Euro Roundup: EMA seeks feedback on assessing the cardiovascular safety of cancer drugs

The European Medicines Agency (EMA) has published a draft reflection paper on investigating and assessing the cardiovascular (CV) safety of oncology medicines.

EMA published a reflection paper on assessing the CV safety of medicines in general in 2016 and shared a guideline on the clinical evaluation of anticancer medicinal products in 2019. International Council for Harmonization (ICH) guidance on safety pharmacology studies for human pharmaceuticals also applies in Europe. Yet EMA said none of the texts specifically address the CV safety of anticancer medicines.

“This has become increasingly important due to the rising incidence of CV toxicities associated with cancer therapies due to several factors,” EMA said. “These [include] the increased age at which cancer treatment is received, the presence of concomitant CV risk factors, and the emergence of anticancer medicinal products with new mechanisms of actions associated with relevant CV side effects.”

About one in three people taking cancer drugs experience CV toxicity, according to EMA, and the adverse events pose significant challenges for patients and healthcare providers. Attempts to characterize the CV safety profile in clinical trials are often complicated by the lack of a comprehensive baseline toxicity risk assessment, enrollment criteria that exclude high-risk patients, prior therapies, and small sample sizes.

In response, EMA has recommended a tailored, risk-based approach characterized by two extremes of CV risk. The approach considers a new molecule to pose a minor CV risk if it is part of a well-established pharmacological class with no known CV safety concerns. At the other extreme, the approach considers a molecule to pose a substantial risk if its class or mechanism is new and data suggests potential toxicity.

Developers of products that pose a substantial or, because of a lack of data or the novelty of the class, an unknown CV risk should conduct more detailed safety assessments. EMA said companies should consider whether a more detailed assessment is warranted when planning registration trials and take steps to better estimate the overall clinical effect of the candidate in the target patient population.

“For the low-cardiac risk category of anticancer products, safety monitoring during clinical experimentation supported by a clinical and nonclinical evaluation of the QT/QTc interval prolongation and pro-arrhythmic potential may suffice, unless CV safety signals do emerge that would require further characterization,” EMA said.

EMA expects its proposed systematic approach to collecting, assessing, and managing CV toxicity in oncology trials to improve patient safety by enabling early detection and management of adverse events. Other anticipated benefits include improved profiling of treatment-related cardiotoxicity that can inform an appropriate risk-based strategy to manage CV risks once a product comes to market.

The draft is open for comment until 31 July.

Reflection Paper

After pushing back against Pfizer feedback, EMA finalizes advice on excipients

EMA has finalized a question-and-answer document about co-processed excipients (CoPEs) used in solid oral dosage forms.

Coprocessing covers actions such as spray drying that process two or more excipients together. While coprocessing can improve functionality, EMA sees quality control, formulation development, and stability risks that are not present when excipients are used individually. The agency released a draft Q&A about its risk-based approach to co-processed excipients for consultation in September 2024.

Since closing the consultation at the end of 2024, EMA has assessed and incorporated feedback from organizations including Pfizer, Teva Pharmaceuticals, and excipient trade group IPEC Europe. EMA rejected many proposed changes.

Pfizer proposed an alternative to EMA’s overarching approach. Instead of risk categorization, Pfizer said companies could ask excipient suppliers to provide the full composition and assay of all components in the certificate of analysis. The company proposed relying on information about the control of critical manufacturing steps when assay information is missing. EMA disagreed with the proposal.

“The concept of risk categorization should be seen as a means of making sure that an appropriate level of information is available to both the product manufacturer and the agencies. As most examples of use of CoPEs are expected to fall under low risk, the risk categorization is essential to the proposed QA,” EMA said.

Teva told EMA the Q&A imposes a significant burden on submission documentation when a co-processed excipient is bought from third parties. According to Teva, it can be very challenging to obtain information on the manufacturing process description, flowchart, and analytical methods and validations because excipient suppliers often keep the information confidential for competitive reasons.

EMA did not accept the comment. The requirements are proportional to the risk of a CoPE, EMA said, and the applicant should have adequate knowledge and control of the co-processed excipient considering the impact it could have on its finished product. The required information should be available when a confidentiality agreement is in place, EMA said.

The Q&A will come into effect on 1 August. An excipient guideline revision is on the workplan at EMA’s Quality Working Party. EMA referred to the planned revision when a respondent questioned the suitability of a Q&A for laying down dossier requirements.

EMA Q&A

EMA shares general principles for product lifecycle management documents

EMA has published general principles about the use of product lifecycle management (PLCM) documents to facilitate global harmonization of post-approval chemistry, manufacturing, and controls changes.

ICH Q12 covers the scientific and technical content of PLCM documents. While the files are optional in the European Union, EMA said “it is recognized that having a globally harmonized tool to facilitate lifecycle management activities can be beneficial for applicants.” The Q&A supports the use of PLCM documents in the EU by explaining the submission process, content, and handling of future variations.

Companies submit the PLCM document via a Type II variation procedure and include the file in Module 3.2.R of the common technical document, which covers regional-specific quality information. The PLCM document location within the quality dossier could change as part of the ongoing revision of the ICH M4Q(R2) guideline.

The PLCM document can cover the full quality dossier or be limited to specific manufacturing steps, analytical procedures, or sites. Companies should clearly state the scope of the document in their variation submissions. In practice, EMA expects companies to use the file for specific information.

EMA Q&A

European Pharmacopoeia Commission adds crab-free endotoxin testing option

The European Pharmacopoeia Commission (EPC) has added a synthetic method to its options for testing for bacterial endotoxins, providing companies with an animal-free alternative to the standard approach.

Laboratories have traditionally used limulus amebocyte lysate (LAL) methods to test for endotoxins that indicate the presence of Gram-negative bacteria. LAL reacts with components of the bacterial capsule to detect and quantify endotoxins. LAL is extracted from horseshoe crabs, spurring interest in alternatives that do not involve animals.

In response, EPC has added a fluorometric endpoint method using recombinant factor C to its general chapter on bacterial endotoxins. As a synthetic, animal-free solution, the test can reduce dependency on horseshoe crabs for detecting bacterial endotoxins. EPC adopted the test after reviewing evidence of its equivalence to traditional LAL methods.

The European Directorate for the Quality of Medicines and HealthCare (EDQM) also clarified its position on recombinant cascade reagents. EDQM called the methods promising but cautioned that they are still in the data-generation phase.

EDQM Notice

Euro Roundup: EMA seeks feedback on assessing the cardiovascular safety of cancer drugs

Related topics

Recommended content

Welcome to the new RAPS Digital Experience