FDA, EMA officials say diverse pharmacovigilance strategies, long-term follow-up needed for ATMPs

BALTIMORE – Advanced therapy medicinal products (ATMPs) are complex products that require diverse pharmacovigilance strategies for monitoring their postmarket safety, said officials from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) at the Drug Information Association’s Global Pharmacovigilance and Risk Management Strategies Conference in Baltimore last week.

Rob Sokolic, chief of the malignant hematology branch at FDA’s Center for Biologics Evaluation and Research (CBER), and Emil Cochino, scientific senior officer specializing in advanced therapies and hematological diseases at EMA, discussed potential pharmacovigilance strategies for monitoring the safety of these products.

Cochino said ATMPs are “game changers with enormous potential” but also are “very complex products that need strong regulatory oversight.”

At the meeting, regulators agreed that the new generations of ATMPs offer unlimited potential to offer a high unmet need for patients with few alternatives.

Long-term monitoring

Sokolic said that ATMPs are similar to traditional drug products where certain drugs are known to cause certain types of reaction. For example, beta-lactam drugs can cause allergic reactions, aminoglycoside antibacterials can cause kidney damage, and nitrogen mustard cytotoxic agents can cause myelodysplastic syndrome (MDS).

Yet with ATMPs “there are a lot more moving parts” and gene therapies can contain biochemical toxicities while cell therapies can cause biologic toxicities.

As a safety officer, he said the following factors are considered in determining the extent of safety monitoring that will be required for a product:

The toxicity of the product, and how likely the toxicity will occur;
How long the patient will be at risk of adverse events; and
How the toxicities should be measured.

Sokolic said that in using these factors, very different safety profiles can emerge for Provenge (sipuleucel-T) or Kymriah (tisagenlecleucel), which are cell therapies, and for Roctavian (valoctocogene roxaparvovec) and Lyfgenia (lovotibeglogene autotemcel), two gene therapies.

He said that for most of these products, “as long as the product is active, someone needs to monitor the long-term effects.”

Cochino said the impact of the manufacturing process on the cells and the potential for these processes to alter the product’s tumorigenicity profiles are further risks posed by these products. Other risks include the long lifespan of the product in patients and the risk of disease transmission with allogenic cells.

He noted that EMA has recommended 26 cell and gene therapies and tissue-based products since 2009. He added that among some of the recent chimeric antigen receptor (CAR) T-cell and gene therapies, products including Carvykti (ciltacabtagene autoleucel), Breyanzi (lisocabtagene maraleucel), Abecma (idecabtagene vicleucel), Zolgensma (onasemnogene abeparvovec), Roctavian, and Casvegy (exagamglogene autotemcel) will require 15 years of follow-up reporting.

Cochino also noted that elevated safety risks for six approved CAR T-cell medicines also prompted EMA’s Pharmacovigilance Risk Assessment Committee (PRAC) to conduct a review of data following reports of secondary malignancies. PRAC’s review follows a similar investigation in the US. (RELATED: FDA investigates risk of secondary malignancies with CAR T-cell therapy, Regulatory Focus 30 November 2023)

FDA, EMA officials say diverse pharmacovigilance strategies, long-term follow-up needed for ATMPs

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