Where do the ATMP RA/CMC challenges arise?
Introduction
The complexity of producing gene and cell therapy products (CGT)) can be daunting, requiring extensive knowledge of biochemistry, molecular biology, and bioengineering. However, as technology advances and more companies enter the market, the costs and complexity of manufacturing these products become more manageable. The rapid viral vector corona vaccines development in 2021, the approved gene therapy rAAV-based therapies (Zolgensma®, HEMGENIX®), and the CAR-T cell therapies (E.g., Kymriah®; Yescarta®; Tecartus®; Carvykti®; Breyanzi®, Abecma®) showcase the success stories and the tip of the iceberg of the progression of Advanced Therapeutic Medicinal Products (ATMPs). As we learn along the line, many important questions have been addressed at Federal Drug Agency (FDA)/European Medical Agency (EMA)-raised questions and answers, FDA/EMA position statements, FDA/EMA reflection papers, and best practice guides (e.g., guidelines from PDA, ISPE, PIC/S).
The large(r) ATMP knowledge base and the great patient need often enable pushing for accelerated (e.g., fast-track) drug-approval tracks at medicine agencies. However, accelerated tracks raise the pressure on the drug development program and the team as many strategic decisions need to be done early on while maintaining oversight of many simultaneous projects influencing each other. Progress consultants have guided many pharmaceutical companies – with their experience, network, and industry best practice guides – on reducing manufacturing challenges, eliminating bottlenecks for speedier market access and turnaround times, and helping in finding the right strategy. In the upcoming four publications, we first review manufacturing risks found in the industry, then have a closer look at the cGMP of ATMPs and their challenges, and finally give an outlook on how to address and prioritize the challenges.
Regulatory challenges
ATMPs have the promise to bring long-lasting therapies to patients, but many ATMPs struggle in the development stages. Where does the challenge arise? Challenges mainly occur in Regulatory Affairs, followed by technical and scientific issues (Ten Ham et al., 2018, 2020. Figure 1). Remarkably, they found no differences in clinical success between ATMPs, small biologics (e.g., antibodies), or small molecules. It indicates that ATMP development is not so much hindered by mode-of-action. Rather, ATMPs scored poorly on regulatory success, which was linked to country-specific regulatory challenges. This matches the real-world data that approval across countries or continents is extremely complex, especially in the EU (Liu, 2022). Furthermore, EMA’s post-authorization procedure requires companies to negotiate reimbursement schemes for ATMPs in the EU member states. If a company fails to achieve a reimbursement scheme, EMA may withdraw the product from the country. This may have been the main reason why 24 ATMPs have already been withdrawn within the EU versus none in the US. Moreover, both US & EU manufacturing companies, have struggled with the reimbursement of out-of-spec (OOS) CAR-T products – a common phenomenon found in 5-20% of all batches (Liu, 2022). Failure to meet FDA commercial specifications generally excludes a product from being reimbursed by health insurance. This is especially problematic as many OOS CAR-T products have the potential to attack cancers efficiently and have presented no additional safety risks to very sick patients (on top of an overall CAR-T drug shortage).
Figure 1. Developer-reported challenges in the European ATMP development. Industry questionnaire in Europe (based on Ten Ham et al., 2018).
Another example of legislators’ impact on ATMP production comes from the requirements to fulfil the strict exclusion criteria on patients. Many gene therapies, such as rAAV-based ones, have strict patient exclusion criteria e.g., neutralizing antibodies, requiring the development of fully validated diagnostic tests for late-stage clinical. For example, BioMarin Pharmaceutical Inc. uses the AAV5 DetectCDxTM (ARUP Laboratories) medical device to screen eligible patients with severe haemophilia A. Many gene therapy companies experience it as challenging to develop these tests because of validation studies (showing precision, accuracy, cross-reactivity, reagent stability, seroprevalence, linearity, detection, and capability) but even more so on establishing clinical validity of the device in clinical trials.
cGMP
The regulatory oversight changes from pre-clinical studies (GDL, GLP) to phase I (Good Scientific Principles) to phase II/III (cGMP, ICH Q2-14, 210, 211, 600s, 820s.). Over the years, ATMPs have received tailored current Good Manufacturing Practice (cGMP) guidance documents from health agencies (EudraLex Vol. 4 Part IV) stemming from unique risks and uncertainty. For example, small trial sizes (limited statistical power to predict adverse events), small batch sizes (limited process robustness information), limited manufacturing experience (less information on e.g., impurities), the drug’s tendency to stay permanently in the body increases the chance of immune responses (immunogenicity), and the potency of the (cellular) drug to differentiate into other cells (tumorigenicity and excretion of toxic proteins). The origin of the risks can be traced back to the pharmacologic aspects of ATMPs compared to small molecules or (small-sized) biologics (physicochemical properties, pharmacodynamics (PD), and pharmacokinetics (PK)). Also, ATMPs tend to rely more on animal model drug biodistribution profiles and immune response profiles rather than the classical PK studies of small molecules.
Nevertheless, health organizations also addressed risks and uncertainties with extensive overall quality risk management (updated ICH Q9(R1), 2023), more ATMP-related viral safety risks (ICH Q5A(R2), under review, 2023), and contamination control strategy risks (updated EudraLex Vol 4, Annex 1, 2022). The guidelines complement the ATMP guideline to tailor the Chemical Manufacturing Control (CMC) dossier on risk management on the individual product and unique production processes and do not exempt ATMPs from the cGMP.
This is part 1 of our four-part publication series. Here you can read the second article.
References
Ten Ham RMT et al. (2018). Challenges in Advanced Therapy Medicinal Product Development: A Survey among Companies in Europe. Molecular Therapy – Methods & Clinical Development, 11:121-130.
Ten Ham RMT et al. (2020). Development and Regulation of Gene and Cell-Based Therapies in Europe: A Quantification and Reflection. Trends in Pharmacological Sciences, 41(2): 67-71.
Liu A (2022). Cancer center leaders lay bare CAR-T makers’ struggles—and an unexpected laggard. Fierce Pharma. https://www.fiercepharma.com/pharma/johnson-johnson-bristol-myers-kite-pharma-car-t-cell-therapy-struggle-sloan-kettering
