Navigating the path to conditional approval: avoiding pitfalls in oncology drug applications

This blog is part of The Regulatory Navigator series, where we explore the evolving regulatory landscape with actionable insight from Parexel's experts, sharing their experience to maximize success for clinical development and patient access.

In the European Union, conditional marketing authorization (CMA) provides a regulatory pathway to bring promising new oncology drugs to patients sooner, based on early evidence of efficacy and safety. However, applying for and obtaining a CMA comes with unique challenges due to the limited data available. 

Our recent paper, published in the British Journal of Clinical Pharmacology, outlines common pitfalls drug developers should avoid when pursuing this accelerated approval route and recommends ways to improve the process. Here, we summarize our key findings and share suggestions for optimizing this approval pathway. 

Understanding CMA requirements

Starting with the fundamental requirements, a new oncology drug must meet four key criteria listed below to be eligible for a CMA:

1. Demonstrate a positive benefit-risk balance
2. Address an unmet medical need 
3. Provide immediate public health benefits that outweigh the risks of limited data
4. Commit to providing comprehensive confirmatory data post-approval

While these requirements may seem straightforward, there are nuances that applicants often misunderstand. For example, demonstrating an unmet need is more challenging when existing treatments are available. In these cases, the new drug must show a "major therapeutic advantage" - either superior efficacy/safety or by significantly expanding treatment options (e.g. a novel mechanism of action).

The "comprehensive data" requirement also causes confusion. This refers to generating the level of evidence typically needed for full approval, not necessarily conducting randomized controlled trials (RCTs) in all cases. The specific studies needed depend on the uncertainties that must be addressed.

Common pitfalls to avoid

There are several mistakes that oncology drug developers frequently make when pursuing CMAs1 

• Trying to "rescue" failed studies: Promising post-hoc analyses from negative trials are generally not sufficient for CMA. Well-planned exploratory studies with strong signals are more convincing.
• Seeking approval too early: CMAs are successful when confirmatory trials are already well underway at the time of submission. This helps ensure timely completion of post-approval commitments.
• Overestimating the value of response rates: Superior tumor response does not automatically constitute a "major advantage" without evidence of clinical benefit. Surrogate endpoints require careful justification.
• Equating non-randomized with non-comprehensive: Single-arm trials can sometimes support CMAs, while RCTs may still leave uncertainties. Focus on addressing key questions rather than study design alone.
• Inadequate communication of uncertainties to different stakeholders: Clear, ongoing communication about remaining questions and how they will be addressed is crucial for informed clinical decision-making.

The EDGE framework for improving CMA applications

To help sponsors navigate these challenges, the "EDGE" framework for developing a comprehensive evidence-generation strategy is proposed:

This approach emphasizes proactive planning of a CMA rather than reactive submissions based on unexpected findings. With an integrated evidence planning approach, mapping out evidence needs, decision points, and stakeholder engagement from the start, developers can optimize their chances of successful CMAs.

Key elements include:

• Initiating confirmatory trials before or soon after the initial CMA submission
• Prospectively defining decision rules for key development choices
• Seeking early scientific advice from regulators and other stakeholders
• Developing a comprehensive plan to address uncertainties over time
• Creating educational materials to clearly communicate limitations of early data

Improving communication is critical

One of the most important recommendations is to enhance communication about CMAs to patients, healthcare providers, and other stakeholders. While CMAs are currently flagged in product information, more extensive educational efforts are needed. We suggest developing tailored materials that:

• Explain remaining uncertainties and how they are being addressed
• Provide context on the strength of available evidence
• Offer guidance on clinical decision-making given limited data
• Share patient preference information when available
• Give regular updates as new data emerge

By improving transparency around the limitations of early approvals, developers can support more informed treatment choices and maintain public trust in the CMA pathway.

Conclusions and recommendations

Conditional marketing authorizations play a vital role in accelerating patient access to promising new cancer therapies. However, obtaining a CMA requires careful planning and execution. By avoiding common pitfalls and embracing a comprehensive, stakeholder-engaged approach to evidence generation, oncology drug developers can optimize their chances of success.

The EDGE framework provides a roadmap for building convincing CMA applications that address key uncertainties over time. With improved communication about the nature of conditional approvals, this pathway can continue to serve patients while maintaining rigorous scientific and regulatory standards.

Ultimately, a well-planned CMA strategy that generates the right evidence at the right time benefits all stakeholders - providing earlier access for patients in need, while ensuring thorough evaluation of benefits and risks over the product lifecycle. By learning from past challenges and embracing best practices, the oncology community can fully leverage CMAs to accelerate innovation responsibly.

Parexel’s Regulatory Consulting group interprets evolving regulatory requirements, prepares robust submissions, and effectively manages interactions with regulatory agencies, ultimately helping to bring innovative therapies to patients more efficiently and effectively. Please contact us  to further discuss on how we can support your drug development.
 

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