BOTTLENECKS

Cell and gene therapies demand a different perspective on procedures from all involved – from diagnosis to treatment. With these new medicines, drug developers and academic centres are wandering off the beaten track. This means they run into new obstacles.

Valuation and reimbursement

Currently, there are no cell and gene therapies available on the market that have a long track record based on which easy lessons can be learned about factors for success or failure. Discussions about costs and benefits and the level of reimbursement by insurance companies are a recurrent topic. This is due to the relatively high cost of many of these therapies, which is paid at a time when the benefits are still unclear, combined with the long development process, complex manufacturing and logistics, and often relative limited markets.
Clinical data for these innovative medicines currently fuel additional de-bate. Market access is often based on small, innovative trials involving only a few dozen patients. This means there is uncertainty about the medical and economic impact of routine clinical use of cell and gene therapy. The de-mand for more clinical data may prolong the debate surrounding reimbursement.
Finally, there is a current lack of evidence regarding the long-term efficacy of these novel technologies. The therapy is often intended as a cure, but it remains uncertain whether the effect will remain in fifteen years or longer. Insurers and companies are considering creating new regulations for payments. The idea is to spread the costs of such medicine over several years, based on the effect of the treatment for the patient.

Manufacturing, logistics and legislation

Cell and gene therapies are significantly different from traditional medicines based on small chemical substances (such as statins or pain medication) and proteins (such as antibodies and enzymes). Traditional pharmaceutical products are often manufactured at a central location at a large scale and prescribed to groups of patients worldwide. They often have a long shelf-life and are easily transported.
In contrast, medication based on patient cell materials in particular are products of which a single batch is made per person, which can only be used for a few days. This requires short lines of communication between hospitals and manufacturing facilities. This manufacturing site must comply with the strict requirements of Good Manufacturing Practice (GMP). Transportation to a central manufacturing facility across national borders places even greater demands on logistics, refrigeration, customs forms and labelling. Therefore, transporting the patient to a central treatment facility in order to avoid complex logistics is often considered.

The development, design and certification of a GMP facility for the manufacture of cell and gene therapies is a long, specialised process. Once the facility is up and running, operating a GMP facility is a significant cost item, as many procedures are performed manually. Additionally, GMP procedures require a range of unique checks and quality controls. Contamination and misidentification are particularly important to rule out for therapies that involve the patient’s own cells. Per item production and delivery of such medicines has a significant impact on the cost of therapy.
Finally, many of these new medicines are covered by regulations on working with genetically modified organisms (GMOs). An immune cell with an extra piece of DNA is seen as a GMO. This also applies to a gene therapy product with a virus-like particle. It means the hospital and the manufacturing facility must have a special permit before patients can receive such treatments. In the Netherlands in 2019, it often takes a year for such permits to be issued, while this process usually takes a few months in other developed countries. This is due to the strict Dutch interpretation of the European legislation.

Long-term and expensive research

In general, the development of new medicines is a long-term, expensive endeavour. Cell and gene therapies are no exception. Additionally, some of these types of medicines are being developed by academic centres and smaller companies, with less experience and operational possibilities than larger companies when it comes to meeting the requirements for marketing authorisation. This frequently means that the final phase of clinical research and dossier building for marketing authorisation is too great a challenge. This slows development significantly.

If marketing authorisation is successfully obtained for cell and gene therapies, it often remains unclear whether the product will succeed when competing with other, existing treatments and other medical innovations. The prolonged debates surrounding reimbursement or requirements for further clinical research may slow down the uptake of these new technologies in medical practice. As a result, poor turnover may strain operations so far that certain therapies may be withdrawn from the market. This places significant demands on the endurance of such companies.