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Peter O’Donnell gauges the impact of FDA guidance on igniting the adaptive pathways debate in Europe.
The FDA’s August release of draft guidance on innovative clinical trial designs for cancer therapies has excited interest not only among the US oncology community but also among some far-sighted drug developers in Europe, too. The FDA document, “Expansion Cohorts: Use in First-In-Human Clinical Trials to Expedite Development of Oncology Drugs and Biologics” (http://bit.ly/2nZ0vN7), offers advice on designing and conducting adaptive designs that can assess multiple aspects of a drug in development in a single trial while enrolling the minimum number of study participants.
The essence of these first-in-human multiple expansion cohort trials is that they can expedite development by proceeding seamlessly from initial determination of a potentially effective dose to individual cohorts, with trial objectives more typical of Phase II than Phase I trials. An FDA statement accompanying the release stresses the merits of targeted treatments, and records rising patient demand to enter these early trials and increasing calls to speed development and approval processes. The advantage of addressing multiple questions in a single trial that is amended as new objectives are identified is to avoid the time lag and additional resources experienced with the opening of new clinical trials, says the FDA.
The avowed objective of greater efficiency in drug development that can make highly effective drugs widely and rapidly available to the public could play well among drug developers in Europe. So, too, will the tone of the FDA invitation to comment: “We want your input to make sure that the final guidance is comprehensive and forward looking and adapts to rapidly changing research developments and technologies. Our regulatory work needs to remain as advanced as the many new cancer therapies currently working their way through development.”
The drive in Europe toward adaptive pathways today gives every appearance of having run into the sand. Half-forgotten now are the heady days earlier in this second decade of the 21st century, when the European Medicines Agency (EMA) ran a pilot project to explore accelerating market access for new medicines.
Around 2015, the potential downsides of targeted medicine and adaptive pathways started to dominate European debate. Prominent European scientists raised concerns over the EMA pilot, questioning the conflation of “new” and “innovative” or the assumption that early market entry is beneficial to society, and flatly rejecting the principle that, “something is better than nothing.” The European Public Health Alliance attacked the EU approach on the grounds that it had “prevented and impeded any political scrutiny.” The European consumer defense body, BEUC, got in on the act with a study whose focus was clear from the title: “Fast-track approval for new medicines – patient safety at risk?”, and which warned of the “unnecessary health risks” of adaptive pathways “because these medicines would be put on the market before there is complete information about their safety.”
Even more substantially, the highly influential German health technology assessment body known as IQWiG (its name in English means the institute for quality and efficiency in healthcare) judged the EMA-backed approach as leaving “open questions unanswered”-particularly what it termed “perplexity” over the concept of real-world data. IQWiG said it “again sees its concerns about adaptive pathways confirmed,” because “evidently neither industry nor EMA has a concept as to how real-world data can be used after drug approval to allow drawing reliable conclusions on benefit and harm.” Since real-world data is “a key component of the adaptive pathways concept,” uncertainty over its nature, its availability, or access to it means that the whole concept needs rethinking, said IQWiG.
Battered by such allegations, the topic has slipped down Europe’s strategic agenda. The FDA draft guidance may restore some vigor to the debate. With its careful enumeration of recommended safeguards, the U.S. document not only makes some contribution to detailing protective mechanisms on the specific questions surrounding expansion cohorts, it also brings a balanced approach to the broader issues of adaptive pathways as a concept. Alongside its forward-looking enthusiasm, it sets out cautions over patient safety and methodological integrity in what amounts to a thoughtful outline of the pros and cons.
“It is critical that investigators, institutional review boards (IRBs), and regulators are updated with new safety information so that they can provide the necessary oversight for protection of human subjects and so that investigators can ensure that patients can provide adequate informed consent,” it continues. And it warns against “inefficient drug development based on possibly missed interpretation of preliminary trial results and unplanned analyses that can lead to delays in proper clinical development.”
The guidance also urges tight constraints on patient populations. Informed consent documents should be updated as new information is obtained during the trial that may affect a patient’s decision to participate in or remain in the trial. Ethics review boards should frequently review evolving new safety information, and the background information for each expansion cohort should contain the scientific rationale for that individual cohort, with descriptions of the prespecified stopping rules.
The relative inactivity of European regulators on adaptive pathways is in part down to Brexit. The distractions for EMA of having to move from London to Amsterdam by next March has severely impacted its ability to do anything more than keep up with its core activity of assessing and monitoring marketing authorization applications. Adaptive pathways is simply one more extra task on which EMA and the Commission were due to act two years ago, but which has been neglected for pressure of resources, admitted the EU health commissioner in mid-August.
However, Europe hasn’t completely gone into hibernation on the subject. Since 2015, an EU-backed project, ADAPT SMART, has been working quietly away at-in its own words-”laying the foundations and building consensus to make adaptive pathways work for all.” The latest FDA entrance into the debate may help.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium