Regulatory Readiness and Preparedness During Companion Diagnostic Development

Key Considerations to Achieving Contemporaneous Drug and CDx Authorizations

Karin Hughes, Ph.D., SVP Global Regulatory and Quality
Authored by: Karin Hughes, Ph.D.
SVP Global Regulatory and Quality

In the realm of precision medicine and targeted therapeutics, a symbiotic relationship between drug and diagnostic co-development is essential. Collaboration across all levels of both organizations, alignment on timelines and goals, and the integration of parallel processes, are all key elements for successful commercialization. While assay development capabilities are important, for pharmaceutical companies, ensuring the regulatory readiness and preparedness of their diagnostic partner is critical and, if not managed effectively, can pose significant financial, regulatory and time to market challenges.

Beaufort offers substantial expertise in assisting pharmaceutical firms throughout the entire co-development process of companion diagnostics (CDx). This encompasses assessing quality assurance measures, such as documenting development processes and assay specifications; designing and developing analytical and clinical performance studies; and supporting consultation with the FDA and other regulators, all essential for ensuring the accuracy and reliability of the companion diagnostic. Our support extends from the pre-clinical stages to clinical trials and market authorization.

Feasibility: Aligning with a Diagnostic Partner

Ideally, pharmaceutical companies are able to identify and partner with a diagnostic sponsor as soon as the potential need for a companion diagnostic (CDx) is recognized. The earlier in the therapeutic product’s development process this partnering occurs, the easier it is to synchronize timelines and identify and address gaps, ensuring that the assay is prepared for clinical trial and that contemporaneous marketing authorizations can be supported.

As drug development and assay development follow different timelines and have unique milestones, design and authorization requirements, it can be burdensome and challenging for pharmaceutical companies to ensure that the CDx partners development processes are robust and aligned to target contemporaneous approvals. Pharmaceutical companies may not be prepared with the knowledge necessary to determine:

Beaufort recognizes the importance of rigorously evaluating how a company’s therapeutic product development program aligns with the capabilities and processes of a potential or current diagnostic partner – and offers a pragmatic approach to better mitigate risks posed by lack of regulatory readiness.

Central to Beaufort’s approach is the repeated evaluation of a CDx partner’s quality documentation and regulatory compliance preparedness against co-development milestones and timelines. This methodology allows the identification and subsequent closure of gaps, mitigating development risks and ensuring alignment between assay analytical and clinical validation strategies and the therapeutic development milestones of our pharmaceutical partners.

Assay Development: Designing with Therapeutic Milestones in Mind

In certain geographies, including both the United States (US) and the European Union (EU), the regulatory landscape for companion diagnostic (CDx) trials involves several key filings and approvals.

U.S. Considerations

In the U.S., investigational device studies are subject to the Investigational Device Exemption (IDE) regulation (21 CFR 812), even if the therapeutic product(s) in the trial is/are exempt from the requirements of 21 CFR Part 312 under 21 CFR 312.2(b). Before initiating clinical trials involving a companion diagnostic, it may be necessary to obtain an Investigational Device Exemption (IDE) from the Food and Drug Administration (FDA). The need for an IDE is based on the intended use of the CDx in the clinical trial and whether the CDx presents a potential for serious risk to the health, safety, or welfare of a subject. When an IDE is not required, the device study typically must follow the abbreviated requirements at 21 CFR 812.2(b).

Beaufort can support this determination, as well as assist in the development of justification as to why an IDE may not be needed or in the preparation of an IDE application for a significant risk device study. We also support pre-IDE meetings with the FDA to discuss the proposed CDx trial, study design, and regulatory requirements.

EU Considerations

In the EU, devices meeting the definition of an in vitro diagnostic, e.g., CDx, must comply with the requirements of Regulation (EU) 2017/746 (IVDR), including those for performance studies. If an IVD is not CE-marked for its use in a clinical trial, a clinical performance evaluation is required.  If, in the clinical trial, the IVD results will be used for medical management decisions, the performance evaluation study is conducted as an interventional study and applications must be submitted for authorization by the Competent Authority (CA) and approval by an Ethics Committee (EC) in each EU Member State where the clinical trial/clinical performance study is to be conducted. 

Here, Beaufort has prepared the documentation required to comply with the relevant In Vitro Diagnostic Regulation (IVDR) requirements as well as national application requirements and Ethics Committee guidelines within the individual Member States.

Ensuring CDx Reliability, Reproducibility, and Consistency

Before going to trial the pharmaceutical company should also have confidence that the CDx they’ve chosen can accurately identify the presence or absence of the specific biomarker(s), antibodies or genetic mutations that are crucial for selecting appropriate patients for the drug therapy being developed. The diagnostic should demonstrate reliability, reproducibility, and consistency across different testing conditions and, if necessary, laboratories. These characteristics are essential in ensuring the population identified by the assay during the Phase 3 trial is the same population identified post-approval and during commercial use. Hence, adequate assay analytical verification and stability data along with a demonstration of sufficiently robust “manufacturability” must be available in time for CDx study protocol to undergo review and approval by Institutional Review Boards (IRB)/Ethics Committees (EC). Simultaneously, applications need to be prepared, submitted, and approved by the FDA and/or EU National Competent Authorities, if applicable.

Additionally, understanding the soundness of the available design documentation pre-clinically may aid in minimizing assay changes that can lead to post clinical changes and the need for bridging studies. An effective study design will also ensure the adequacy of available biomarker-positive and –negative samples obtained during trial to provide interpretable clinical study results.

Beaufort’s extensive experience with the quality system and regulatory requirements for IVD development includes analytical protocol and report development and review, ensuring that analytical verification requirements are satisfied. We bring an understanding of how IDE risk determinations, humanitarian use or breakthrough device designations, and IVDR performance study requirements can all impact trial planning.  

Aligning Goals for Simultaneous Approvals

Clinical trial protocol development for a therapeutic product trial involving a CDx presents unique challenges, as it requires integrating evaluation of both the diagnostic test and the therapeutic intervention. Often, the CDx will inform the enrollment or management of trial participants. The design of the CDx performance study must guarantee that the data acquired during the trial are sufficient to demonstrate the safety and effectiveness of the CDx for a Class III device PMA in the U.S. and/or provide state-of-the-art clinical evidence for a Class C CDX technical documentation assessment in the EU.

Our team excels in finding that balance and collaborates with pharmaceutical sponsors and their diagnostic partners to design CDx clinical validation strategies that align with the clinical trials design and goals of the therapeutic product.

Beaufort’s approach takes into account factors that add complexity due to the use of a CDx, particularly the differences in documentation requirements that can sometimes delay or impede simultaneous approvals for both the clinical trial and the CDx performance study applications. These differences, if not understood and properly managed, can result in delayed or slowed Phase 3 enrollment, especially in the EU.

Regulatory Submission Planning and Support

A significant challenge faced by pharmaceutical companies is anticipating regulatory readiness issues throughout the process and effectively addressing identified gaps. Prior to regulatory submission, the companion diagnostic must be supported by sufficient data to demonstrate safety and effectiveness of the assay and the assay sponsor must be prepared for Quality Management System (QMS), Bioresearch Monitoring (BIMO), and manufacturing inspections. The chosen submission pathway for the CDx will not only dictate the content of the submission package but also influence the timing of the submission, as review timelines can vary.  The documentation required to support a Pre-Market Approval PMA or other diagnostic regulatory submission package is extensive, and pharmaceutical developers may lack access to suitable regulatory and medical writing staff to support the CDx submission.  

Beaufort is well-equipped to support the development and submission of U.S. PMA and De Novo Classification requests and EU Technical Documentation as well as conduct mock QMS, IVDR, BIMO and manufacturing audits and inspections to ensure the regulatory readiness of diagnostic partners.

Harmonizing development timelines to achieve contemporaneous marketing approval provides for the fastest time to market. The cost and time ramifications can be substantial when a therapeutic product is ready for regulatory submission, while its companion diagnostic is not. However, alternative strategies are available when contemporaneous approval is not achievable.

Beaufort offers extensive expertise in diagnostic regulatory affairs and CDx co-development, allowing us to tailor an alternative co-development strategy to ensure an assay is commercially available in time for the therapeutic product launch.

How We Can Help

Ensuring regulatory readiness by a companion diagnostic provider is a pivotal aspect of companion diagnostic development, ensuring CDx adherence to quality, safety, and efficacy regulations and standards while achieving contemporaneous marketing approval.

With Beaufort’s extensive expertise within the diagnostic industry and a deep understanding of the complex and evolving CDx global regulatory landscape, we offer our pharmaceutical partners invaluable insights and guidance in evaluating and coordinating with their diagnostic partner. We can conduct comprehensive assessments of their regulatory readiness, identify any gaps and provide resources to address those gaps throughout the co-development process. Our experience spans programs at every stage of development, enabling us to devise regulatory strategies that facilitate the most efficient path to marketing approval.

Contact us today to see how we can help support your current or future diagnostic project.

View all news & insights