Comments on 'Concept paper on predictive biomarker-based assay development in the context of drug development and lifecycle' (EMA/CHMP/800914/2016)

Comments from:

Institute for Quality and Efficiency in Health Care (IQWiG)

Please note that these comments and the identity of the sender will be published unless a specificjustified objection is received.  When completed, this form should be sent to the European Medicines Agency electronically, in Word format (not PDF).

1. General comments

IQWiG appreciates this guideline development project, replacing the draft “Reflection paper on co-development of pharmacogenomics biomarkers and Assays in the context of drug Development” (2008), because it addresses a relevant topic in patient care and the area of a so-called personalised or precision medicine. From our HTA perspective we suggest that the guideline will not only discuss biomarker-based assay development but recommend a comprehensive methodological framework to evaluate safety and clinical benefit of combined diagnostic and therapeutic measures. This should be done by incorporating the content of the “Reflection paper on methodological issues associated with pharmacogenomics biomarkers in relation to clinical development and patient selection” (EMA/446337/2011, draft version). Please see our specific comments for further details.

2. Specific comments on text

Lines 4 - 6

Comment: The wording of the guideline title “… biomarker-based assay development in the context of...” seems to suggest that it is feasible to generate conclusive evidence concerning the benefits of diagnostic test and drug treatment components separately.

Proposed change (if any): To prevent such a misunderstanding, the guideline title should better express this close companionship in the process of biomarker-based assay and drug development and the subsequent benefit and safety assessment.

Lines 36 - 40

Comment: We agree that independent and uncoordinated development of drugs and IVDs results in evidence gaps relevant for regulators as well as for HTA bodies. However, we suggest that the scope of the guideline should not be limited to assay development. From an HTA point of view the problem statement should also include the requirement of studies designed to demonstrate the (additional) clinical benefits of the overall biomarker based diagnostic / medicinal product treatment strategy. Therefore, we suggest to integrate the content of the “Reflection paper on methodological issues associated with pharmacogenomics biomarkers in relation to clinical development and patient selection” (EMA/446337/2011, draft version) and the content of the current concept paper in one guideline covering both drug and associated assay development.

Proposed change (if any): Include biomarker-based medicinal product development in the problem statement. Incorporate updated content from draft reflection paper EMA446337/2011.

Lines 53 - 55

Comment: We take the view that it will be crucial to have detailed sections in this guideline part dealing with study design issues (e.g. as outlined in draft reflection paper EMA/446337/2011). It should be pointed out that it is not only desirable but feasible and necessary to conduct RCTs in the clinical co-development programs in order to demonstrate relevant treatment – marker interactions accompanied by relevant clinical benefits through stratification, see e.g.

Saad ED, Paoletti X, Burzykowski T, Buyse M. Precision medicine needs randomized clinical trials. Nat Rev Clin Oncol. 2017;14(5):317-23.

We suggest that the guideline will recommend not only the currently predominant study type (Enrichment design), but also discuss e.g. Randomise-all designs, Biomarker-strategy designs and Hybrid-Designs which all can contribute to answer relevant research questions (prognosis, treatment effect, treatment x marker interaction, effect of testing). The guideline should thereby inform about the different scientific conclusions which can be drawn from results of the various types of study design.

Proposed change (if any): Add new sentence in line 55: “As study design issues are very relevant for a linked biomarker-based assay and drug development, the guideline will consider these aspects in depth.”

Lines 55 - 60

Comment: From an HTA perspective technical validation of a biomarker-assay is a basic and necessary but not a sufficient step in the chain of evaluation. The clinical co-development phase can and should be used (see ref. Saad et al.) to generate evidence on the clinical utility of the diagnostic test = predictive biomarker-based assay in conjunction with the drug. To gain high-quality evidence on the clinical utility it is again important to recommend here adequate (randomised) study designs.

Lines 65 - 67

Comment: We support this idea and framework for subsequent concordance studies of new biomarker-based assays.

Lines 72 - 75

Comment: We support this proposed inclusion of information in the SmPC of the drug.

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