On December 6th, 2023, EMA released a Questions and Answers (Q&As) document that aims to provide an overview of the Agency’s current line of thinking on specific issues related to predictive biomarker-guided medicinal products development and assessment including a companion diagnostic (CDx) development. This Q&As document does not address assessment requirements for clinical trial approval by National Competent Authorities (NCA) or conformity assessment of candidate CDx by a notified body but provides guidance for generating adequate data for the marketing authorisation application for medicinal products.
The Q&As aim to offer clarity on issues concerning predictive biomarker-guided medicinal product development and assessment, particularly in light of the implementation of the In Vitro Diagnostic Regulation (IVDR) 2017/746 and provides an overview of all current regulations, scientific and regulatory guidelines and procedural guidance documents that apply to CDx.
Below an excerpt of some of the questions addressed in the document:
1. What are the elements to present in drug regulatory submissions when predictive biomarker assays have been used for defining patients’ eligibility for specific treatment with a medicinal product in clinical trial(s)?
In the application form: is the medicinal product is to be used with (a) CDx within the meaning of Article 2(7) of the IVDR. If the candidate CDx has not been CE marked or submitted for conformity assessment yet, preliminary information on the possible CDx should still be provided with anticipated timelines for the conformity assessment.
In the eCTD (P.2.5 and P.5): clarify whether the assay is considered as a predictive biomarker assay for efficacy/safety of the corresponding medicinal product and specify which assay version was used in the pivotal trial(s). Further, the testing laboratories should be stated as well as their adequate accreditation should be demonstrated. A discussion on the scientific rationale for biomarker selection and methodology used for analytical and clinical validation should be provided.
In addition, information related to the different assay versions used during development and their concordance, as well as their analytical and clinical validity, may be expected (see Question 2).
Lastly, the Applicant should make a proposal to adequately reflect the target population (i.e. claimed indication for the treatment) and the study results in relevant sections of the summary of product characteristics (see question 3).
2. What are the elements to consider when more than one assay has been used to measure the same biomarker for defining patients’ eligibility for specific treatment with a medicinal product in a clinical trial intended to support drug regulatory submission?
In clinical trials utilizing multiple assays to measure the same biomarker, the principles outlined earlier apply to each assay. If the assays are intended for interchangeable use, such as different tissue-based assays or liquid biopsy as a surrogate for tissue biopsy, concordance analyses are necessary. When employing a sequential testing approach for patient selection, justification for the testing strategy is crucial. Examples include using assays with increased sensitivity or different methods with varying sensitivity and specificity (e.g., liquid biopsy followed by reflex tumour testing). The use of multiple assays with distinct performance characteristics may introduce population heterogeneity, potentially complicating the interpretation of trial results. Heterogeneity can impact the interpretability of concordance data between assays. To mitigate such issues, central testing is recommended, emphasizing the need for consideration during study design.
3. How should the information about biomarker-based assays used as companion diagnostic be reflected in the summary of product characteristics (SmPC) of the medicinal product?
Information about the biomarker should be included in relevant sections of the SmPC in line with the SmPC guideline and considering the recommendations from the SmPC advisory group on pharmacogenomics information in the SmPC.)
4. To facilitate access to medicines, can a validated assay manufactured and used only within a health institution located in the EU be used for defining patients’ eligibility for specific treatment with a medicinal product?
In accordance with the IVDR, CDx devices require a conformity assessment by a notified body to obtain CE marking and be placed on the market. Applicants are advised to plan biomarker assay/CDx development as early as possible during drug development to ensure timely access to new medicines approved for patients. Co-development of biomarker assay/CDx and drug candidate is recommended.
Devices manufactured and used only within health institutions established in the Union (“in-house devices”) are exempted from most of the requirements of the IVDR provided that a number of conditions is satisfied. Regarding the possibility of their use for defining patients’ eligibility for treatment with a medicinal product, applicants are referred to the IVDR and relevant guidance documents from the MDCG. To be noted, the use of “in-house” devices is limited to within one legal entity.
5. If the IVD assay/test is used outside its intended purpose for defining patients’ eligibility for specific treatment with a medicinal product, what level of scientific evidence is required to justify such use?
If the assay is assigned an intended purpose that fulfils the definition of an IVD according to IVDR Article 2, then it must comply with the relevant requirements of the IVDR. This is the case for assays used for defining patients’ eligibility for treatment with a medicinal product. Applicants/sponsors are referred to relevant MDCG guidance documents and advised to consult with the respective NCAs regarding IVD requirements in the context of CTAs.
In the context of drug regulatory submissions, sponsors should clarify the regulatory status of the assay(s) used in the clinical trial(s) (i.e., in-house assay, certified in other regions, CE-marked in EU under IVDD, CE-marked in EU under IVDR as CDx, device for performance study under IVDR as CDx, etc.).
If already CE-marked in EU, the sponsor should specify whether the proposed use is within or outside its prescribed intended purpose. When IVD(s) are used in the context of drug development, it is the applicant/sponsor responsibility to provide sufficient information to ensure compliance with relevant requirements of the IVDR, justify the suitability of the IVD(s) for the intended use and to allow evaluation of the robustness of data to be generated for the benefit/risk assessment of the drug and for patient safety with regards to false testing results. In that respect, adequate analytical validation of the assay should be demonstrated, and scientific validity of the biomarker substantiated with data.
6. Is a completed conformity assessment for an IVD intended to be used as CDx with a specific drug required to support the regulatory approval of the concerned drug?
From the medicine authorization perspective, sufficient documentation on the IVD assay/test needs to be provided to support the robustness of the clinical data generated. There is no legal requirement that the evaluation of the medicinal product and the device certification take place in parallel, and therefore they do not have mandatory simultaneous review periods. Early interactions between the NCA/EMA and the relevant notified body are recommended to enable timely access for patients to both the medicinal product and the CDx.
What does this mean to you?
This document provides detailed guidance for stakeholders involved in the development, assessment, and regulatory approval of medicinal products with companion diagnostics in the EU.
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