Personalized medicine

Personalized medicine is use of information and data from a patient's genotype, level of gene expression and/or other clinical information to stratify disease, select a medication, provide a therapy, or initiate a preventative measure that is particularly suited to that patient at the time of administration. Personalized medicine makes it possible to give: "the appropriate drug, at the appropriate dose, to the appropriate patient, at the appropriate time". The benefits of this approach are in its accuracy, efficacy, safety and speed. The term emerged in the late 1990s with progress in the Human Genome Project. Research findings over the past decade, or so, in biomedical research have unfolded a series of new, predictive sciences that share the appendage -omics (genomics, proteomics, lipidomics, metabolomics, cytomics). These are opening the possibility of a new approach to drug development as well as unleashing the potential of significantly more effective diagnosis, therapeutics, and patient care. Laboratories that support personalized molecular medicine develop patient-specific tests that monitor the effectiveness of treatment and can identify the recurrence of disease far earlier than was once possible.

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Limitations of traditional medicine

Traditional diagnosis focuses on the symptoms of a patient's illness whereas a personalized medicine approach can directly examine and analyse the genetic basis of a disease and stratify the total population into different sub-sets each with common, but unique, disease characteristics.

The pharmaceutical industry has worked on the basis of offering a therapy that is intended to suit the population at large based on what is known as the 'blockbuster drug model'. A blockbuster drug is a product capable of achieving sales of over $1 billion per annum. The pharmaceutical industry is facing severe difficulties across several spectrums with its blockbuster approach:

• A great number of patients suffer adverse side-effects from prescribed medicines. Deaths (as a consequence of adverse side-effects) are statistically very significant. If a product, such as Vioxx, has to be recalled from the market, the consequences are far reaching and enduring.

• It costs an average of $1 billion and 12 to 15 years to develop a new therapeutic and further $1 billion to successfully market a new product. The failure rate of product development is very high and in many cases failure is not evident until a great proportion of this investment has been committed to large scale clinical trials.

• Despite spending in the region of $27 billion and employing the genius of almost 200,000 scientists on research and development, very few new, unique therapeutics have emerged over the past decade.

• Many established branded blockbuster drugs are coming, or have already, come to the end of their patent-protected lives. These products can typically lose up to 40% market share in the year following patent expiry as generic alternatives become available.

• Consumer knowledge is making the market more cost sensitive.

Response of stakeholders to personalized medicine

There are several stakeholders: the industry, the regulators, the patients and the general public.

Pharmaceutical industry

The pharmaceutical industry, in general, has been reluctant to immediately embrace the potential of personalized medicine. It is believed that they are concerned that the emergence of personalized medicine will destroy the foundations of the mass-market blockbuster drug model because personalized therapeutics will cater for particular sub-sets of the general population.

Another reason for the skepticism of the pharmaceutical industry is the threat to existing products. Many blockbuster drugs, such as Lipitor, compare favorably with cheaper generic drugs only in a small percentage of patients. But since it is not known how to identify these, many physicians prescribe the expensive drug to all their patients. If a test could be devised to determine who actually benefits from the more expensive drug, all other patients could use the generic.

However, the technologies underpinning personalized medicine could enable the pharmaceutical industry to become more sure-footed. A more efficient drug development process, based on sound, robust genetic evidence could require less investment and, perhaps less elapsed time, to identify and develop new products as confidence deepens. Furthermore, the idea of a therapeutic being marketed on the basis of a companion theranostic test result could deepen and prolong consumer loyalty if sustainable benefits are evident.

Diagnostics industry

The traditional diagnostics industry is mature and only achieving a growth rate of the order of 4% per annum. Its products are very cost sensitive and have a relatively short life cycle. The diagnostics industry has not been as successful as the pharmaceutical industry in attracting investment funding.

However, the advent of molecular diagnostic tests, or theranostics, opens new opportunities in a small but believed to be rapidly growing niche market. New relationships are likely to develop between industry partners committed to personalized medicine embracing the approach of successful, specialised pharmaceutical firms. Such has been the case with IBM. This corporation has made strategic partnerships with Mayo Clinic Medical Center and several other healthcare and testing centres. Its plan entails developing bioinformatics systems which will allow greater growth in tests that are available. in growth of tests such as these is their clinical utility as well as reimbursement from third party payors.

Customers

The emergence of personalized medicine raises issues for those who pay for treatment. The unit cost is likely to he higher but it is argued that the total cost of a treatment cycle will be lower overall. Furthermore, the possibilities of the predictive potential of personalized medicine ought to avert costly intensive care treatment when a disease is established.

The response of payers will be influenced by the nature of the relationship they have with those whom they are paying for. Is it a long-term relationship, which is the case with nationally funded medical care, or is it short term? New policies and procedures will be necessary.

Countries such as the United States are currently struggling with the burgeoning of healthcare expenditure. Perhaps personalized medicine is the cure. However, most US private insurers unlike the governmental system are not embracing this potential. Less than 5% of all private companies reimburse for genetic tests.

Regulators

The Food and Drug Administration in the United States and their counterparts appear convinced that personalized medicine is going to make a profound impact on society and they are guiding this process.

Dr Andrew VonEschenbach, Director of the FDA recently gave a briefing to the Personalized Medicine Coalition at the National Press Club. He and the organization are truly committed to bring new testing and treatment to market which is molcularly based. His feeling is that the Molecular Metamorphosis is equivalent if not greater than the bacterial theory and its revolution of medicine.

United States policy

Personalized medicine has the potential to revolutionize the practice of medicine, but despite significant scientific advances, very few genomics-based tests or treatments have reached consumers. Senator Barack Obama introduced the Genomics and Personalized Medicine Act to overcome the scientific barriers, adverse market pressures, and regulatory obstacles that have stood in the way of better medicine.[1] In addition, in the United States, the Secretary of Health and Human Services Mike Leavitt has made personalized medicine the top priority during his tenure. He has created a committee that is called the Secretary's Advisory Committee on Genetics Health and Society aka. SACGHS During the March meeting there was briefing re-affirming his commitment to this wonderful new phase of medical care.

Genetics discrimination

One of the significant barriers to genetic testing is thought to be the fear of discrimination. Discrimination from an insurer or even worse an employer. This fear has been indicated in several polls, including the Harris Poll in 2002. For the last decade there has been some form of legislation which had been mired in the House of Representatives in the United States. The current bill is called the Genetic Information Nondiscrimination Act H.R. 493, S.358 aka GINA. It was passed in the House of Representatives 420-3 and appears to have major support in the Senate. This will legislation will break down a significant barrier to this technology

Patients

Patients will clearly be influenced by proven success as is the case with Herceptin and Gleevec. Theranostic tests are proving effective in other areas such as the identification of anti-retroviral drug for use with different strains of HIV.

At a recent meeting of the US Secretary's Advisory Committee on Genetics Health and Society it was revealed that a majority of the public supports the utilization of genetic testing, especially if this testing could be used to improve health outcomes.

Public

Public education about the potential benefits of personalized medicine will be an important facet of its widespread acceptance. This includes about the research itself and the science underlying it; disease variations and the approach to prevention, treatment and care; and a deeper awareness of risks and benefits attaching to clinical trials.

Collaboration, infrastructure and technology : key enablers

The march toward personalized medicine is not driven, in some instances, on the basis of scientific hypothesis but through hypothesis generation sometimes starting with natural history. The key task is to find genes and gene variations that play a role in a disease. The first step is to associate the occurrence of a particular gene variant with the incidence of a particular disease or disease predisposition - an association that can vary from one individual to another depending on many factors, including environmental circumstances. The outcome is the development of biomarkers which are stable and predictive. Today's biomarker is tomorrow's theranostic.

The infrastructure necessary includes molecular information -biological specimens derived from tissue, cells, or blood provided on the basis of informed donor consent and suitably annotated. Clinical information is also necessary based on patient medical records or clinical trial data.

A very high level of collaboration involving scientists and specialists from varying disciplines is required to integrate and make sense of all this information.

The Harvard Partners Center for Genetics and Genomics was founded in 2001 with the specific goal of accelerating the realization of personalized medicine. The Personal Genome Project was announced by George Church in 2006; it will publish full genome sequences and medical records of volunteers in order to enable research into personalized medicine. The Laboratory for Personalized Molecular Medicine was founded in 2007 to identify specific mutations in genes linked to clinical outcome in patients with leukemia and lymphoma. Identifying the presence or absence of these mutations is becoming a standard of care for patients with acute myeloid leukemia. LabPMM also developments patient-specific molecular tests from patient tumor DNA samples. The ultra-sensitive tests are used by leading cancer treatment centers world-wide to monitor residual disease and treatment.

Not only is personalized medicine tailoring the right drug, for the right person, at the right time but it also includes evaluating predisposition to disease sometimes decades in advance of its threatened onset.

Personalized medicine and cancer

Cancer genetics is a subspecialized field of genetics. This field initially dealt with the relatively small amount of inherited cancers. This amounted to about 5-10% of all cancers as estimated by the National Institutes of Health.

Individuals diagnosed with familial breast, ovarian, colon cancer had been counseled in the past that they would receive standardized treatments and had limited options before their "condition" arrived. These options included removal of the organs that may give rise to cancer. Recent medical research indicates that medications, lifestyle changes and increased screening can mitigate some risk. An example is BRCA mutations where the carrier can have an increased lifetime risk of 85% for developing a breast cancer or up to 40% increased risk of getting ovarian cancer. Now medications such as tamoxifen are being shown to reduce incidence of disease. The Laboratory of Personalized Molecular Medicine tests DNA from patients diagnosed with acute myeloid leukemia for mutations in the FLT3 gene that are associated with poor prognosis. Clinical data suggests patients with FLT3-ITD mutations may benefit from more aggressive treatment and closer monitoring, and several promising drug candidates that target this gene are currently in clinical trials. Ultra-sensitive minimal residual disease (MRD) tests developed from DNA sequence information from individual patient's are used to to quantify residual cancer. This assists physicians in making clinical decisions earlier prior to cancer recurrence and relapse. Somatic hypermutation test results using sequence information from the same gene is associated with outcome and survival in patients with chronic lymphocytic leukemia.

The exciting news is that cancer predisposition genes and families are being identified by genetic testing and research at a break neck pace. Because all cancers require a dysfunction in the DNA of cells that regulate growth, it would be foolhardy not to expect all cancers to have some heritable predisposition as well as environmental influence.

Personalized medicine aims to identify these families at risk for cancer, heart disease, diabetes, etc. Once identified by simple family history including a 3 generation pedigree or advanced genetic testing, the person could take preventative action. This might include changes in diet, cessation of toxic habits, earlier screening, exercise, prophylactic medications or surgery.

Herceptin and Gleevec

Two products, Herceptin supplied by Genentech and Gleevec supplied by Novartis,are prescribed on the basis of the outcome of a companion theranostic test. Herceptin treats a category of breast cancer in woman and the test helps identify those patients whose cancer cells express the protein HER2 making them eligible. Herceptin sales have grown from $30.5 million in 1998, its year of introduction, to $764 million in 2005. Gleevec treats chronic myeloid leukaemia (CML) arrived in 2004 and it is known as a targeted cancer drug. In addition because of new molecular testing for c-kit, tumors such as GIST GastroIntestinal Stromal Tumours a solid malignancy never associated with blood bourne cancer are also treated with this drug. It works by killing specific cells whereas chemotherapy can kill both deranged and healthy cells. Because of this ability to molecularly detect true disease causing mutation a whole new reclassification of cancer has begun. So has the unimagined use of several of these "targeted" drugs. Gleevec sales exceeded US$2.5 billion in 2006.

Personalized medicine and education

There are several universities involved in translating the burgeoning science into use. The difficulty is that medical education in all countries does not provide adequate genetic instruction.

A small number of universities are currently developing a subspecialty in medicine that is known by several names including, molecular medicine, personalized medicine, or even prospective medicine. These include, Duke University in North Carolina USA, Harvard in Cambridge USA, The Mount Sinai Hospital in New York City. A medical school is currently being constructed in Arizona USA to teach the field of personalized medicine; this is a project of Arizona State University and a company called TGen. In addition to academia, the first personalized medicine practice in the United States was founded in 2007. Helix Health sees patients in New York City and the surrounding suburbs. The Laboratory for Personalized Molecular Medicine founded in 2007 to identify specific mutations in genes linked to clinical outcome in patients with leukemia and lymphoma, actively collaborates and assists academic centers and hospitals in the development of patient-specific molecular tests from patient tumor DNA samples. This has expanded and accelerated patient access to personalized medicine in test centers that otherwise do not have the resources to provide this care. The ultra-sensitive tests developed by LabPMM are used world-wide to monitor residual disease and treatment.

See also

• P4 medicine
• Predictive medicine
• Theranostics
• Drug development
• Targeted therapy

References

• Sadee W, Dai Z. (2005), Pharmacogenetics/genomics and personalized medicine, Hum Mol Genet. 2005 October 15;14 Spec No. 2:R207-14.
• Steven H. Y. Wong (2006), Pharmacogenomics and Proteomics: Enabling the Practice of Personalized Medicine, American Association for Clinical Chemistry, ISBN 1-59425-046-4