Rebalancing Risk:Benefit Appraisal in Clinical Trials (University of Oxford / Centre for the Advancement of Sustainable Medical Innovations (CASMI))
Since the days of the “blockbuster drugs” of the 1990s, there has been a worrying trend of declining productivity in biomedical research. Pharmaceutical companies are spending more and more money on research to bring new therapies to market, and yet fewer drugs are being approved. This is despite major achievements and opportunities in novel technological platforms. Most of this increased failure rate appears to occur at the clinical trial phase; one key contributor to this is an inherently and perhaps increasingly risk-averse regulatory system.
In this environment, rejuvenation biotechnologies may suffer an exceptionally high burden. Nearly all drugs today can be tested with fairly clear near-term outcomes, because they are designed to alleviate symptoms or reduce the rate of catastrophic outcomes in people with existing disease. Rejuvenation biotechnologies, by contrast, are designed to prevent people from developing age-related disease in the first place, or greatly delay its onset. This implies that rejuvenation biotechnologies are best tested in people who are aging, but still basically healthy — which tends to break the conventional model of weighing risks against benefits. If we are to continue to make medical progress, particularly against the diseases and disabilities of aging, regulators will need to adopt new ways of balancing the risks and benefits of clinical trials.
This investigation aims to assess risk-to-benefit appraisal methodologies used in the analysis of randomized controlled trials for innovative medicines, medical devices, and surgical procedures prior to regulatory approval. A panel of 16 quality factors for such methodologies was gathered from published literature and from practitioners from life sciences and non-life-science industries. These quality factors were prioritized through a consultation with external experts, weighed for utility, and used to produce a scorecard to assess the quality and effectiveness of the risk-to-benefit appraisal techniques surveyed in a systematic review of published methodologies. Ultimately, 6 records of the original 272 exceeded the predefined minimum quality threshold, and met the minimum stakeholder needs as determined by multi-stakeholder expert elicitation.
In response to feedback, an additional international survey was distributed to nearly 4000 European pharmacists, which indicated a very strong desire by pharmacists (92.6%) to participate in risk-to-benefit appraisal. In order to evaluate the impact of system risks in risk-to- benefit appraisal, an investigation into barriers to the translation of regenerative medicines was conducted concurrently.
The key finding was that regenerative therapies (as compared with ‘conventional’ biomedical innovations) are subject to a number of unique systems risks, pertaining to intellectual property, biomanufacturing, the formation of strategic partnerships, and ensuring that licensed therapies are actually adopted in the clinic. Clearly, more work must be done to ensure that rejuvenation research is translated into working regenerative medicine.