Changing the Face of Clinical Trials

Changing the Face of Clinical Trials

Judging the value of new drugs and medical devices is becoming an increasingly important issue with the proliferation of alternative treatment options. Beyond key aspects such as clinical efficacy and safety, other considerations such as quality of life and costs are increasingly being scrutinised. The cost of drugs is a particularly complex issue generating considerable debate within governments and health-care systems.

In some countries, such as the UK, part of the role of The National Institute for Health and Care Excellence is to determine the cost-effectiveness of potential treatments for the National Health Service. In the USA, which has a much more complicated health payer structure, there is no official body that makes these sorts of calculations, but this role is partly fulfilled by The Institute for Clinical and Economic Review (ICER), an independent and non-partisan research organisation that objectively evaluates the clinical and economic value of drugs, medical tests, and other health-care innovations. Assessments done by ICER can be used by insurance providers to determine whether a particular treatment or test is covered by their policies.

On Sept 20, in response to an open consultation on a draft scoping document by ICER about an upcoming assessment on crizanlizumab and voxelotor for patients with sickle-cell disease, the American Society of Hematology published a letter emphasising the need for the process to be respectful of the history of the disease. Sickle-cell disease is a rare disease and affects primarily those of African ethnicity. Concerns were raised about the nature of the ICER analysis, including the lack of information about baseline data—there is still uncertainty over just how many individuals are affected by sickle-cell disease, and many of those who are known do not necessarily receive usual care, the comparator in these analyses.

Another concern raised by the ASH response, and by other commentators, is that ICER is acting prematurely in assessing these drugs for sickle-cell disease. They are both currently under review by the FDA with decisions expected next year. If approved, these drugs will mark the first targeted therapies for patients with sickle-cell disease beyond transfusion and hydroxurea. A salient question is whether a full cost analysis can be effectively done on limited clinical data. Although randomised clinical trials provide the best clinical evidence of effectiveness, they are increasingly finding themselves under scrutiny.

A recent study published in JAMA Oncology examining phase 3 trials in patients with cancer showed that for all trials, the median age of participants in clinical trials was 6·5 years younger than that of patients with the disease from the Surveillance, Epidemiology, and End Results database not enrolled in clinical trials. There are efforts being made to make clinical trials more reflective of the actual pool of patients who will be treated with the drugs tested. In June, the FDA released a draft guidance promoting diversity and inclusion in clinical trials, focusing on enrolment practices, primarily through broadening eligibility criteria. It is hoped that this change will lead to clinical trials that better reflect the population most likely to use the drug once approved. Beyond the trials on which drugs are approved for safety and efficacy, post-marketing trials can be of great value to patients because of the opportunity to uncover new safety signals and provide more data about efficacy, and, as these trials tend to be less restrictive in enrolment than licencing trials, they are also more reflective of the general patient population. The recent boxed warnings of increased risk of blood clots and pulmonary embolism associated with 10 mg twice daily doses of the JAK inhibitor tofacitinib for the treatment ulcerative colitis arose from an FDA mandated post-marketing study.

There needs to be serious consideration put into how value is applied to clinical research. Cost-effectiveness should not be ignored but must be considered in a way that still provides value to both patients and additional stakeholders. Mandated, post-marketing studies should be completed and timely reported as they can have important public health implications after approval. These studies should be required as standard for novel drugs. More reflective populations enrolled in clinical trials and real-world evidence will help reassure stakeholders that the tested drugs will benefit those patients who will ultimately receive them. The right time to better serve patients by ensuring accurate reflection in regulatory studies is now.

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