Stem Cell Clinical Trials and the Challenges
The therapeutic stem cell and Advanced Therapeutic Medicinal Product (ATMP) market is continuing to develop. Over the last two years the focus of industry discussion groups within the UK has moved forward from research techniques during development to the challenges of GMP manufacturing these products. Once manufacturing issues are resolved focus will move onto the challenges of stem cell clinical trials.
The difficulties of obtaining approval from authorities to conduct the trials will be the main focus of the sponsor. With these challenges ahead, there may be little time to focus on the actual method of labelling, storage and distribution of the product to the trial sites.
Challenges of Stem Cell Clinical Trials
Phase I trials are generally conducted at a single site with a single investigator and a close relationship between the investigator and the sponsor. The investigator in these trials is often a pioneer in their field and closely involved with the development of the product.
Trials involving autologous products require collection of cells, processing of the cells and delivery back to the cell donor; this whole operation may be conducted on a single site or alternatively it may require transport to a separate site for cell processing and then return of the material to the same patient. Although the manipulation of the material and the technology to process the cells is extremely complex, the logistics of the trial are relatively simple. It requires secure traceability of the sample, obtained by following good manufacturing practice (GMP) guidelines and a validated shipper, which transports the material at the desired temperature between the patient and the processing site. Following production and labelling the material will require confirmation that it is GMP compliant; in the EU this is confirmed by a Qualified Person (QP).
At Phase II the study is likely to take place at more than one investigator site. For autologous treatments this has the added complication of more than one patient’s treatment being processed at the same time. Traceability of samples is critical and the synchronisation of patients, the manufacturing site and QP availability becomes more complex. Competent project management and good planning should overcome these difficulties. Additionally tracking systems for these samples using patient biometrics are being developed which would flag up an incorrect sample being returned to a patient.
Allogeneic products are derived from stem cells which are used to treat people other than the donor. These cells are typically manufactured in batches, on a larger scale and may be intended for use in trials in a number of countries.
One issue faced with clinical trials of ATMP products is ensuring regulatory compliant labelling. The primary containers must be labelled during the manufacture and prior to freezing.
Consideration needs to be given to the labelling process of the primary containers,once frozen to -80 or -196°C, the primary container cannot be labelled, therefore producing bulk unlabelled batches and then determining which trials the goods
will be allocated to at a later date is not possible.
Once the product is packed in primary containers (units), it may be shipped to a second site for secondary packaging, storage and distribution to clinical sites. This is similar to the logistics of more traditional pharmaceuticals.
For example, bulk batches of labelled material could be shipped from the manufacturer to a storage site. These could then be assembled into kits in a cryostorage box, containing enough material to dose one patient. Alternatively, to avoid cell wastage material could be handled with a ‘just in time’ packing method, which has proved successful in more conventional drug trials where the drug is either very scarce or very expensive.
Receipt at the investigational site would be simpler using the kit model, the site would not have to record receipt of each individual tube into inventory. In addition the secondary container could be tamper proof, giving added protection to the primary tubes. This can be particularly important if the cells are to be stored at the investigator site’s own cryostorage facilities rather than in the nitrogen shipper, as cross contamination could be a risk.
None of the issues in the clinical trial supply chain of stem cell products are impossible to overcome as long as there is consideration very early in the trial process for the method of labelling, distribution and on site storage of the product.
Even for conventional products, it is a challenge to persuade sponsors to carefully consider the clinical supply chain at a sufficiently early stage. For stem cell products this is perhaps even more essential and it will be a continued challenge over the coming years for the supply chain companies capable of supporting ATMPs to engage with sponsors at an early enough stage to ensure the provision of a service that can meet patient recruitment needs and is affordable for the sponsors.