viernes, 18 de junio de 2010

NEJM -- The Path to Personalized Medicine


Published at www.nejm.org June 15, 2010 (10.1056/NEJMp1006304)
The Path to Personalized Medicine
Margaret A. Hamburg, M.D., and Francis S. Collins, M.D., Ph.D.


Major investments in basic science have created an opportunity for significant progress in clinical medicine. Researchers have discovered hundreds of genes that harbor variations contributing to human illness, identified genetic variability in patients' responses to dozens of treatments, and begun to target the molecular causes of some diseases. In addition, scientists are developing and using diagnostic tests based on genetics or other molecular mechanisms to better predict patients' responses to targeted therapy.

The challenge is to deliver the benefits of this work to patients. As the leaders of the National Institutes of Health (NIH) and the Food and Drug Administration (FDA), we have a shared vision of personalized medicine and the scientific and regulatory structure needed to support its growth. Together, we have been focusing on the best ways to develop new therapies and optimize prescribing by steering patients to the right drug at the right dose at the right time.

We recognize that myriad obstacles must be overcome to achieve these goals. These include scientific challenges, such as determining which genetic markers have the most clinical significance, limiting the off-target effects of gene-based therapies, and conducting clinical studies to identify genetic variants that are correlated with a drug response. There are also policy challenges, such as finding a level of regulation for genetic tests that both protects patients and encourages innovation. To make progress, the NIH and the FDA will invest in advancing translational and regulatory science, better define regulatory pathways for coordinated approval of codeveloped diagnostics and therapeutics, develop risk-based approaches for appropriate review of diagnostics to more accurately assess their validity and clinical utility, and make information about tests readily available.

Moving from concept to clinical use requires basic, translational, and regulatory science. On the basic-science front, studies are identifying many genetic variations underlying the risks of both rare and common diseases. These newly discovered genes, proteins, and pathways can represent powerful new drug targets, but currently there is insufficient evidence of a downstream market to entice the private sector to explore most of them. To fill that void, the NIH and the FDA will develop a more integrated pathway that connects all the steps between the identification of a potential therapeutic target by academic researchers and the approval of a therapy for clinical use. This pathway will include NIH-supported centers where researchers can screen thousands of chemicals to find potential drug candidates, as well as public–private partnerships to help move candidate compounds into commercial development.

The NIH will implement this strategy through such efforts as the Therapeutics for Rare and Neglected Diseases (TRND) program. With an open environment, permitting the involvement of all the world's top experts on a given disease, the TRND program will enable certain promising compounds to be taken through the preclinical development phase — a time-consuming, high-risk phase that pharmaceutical firms call "the valley of death." Besides accelerating the development of drugs to treat rare and neglected diseases, the TRND program may also help to identify molecularly distinct subtypes of some common diseases, which may lead to new therapeutic possibilities, either through the development of targeted drugs or the salvaging of abandoned or failed drugs by identifying subgroups of patients likely to benefit from them.

Another important step will be expanding efforts to develop tissue banks containing specimens along with information linking them to clinical outcomes. Such a resource will allow for a much broader assessment of the clinical importance of genetic variation across a range of conditions. For example, the NIH is now supporting genome analysis in participants in the Framingham Heart Study, obtaining biologic specimens from babies enrolled in the National Children's Study, and performing detailed genetic analysis of 20 types of tumors to improve our understanding of their molecular basis.

As for translational science, the NIH is harnessing the talents and strengths of its Clinical and Translational Sciences Award program, which currently funds 46 centers and has awardees in 26 states, and its Mark O. Hatfield Clinical Research Center (the country's largest research hospital, in Bethesda, MD) to translate basic research findings into clinical applications. Just as the NIH served as an initial home for human gene therapy, the Hatfield Center can provide specialized diagnostic services for rare and neglected diseases, offer a state-of-the-art manufacturing facility for novel therapies, and pioneer clinical trials of other innovative biologic therapies, such as those using human embryonic stem cells or induced pluripotent stem cells.

As genetics researchers generate enormous amounts of new information, the FDA is developing the regulatory science standards and evidence needed to use genetic information in drug and device development and clinical decision making. The agency's Critical Path Initiative aims to develop better evaluation tools, such as biomarkers and new assays. Under the Voluntary Genomic Data Submission program, companies can discuss genetic information with the FDA in a forum separate from the product-review process. These discussions give the agency and companies a better understanding of the scientific issues involved in applying pharmacogenomic information to drug development and offer an opportunity for early, informal feedback that may assist companies in reaching important strategic decisions. The goal is to help companies integrate genomics into their clinical-development plans.

Today, about 10% of labels for FDA-approved drugs contain pharmacogenomic information — a substantial increase since the 1990s but hardly the limit of the possibilities for this aspect of personalized medicine.1 There has been an explosion in the number of validated markers but relatively little independent analysis of the validity of the tests used to identify them in biologic specimens.

The success of personalized medicine depends on having accurate diagnostic tests that identify patients who can benefit from targeted therapies. For example, clinicians now commonly use diagnostics to determine which breast tumors overexpress the human epidermal growth factor receptor type 2 (HER2), which is associated with a worse prognosis but also predicts a better response to the medication trastuzumab. A test for HER2 was approved along with the drug (as a "companion diagnostic") so that clinicians can better target patients' treatment (see table).

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NEJM -- The Path to Personalized Medicine

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