* Summary of discussions at the CIOMS Working Group Meeting on Pharmacogenetics and Pharmacoeconomics, held from 11-15 September 2001 at the World Health Organization, Geneva, Switzerland.

Recent progress in unravelling the secrets of the human genome has led to increased knowledge of genetics in many fields of medicine and supports the promising development of two new branches of science - pharmacogenetics and pharmacogenomics. Pharmacogenetics refers to the study of DNA sequence variation as it relates to differential drug response of individuals, i.e. the use of genomics to determine an individual’s response. Pharmacogenomics refers to the use of DNA-based genotyping in order to target pharmaceutical agents to specific patient populations in the design of drugs.

Pharmacogenetics - genetic factors affecting a patient’s response to drugs - promises to change the way health care is practised. Increased understanding of genetic mechanisms responsible for drug response, non-response and toxicity offers new possibilities of meeting the needs of health care systems and the demands made upon them. For the individual patient, quality of life can be enhanced by improved selection of the most effective drug at the appropriate dose. Although pharmacogenetic diagnostics will increase the cost of health care initially, this is expected to be offset by the savings made in reducing the occurrence of unnecessary and inadequate drug use and adverse drug reactions - in particular those which are dose dependent. Getting the right drug at the right dose to the right patient first time and avoiding a “try and see” method will also reduce the number of visits to the physician.

Application of pharmacogenetics to drug development will also streamline the drug development process. It affects both pre-clinical drug development studies and, even more, clinical research. With more focused stratification of patient groups it is possible to make narrow, more specific indications. Such indications will apply to those diseases having certain established and clearly measurable features, such as multiple sclerosis. Given that such patient groups may not always represent commercially attractive markets for the pharmaceutical industry with current marketing paradigms, strategies will have to be remodelled. The ability to target patients more accurately, however, may represent considerable commercial value within a specific market sector, such as hypertensives.

Additionally, health care policies and structures must ensure that any short-term budget constraints are not allowed to take precedence over mid to long-term benefits. To realize the potential of pharmacogenetics, tailored communications and educational programmes will be necessary for key stakeholders - patients, patient groups, health care professionals, regulators, the health care industry and the biotechnology, pharmaceutical and diagnostic industry, health care funding and reimbursement organizations, governments and academia. Pharmacogenetics is likely to be introduced according to need, clinical validity and value, with resources first being directed at diseases for which it is vital to prescribe the right drug at the right dose from the outset.

The practice of drug therapy is confronted with two major problems: adverse drug reactions and non-response to treatment. Adverse drug reactions (ADRs) contribute substantially to morbidity and mortality according to a recent meta-analysis (1). To what extent pharmacogenetic factors are involved in ADRs remains open to discussion because this aspect has not been addressed in clinical studies. A substantial proportion of patients will show no or insufficient response to drugs. For instance, 15-25 % of patients are unresponsive to β-adrenoreceptor antagonists. The same holds true for statins: at least 30% of patients show no lowering of cholesterol levels.

In principle, there are three mechanisms responsible for genetic variability in drug response, non-response and toxicity.

• Genetic polymorphism of proteins involved in the biotransformation and transport of drugs following administration of the same dose. Large inter-individual differences in drug concentrations are observed and, as a consequence, the intensity and duration of drug action and ADRs will vary substantially.

• Even if drug dose is individualized to achieve identical plasma concentrations, substantial variability in response will still be observed because concentrations at the site of action vary. It is increasingly recognized that transfer in and out of cells involves active transport. Moreover, variable expression of drug metabolizing enzymes at the site of action can modify drug response in albeit identical plasma concentrations.

• Finally, the same concentration of a drug at the site of action does not necessarily mean identical response, because drug target mutations can profoundly alter response.

Although examples show that pharmacogenetic testing can assist in selecting the appropriate dose for an individual patient, pharmacogenetics is still in its infancy and the majority of those genes which are of relevance to pharmacogenetics have not yet been identified. Clinical trials are lacking to demonstrate that pharmacogenetic testing can accomplish the selection of the appropriate drug and dose for the individual patient to achieve optimal therapeutic response, avoid therapeutic failure and minimize side effects and toxicity. With the rapid advances being made in molecular genetics, these questions will no doubt soon be answered. Pharmacogenetics will also have implications for the use of drugs among different ethnic groups. As a consequence of differences in allele frequencies for polymorphic enzymes or the occurrence of different mutations, drug response and dose can differ among different races. For obvious reasons, this has implications for drugs developed for international use.

Health economics and pharmacogenetics

Pharmacogenetics will have an impact on society as a whole. The better understanding of factors governing individual drug response will facilitate a more data-driven approach to drug prescribing and may contribute to the distribution of financial resources in the health care system in a more rational way. Drugs may be prescribed to those who are likely to derive the most benefit, while patients who are likely to derive little therapeutic benefit from a given drug or may experience a serious adverse drug reaction can receive different medication or non-therapeutic interventions, as appropriate.

In other words, the negative economic consequences of ADRs are likely to be reduced. Targeting health care to those who will benefit the most implies a more efficient use of health care expenditure with better health outcomes, on average, for those treated, and a freeing up of resources, including manpower. The potential exists for the identification of patients for whom current therapeutic options do not provide an adequate risk/benefit outcome, and therefore new therapies may be needed to target these patients to meet their clinical needs.

Pharmacogenetics and marketing

Experience with pharmacogenomics has already taken place. For example, administration of trastuzimab (Herceptin®), registered for the treatment of breast cancer, requires that subjects are tested to determine if their tumors express the Her2 gene. Response to the antibody is related to expression levels of Her2 (2). Only those women with breast cancer who have a very active Her2 gene may be treated (about 30% of all breast-cancer cases), while women with low expression of Her2 do not benefit and should therefore not be treated. Although the test does not determine the genotype, this product does provide an example of how understanding of a disease at the molecular level and being able to identify patients who would benefit from treatment, has enabled a focused drug development strategy and has been a critical component of successful regulatory approval.

Need to determine risk-benefit ratio

Clinical trial design, monitoring and pharmacovigilance methodology have all become more sophisticated over time. However, the ability to more precisely determine the risk-benefit ratio of a drug for an individual patient will be a major advance. During clinical trials, the risk-benefit ratio is assessed only for those subjects entering the trial and may not be a true reflection of the environment in which the product will ultimately be prescribed. There is a need to better define the drug response pattern and, with this knowledge, facilitate the use and safety monitoring of drugs to treat disease more effectively. Since it is acknowledged that drug interactions and especially adverse reactions can be a significant cause of hospitalization, the inclusion of drug response profiles in the prescribing process will help reduce such admissions.

The genetic constitution of a patient is an important factor explaining positive and negative reactions to treatment. In future clinical trials, randomization according to genetic make-up will become as important as age, sex, or ethnic affiliation.

Health care and pharmacogenetics

The main focus of pharmacogenetics will be on the individual patient, who will benefit in the following ways:

• Diagnosis and therapy will be individualized for each patient.

• The clinician will have enhanced ability to predict the benefit or value of treatment against the risks of the drug for each individual patient.

• Enhanced ability to prescribe the most appropriate drug at optimal dose - in terms of risk/benefit - will lead to more effective treatment and potentially fewer ineffective medicines. There will be a reduced number of adverse events and overall increased quality of life.

The limits of pharmacogenetics

Gene-dose effect

In the case of polymorphisms of drug metabolizing enzymes there are no good data demonstrating that patients will achieve the required plasma concentration. The genotype is predictive only for patients who are homozygous for loss of function alleles. Better understanding of the genotype for dose selection is needed of promoter mutations, mutations of transcription factors, etc. No prospective clinical studies have yet been undertaken to show that pharmacogenetic testing can reduce toxicity and improve drug response.

Ignorance by physicians of the existence of these pharmacogenetic factors is a major problem. Although there are good data to show that toxicity can be avoided, genotyping is still the exception rather than the rule in clinical practice.

Genotyping methods are still laborious and expensive, but with rapid advances being made tests should soon be available at reasonable cost. Increased availability of such tests may allow clinical trials to be randomized on the basis of genotyping.

Conclusion

Advances in pharmacogenetics provide an opportunity to improve rational prescribing. However, this new specialty also brings challenges to health care systems. It will be the responsibility of the innovative pharmaceutical industry, in partnership with health care providers, to develop new treatment methods and provide evidence of their benefits. Health care systems will need to integrate pharmacogenetics into health care and develop relationship with industry to ensure development of future treatments. Health care providers will need training to understand and apply the new treatments in the best way. The initial costs and challenges of implementing pharmacogenetics need to be viewed as an investment in health which will be off-set by improvements in patient health and quality of life, reductions in demands on the health care system and value for money.

Future action

The second CIOMS Working Group meeting on the impact of pharmacogenetics on drug development to optimize benefit/risk ratio in pharmacotherapy was held in February 2002 at the European Agency for the Evaluation of Medicinal Products (EMEA) in London, and included participants from the World Health Organization, drug regulatory agencies, the pharmaceutical industry and universities. The following items were discussed:

• Terminology.

• Molecular knowledge of disease, drug action and evolution in clinical practice.

• Optimizing benefit/risk ratio (and risk management).

• New possibilities in therapeutics (e.g. individualized medicine) and tools for physicians.

• Cost/economics of innovative pharmacogenetics - who pays?

• Aspects of pre-clinical drug development.

• Understanding the genetic molecular basis for serious adverse reactions.

• Facilitating global drug development through identification of the genetic basis of drug action and optimizing the benefit of new drugs.

• Improvements of existing (generic) therapies (“well-established drugs”)

• Barriers to progress

• Case studies to illustrate principles and basic problems.

• Creation of a database of clinical trials using pharmacogenetics.

• Financial impact of new technology.

• Cost of adverse drug reactions.

• Regulatory perspectives (EMEA, FDA, MCA)

• Ethical implications.

• Implementation of knowledge and education of stakeholders.

• Definition of data.

• Co-development of diagnostic tests.

References

1. Lazarou et al. Journal of the American Medical Association, 279: 1200-1205 (1998).

2. Stebbing, J., Copson, E. and O’Reilly, S. Herceptin (trastuzamab) in advanced breast cancer. Cancer Treatment Reviews, 26(4): 287-290 (2000).

Further reading:

1. Foot, E., Weihrauch, T.R., et al. The Society of Pharmaceutical Medicine Working Party Subgroup on Pharmacogenetics. Impact on Healthcare and Health economics. International Journal of Pharmaceutical Medicine (in press)

2. CIOMS/WHO Planning Meeting: Global Network for Drug Regulatory Harmonisation. International Journal of Pharmaceutical Medicine, 14: 295 (2000).

3. Human Genome Project. http://www.ornl.gov/hgmis/

4. Roses, A.D. Pharmacogenetics and the practice of medicine. Nature; 405: 857-865 (2000).

5. Marchant, N. Drivers of growth in medical expenditure. Office of Health Economics, London, 1997.

6. Zuehlsdorf, M.T. Relevance of pheno- and genotyping in clinical drug development. International Journal of Clinical Pharmacology and Therapeutics, 36: 607-612 (1998).

7. Fears, R., Roberts, D., Poste, G. Rational or rationed medicine? The promise of genetics for improved practice? British Medical Journal, 320: 933-935 (2000).

8. Wolf, C.R., Smithm G., Smith, R.L. Pharmacogenetics, British Medical Journal, 320: 987-990 (2000).

9. Genomics, Healthcare and Public Policy. Based on papers delivered at the OHE Conference on Genomics, Healthcare and Public Policy, London, 11 February 1999. Edited by Paul Williams and Sarah Crow, OHE, 1999

10. Venulet, J., ten Ham, M.: Methods for monitoring and documenting adverse drug reactions: International Journal of Clinical Pharmacology and Therapeutics., 34: 112-129 (1996).

11. The Pharmacogenetics Working Group. Terminology for sample collection in clinical genetic studies. Pharmacogenetics Journal, 1: 101-105 (2001).

12. Danzon, P., Towse, A. The economics of gene therapy and of pharmacogenetics. Office of Health Economics. http://www.ohe.org

13. Mach, E.P., Venulet, J. The economics of adverse drug reactions to drugs. WHO Chronicle, 29: 79-81 (1975).

14. Shah, R.R. Implications of pharcogenetics for the regulatory assessment of new chemical entities. Pharmaceutical News, 7; 32-38 (2000).

15. Committee for Proprietary Medicinal Products. Position paper on terminology in pharmacogenetics. London, December 2001. EMEA/CPMP/3070/01.