The completion of the Human Genome Project in 2003 led to a flurry of predictions regarding the application of pharmacogenomics to drug development. With US and European regulatory authorities finally on the verge of issuing guidance on the use of pharmacogenomics, drug development is all set to change.
Despite advances in modern medicine, in practice it remains difficult for physicians to determine a patient's response to a treatment. A drug that is safe and effective for one patient may prove to be dangerous or ineffective in another.1,2 In some cases, the lack of effectiveness of a drug or the occurrence of side-effects can be linked to factors such as medication errors. However, it is now known that a significant proportion of differential drug response is genetic in origin.2 This genetic angle has often not been fully appreciated, but new developments are driving the use of this information in medicine.1
Pharmacogenetics is the study of how genetic variation between individuals affects their response to medicines.2 The term is often used interchangeably with pharmacogenomics, which uses genetic analysis to identify putative targets for medicines or to identify large-scale differences in the patterns of gene expression in response to chemical compounds.2 One of the hopes within the pharmaceutical industry is that pharmacogenomics will enable companies to improve success rates within certain therapeutic classes and develop tailor-made treatments for individuals.1
Doctors will be able to examine the genetic make-up of a patient and determine which drugs on the market would be best for them.1 In 2001, a review of major drugs in several major therapeutic classes revealed considerable variation in patient response rates. In this review, patient response rates to asthma drugs were described as being around 60%, whereas the rates were only 30% for Alzheimer's disease therapies and 25% for cancer chemotherapy.3
Pharmacogenomics is also predicted to have an impact on reducing the number of medical adverse events.1 Adverse effects remain a problem despite industry efforts to conduct extensive testing of investigational products, and the numerous measures brought in by regulatory agencies to improve safety measures. According to one estimate, 100000 deaths and 2 million hospitalizations occur each year in the US because of adverse drug responses. The continuing controversy regarding drugs such as Vioxx highlights public concern about drug-related side-effects. If pharmacogenomics can be harnessed to identify the genetic basis of these adverse events, lives will be saved and public confidence in the pharmaceutical industry will also be improved.
Supporters of pharmacogenomics believe that it will revolutionize clinical trials, as more will be known about the compounds being tested in relation to the genetic make-up of participants (Figure 1). In this scenario, pharmaceutical companies could exclude subjects for whom a particular drug would be harmful or ineffective. By then screening patients who would be appropriate for the drug being tested in the trial, considerable resources and time may be saved. This would reduce the costs of clinical development as well as enhancing success rates. From a marketing perspective, companies would be able to provide greater information on how different patients might respond to their drug and this would boost physician confidence in their products.1
There have also been suggestions that pharmacogenomics could be used for drugs that were discontinued or withdrawn from major markets, because of safety concerns, so that they could be reintroduced by matching them to a niche patient population.1 One study recently estimated that 38 drugs have been withdrawn from major markets because of such concerns since 1990.4 However, the slow progress in identifying genetic traits that could be associated with the reported toxicity for these withdrawn products means that the full potential of pharmacogenomics in this area is yet to be realized.4
Many companies have been very successful in developing drugs that can be used by a variety of patients, and there is a fear that pharmacogenomics will segment markets and drastically reduce revenues.1 Given that it costs pharmaceutical companies a tremendous amount of money to develop a new drug, will they be willing to invest in the R&D process if the end-product is only considered applicable to a small portion of the population? Those in favour of utilizing pharmacogenomics argue that the R&D process will be made more efficient and less expensive through the use of pharmacogenomics, thereby compensating for a reduced patient population.1 Furthermore, the commercial success of drugs such as Glivec (imatinib) and Herceptin (trastuzumab) has shown the power of the genetic approach to drug development.5 These drugs are widely seen as advances in cancer treatment and have been well received by patients. In fact, many see cancer as the area in which pharmacogenomics will have its initial impact within the pharmaceutical industry.
Another worry of pharmaceutical companies is that they are still unclear about what regulatory agencies are seeking in terms of pharmacogenomic information for heir products. However, this situation is changing, with FDA appearing to be the regulatory leader in this respect. It is developing detailed guidance documents that provide information on its current thinking and the use of pharmacogenomics for regulatory decision making. It has also introduced a genomics training programme for its staff. In conjunction with EMEA, it recently issued guidance documents to encourage the voluntary submission of genomic data by companies to the agencies.
The completion of the Human Genome Project in 2003 led to a flurry of interest in pharmacogenomics, but many of the predictions regarding its impact in medicine proved premature. Nevertheless there is now a clear move towards applying the principles of pharmacogenomics to drug development. Guidance from regulators will be key to how fast these are incorporated into mainstream pharmaceutical R&D.
1. Pharmaceutical Research and Development in the 21st Century., Pharmbiosys (2007). www.pharmbiosys.com
2. Pharmacogenetics and Personalised Medicine — Key Facts. www.dxsgenotyping.com
3. B.B. Spear, Trends in Molecular Medicine, Vol.7(5), 201–204 (2001).
4. R.R. Shah, Pharmacogenomics, 7(6), 889–908 (2006).
5. Anon, Pharmafocus (2002). www.pharmafocus.com/cda/focusH/1,2109,21-0-0-NOV_2002-focus_news_detail-0-75441,00.html