EU official: Regulatory requirements for conditional marketing authorization ‘evolving’
BRUSSELS – Regulatory requirements for conditional marketing authorizations (CMAs) are “evolving” and more complicated than in the past in terms of demonstrating a product’s major therapeutic advantage (MTA). Regulators hold differing views on criteria for CMAs, according to EU officials who spoke at a panel on conditional approval of cancer drugs at DIA Europe 2024 on 13 March.The EU has authorized more than 55 products with CMA since the launch of the pathway in 2006; the conditional pathway was established to expedite access to new medicines in areas of unmet or serious need by allowing sponsors to market a product based on incomplete clinical data until the sponsor is able to provide more comprehensive data.
Filip Josephson of the Swedish Medical Products Agency (MPA) said that most CMAs are for oncology treatments that are late or last-line treatment and where no satisfactory treatment options exist. Josephson represents MPA at the EMA’s Committee for Human Medicinal Products (CHMP), and is a rapporteur for infectious disease, oncology, and onco-hematology products.
To qualify for conditional authorization, products must meet one of four criteria: the available data shows that the benefit and risk balance is positive; it is likely that the comprehensive data will be provided in the postmarketing phase; the drug meets an unmet medical need and represents a major therapeutic advantage (MTA) over available therapies; and the benefit of the drug outweighs the risk.
Josephson said the program differs from the accelerated approval (AA) program in the US in several ways; while the CMA is granted for a medicinal product, the AA is granted for a therapeutic indication. In addition, while the CMA is relevant due to the non-comprehensiveness of the data, whereas the AA is relevant when an effect of the drug is shown on a surrogate endpoint and clinical studies are needed to demonstrate an impact on an endpoint that represents the clinical benefit.
Douwe Postmus, assistant professor at the University Medical Center in Groningen, said that the CMA is a “controversial” review pathway, and while it “allows for timely access to potentially beneficial medicines, the CMA may also “result in unnecessary harm if postmarketing data do not confirm the expected benefits or raise significant safety concerns.”
Changing regulatory requirements
Josephson noted that the regulatory requirements for CMAs are “evolving” and that “it used to relatively simple” in demonstrating the MTA for a product. Under the traditional approach, if the objective response rate (ORR) of a product was higher than an existing therapy the MTA was “inferred” and did not have to be further justified by sponsors. Yet now, the “onus is on the applicant to provide the arguments to support MTA for its product rather than the CHMP supplying them.”
To increase their chances of getting a product conditionally authorized, Josephson urged sponsors to read the European public assessment report (EPAR) to understand the CHMP reasoning in similar cases. They should also avoid finding “hidden meanings” when regulators request sponsors justify the MTA.
Sponsors should ask for clarity from regulators if they are unsure how to address certain questions, and carefully consider that confirmatory studies provide the necessary comprehensive data.
His other recommendations are that sponsors should not use the CMA pathway to “rescue negative studies” and should pay attention to generating “strong corroborating evidence.”
Survey finds different attitudes towards CMAs
Postmus shared the preliminary findings of a survey of 39 regulators on their attitudes related to the use of CMAs in oncology. Respondents offered different views when asked to discuss the factors that influenced acceptability of CMAs.
For example, differing views were expressed on whether antitumor activity may be enough to grant CMA, whether real-world evidence is useful, whether randomized controlled trials should be ongoing, whether a CMA is better than other types of review mechanism for cancer, and whether they are more concerned about early access or toxicity of products.
Postmus said that the survey showed that there are a “wide range of views” on CMAs and that they will remain controversial.
DIA Europe
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