Quality and Ethical considerations for Advanced therapy medicinal products

What are ATMPs?
ATMPs are a relatively new group of medicinal products. As a group they encompass a large variety of different individual products, but in their variety they are combined by a number of characteristics. These characteristics make them a unique class of products.

ATMPs are typically composed of biological materials and they are often designed to provide a truly personalised medicinal therapy. ATMPs are in general intended to repair or add a specific biological function in a single individual patient or small group of patients and contrary to more traditional medicines they are not intended to treat large groups of patients. Each patient is considered individually and the ATMP treatment is adjusted to the specific needs of that one person.

The purpose of application of ATMPs is in general aimed at improving the quality of life, enhance the chance on survival or even full recovery from devastating diseases such as genetic disorders or cancers for which otherwise there is no suitable therapy.

ATMPs are often made up from genetic constructs with which repair of genetic disorders is strived for, or they are made up of cells and tissues that are significantly manipulated, often by genetic modification, and that can provide genetic repair to dysfunctional tissues or that can specifically target and eradicate morbid tissues. In this article we are mainly focussing on cellular therapy products, but the discussed principles are also applicable for other ATMPs.

Chain of custody
Especially for cellular product manufacturing in the EEA the chain of custody from patient to manufacturer of ATMP and then back again to the patient needs to be considered with care and established well before production for clinical trial is initiated.

The donation of cells may take place in a hospital setting or a licensed donation centre, but the first (minimal) manipulation – e.g. cell selection by centrifugation- and storage of cells must take place at a registered tissue establishment. The next step in the process, the manufacture of the product and therewith the genetic modification and culturing of the cells, as well as other more than minimal manipulations, must be done at a GMP licensed establishment.

Often the donation centre is also accredited or licensed as tissue establishment, or alternatively the manufacturing site could be authorised as such.

For each donation of cells for further processing the donor shall be tested for transmissible diseases, this testing must be done at a laboratory licensed for this type of testing. Again, often this shall be part of the donation centre.

The product batch shall be certified for release by a QP employed or under contract by the GMP licensed manufacturing company. And after the product is certified by a QP the product shall be released for administration either by the QP, or by an appointed responsible person of the company that acts as sponsor for the clinical trial. Only after certification and release the product shall be transferred to the hospital responsible for the treatment of the patient.

Check the steps in your process and ensure that each step is performed in a manner compliant with the current regulations and ensure there are written agreements between the different players in this field.

Market for ATMPs
The promise ATMPs offer has been clear for several decades already, but only in the last 10 to 15 years ATMP therapies have outgrown the juvenile development stage and only recently some of them have been brought to the stage of marketing authorisation (for instance CAR-T). Expectation is that the importance of ATMPs will grow in the coming years and this growth could potentially be very strong.

Because ATMPs are mostly used for personalised therapies they are typically manufactured as small batches and often also in a limited number of batches.

When considering that ATMPs are to be manufactured in low numbers and considering that developing an effective advanced therapy is a complex and costly enterprise, it may not be surprising that in order to make ATMPs commercially feasible they can only be placed at the market at a considerable market price.

At the positive side for the financial profile of ATMPs it can be stated that for many of them the therapy is such that they are only produced for an individual patient to be administered once to cure the patient, or at long intervals. When successful this could give them an advantage over more traditional medicines that in general do not provide full recovery and will need to be administered regularly or even daily over very long periods, potentially life-long.

Special Quality and Ethical Considerations
ATMPs also pose special ethical considerations. ATMPs are typically designed for seriously, or even terminally, ill patients, suffering from devastating diseases for which often no other suitable treatment is available.

If the product does not meet its specifications, or when a serious deviation has occurred, then with a traditional medicinal product such event would lead to rejection of the batch, or a decision for reprocessing can be made.

For ATMPs however the product was designed and produced for a specific patient and when there is something wrong with the  product there may still be a need to treat the patient, especially when the patient was meanwhile prepared for receiving the ATMP. Aborting the therapy because of a serious process deviation or out of specification results could then lead to further degradation of the patient’s health or even an enhanced chance of mortality.

In these cases there are possibilities to justify administration of the non-conforming product, the principles for guiding such a decision are included in the EU-GMP for ATMPs. This is one of the characteristics by which the ATMPs are unique products. The process to make this possible will require the treating physician to be closely involved in the decision process and ultimately it is the doctor who has to order the product and justify its use. In the decision process alternative options for the patient and the consequences of not receiving the ATMP must be assessed for their risks and potential benefits.

Whereas compliant ATMPs are certified by a QP before release, when the product does not meet its specifications there will be close contact between the QP and the physician, completed with the QA department of the trial sponsor in case of a clinical trial, or marketing authorisation holder QA in case of authorised product. The QP, together with the Sponsor’s QA, will provide all required information to the medical team, including an assessment of risks, and prepare the batch for administration on request of the physician, but the QP shall not certify the batch. The batch can only be supplied to the physician on justification for use by the QP and sponsor QA and explicit request of the physician.

The manufacturer shall ensure that a confirmation of the treating physician to accept the product will be recorded in the batch documentation. In a clinical trial setting, the manufacturer should immediately notify the sponsor of such events. In turn, the sponsor shall inform the relevant competent authority. For marketed products, the competent authority for the batch release site shall have to be informed.

The EU-GMP for ATMPs also defines that ATMPs may be released for administration before results of all tests are collected and evaluated, again something you cannot do with classical medicinal products. When there is a need for early treatment of the patient, or when the use-by period of the product is shorter than the period required for full execution of the tests, then the administration of such product may be justified. Like with the non-conforming product the justification shall require good justification of the decision process and close cooperation between the manufacturer, the sponsor, the treating physician and the competent authorities. The QP can provide an initial certification based on the review of all batch documentation and the available results, based on the certification the product can then be released.

When all test results are obtained and evaluated then a final certification of the batch is required.

Here above some general characteristics are discussed by which the products classified as ATMPs may be considered unique in the total field of medicinal products.

Actually, even when designed as platform technique, each ATMP is an individually unique product tailored to the needs of a single patient, or for a small group of patients and that could potentially provide a cure for the involved patients.

Developing and producing ATMPs requires a specific mind-set that allows for considering taking steps that would not be possible for the classical medicinal products. It also requires that developers and manufacturers will be more close to the patient and the treating physicians then what is normal for other medicinal products.

Our specialists can assist you in many aspects related to the development and manufacture of your ATMP product. We can assist in designing a suitable quality system fitting to the specific product you are developing, help you in defining the qualification and validation requirements, help with necessary risk assessments and help with a regulatory application strategy. Progress-PME can also help you to prepare for audits and inspections to ensure you will pass these without major observations.

For more information on ATMPs we would like to invite you for a personal consultation to discuss what we can offer you.

Schematic representation of T-cell modification; e.g. CAR-T

By inserting a genetic vector specific genes will be expressed that can e.g. bring a defined group of T-cell receptors being expressed at the surface of the T-cell.