Biotec can assist with your Regenerative Medicine clinical trials

A high percentage of new therapies being announced and discussed in the news currently are based on stem cell products. Products derived from embryonic stem cells and adult cells are now beginning to enter the clinical trial phase of development. As research has developed in this field, so too have the regulations to control not only the use and production of the cells, but also the products derived from these cells.

The clinical trial supplies for these products needs to be conducted under similar regulations to conventional pharmaceuticals, which can be a challenge when many of the products are unconventional, and are stored at temperatures as low as -196ºC. Within this article I will assess some of the present challenges and consider some possible solutions.

The Current Regulations

In the US, the National Institute for Health (NIH) is the central governing body for stem cell research, but each state is entitled to determine its own legislation. Similarly, in the European Union, the European Medicines Agency (EMA) is the central body but each member state maintains its own national legislation.
In the US, regulation of the cell therapy products derived from stem cells comes under the responsibility of the FDA, under their Center for Biological Evaluation and Research (CBER). In Europe, EMA has the overall authority for the products, but their quality, safety and efficacy is assessed by the Committee for Advanced Therapies (CAT), a Europe-wide committee of experts, whose opinion is submitted to EMA’s Committee for Medicinal Products for Human Use (CHMP) for final approval. Due to the very specific nature of the products, the expertise required to assess the material goes beyond the traditional pharmaceutical field, covering biotechnology and often medical devices. To locate such expertise within each European member state is not currently possible, therefore unlike standard investigational medicinal products (IMP), which can be submitted to the EU country authority in which the trial will be conducted, Advanced Therapy Medicinal Products (ATMPs) must be submitted centrally to EMA.

Challenges of Trials

Having successfully developed an advanced therapy medicinal product that has clinical potential, identified a method for production, and met the initial regulatory criteria for efficacy and safety required by authorities, the product is ready for clinical trial.

Phase I trials are generally conducted at a single site with one investigator and a close relationship between the investigator and the sponsor. The investigator in trials of this type of material is often a pioneer in his or her field, and closely involved with the development of the product. The products may have been developed using the patients’ own cells (autologous) as well as products from a donor source other than the recipient. There are difficulties in the clinical supply chain with both types of material.

Trials involving autologous products require collection of cells, treatment of the cells, and delivery back to the same patient; 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 the 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 nitrogen shipper, which transports the material at -196°C 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 a Qualified Person (QP) certification and this can be the first of the obstacles to be overcome.

Often, the tests which must be satisfied to confirm that the cells have been manufactured correctly and are suitable for use (for example are free from infection), take longer than the shelf life of the product, which may only be a few days. In the EU this has been overcome by applying a similar release process to that of radioactive treatments which have a half-life shorter than the testing time. Great emphasis is placed on prevention, ensuring good GMP in the manufacturing facility. Key tests are carried out before use; the product is then certified for use in the trial and the full testing results are completed after the patient has received treatment. It is important that the Qualified Person releasing this product is experienced in the release requirements for the cells, as well as being comfortable with the principles for releasing radioactive pharmaceuticals. This experience is very different to releasing traditional pharmaceuticals or even biopharmaceuticals, and until these trials become more common, it may be difficult to find a Qualified Person able to release these products.

The requirement to have the manufacturing site, the patient and the QP all available at the same time adds considerable complexity to the process. For small numbers of patients this can be achieved, but it becomes increasingly difficult to co-ordinate as more patients are treated, and as the product progresses from Phase I to Phase II testing.

Following the successful completion of the Phase I trial, the product may proceed into Phase II. At this phase, treatment 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 even more complex. However, competent project management and good planning should overcome these difficulties.

Another issue may arise when initiating recruitment of patients at more than one site. Some treatments require devices to deliver the cells to the appropriate site within the patient. Where these devices are ‘off the shelf’ marketed equipment in that country, being used in the standard way, there is no issue. However, if a device has been used by an investigator in the US very successfully, the sponsor may prefer to use the same device in Europe, but find that it is not CE marked. Alternatively there could be a device available, but it needs to be used in a different way to its current licensed use. In the EU the use of these devices should be included in the Clinical Trial Application (CTA). Where it is a new device, and the device is determined to be a combination medicinal product, the application will be considered under the Advanced Therapy Products Directive1, rather than requiring a separate device application. Conversely, in the US a separate device application would need to be made.

For the drug developer, considering all the other hurdles and complexities they face, this issue may appear minor. However it is important to give consideration to the equipment being used to deliver the treatment, not just for its
medical capability but also for its licensing status, as it could prevent the need to submit a device application which adds cost and could delay the IMP trial proces
The other type of product is allogeneic products. These are products derived from stem cells which are used to treat people other than the donor. These cells are generally manufactured in batches and then delivered to the patient for treatment. Generally these cells have a longer shelf life and the QP certificate process for manufacture of the product can be more like that of biopharmaceuticals, with full test results available before the product is used.

Unlike autologous products which are made to order and labelled for the known patient as they are manufactured, these cells are typically manufactured on a larger scale, and may be intended for use in trials in a number of countries. The regulatory labelling requirements for ATMPs are very similar to those of other materials, but in addition they must identify the source of the cells.

Possible Solutions

There have been trials conducted in the EU where the material was produced and identified with a unique number and basic information on the primary container, but was not designated for use in a trial until after manufacture, therefore the primary label did not meet the regulatory requirements. The cells were frozen to -196ºC following manufacture and had to be maintained at this temperature until they were thawed at the trial site and injected into the patient. Applying a new label at -196ºC was impossible, as glue will not adhere at this temperature

The solution used for this material was to import the material into the EU, QP release the manufacturing stage of production, and store the material at -196ºC. Prior to dispatch to site, the required tubes of cells for the patient were selected and transferred into a nitrogen shipper which was then labelled with fully compliant labelling, in effect making the shipper the secondary packaging. The cells then stayed in the shipper at site until the patients had been treated, before returning the shipper ready for the next patient delivery.

The drawback to this method was the requirement to secure specific permission from the regulatory authority to use this method of labelling, as the primary label was not compliant. In addition, using the shipper as the secondary packaging meant that the cell transfer to the shipper and the shipper labelling had to be treated as an assembly operation, which was effectively equivalent to packing a drug kit, and therefore this required batch documents to be completed and a final QP release to be performed before the cells could be shipped. This method was possible for a small Phase I trial to a single site, but would not be practical for larger trials.

From experience to date with clinical trials of ATMPs, the sponsor defines the product as a single tube containing cells, with patients requiring a varying number of tubes to supply the clinical dose. Orders for the product are made requesting tube numbers XXX to YYY of a particular batch to be sent to the site. These are selected, put into tube carriers and sent to the site. On arrival the investigator removes the tubes from the tube holders, identifies those designated to the patient, calculates how many tubes are required to deliver the determined dose of cells and proceeds with treatment.

The process is very similar, in logistical terms, to dosing oncology patients who require titration to determine their dose, and can be translated for stem cell studies. Successful packaging and clinical supply for these trials has been performed for many years. Although many of these products are cold (2-8ºC) rather than -196ºC, the same general principles of supply chain can still be applied.

For example, kits of tubes could be prepared containing fully compliant primary labelled tubes placed into a cryostorage box. The box would be labelled with the secondary label at ambient temperature prior to the tubes being added, eliminating the issue of labels not adhering at very cold temperatures. The tubes would then be transferred to the labelled boxes as part of an assembly operation which would then be QP certified. This style of kit could be prepared in advance of an order and allows for a number of kits to be prepared and QP released at the same time, reducing QP time and therefore keeping costs low also. Furthermore, material is available for shipping as soon as an order is received.

There could be difficulties with cell wastage if there is a set number of tubes per kit, but this 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. This method does not save the QP costs, as QP certification would be required for each dispatch, but does mean the product is compliant with the labelling regulations.

Placing the materials into kits makes the logistics of the trial far simpler. However it does not address the issue of primary labelling. An option could be to print the primary labels for the trial in advance of the cells being dispensed. The tubes would be labelled at ambient temperature prior to being filled and then frozen to -196ºC. This method overcomes the issues of labels not adhering at -196ºC but would require the label text to be agreed very early in the trial phase, before manufacture has taken place.

Receipt at the investigational site would be simpler using the kit model, allowing receipt of a kit containing tubes in the range of XXX to YYY rather than having to check 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. Although long-term on-site storage is not common at the moment, as stem cell products enter Phase II and Phase III trials, storage at site will need to be addressed. It will not be realistic to send the material to site on a patient by patient basis. If the shippers are sent with a number of kits and then remain at the site acting as the storage vessel until all the material is used, they will need to be properly maintained and monitored under GMP compliant conditions. Also the company performing the distribution of the products in the trials would have to have enough nitrogen shippers and monitors available to meet the shipment demands. These are not as readily available as polystyrene-based shippers used for most other low temperature shipments, and they are considerably more expensive, and will need to be returned and cleaned before re-use. Therefore last minute changes to shipping forecasts and site initiation ahead of schedule will be more difficult to accommodate.

None of the issues in the clinical trial supply chain of stem cell products is impossible to overcome, as long as there is consideration given very early in the trial process to the method of labelling, distribution and on-site storage of the product. Unlike the more conventional trials, products cannot be over-labelled at a later date to meet regulations, although to date the regulatory authorities have been understanding and open to alternative solutions. However sponsors will be expected to comply fully with the legislation as trial procedures develop

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, but because of the academic nature of much of the research, seems likely to be one of the last considerations for the sponsor. It will be a continuing challenge over the coming years for the supply chain companies capable of supporting ATMPs to convince the sponsors to engage with them at an early enough stage to ensure the provision of a service that can meet patient recruitment needs and is affordable for the sponsors.

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