Tom Jefferson: Adapting pharmaceutical regulation to more transparency

On the 8 December the European Medicines Agency (EMA) and the EU Commission hosted a workshop to discuss Adaptive Pathways, formerly known as Adaptive Licensing. The 180 physical and 155 remote attendees included regulators, representatives of patients’ organisations, payers, academics, industry, and health technology assessment bodies. The aim of the meeting was ostensibly to discuss the results of a pilot study held by EMA which reported last summer. In reality the venue was used to air and discuss some of the potential problems with adaptive pathways highlighted in The BMJ and on various other outlets, especially the lack of transparency in the process. An outline description of adaptive pathways is available here and further details of the workshop are here (although at the time of writing the list of participants, slide presentations and a video recording of the workshop are not available yet on EMA’s website). A pharmaceutical industry view of the initiative is available.

In preparation for the meeting, attendees were sent a brief report of the pilot which was heavily restricted in detail by the need for commercial confidentiality, which had been guaranteed to sponsors of drugs or biologics taking part in the pilot study.

The discussion was wide. It ranged from the definition of unmet medical need to the need to manage uncertainty when licensing new drugs or biologics, to the appropriateness and value of using observational evidence in licensing. Adaptive pathways were presented as a mechanism for identifying promising drugs for conditions with high unmedical need and getting them to market early with a licence and possibly reimbursement proportional to the quality and completeness of evidence presented. We were assured repeatedly that adaptive pathways would not entail a change of regulatory rules and would not usher in a glut of compounds of dubious merits and high cost— a point forcefully made by payers. I believe the statement, as the glut is with us already. The appropriate niche for adaptive pathways is likely to be in rare diseases or conditions for which in the future we will have a biomarker-therapy combination which will reduce the populations in each arm to very small numbers, especially in oncology.

Adaptive trial designs (which are being developed for these situations) will not be able to rely on frequency testing and this could have been the underlying theme of the workshop, but was not discussed at all. If the promise of so-called precision medicine is fulfilled, trial participants will be stratified on the basis of the genetic sequencing or more precise personal characteristics. In this case the scientific community will have to find another way of accepting significance of effect of drug versus a comparator, away from the conventional unattainable statistical significance rules. One obvious candidate is “clinical significance”, to be defined probably case by case by a combination of treating physicians, patients, family, and payers.

Irrespective of the merits of adaptive pathways, the possibility of a frank face to face and at times robust discussion was a good opportunity to exchange ideas and clarify points. The most contentious point of adaptive pathways remains the role of observational evidence (recycled under the term of real world evidence) in support for assessment of the effects of a drug. Representatives of German HTA bodies suggested that we should invest in improving trial design while payers demanded a methods and procedure for adaptive disinvestment and de-marketing of failed or superfluous compounds. Representatives of small biotech companies repeatedly praised the adaptive pathways pilot which helped them develop an evidence plan. The Commission’s representatives intimated that adaptive pathways are “on track”, a rather odd statement given the amount of doubts voiced during the meeting.

We should not condemn adaptive pathways out of hand, but its assessment requires clear knowledge of the methods used in the pilot. These are not available at present. Whatever the merits, adaptive pathways will not be accepted unless EMA provides transparency and visibility of the process each step of the way. In an industry addicted to secrecy, this will be a tall order even for the EMA who are the world’s most transparent regulator.

Tom Jefferson, honorary research fellow, the Centre for Evidence Based Medicine, Oxford.

Disclosure: TJ was a recipient of a UK National Institute for Health Research grant for a Cochrane review of neuraminidase inhibitors for influenza. In addition, TJ receives royalties from his books published by Il Pensiero Scientifico Editore, Rome and Blackwells. TJ is occasionally interviewed by market research companies about phase I or II pharmaceutical products. In 2011-13, TJ acted as an expert witness in litigation related to the antiviral oseltamivir, in two litigation cases on potential vaccine-related damage and in a labour case on influenza vaccines in healthcare workers in Canada. He has acted as a consultant for Roche (1997-99), GSK (2001-2), Sanofi-Synthelabo (2003), and IMS Health (2013).In 2014 he was retained as a scientific adviser to a legal team acting on oseltamivir. TJ has a potential financial conflict of interest in the drug oseltamivir. In 2014-16, TJ was a member of three advisory boards for Boerhinger Ingelheim. He is holder of a Cochrane Methods Innovations Fund grant to develop guidance on the use of regulatory data in Cochrane reviews. TJ was a member of an independent data monitoring committee for a Sanofi Pasteur clinical trial on an influenza vaccine. Between 1994 and 2013, TJ was the coordinator of the Cochrane Vaccines Field. TJ is a co-signatory of the Nordic Cochrane Centre Complaint to the European Medicines Agency (EMA) over maladministration at the EMA in relation to the investigation of alleged harms f HPV vaccines and consequent complaints to the European Ombudsman.

TJ attended the EMA workshop by invitation and had his expenses paid or reimbursed by EMA.