This article is the fourth in our 2022 series, “Trends in Cell, Tissue and Gene Therapies”, which aims to help you stay informed about the wide range of legal and regulatory issues affecting companies operating in the field of regenerative medicine.
The European Union (EU) provided a harmonized legal framework for cell and gene therapies with the “ATMP Regulation” (No. 1394/2007) in 2007, but there are still many pitfalls to launch these products in the EU . The local laws of EU member states also bring another level of complexity.
In many gene and cell therapies, cells are taken from the patient at clinical centers, reshaped, and then administered as autologous or allogeneic products. This manufacturing process can present several legal challenges:
- Cells and tissues are – depending on local legislation and specific manufacturing steps – already considered as “active ingredients” of the subsequent finished drug, or only as “other components” for the manufacturing of a drug. In addition, collection at the cell/tissue or blood collection center may, in many jurisdictions, be regulated as a (first) manufacturing step, thus requiring a manufacturing license or the need to operate under the control and the license of the technical manufacturing site. This has a significant impact on the Good Manufacturing Practices (GMP) requirements that a pharmaceutical company must ensure with collection centers (e.g. testing samples for infectious diseases).
- Cells can be regulated like tissues or like blood, and this can vary from country to country. Additionally, cells taken from the human body may be regulated differently in European and local jurisdictions. Under the “EU Tissue Directive” (2004/23/EC), stem cells are considered “tissues”. For example, in Germany, where stem cells are taken directly from bone marrow, stem cells are considered tissue; however, peripheral blood stem cells fall under blood regulations. This has implications for the requirement for collection centers to be able to work under the manufacturing license of the cell-engineered biotech company or its CMO – or to fall under the requirement to have their own independent manufacturing license. . The procedures applied in local markets must be adapted accordingly.
- The supply chain from cell collection to autologous product processing needs to be properly designed from a privacy perspective due to the handling of sensitive health data (e.g. controller-to-controller (C2C) structure or controller-to-processor (C2P), information notices, contractual clauses).
- Structuring the supply chain also requires tracking various other requirements. For example, shipping autologous cells and products across EU borders or even within the EU may result in import/export issues and notification/authorization requirements. This is particularly relevant if the manufacturing steps are carried out outside the EU. The main issues for non-EU manufacturers include: entry point and local import requirements when the product is imported into an EU country (and import licenses required); flow of legal products typically through low-tax countries outside the EU and related licenses required for the first company to purchase and import the legal title of the product; the associated quality agreements; etc
Contracts should address the above concerns from both a supply chain and regulatory perspective. Education of supply agencies and treatment centers on cell collection and infusion contracts is an additional concern that needs to be planned, bearing in mind the conflicting agendas between physician pressure for access to processing and the slower inherent pace of purchasing organizations.
Gene and cell therapies are often curative, but their personalized nature can also make them expensive. Pricing and reimbursement can be a challenge:
- Statutory health insurance may not be willing to make the (often) very expensive reimbursements. In many EU countries this depends on a health technology assessment for the product to demonstrate the actual benefit of the cell/tissue product to the patient in the practice of treatment.
- Additionally, we have seen patients travel from one EU country to another EU country in order to receive cell or gene therapy treatment – or to receive it at a lower cost. This complicates product pricing across countries, especially given EU-wide reimbursement regulations.
- Companies should plan whether clinical collection centers will be paid for by health insurance or by the company.
Finally, companies operating in the ATMP space in Europe may see competition from clinical treatment centers themselves. In some EU member states, academic or non-industrial treatment centers can perform advanced therapies themselves under the interpretation of the ‘hospital exemption rule’. Thus, manufacturers of finished products may see treatment centers copying their therapy or offering very similar therapies, although the latter do not provide similar strong scientific evidence for their therapies. However, businesses can take action under local laws to prevent this. MTI manufacturers are advised to consider this issue when collaborating and contracting with hospitals in the development and use of gene and cell products.
This article is the fourth in our 2022 series, “Trends in Cell, Tissue and Gene Therapies”, which aims to help you stay informed about the wide range of legal and regulatory issues affecting companies operating in the field of regenerative medicine. From clinical studies to obtaining patents to scaling up manufacturing, our global team will discuss emerging issues arising in all regions of the world, including the unique issues of negotiation, litigation and inspections for CTGT companies.