Mapping Out the Future of Regulatory Pharmacogenetics

Pharmacogenetics is the name given to the study of inter-individual variations in our DNA and how these can affect our individual responses to pharmaceutical drugs. A more individualised understanding of how drugs affect different people has the potential to promise a future of personalised medicine based on an analysis of our individual genotype where toxic side effects of drugs are greatly reduced and drugs even have a guarantee of efficacy. This article aims to summarise the current status of pharmacogenetics within the EMEA from a regulatory perspective.

It remains a startling fact to most of us that a pharmaceutical that is regarded as a breakthrough leading treatment may in fact be effective in perhaps half the population of the people it is prescribed to. Whilst the popular press would have us believe that the latest drug is the next ‘magic bullet’ treatment for everyone with the relevant indication, the reality of variable efficacy between individuals has been known to the medical establishment for decades.

In fact, the inter-individual variations in our responses to drugs are as variable as the inter individual variations in, say, our eye and hair colour – much of it boils down to our inherited genotype. Whilst inherited variations in eye colour may not affect the way we see, differences in DNA (genotype) may result in significant changes to functional proteins. Typically these might be receptors for drugs, transporter proteins that move drugs and other substances through our cell walls, or the metabolic enzymes that convert the drugs we take into something our bodies can eventually excrete.

Genetic variations between individuals clearly present a number of challenges to the healthcare sector, as not only will some drugs work not at all or only poorly with certain people, of even greater concern is the possibility that some drugs may even prove to be toxic to certain individuals. However, the nature of medical research dictates that it is best to promote a treatment that isn’t too toxic and works for a reasonable number of people, instead of waiting until the science of exactly how and why the drug works is fully elucidated before using the drug. After all, for many conditions, we do not understand what causes disease in the first place, and the exact molecular mechanisms a new drug may trigger once administered may also be difficult to unravel.

Despite the best efforts of the pharmaceutical industry, even approved drugs often have known (and unknown) side effects, and there is a trade off between the nature of the disease under consideration, the effectiveness of the drug in a clinical setting and the type of side effects that are acceptable under the circumstances. This is part of the risk/benefit assessment made by regulatory agencies based on safety, quality and efficacy. As the recent withdrawal from the market of Merck’s Vioxx pain killer drug illustrates, the formal regulatory response to documented evidence of the elevated risk of heart attacks in patients was to act decisively – the drugs came off the shelves. This is to be expected; after all, the regulatory agencies operate to maintain confidence in the marketing approvals system, and there is high profile and costly litigation to be expected where a drug turns out to have contributed to the death of patients.

But what if the unpleasant or toxic side effects of a drug only actually affected a certain part of the population? If it were possible to identify which patients will receive the benefit of the treatment but not suffer the worst side effects, then perhaps a number of existing drugs could come back off the shelves. New drugs could be targeted at specific individuals, and people would not receive prescriptions for drugs that, due to their particular genotype, aren’t any better than a placebo. This is the promise of pharmacogenomics and pharmacogenetics.

Pharmacogenetics is a term often used to describe, amongst other things, the study of our individual genetic variations and their impact on drug efficacy and toxicity. Pharmacogenomics relates to the wider study of genetic information and how it relates to the origins of diseases as well as drug development, although the terms pharmacogenomics and pharmacogenetics are often used interchangeably.

In setting out its Road Map to 2010¹, The European Medicines Agency (EMEA) describes Pharmacogenetics as an ‘emerging technology’. As is typical of promising but still-developing technologies, the regulatory framework validating the results of the pharmacogenetic healthcare establishment is itself simultaneously evolving. Indeed, only in the last few years has the EMEA started to focus on how genetic data can be applied as a factor in determining whether regulatory approval for new or existing pharmaceuticals should be given or maintained.

The EMEA has adopted a position paper² on terminology explaining what pharmacogenetics and pharmacogenomics are. The European Medicines Agency (EMEA) describes Pharmacogenetics as the study of interindividual variations in DNA sequence related to drug response and Pharmacogenomics as the study of the variability of the expression of individual genes relevant to disease susceptibility as well as drug response at cellular, tissue, individual or population level. It is further stated that the Pharmacogenomics is a term broadly applicable to drug design, discovery and clinical development, although the paper itself acknowledges that the terminology in common usage is variable and inconsistent.

Importantly, the position paper also deals with the various options relating to the manner in which patient information may handled and retained following clinical trials. This highlights a concern of certain patient groups and ethics observers; the rules concerning the collection, analysis and storage of individuals’ genetic information. Of course, pharmacogenetics cannot properly advance without knowledge of the genetic data from people taking part in clinical trials, and concerns about data protection may ultimately determine how effectively a future drug designed with pharmacogenetic considerations in mind will be prescribed. The EMEA has published a leaflet³ aimed at volunteers participating in clinical trials setting out various ways in which genetic data may be linked to clinical data, which touches on the potential conflict between maintaining high levels of privacy/data protection and the ability to provide a benefit to participants in the clinical trial based on that data.

The EMEA has also set up a Pharmacogenetics Working Party, part of the Pharmacogenetics Working Group (‘PWG’), and the objectives and rules of procedures of the working party have been set down⁴. In particular, a wider objective of the PWG is to provide the CHMP Committee with guidelines for the preparation and assessment of future pharmacogenetic elements of the regulatory submissions. Accordingly, the input of the PWG and its working party is likely to have a significant impact on the way the regulatory approvals process develops to deal with the inclusion of pharmacogenetic portfolio data.

An obvious area of concern for the pharmaceutical industry is the manner in which pharmacogenetic data will be considered by the relevant regulatory bodies. The quality and reliability of scientific data are often dependant upon more recent technologies, for example, data processed by computer analysis of hybridisation results arising from multiple microarray screenings. Pharmacogenetic information of gene expression studies is typically complex, and rarely gives a black and white answer, although this isn’t surprising bearing in mind that numerous genes may be responsible for determining particular drug interactions.

Further, if a pharmaceutical company has only acquired a limited amount of pharmacogenetic data, must it always supply such data to the regulatory authorities, whether it may wish to rely on the data for regulatory approval or not? What if the data is only available from a sub-population, or more seriously, if that data tentatively indicates that a pharmacogenetic marker indicates that toxicity may be a problem when a given drug is administered? How much weight will be given to such data by the regulatory body? When can a genetic marker be regarded as an established "biomarker" for a given drug reaction?

Inevitably, we do not yet have many answers to these questions, but the EMEA has published a proposal to allow applicants to meet with the Pharmacogenetic Working Party for the purpose of exchanging information and addressing the likely regulatory hurdles, before new guidelines and laws are set down. In March 2005, the EMEA published a Guideline on Pharmacogenetics Briefing Meetings⁵. This document sets out the manner in which the EMEA would like the pharmaceutical industry to involve itself in the development of the regulatory framework via the Pharmacogenetic Working Party.

Under the proposed guidelines, a pharmaceutical company has the opportunity to discuss various aspects of pharmacogenetics with the expert members of the Pharmacogenetic Working Party. Most importantly, the meetings are informal, and the data presented to the Pharmacogenetic Working Party regarding a current drug in development will not be formally subject to regulatory pre-assessment. Further, the Pharmacogenetic Working Party is likely to discuss with the drug sponsor various technical and regulatory issues that might cause difficulties or concerns during the initial selection of drug targets and throughout the regulatory clinical trials procedures. Accordingly, pharmaceutical companies may wish to consider such an informal forum as an important route to both refining the manner in which they gather and present future pharmacogenetic data for regulatory purposes, but also to air their concerns, and even influence the way in which the regulatory regime will address the arrival of new and complex pharmacogenetic data in the approvals process. The guideline also notes that such informal meetings regarding new drug data should take place prior to the applicant having made contact with the actual regulators, including national agencies or the CHMP.

The guideline in its current form sets out further detail both on how the Pharmacogenetic Working Party envisages meetings between it and drug sponsors proceeding, and additionally on the format of submission of pharmacogenetic data. This latter aspect of the proposal may be of particular interest to pharmaceutical companies, as the scale of these requirements may form the basis of what will actually be required under future regulatory laws. If these requirements are simply too onerous, pharmaceutical companies may well be put off carrying out pharmacogenetic based trials and research, perhaps until forced to do so. However, it is possible to envisage that in the future, for reasons of safety perhaps more than efficacy, all new drugs applications will require a pharmacogenetic section included in their marketing approval application, in addition to the current requirements of a portfolio containing physicochemical/biological/microbiological, toxicological & pharmaceutical and clinical trials data.

The EMEA is inviting comments on the current draft guideline by 30 September 2005.

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