Innovation and off‐label use, the French case and more

The review by Borysowski et al does not deal with all of the issues surrounding off‐label use in France.1

First, the claim “treatment with unproven drugs seems to be permissible under the French Code (of Medical Ethics by the French National Medical Council), though this is not stated explicitly”1 misconstrues the origin of the Code and the nature of the Council:

1. The Code is not issued by the Council, it is a small part of the legal code (3,500 pages) about healthcare.

2. The French Medical Council differs from an equivalent body in the United Kingdom, The General Medical Council of the United Kingdom, which is a charity composed equally of medical and lay members. In contrast, the national governing body of the French council, is composed only of doctors who are not directly elected by their peers. Presently, it is suing for libel practitioners who claimed that homeopathy was “dangerous and fantasist”.2 Moreover, the internal workings of the Council have recently come into question in a confidential investigation from the Supreme Audit Office (Cour de Comptes).3

Second, the regulation of off‐label prescribing in France needs to be strengthened as illustrated by the following examples:

1. In 2006, the national agency in charge of assessing drugs for reimbursement purposes and improving the quality of care (Haute Autorité de Santé) recommended the use of screening plus the off‐label prescribing of aspirin in primary prevention of peripheral arterial disease despite the lack of evidence for the value of either.4

2. In 2014, the French Medicines Agency (in charge of drug approvals) issued a framework for dealing with off‐label use, the Temporary Recommendations for Use (RTU). The RTU requires patient monitoring with data collection and was utilized in an attempt to cope with an epidemic off‐label use of baclofen for alcohol use disorder. Only 6,000 patients out of an estimated 100,000 eligible ones receiving baclofen off‐label have been registered under this scheme.4 In July 2017, a pharmaco‐ epidemiological study showed a dose related increase in mortality with off‐label baclofen. However, this study and robust clinical trials that failed to show evidence of even a minimal benefit did not preclude the Agency from renewing the RTU.5 In October 2018 the Agency terminated the RTU and granted a marketing authorization for baclofen for alcohol use disorder. The authorization, to a French corporation, is limited to France, a most unusual regulatory practice in the European Union where drugs are typically granted approval for the entire EU membership.

Indeed, Borysowski et al agree that the medical professional codes that they reviewed do not adequately address the problem of how new and innovative drugs are used.1

Third, the review's title focuses on ethics but other issues may be even more important:

1. Scientific evidence and safety. Seventy‐nine percent of off‐label drug use lacks sound scientific evidence6 and the less the evidence for off‐label use the greater the likelihood of an adverse drug event.7 A recent systematic review of off‐label uses of lisinopril demonstrates the variable evidence for different uses.8 Furthermore, off‐label prescribing hinders the development of evidence‐based medicine by decreasing the incentive to research new indications and is costly to the healthcare system.

2. Economics. Commercial endeavours flood prescribers with biased and/or incomplete information during sham “educational events” that are designed to promote off‐label use and to weaken regulations.9, 10 The reimbursement of off‐label prescriptions by health care insurance schemes, despite the existence of databases that can detect inappropriate prescribing, is difficult to understand.

3. Promotion. Habibi et al found that sales representatives in France made claims of morbidity and mortality benefit for drugs approved on the basis of surrogate outcomes in almost 60% of visits.11 Making these types of claims without supporting evidence is one example of promotion of how companies are engaging in off‐label promotion.

Finally, off‐label use is only one way that the quality of prescribing is being compromised. On one hand, more and more drugs are granted accelerated approval by regulatory agencies on the basis of surrogate outcomes (with tenuous or unknown links for relevant clinical outcomes such as morbidity and quality of life) and on the promise of post‐marketing studies which are only performed in two thirds of cases, and with a median delay of four years.12 On the other hand, market withdrawal is often unreasonably delayed, even in the case of drug‐related deaths.13 Finding a prudent, middle ground to protect patient interests is an ongoing dilemma for drug regulators and prescribers, but moving too fast with approvals or prescriptions and too slow for withdrawals is the wrong path to follow.

COMPETING INTERESTS

A.B. is a member of several task forces at the French Medicines Agency (Agence Nationale de Sécurité du Medicament). J.L. was a paid consultant on indication‐based prescribing (United States Agency for Healthcare Research and Quality) and received payment for being on a panel that discussed a pharmacare plan for Canada (Canadian Institute, a for‐profit organization). He is currently a member of The Jean Monnet Network in Health Law and Policy funded by the European Union (http://jmhealthnet.org/).

Braillon A, Lexchin J. Innovation and off‐label use, the French case and more. Br J Clin Pharmacol. 2019;85:2446–2447. 10.1111/bcp.13993