Generating comparative evidence on new drugs and devices after approval

Abstract

Certain limitations of evidence available on drugs and devices at the time of market approval often persist in the post-marketing period. Too often, post-marketing research landscape is fragmented. When regulatory agencies require pharmaceutical and device manufacturers to conduct studies in the post-marketing period, these studies may remain incomplete many years after approval. Even when completed, many post-marketing studies lack meaningful active comparators, have observational designs, and may not collect patient-relevant outcomes. It is crucial for regulators, in collaboration with the industry and patients, to ensure that the important questions that are unanswered at the time of drug and device approval are resolved in a timely fashion during the post-marketing phase. We propose a set of seven key guiding principles that we believe will provide the necessary incentives for pharmaceutical and device manufacturers to generate comparative data in the post-marketing period. First, regulators and pharmaceutical companies (for drugs), notified bodies and manufacturers (for devices) should develop customised evidence generation plans, ensuring that future post-approval studies address any limitations of the data available at the time of market entry that would influence the benefit-risk profiles of drugs and devices. Second, post-marketing studies should be designed hierarchically: priority should be given to efforts aimed at evaluating a product's net clinical benefit in randomised trials compared with current known effective therapy, whenever possible, to address common decisional dilemmas. Third, post-marketing studies should incorporate active comparators as appropriate. Fourth, use of non-randomised studies for the evaluation of clinical benefit in the post-marketing period should be limited to instances when the magnitude of effect is deemed to be very large or when it is possible to reasonably infer the comparative benefits or risks in settings where doing a randomised trial is not feasible. Fifth, efficiency of randomised trials should be improved by streamlining patient recruitment and data collection through innovative design elements. Sixth, governments should directly support and facilitate the production of comparative post-marketing data by investing in the development of collaborative research networks and data systems that reduce the complexity, cost, and waste of rigorous postmarketing research efforts. Seventh, financial incentives and penalties should be developed or more actively reinforced.

Getting the Right Evidence After Drug Approval

“…In a previous study, seven guiding principles were put forward to guide the generation of evidence post-approval. One of the principles states that it is necessary to create the right incentives for generating comparative evidence post-approval (Cipriani et al, 2020). One way to do this would be to make drug prices conditional upon resolving the most important uncertainties, leading to price premiums for more certainty and price penalties for delayed evidence generation.…”

Central statistical monitoring of investigator-led clinical trials in oncology

“…These agencies must determine whether a new drug is sufficiently safe and effective to be made available for clinical use, which requires a careful assessment of the quality of the pivotal trial design, conduct, data and analysis whilst allowing safe and effective new drugs to enter the market quickly [6]. However, the need remains to generate additional, post-approval evidence on novel drugs or devices [6,7]. Such evidence is required for clinical practice, as it provides a far better understanding of the effectiveness and safety of competing interventions in "real life".…”

Cluster randomised trials of prescribing policy: an ethical approach to generating drug safety evidence? A discussion of the ethical application of a new research method

“…But randomisation, by significantly reducing baseline imbalance, allows researchers to make stronger claims of cause and effect. Post-licensing randomised drug comparisons remain uncommon as there is little incentive for a company to test their product against a competitor's [7]. Surveillance systems, such as the UK Yellow Card Scheme [8], are designed to detect safety signals post-licensing but rely on individuals recognising events as potential adverse drug effects.…”