Genomic Data and Drug Development: EMA Offers New Draft Guidance

Regulatory NewsRegulatory News
| 02 May 2016 | By Zachary Brennan 

As the push for personalized medicine garners more attention, the European Medicines Agency (EMA) on Monday released new draft guidance to provide industry with more insight on how to identify and understand genomic factors that influence drug responses.

The aim of the guidance, according to EMA, is to lay out the requirements related to the choice of appropriate genomic methodologies during the development and lifecycle of a drug.


Pharmacogenomics research has revealed a number of variable genetic loci that influence drug response.

However, EMA warns that some clinical studies on pharmacogenomics have resulted in “ambiguous findings,” which highlights the importance of correctly measuring, interpreting and translating pharmacogenomic data into clinical treatment.

EMA says that some important pitfalls identified in published studies include:

  • Poor quality of the employed analytics
  • Analyses of non-relevant Single Nucleotide Variations (SNVs)
  • Analyzing somatic instead of germline DNA when germline DNA analysis is intended
  • Lack of appropriate patient selection
  • Lack of appropriate phenotype identification
  • Lack of power in relation to the frequency of the genetic variation studied
  • Non relevant endpoints selected for the basis of the study
  • Failure to take into account the pharmacology of the drug in the design of the study

In addition, the identification of genomic factors influencing variability in drug response has focused mainly on variations in genes encoding: (i) drug-metabolizing enzymes (cytochrome P450 enzymes, (CYPs), phase II enzymes), (ii) drug transporters, and (iii) drug targets (e.g. receptors, signal transduction molecules).

Guidance Details

EMA lays out its guidance on pharmacogenomic variants: phenotyping and genotyping; important issues to consider when analyzing the tumor genome, including info on the hot topic of liquid biopsies and identifying circulating tumour DNA; DNA sequencing design; quality aspects of pharmacogenomic analyses, including guidance on analytics; study design; pharmacogenomic biomarkers and translation in the clinic today; and the future dynamics of drug labels.

The guidance also includes more details on problems encountered in previous studies evaluating genetic variation in drug response, including the complex relationship between determining a phenotype vs. the identified genotype.

“With the continuing developments in genomic technologies, we also include sections on (a) emerging knowledge of epigenetic alterations and the future usefulness of epigenetic alterations in tumour DNA as predictors for drug resistance and response; (b) increasing awareness of the importance of rare mutations in drug response together with a comparison of the different methods for DNA sequencing; (c) the importance of sample preparation and methods for evaluation of mutations and Copy Number Variations (CNV) of relevance for pharmacotherapy; (d) the design of in vivo studies including randomized controlled trials (RCT) for analyses of the influence of genetic variation for adverse drug reactions and response; and (e) the translation of knowledge of pharmacogenomic biomarkers into the clinics including the relevance of pharmacogenomic drug labels.”

As far as the labels, EMA notes that Summaries of Product Characteristics (SmPCs) of about 150 drugs approved by the European Commission, mainly used in oncology, include pharmacogenomic information and for the US Food and Drug Administration, a similar number of drug labels apply.

“Furthermore, pharmacogenomic labels are of particular importance for treatments where the therapeutic index is narrow and thus where a small over-dosing poses a substantially increased risk for adverse drug reactions,” EMA says. Where possible, the SmPC should inform on important inter-individual variability in drug pharmacokinetics or response, and, to which extent, such variability may have a genetic basis.”

Comments on the draft guideline will be accepted until 16 September 2016.

Guideline on good pharmacogenomic practice


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