Perspective: Does personalized medicine hold the future for medicine?

With the upsurge of personalizing virtually anything such as mugs, stationery, T-shirts, phone cases, gift items and most recently the ongoing personalized Coca-Cola UK summer campaign, it is not surprising that medicine is fully taking root in this domain.[1] Over the years, there has been a gradual paradigm shift from traditional medicine as a result of increase in scientific knowledge. The traditional path of drug development which has conventionally influenced the practice of medicine has been based on identifying therapies which target an entire population.[2] However, there has been the recognition of patients bearing distinctive inherent traits which cause variations in response to therapy and subsequently tailoring medicines toward these unique responses. It is in this light that personalized medicine (PM) evolved which is the tailoring of treatment to the unique molecular or genetic mapping of individual patients and how these unique features contribute to the occurrence of certain disease pattern and progression.[3] The concepts of PM have been subtly appreciated in medicine since the 1960s with its fist mention in a monograph title in 1998 and subsequent publication on the Medline interface in 1999.[4] Advancement in genetic technologies, primarily; single nucleotide polymorphism (SNP) genotyping and microarray/biochips has been the pillar and drive toward PM.[4] Before 1990, the issue of biomarkers was addressed in about one out of twenty clinical trials performed. Nevertheless, since 2005, a record of 20% clinical trials performed addressed biomarkers. Biomarkers are becoming an additional focus area in PM as researchers are rapidly expanding knowledge in that regard.[2] The rest of this work will initially discuss the scope of PM in present day medicine, the key players in the development of PM and finally the future of PM. Scope of Personalized Medicine in Present day Medicine Conventional medicine originated from empirical treatments and gradually evolved to mechanism-based treatments.[4] Further improvements in conventional medicine led to the current guideline or evidence-based medicine where the approach to solving a clinical problem is based on a number of randomized controlled trials (RCT) recognized to be of highest level of evidence. RCT, which usually includes patients with predefined characteristics with findings applicable to a heterogeneous patient population still leaves room for a more tailored approach to meet the needs of peculiar cases.[5] In this regard, some of the shortcomings in conventional medicine which PM seeks to address include differences in treatment response and incidence of adverse reactions based on genetic variations, exploring therapies resulting in absolute lack of efficacy and taking into account individual variations to drug response other than applying statistically significant outcome of an investigation involving a general population to an individual.[4] The advancement in Genetic Medicine forms the basis of PM. The human genome sequencing was completed in 2000[4] and by 2003 the Human Genome Project was completed by the Unites States department of Energy and the National Institutes of Health by identifying 22,000–23,000 genes in the human genome.[6] The human genome is the total genetic makeup which is composed of about 3 billion nucleotides.[7] The distinct nature of the genome to each individual provides useful information about disease development and progression as well as response to treatment. Variations in the human genome may be as a result of SNP, insertions and deletions, structural variants, and copy number variation of the human genome.[4] PM is distinct from genetic medicine in that, with PM, more complex diseases such as cancer, diabetes, neurodegenerative, and cardiovascular diseases are addressed by taking into account both genetic and environmental factors. Genetic medicine is limited to the clinical effect of a single genetic variation such as in the case of dystrophy, cystic fibrosis, and sickle cell anemia.[6] The complex nature of drug response is as a result of a combination of both genetic and environmental factors. Predicted treatment success based on genotype test may result in poor response due to environmental influence.[4] For example, in the management of Hepatitis C, which is based on genetic response, nongenetic factors such as age, obesity, and alcohol consumption have been reported to influence treatment outcomes.[8] Another area of advancement which greatly impacts PM is Systems Biology and Pharmacology. System Biology translates to PM by elucidating mechanism-based disease development, disease risk estimation, preventive medicine, personalized disease, and treatment monitoring.[9] Systems biology is most useful in preventive PM by developing tools to detect minute changes in molecular profiles at the early stages of disease development. It also takes into account physiological environmental factors exposed to gene expression such as body cells, tissues, body fluids, and body surface area.[9] With regards to Systems Pharmacology, integration into PM seeks to identity the genes and proteins responsible for drug treatment and resistance which may be targeted to augment treatment outcomes through synergistic effect.[10] Biomarkers are also gaining popularity in PM. They are characteristics that measure indicators of the actual biology, disease or drug response. Biomarkers exist as proteins, deoxyribonucleic acid (DNA), messenger ribonucleic acid or radiological parameters which are applicable in areas of disease risk estimation, diagnostic screening, diagnosis, prognosis, prediction, and response monitoring.[11] One application of biomarkers is the use in determining dose size for clinical trials. Pharmacodynamics tests are usually based on the occurrence of toxicity to determine the maximum tolerated dose. With the application of biomarkers, maximum doses are determined by the presence of specific biomarkers. For example, the reduction of Ki67 in tumor tissue as a response to MEK inhibitors in cancer chemotherapy can be used to ascertain appropriate dose size based on the extent of reduction of the Ki67 biomarker.[11] Moving on to drug development, PM has found its place in drug discovery, clinical trial design and the practice of medicine. For drug discovery, one of the earliest discoveries pertains to trastuzumab which is used in breast cancer. This was targeted at the approximate 30% of breast cancer patients who were unresponsive to standard treatment due to over-expression of Human Epidermal Growth Factor Receptor 2.[12] Another discovery is in cardiovascular medicine whereby genetic based noninvasive diagnostic test has replaced the invasive endomyocardial biopsy.[12] Further discovery in cancer therapy is the discovery of vemurafenib; a B-Raf protein inhibitor targeted at the human genome known as BRAF, which is responsible for the development of melanoma.[12] In clinical trial design, PM is gradually redefining the traditional RCT and implementing trials with no control or placebo arms. Furthermore, targeted predictive trials as presented through PM eliminate ethical concerns of administering placebo or no treatment to patients when standard treatments are available. Most oncology drugs are approaching PM trial design and a typical example is the success of Crizotinib; an anaplastic lymphoma kinase-echinoderm microtubule-associated protein-like 4 (ALK-EML4) inhibitor. ALK-EML4 fusion is the driver for lung cancer progression. The Crizotinib trial included 82 lung cancer patients tested positive for the biomarker ALK with no control group. Favorable results of tumor shrinkage were observed as early as after 48 h with statistically significant outcome as well.[13] In the practice of medicine, PM has facilitated genetic-based assessment of efficacy, adverse drug reactions, and appropriate dose regimen. For example, abacavir is reported to yield hypersensitivity reactions in some patients. Traditionally, these hypersensitivity reactions were diagnosed after clinical manifestations of symptoms. A study by Mallal et al.,[14] proved a genetic linkage with the hypersensitivity by identifying the driving gene as the major histocompatibility complex class I allele HLA-B*57:01. Upon investigation, patients who were tested negative for this gene were not hypersensitive to abacavir and vice versa. This steered both the Food and Drugs Administration (FDA) and European Medicines Agency to require of the pharmaceutical industries to include in their label precautions the need to have gene testing prior to abacavir therapy (Novelli, 2010 cited by Pucheril (2011)).[3] Ethical considerations in PM primarily concern the protection of genetic information and other private information of participating individuals. In the USA, the Genetic Information nondisclosure Act ensures the ethical use of genetic information.[4] With regards to PM regulation, the focus is on obtaining approval for the molecular diagnostic tests and the drugs related to the PM. This is typical in the USA where the FDA encourages but does not make it mandatory to submit pharmacogenetic and pharmacogenomic data during the drug development.[4] From the economic perspective, two key concerns arise with PM; that is, will PM render efforts by biopharmaceutical companies profitable and can healthcare providers and patients afford PM? According to a report by PricewaterhouseCoopers, PM is estimated to grow to US$452 billion by 2015 in USA alone.[15] Though high cost is involved in driving PM, the wholistic benefit of PM proves cost-effective. With improved healthcare and quality of life of patients and the targeted treatment which eliminates wastage, PM proves to be cost-effective compared with conventional medicine.[4] Key Players in the Development of Personalized Medicine The development of PM is a multidisciplinary approach requiring team effort from players which may be categorized as industrial players, the academia, scientific players, political, and socioeconomic players.[4] The industrial players which are predominantly the pharmaceutical industry and the biotechnology companies have taken lead roles in the advancement of PM. Most often, the pharmaceutical companies rely on technologies and data from biotechnology companies for the application of pharmacogenetics and pharmacogenomics in clinical trials. However, among the top five pharmaceutical companies (i.e. Hoffman-La Roche, GlaxoSmithKline, AstraZeneca, Perlegen Sciences Inc., and Clinical Data Inc.,) advancing in PM, Hoffman-La Roche has strategically distinguished and positioned itself to be at the top of the ladder by pioneering in the development of products which integrates both diagnostics and therapeutics.[4] An example of such product by Hoffman-La Roche is the drug vemurafenib and its diagnostic tool BRAF V600E Mutation Test for the management of melanoma.[3] Likewise, smaller biotechnology companies after innovating technologies do rely on the pharmaceutical companies or other big biotechnology companies for production. Both the pharmaceutical industry and biotechnology companies also collaborate with academic institutions in the development of PM. One such coalition is the PM Coalition located in Washington DC. It is a nonprofit organization, whose membership is open to interest groups in PM such as pharmaceutical industry, biotechnology companies, universities, government agencies, patient groups, information technology companies, and healthcare providers.[16] In facilitating the coalition with academic institutions, the industrial partners make available patient data from clinical trials to the academic researchers for synthesis of results and further research. The results obtained by the academic researchers are relayed to the industry partners for input into bioinformatics tools developed by the industry. Examples of such collaborations include Pfizer/Harvard Medical School, Perlegen/George Washington University and Pathway Diagnostics/Duke University.[4] The scientific players include clinical laboratories, Health Information Technology (HIT) and medical professionals. Clinical laboratories usually fall within the biomedical sciences which carry out most of the genetic projects. In the USA, Genomas®; a biomedical company with a specialized unit into PM known as Laboratory of Personalized Health received a license to expand in New York, Florida, and California. By 2012, the PM services of Genomas® had extended to Texas, Pennslyvania, and Connecticut. In Connecticut, a record of 500 clinicians and 5000 patients had benefited from LHP covering disease such as diabetes, heart diseases, and neuropsychiatric drugs.[17] HIT is also contributing hugely to the advancement of PM. Such technology creates a central electronic system which enables the smooth flow of information such as medical images, genomics, biospecimens, and patient outcomes among collaborating partners whiles ensuring protection of data. This system of communication is effectively being applied through a system known as the cancer Biomedical Informatics Grid, launched in 2003 by the National Cancer Institute (NCI), USA. Through this network, more than 50 NCI cancer units together with academic and commercial institutions share biomedical information in a more integrated way with an open source software applications.[18] Medical professions are also key scientific drivers as they are at the application end of the entire genomic findings. Efforts are being made to expand the knowledge of medical professionals in genomics through continuing education programs organized at conferences and symposia sponsored by the biopharmaceutical industries.[4] Last but not least, political and socioeconomic players drive medicine toward PM. Especially in the USA and Europe, policies have been made to integrate PM into healthcare systems as well as funding toward genomic projects.[4] Health Insurance companies too on the other end are supporting the shift toward PM in order to minimize expenditure on ineffective treatments and long duration of trial-and-error treatments for clients.[4] The general public with its enormous pressure on the government and pharmaceutical industries to provide safer and more effective treatments have also supported activities toward PM. A typical example is the Personalized Genome Project which started with only 10 volunteers is currently recording 2086 volunteers.[19] Future of Personalized Medicine The prospect of PM being an integral part of detecting, managing and preventing diseases is primarily dependent on its progress and impact of PM in field medicine. Progress has been in areas such as ongoing genomic medicine with PM, toward genetic and the observed of conventional medicine to PM. ongoing genomic are targeted at a toward PM. 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