on COVID (single agreement, CPP[3][4][5][6]).

• The ACT accelerator[7] set up by WHO.

• The implementation of derogatory measures for early access to innovative drugs, including COVID (a subject that we will develop in a future post).

But how can we not be saddened by the vehement and destructive positions we have seen around the strength / weakness of the evidence for this or that drug supposed to treat COVID infections? Why these sterile polemics rather than controversies allowing the protagonists to explain their arguments? The authorizations granted in urgency immediately revoked, Recommendation for Temporary Use (RTUs) refused or sometimes granted on evidence that the rules of the Evidence Based Medicine (EBM) would usually consider as insufficient testify to a certain unease, some bracing themselves on the need to have convincing results of  therapeutic trials well conducted before acting, others being satisfied with weak inductive evidence or even pure mechanistic evidence while waiting for better.

If we ask the question of the effectiveness of a curative drug in COVID-19 subjects without signs of severity, knowing that the natural course of the COVID disease is in the vast majority of cases favorable, probably few reviewers will disagree with the need for a convincing randomized controlled trial. But do we have to wait for the positive results of a trial to make a drug available? If the answer is no, what is the sufficient evidence to do so? And what to do with other arguments, including non-clinical ones?

The lack of consensus on the therapeutic evidence to be acquired in the circumstances seems to us to be the source of the unease we feel. The therapeutic deprivation in which the pandemic finds us poses for the evaluator and the decision-maker a temporal dilemma from which it is impossible to escape: act immediately in a situation of uncertainty, at the risk of errors of assessment or wait for a level of solid evidence with a loss of opportunity for the patient.

How to decide? The dilemma imposed by the pandemic leads us to question ourselves more generally about the evidence concerning other urgent therapeutic needs in serious situations, for example in oncology or in rare diseases without therapeutic alternatives.

We do not claim to provide the answer to this question here, but rather invite to open a debate so that the decisions taken by the health authorities are more explicit as much for the COVID therapies as for all the uncertain treatments admitted due to an urgent need and / or the impossibility of obtaining “standard” evidence, that is to say from well-conducted randomized controlled trials (Marketing Authorization under conditions, reservations, exceptional circumstances, etc.).

But such an interrogation cannot take place without questioning the hierarchy of evidence.
However, if the idea of ​​a hierarchy of evidence is well suited to establishing the level of confirmation of a hypothesis of therapeutic efficacy, it seems to us to be a reductive and even inept concept for establishing the level of a therapeutic proof (we will explain more about this in a future post). Established before the digital revolution, the hierarchy of evidence also needs, in our opinion and for cases where it remains useful, to be dusted off. On the one hand, it will be a question of revaluing and putting in their proper place mechanistic evidence and clinical cases. It will also be necessary to include in the hierarchy the new methods of acquiring knowledge, whether it is about real life data whose power and collection have been more than tenfold thanks to digital technology and which are sometimes sufficient to obtain approval, or whether it concerns new clinical research methods such as, for example, adaptive designs, used for COVID, n-of-one trials (for stable chronic diseases), Master Observational Trials (MOT), which hybridizes the power of molecularly based master interventional protocols with the breadth of real-world data, in particular in oncology, or finally the in silico modeling of clinical trials as carried out by our partners in the company NOVADISOVERY.

Hopefully the COVID episode will be an opportunity to clarify the evidence required for situations of urgent therapeutic needs and, at the same time, to adapt the hierarchy of the level of evidence in therapy, by specifying the limited conditions for its application.

— Written by Jacques Massol, MD PhD, AIXIAL consultant

[1] https://covid-nma.com/

[2] https://www.nejm.org/doi/full/10.1056/NEJMoa2023184 (consulted on 04/07/2021)

[3] https://solidarites-sante.gouv.fr/soins-et-maladies/maladies/maladies-infectieuses/coronavirus/professionnels-de-sante/recherche-sur-la-covid-19/article/le-label-priorite-nationale-de-recherche-et-les-demarches-pour-le-demander

[4] https://solidarites-sante.gouv.fr/systeme-de-sante-et-medico-social/recherche-et-innovation/l-innovation-et-la-recherche-clinique/convention-unique

[5] https://www.ansm.sante.fr/Activites/Essais-cliniques/COVID-19-Essais-cliniques-en-cours/(offset)/0 (consulted on 04/07/2021)

[6] https ://ec.europa.eu/health/sites/health/files/files/eudralex/vol-10/guidanceclinicaltrials_covid19_ en.pdf

[7] https://www.who.int/fr/news/item/26-06-2020-act-accelerator-update (consulted on 04/07/2021)

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