Reply to “Innovation and off‐label use, the French case and more” by Braillon and Lexchin
2019-08-13

We appreciate the additional information on off-label use of medications provided by Braillon and Lexchin1 in response to our review2. However, we also want to clarify some issues they raise in their critical remarks. The authors start their letter stating that our review does not deal with all of the issues surrounding off-label use in France.1 Indeed, it does not; however, the objective of our review was not to discuss in detail off-label use of medications in France or any other country. Rather, our review focused on ethical aspects of use of new and innovative drugs, especially on guidance on the use of such drugs contained in major international codes and guidelines pertaining to medical ethics and biomedical research, as well as in national codes of medical ethics and professional conduct of selected countries (including but not limited to France).2 Thus, the scope of our review is fairly broad and encompasses not only innovative off-label applications of drugs but also therapeutic use of investigational drugs (termed expanded access or compassionate use). According to Braillon and Lexchin, the statement from our review that “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” misconstrues the origin of the Code and the nature of the Council. In addition, according to them, “the Code is not issued by the Council.”1 We cannot agree with these claims. Indeed, as mentioned by Braillon and Lexchin, the French Code of Medical Ethics is an integral part of the French Public Health Code. However, it was also published as a separate entity by the French National Medical Council (relevant information can be found in the Preface to this Code). Furthermore, according to Art. 1 from the Code, the French National Medical Council shall supervise compliance with the provisions listed in this Code and any infringement thereof shall be liable to its disciplinary proceedings. Moreover, Braillon and Lexchin report on different composition of the French and the UK's medical councils and controversies regarding some of the former's activities.1 However, they fail to explain how these data relate to information contained in our review, which did not evaluate any activities or the composition of the French Council. A larger part of the letter by Braillon and Lexchin is devoted to off-label use of drugs. The authors rightly point out to serious problems associated with dishonest promotional activities of drug manufacturers aimed to increase the number of off-label drug prescriptions.1 In addition, they cite a paper, according to which 79% of off-label use of drugs is not based on sound scientific evidence and the less the evidence for off-label use the greater the likelihood of an adverse drug event.3 However, this paper was cited in our review as well. Furthermore, unlike the authors of the Letter we are responding to, we cited another important finding from that study—off-label applications supported by solid scientific evidence have the same risk for adverse events as on-label use.2, 3 Moreover, in the context of this discussion, it is worth mentioning a recent meta-epidemiological analysis which showed that drugs used off-label are generally not less effective than those used as approved treatments for the same indication.4 The authors of this study analysed 25 different treatment comparisons involving 153 randomized controlled trials and 24 592 patients. Analysis of all trial outcomes showed more favourable effects in off-label treatments compared with approved treatments. However, an analysis using only primary outcomes revealed no statistically significant difference between off-label and on-label treatments.4 While this study has some limitations, it does show that an assumption that drugs used off-label are generally less effective than approved treatments is questionable. Braillon and Lexchin also claim that “off-label prescribing hinders the development of evidence-based medicine by decreasing the incentive to research new indications” (though they do not cite any data to support this).1 In our view, this statement is oversimplified. First, contrary to this claim, off-label use did lead to new and important applications of some drugs, eg, β-blockers.5 Second, major barriers to research into new indications of drugs include very high costs of clinical trials and time required to conduct them rather than off-label use.6 Third, in some specialties, especially in paediatrics, off-label prescribing is particularly prevalent due to a lack of on-label information about use of many drugs in children, which in turn is a consequence of inadequate number of clinical trials performed on children.7 Thus, prevalent off-label use in paediatrics is not a cause but rather a result of a lack of approved treatments meeting the contemporary standards of evidence-based medicine. In our view, Braillon and Lexchin are also misguided to separate and contrast ethical aspects from scientific, economic, and promotional aspects of off-label use.1 In fact, all the latter aspects are closely linked to ethical aspects. Scientific validity is also a necessary condition of both clinical research and medical practice as evaluated from an ethical perspective. All those aspects together affect the health and well-being of patients. Importantly, off-label use of drugs is officially promoted by some professional medical associations. For instance, the guidelines developed by the American Academy of Dermatology endorse off-label use of drugs for a number of common diseases including atopic dermatitis, psoriasis and acne.8 Moreover, according to a policy statement by the American Academy of Pediatrics, “evidence, not label indication, remains the gold standard from which practitioners should draw when making therapeutic decisions for their patients.”9 Responding to critical remarks by Braillon and Lexchin, we also would like to underscore that our review2 was not meant to encourage doctors to prescribe drugs off-label, or to promote use of investigational drugs (nor does this reply have that objective). Treatment decisions should always be made on a case-by-case basis considering the best available evidence. In particular, in cases where no approved treatments exist, or cannot be satisfactorily used, innovative off-label use and expanded access may provide “last resort” treatment options. There are no competing interests to declare.