Translation and Reimbursement: The Twin Challenges for Cell and Gene Therapies Reflections of an Ex-Regulator.

Abstract

NOT A DAY GOES BY without news related to a scientific advance involving cell and/or gene therapies (also referred to as advanced therapy medicinal products, or ATMPs, in the European Union) for various poorly met medical needs. Per Clinicaltrials.gov (16 August, 2016), there are more than 9,700 studies that involve either gene therapy or stem cell therapy. However, there are two aspects of development of these products that could pose significant challenges to make them successful therapeutic reality. The first potentially challenging aspect is early translation to clinical studies. Traditional approaches to medicine development for early phase human studies that have evolved from small molecule chemicals are usually not very helpful for many reasons. Healthy volunteer studies may be difficult to carry out for ethical and scientific reasons. For example, it might not be feasible to administer the test product if the intended clinical use involves direct delivery into an organ. When planning studies in patients, a control (e.g., placebo) arm may or may not be acceptable for similar reasons. Another significant challenge is dose-finding studies, which are usually only possible in patients. It is not generally ideal to give suboptimal doses to patients, as many of these products are for single administration only. Further, factors such as immunogenicity could make it impossible for those patients to receive the therapeutic dose at a later date. Many such therapies are being developed for rare diseases such as inborn errors of metabolism. As there are limited numbers of patients who will be eligible and willing to volunteer for a clinical trial, this puts additional emphasis on getting it right for the design and strategy of clinical development as a whole. While regulators are sympathetic and realistic about these factors, the combination of a complex therapy such as geneor cell-based therapies and a rare disease can make evidence generation that is robust and reproducible for regulatory approval difficult. The second significant hurdle for successful commercialization of these products is the issue of reimbursement. The complexity of manufacturing these products requiring highly skilled professionals and the regulatory requirement for strict quality control can have a significant impact on the cost of manufacturing. This will inevitably need to be recovered through appropriate pricing and reimbursement. Establishing such a complex facility for a rare disease indication can add to the pressure, as it will have additional impact on pricing. Another important factor to consider is transport and storage. Some of the autologous products may need to be prepared and administered close to the manufacturing site, which will require patients (and parents in cases of children needing the product) to travel to receive the product and stay close to the site for a certain period following administration, further increasing the expenses thus incurred. The challenge for health technology assessment (HTA) bodies for these products is significant. Since these products are typically developed for chronic and/or serious diseases, evidence for realworld effectiveness over time will be needed. As