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Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

BMJ 2017; 359 doi: (Published 04 October 2017) Cite this as: BMJ 2017;359:j4530

Re: Availability of evidence of benefits on overall survival and quality of life of cancer drugs approved by European Medicines Agency: retrospective cohort study of drug approvals 2009-13

The high price of new cancer drugs has fuelled a debate on their added value and the evidentiary standards for regulatory approval. The findings by Davis et al. (BMJ 2017;359:j4530) that several cancer drugs entered the European market without clear evidence of extending duration of survival or improving quality of life (QoL) are not surprising to anyone familiar with cancer drug development. It is well known that in many situations demonstrating a clear effect on survival or QoL is not feasible and a benefit can be shown on the basis of other endpoints. There are several reasons for this.

First, there are good reasons why an effect on overall survival may be difficult to detect, such as when control-group patients in a randomized clinical trial (RCT) switch to the experimental treatment after progression, or when multiple subsequent lines of effective treatments “dilute” the effect of a drug used in earlier lines. In these and other situations, progression-free survival (PFS, the time during which treatment can induce and maintain a response or at least delay the growth of cancer) has been the efficacy outcome on which many cancer drugs have been approved; the justification being that (if of sufficient duration, with acceptable toxicity and no detriment in overall survival) prolonging PFS will delay onset and worsening of symptoms. Importantly, if a sufficient effect is observed based on this endpoint, it is generally considered to reflect an intrinsic clinical benefit and is not a “surrogate” for survival requiring subsequent confirmation, as Davis et al. seem to imply.(1,2,3)

Second, when “dramatic activity” is observed in terms of objective response (tumour shrinkage) and response duration on the basis of single-arm trials in a well-defined patient population with high unmet medical need, RCTs are considered unethical or unfeasible and “early approval” mechanisms can be used. This applies to a minority of cases and requires that the course of the disease is highly predictable, that there are no good therapeutic alternatives and that there are sufficient supportive clinical and non-clinical data to show a positive benefit-risk balance. Confirmatory data on long-term endpoints are generally requested in these situations, although the evidence may sometimes be extrapolated from related indications when direct confirmation in the same indication is not possible (e.g., when RCTs are not well underway at the time of approval).

Third, QoL is often difficult to assess for a number of reasons, including when double-blind trials cannot be conducted because the distinct toxicity profiles of drugs make them difficult to mask, or there is poor compliance with questionnaire completion. Drawing conclusions on the basis of single items or domains of a QoL instrument is also generally challenging due to the risk of chance findings. Therefore, QoL is rarely used as the primary efficacy endpoint in cancer clinical trials and convincing clinical benefits in terms of QoL are only rarely shown. This, however, does not mean that EMA does not value such studies, which are encouraged even if often they do not lead to robust conclusions. (1,4)

Lastly, there are indeed situations when drugs are approved on the basis of small incremental benefits instead of giant leaps, which are relatively rare. The European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) used by Davies et al. to identify drugs that bring a clinically meaningful benefit has its limitations including failure to recognise small incremental benefits. This scale was never designed for the purpose of clinical decision-making and was mainly constructed on the basis of oncologists’ views rather than a systematic evaluation of patient preferences. Patients play a key role in informing value judgments of benefits and risks of treatments, and EMA has been active over the years in implementing its framework for patient involvement in benefit-risk assessment.

A detailed discussion of the examples mentioned in the article, as well as a response to the claim that “EMA has either failed to identify or overlooked” methodological problems made in the accompanying Feature (doi:10.1136/bmj.j4543), is not possible here. It suffices to say that approval is not a ruling on drug development or whether the ideal trial designs, comparators and methods of analysis have been used, but a scientific conclusion on the balance of the benefits and risks based on available data. Thus, the conduct of trials according to the most rigorous methodology is strongly encouraged whenever possible but in general is not a pre-requisite for approval provided that existing uncertainties can be addressed on the basis of the totality of the data, including future studies, where appropriate.(5) For every assessment, EMA publishes on its website all the details about the data submitted, benefit-risk assessment evaluations, remaining uncertainties and how they were handled, and justifications of any deviations from standard methodology in the context of the available evidence and therapeutic context.

We all strive to help patients live better and longer. However, restricting approvals of cancer drugs only to situations where there is indisputable evidence of improvement in survival or QoL will not improve the lives of cancer patients. On the contrary, such an approach may deprive patients in urgent need of early access to effective medicines. In such situations, early access to new drugs that fulfil an unmet medical need has to take precedence over generating evidence according to the highest standards for health economic evaluation. Science and standards are here to serve patients and not the other way round.

1. European Medicines Agency. Guideline on the evaluation of anticancer medicinal products in man. 2012.
2. Pazdur R. Endpoints for assessing drug activity in clinical trials. Oncologist 2008;13 Suppl 2:19-21.
3. European Medicines Agency. Appendix 1 to the guideline on the evaluation of anticancer medicinal products in man - methodological consideration for using progression-free survival (PFS) or disease-free survival (DFS) in confirmatory trials. 2012.
4. European Medicines Agency. Appendix 2 to the guideline on the evaluation of anticancer medicinal products in man: The use of patient-reported outcome (PRO) measures in oncology studies. 2016.
5. Jonsson B, Bergh J. Hurdles in anticancer drug development from a regulatory perspective. Nat Rev Clin Oncol 2012;9(4):236-43.

Competing interests: No competing interests

12 October 2017
Francesco Pignatti
Head of Oncology, Haematology and Diagnostics
European Medicines Agency
30 Churchill Place, Canary Wharf, London E14 5EU, United Kingdom