Removing the Risks from Adaptive Pathways: Planning for the Possible?

Taking advantage of adaptive pathways for medicines authorization is not as risky as made out by many critics, according to a wide-ranging European project now reaching its conclusion. When the project is finalized this month, it may help to give some renewed stimulus to the flagging attempts to update drug approval systems. Some stimulus, but will it be enough?

Medicines Adaptive Pathway to Patients, or MAPPs, looked like the great white hope of the innovative drug industry five years ago, with pioneers on both sides of the Atlantic claiming it could bring a 20th century drug development system up to speed for the 21st century. By providing earlier access to valuable treatments in limited patient populations, MAPPs would drive therapeutic innovation and even reduce side-effects and waste among wider populations, its advocates argued. It sprang from an almost missionary attitude among its most prominent proponents-epitomized by Hans-Georg Eichler of the European Medicines Agency (EMA), who initiated this project with the prediction that “in the long-term, we’ll see a growing number of products and research questions that can’t be addressed in the conventional, randomized controlled trials (RCTs). If our attitude is ‘RCT or die,’ we won’t succeed.”

 But sharp criticism emerged-partly from Europe’s agencies that pay for healthcare, fearful of waves of expensive unproven medicines breaking their budgets. Some regulators, too, saw a threat to their cherished gold standard of RCTs. Patient groups and healthcare activists characterized MAPPs as an industry plot to duck out of approval processes, heedless of the risks to patients. And from a purely legal perspective, doubts emerged that MAPPs would be possible in the current European regulatory framework.

 Some of these risks are overstated, say the participants in the EU’s ADAPTSMART project, which has been exploring the feasibility of MAPPs for the last three years. It has been examining where MAPPs will fit into Europe’s complex drug regulation landscape, and has identified some of the questions, and had a shot at producing some answers.

No obstacles arise from Europe’s regulations, the study suggests. “The current legal framework does not include any legal constraints in implementing MAPPs at both European and national level or prevent the implementation of an adaptive approach to medicines development,” it says. “MAPPs can work well within the existing legal framework.”

Demonstration “will be no different”

Because the MAPPs concept foresees utilizing existing regulatory approval pathways in stages without changing the current regulatory standards for evaluation, demonstrating a positive benefit/risk balance “will be no different,” it says. The application might result in a  standard “full” marketing authorization (MA) for use in a well-defined subpopulation, subject to conditions such as post-authorization safety and/or efficacy studies; or in an MA under exceptional circumstances, where comprehensive data on efficacy and safety are not available; or in a conditional MA valid  for one year, on a renewable basis, subject to requirements to complete ongoing studies or  to confirming the benefit/risk balance. But, it suggests, a compassionate use program or named patient supply route would not be appropriate.

“The applicant will have to provide a full dossier containing all required quality, non-clinical and clinical data in order to provide the required evidence for the quality, safety, and efficacy of the product.” That statement may reassure those nervous about lower standards. But it may, at the same time, discourage those who hoped that MAPPs might offer something radically new in the approval system. All it recommends is that action should be taken to improve some timelines, such as for the submission of the pediatric investigational plan required by the EU’s pediatric regulation, or to allow greater latitude in the use of surrogate endpoints in the EU’s orphan drug scheme, “as with MAPPs there may be greater reliance on surrogate endpoints in rare diseases where hard clinical endpoints are not (yet) possible.”

Ethics

The project has also been reflecting on some of the ethics issues raised by MAPPs. In particular, it has focused on a perceived gap in understanding. Prescribing physicians may not know enough about the product they are prescribing, and, consequently, may not provide enough information to patients. 

“An educational opportunity exists to inform prescribers, so that they, in turn, can explain to patients the novel nature of a MAPPs product, the degree of (un)certainty, and how it will be managed. Prescribers also need to maintain an up-to-date knowledge to avoid the accusation by a patient that they have not been informed of a potential risk or change in risk which had, nonetheless, been identified to prescribers in approved regulatory materials,” the project recommends.

Questions of consent also received attention from the project-not just consent to a particular treatment, but also the wider issue of consent for patient data to be used for further study. This area is tangled, the project suggests, highlighting “the need for ongoing data collection, and the burden this entails for patient and [healthcare provider], and the degree and format of information available to patients in order to make an informed decision and implicit or explicit patient consent to treatment.”

For MAPPs to function as intended, registries will be needed for collection and curation of the real-world evidence on which evaluation will depend. But this presents a dilemma, the project recognizes: “While it is highly desirable for products that have used an adaptive pathway to approval to be the subject of careful surveillance and for confirmatory data to be collected and analyzed, there is ethical tension between an individual patient’s right to consent to their data being collected and used, and that of the broader societal need to collect more data to support the reduction of uncertainty. “

* Drug access may be a potentially even greater challenge in this debate. Read more online at http://www.appliedclinicaltrialsonline.com/view-brussels

 - Peter O’Donnell