Feature: ATMP Regulations

Within the EU, these therapies are regulated as biological products. As of October 2021, 13 ATMPs have been approved by the EMA, and are being commercialised (see Figure 1). Among these are adeno-associated virus (AAV)-based gene therapies (e.g., voretigene neparvovec), CAR T (e.g., tisagenlecleucel and axicabtagene ciloleucel), and stem cell-based therapies, such as modified CD34+ haematopoietic stem cells.

Despite these approvals, the path to successful market authorisation can be challenging, requiring extensive and complex preclinical and clinical studies. ATMP development is typically faced with hurdles in three main areas: scientific, technical, and regulatory (2). A case-by-case approach is required for the first two, while regulatory challenges generally span all types of ATMPs.

ATMP developers face two types of regulatory challenges in Europe: the limited experience of European regulatory authorities with this class of medicines and the necessity to discuss with each member state the approval for both the clinical trial applications (CTA) and genetically modified organisms (GMO) legislation. While the first challenge is shared with regulatory agencies worldwide, the second is specific to the EU.

ATMPs represent a formidable challenge for which regulatory agencies are not fully prepared. These drugs are assessed based on benefit-risk analysis. Standardising regulatory requirements is complex, particularly as regulators must deal with issues not reported previously in other regulatory procedures (3). Furthermore, the field is characterised by significant heterogeneity and variation in isolation methods across the entire spectrum – from a single intravenous injection to surgical interventions (4).

With this in mind, companies and academic institutions working on ATMPs should outline a balanced development strategy – foreseeing as many potential roadblocks as possible – and prepare a comprehensive regulatory dossier to avoid additional studies to support their market authorisation applications (MAAs).

It seems reasonable that to increase the likelihood of successfully bringing ATMP therapies to market, sponsors should comply with quality and regulatory standards wherever possible and adopt a systematic approach to product development. However, based on feedback from developers working within the field, several aspects require extra care to minimise risks. These include:

This aspect should be addressed as early as possible, since it will be vital to demonstrate efficacy and safety before progressing to first-in-human (FIH) trials. The selected animal model should mimic as many critical features of the human disease as possible, and care should be taken to consider which species is best for each type of preclinical study. To demonstrate the proof of concept, the preferred option is typically rodents, while larger animals may be better suited for pre-investigational new drug (IND) studies (e.g., canine, rabbits, miniature pigs), as they better represent the anatomy and physiology of humans.

Since data is extrapolated from in vivo studies, and most gene therapy applications only involve a single injection, choosing an incorrect dose can trigger safety concerns. To minimise this issue, developers should use the lowest dose that provided a good safety profile during in vivo studies and consider enrolling only a small number of participants into initial clinical trials. Alongside this, it is essential to consider the immunogenicity profile of those enrolled; developers must decide whether it is better to consider neutralising antibodies or overall IgGs in trial participants – achoice entirely dependent on the therapeutic indication. The cut-off point to determine the threshold for subject enrolment is also delicate. This is due to a lack of official guidance by European regulators as to which antibody titres are detrimental for the gene therapy of interest.

Wherever possible, developers should use fully traceable and certified materials from animal or human sources, since regulators may require this information if safety issues arise during clinical assessment. In addition, the guidelines on GMP specific to ATMPs from the European Commission (EC) state that “a system enabling bidirectional tracking of cells/tissues contained in ATMPs from the point of donation to the delivery of the finished product to recipients should be created. This system should be established from the beginning of batch manufacturing for clinical use” (5).

Assay validation is critical to identify off-target effects that may lead to unwanted genome instability events, such as chromosomal translocations. US developers expect FDA guidance on this before the end of 2021, but, to the best of our knowledge, there is no official release date for similar guidelines in Europe. Next-generation sequencing technologies are expected to be paramount in helping address this safety risk. However, these platforms will need to provide unbiased results in terms of sensitivity and reliability. Meanwhile, other unbiased genome-wide approaches are available to detect off-target events (e.g., GUIDE-Seq, CIRCLE-Seq, etc.). These approaches can be validated and quantitated using targeted amplicon sequencing with primers designed for the genomic loci involved (6).

Not doing so would likely lead to delays in the initiation of Phase III clinical trials due to material comparability concerns. Developers should focus on validating a suitable potency assay as early as possible during programme development since this is the best way to ensure material comparability.

A well thought-through CMC process must be defined early on. Careful evaluation of critical quality attributes, safety, identity, strength, purity, and quality of the ATMP is recommended, and a comprehensive risk assessment should be ready for the ongoing programme. Relevant considerations include:

The EU’s legal and regulatory framework can be a major hurdle for developers, since it requires dealing with each member state individually. These hurdles occur at two key points: the approval of CTAs and the assessment of GMOs.

Thankfully, the process of CTA approval is about to become much more straightforward. It is expected that from 31 January 2022, the Clinical Trials Regulation (EU) 536/2014 will come into effect. This will mean that once approved, the assessment and supervision processes for clinical trials will be harmonised among all member states, promoting a favourable environment to conduct clinical trials in the EU. This efficiency is possible thanks to the completion and independent audit of the Clinical Trials Information System (CTIS) (7). The CTIS contains a centralised EU portal and database for clinical trials, and will be maintained by the EMA in collaboration with all member states and the EC. The regulation is expected to be in full effect by January 2025, once the three-year transition period for ongoing trials ends.

These regulatory innovations will overcome the biggest hurdle in the EU for clinical development: the necessity to deal with multiple regulatory authorities regarding the best way to approach clinical phases. In addition, it is expected to streamline CMC considerations and trial design, removing uncertainty and facilitating the process of preparing a final trial protocol, dossier, and related paperwork.

Unfortunately, this is not the case with the EU’s GMO legislation, such as Directive 2001/18/EC. Before any clinical trial for an ATMP can start, developers must comply with this legislation, which each member state applies in different ways.

Different assessment processes, timelines, and outcomes exist across the EU, since the directives are transposed with variations and a lack of clear operational methodology about when to apply for the GMO and clinical trial legislations. This lack of consistent application of the methodology is particularly challenging when it comes to the management of multi-centre clinical trials, as these tend to involve several member states, meaning approval must be sought from each one (8). The result is a lengthy application process that causes significant delays in the initiation of clinical trials while creating frustration for patients because they cannot access ATMPs in a timely manner.

The varying implementation of the GMO legislation makes the EU less attractive to conduct clinical trials, while having other associated consequences, such as the need for additional financial resources.

Developers should take advantage of all communication opportunities and support offered by the EU to interact with regulators (see Figure 2, page 55).

The EU-Innovation Network provides additional support, addressing early regulatory gaps by offering a platform to share best practices and improving the flow of knowledge derived from emerging therapies and technologies to national competent authorities and EMA scientific committees (9). The network is spread throughout the EU and overseen by the Heads of Medicines Agencies and the EMA.

Developers can request scientific advice and protocol assistance at any stage of the development process for those focusing on orphan diseases. However, requesting such help is perhaps more advantageous early on. It can help define, and refine, the types of assays to be conducted before the IND process and discuss clinical development, CMC strategies, and other related matters. The goal is to find the best way to generate robust information to demonstrate efficacy, safety, and good quality to support the programme of interest. For human medicines, assistance is given by the Committee for Medicinal Products for Human Use on the recommendation of the Scientific Advice Working Party (10).

Additional meetings can be arranged between developers and the competent authority during clinical development, including the end of Phase Ia and Phase II meetings, and during a presubmission meeting before proceeding to the MAA process. These will help avoid delays and the possibility of having to generate additional data for regulators.

As ATMP developers continue to innovate scientifically and medically, global regulators and industry groups are working tirelessly to keep pace with innovative guidance and regulatory frameworks to ensure the health and safety of their respective populations. The results will be streamlined review and approval, and faster access to these life-changing medicines for patients.