The way of personalized medicines

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2340-health-1100024554-10182013Personalized medicines are not as widespread as expected. Defining and quantifying their use could be of interest to better understand the best policies to propose to aid their adoption

Caterina Lucchini

The development of personalized medicine has been limited in these years and the application and entrance in the Pharmacopaeia marker lowered than expected. Quantifying the use of personalized medicines in multiple geographical regions over time would help monitor the extent to which different policies and health care systems might support their adoption. Recently Nofziger et al proposes, to their knowledge, the first replicable, objective and longitudinal quantification of worldwide use of personalized medicines. The study includes all personalized medicines from 1998 to 2009 that met the following two criteria:

  • a medicine that has a US Food and Drug Administration (FDA) or a European Medicines Agency (EMA) label stating that its choice as a treatment must be governed by results from a companion diagnostic test;
  • a medicine that has a label that recommends (but does not require) the companion diagnostic, and at least one authoritative professional organization also recommends use of the test to guide treatment.

Based on the survey a total of 27 unique personalized medicines were identified. Of these, 22 personalized medicines were used in oncology indications, 2 were used in virology indications, and 1 each was used in metabolic, central nervous system and immunological conditions. In 2009, these personalized medicines had combined total sales of US $19.72 billion ($8.65 billion for the 8 biologics and $11.07 billion for the 19 small molecules), and accounted for 3% of global pharmaceutical expenditures. Oncology personalized medicines dominate the market representing 88% of total personalized medicine sales). Worldwide utilization of biologic personalized medicines grew from 0.13 million to 9.65 million standard units from 1998 to 2009, with an average annual growth rate (AAGR) of 48%. Interestingly, although the per capita utilization of biologic personalized medicines was initially greatest in the United States, by 2007 per capita utilization in the five major EU markets (EU5; France, Germany, Italy, Spain and the United Kingdom) exceeded the United States, and by 2009 Japan also surpassed the United States and nearly converged with the EU5 markets.

Policies in favour of personalized medicine

The development and application of personalized medicines has been more limited than hoped. Given this, a range of recent policy initiatives in the European Union (EU), the United States and elsewhere aim to more effectively address some of the issues that have hampered progress in the field. The new EU regulatory framework revises and augments legislation to tackle issues including biomarker validation, biobanking, clinical trials, protection of personal health information, funding and the value of personalized medicines. Recent guidance from the EMA integrates “genetic” end points at the earliest stages of drug development. That is, if in vitro or in vivo data indicate that >50% or >25%, respectively, of a drug is “cleared” by a single functionally polymorphic protein, the relevant gene is to be genotyped in the first-in-human study population, as well as in all consecutive phases, to avoid safety issues related to genetic differences in active substance exposure. Potential clinically relevant pharmacogenetic influences on drug pharmacokinetic properties from phase I studies must be considered in consecutive phases, either by investigating genotype/phenotype-based dosing, or by exploring therapeutic drug monitoring or biomarker guided. Moreover the European Commission (EC) has proposed a regulation for in vitro diagnostics (IVDs) that provides a new legislative framework for biomarker assays — strengthening oversight through dedicated centers throughout Europe, post-market safety, transparency, traceability and overall regulatory management. If implemented, the proposals would limit the exemption for lower-risk “in-house” IVDs by requiring that their manufacture and use occurs under the quality management system of a single health institution that is compliant with recognized standards. High-risk “in-house” tests (when failure predisposes to serious health risk) and ‘companion diagnostics’ would be subject to requirements of the new regulation.

EMA guidelines also highlight the importance of prospective DNA banking for genotyping in all phases of drug development, even when no obvious indications of a relevant genetic influence on pharmacokinetic properties or drug response exist, thus ensuring that unknown genetic variants or biochemical pathways of importance can be retrospectively identified and their clinical effects tested with adequate statistical power. Similar efforts to address such issues are in progress at the US FDA and the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan, and further global harmonization might soon be a realistic goal.

In Europe the European Commission (EC) proposed and recently approved a new EU regulation in place of the current directive for clinical trials that is important for personalized medicine, as it includes drugs targeted to a narrowly defined patient population, for which the involvement of several member states in trials may be important in reaching recruitment target. The new EU Framework Programme for Research and Development (Horizon 2020) will invest €70 billion in collaborative health research which could enable personalized medicine approaches. Another important topic is the protection of personal health information. Anonymization is impractical because traceability is required to link biomarker profiles to the disease phenotype and treatment outcomes of patients. So sufficient harmonization of data protection statutes is needed to allow safe cross-border data transfer in multinationals collaborations. The EC is modernizing the current General Data Protection Regulation to meet the digital challenges of new technologies and the harmonization data protection requirements across EU.

Last but not least, the concern that the new wave of expensive personalized medicines could overwhelm health care system. At the moment there is no unified approach on how to value a personalized medicine at individual and public-health levels. Health Technology Assessment (HTA) could be used to evaluate therapeutic benefits and economic impacts of the use of personalized medicines for individual patients and society overall. EUnetHTA is established with this aim. It is a permanent HTA network between EU member states including regional organizations and stakeholders’ representative. In addition, general initiatives that could facilitate the adoption of personalized medicine are steadily progressing in Europe, including EMA Innovation Task Force Network, the qualification of novel methods for medicines development, the provision of scientific advice through EMA working parties involving experts from Academia and the participation of HTA specialists, health-care professionals and patients’ representatives.

Bibliography

  • Nofziger C et al. Policies to aid the adoption of personalized medicine. Nat Drug Discover 2014;13:159-160
  • Sean X et al. Defining and quantifying the use of personalized medicines. Nat Drug Discover 2013;12:896-897
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