Personalized medicine
The emergence of personalized medicine, the main principle of which is the selection of treatment methods in accordance with the genetic characteristics of patients and their pathologically altered cells, stimulated an increasing flow of genetic data and diagnostic approaches, which began 10 years ago with the decoding of the human genome.
Many experts consider the emergence of personalized medicine as a transition to a qualitatively new level, suggesting a rejection of the now generally accepted approach – the development and use of standard drugs that are effective against most patients with a certain pathology. If the situation continues to develop in the same direction, over time it will lead to a radical change in the principles of research work in medicine and pharmacology.
However, despite the enthusiasm shown, the work is moving very slowly. Deciphering the genetic code allowed drug developers to confidently declare the possibility of treating diseases such as cancer and neurodegenerative diseases, however, attempts made over the past decade to understand new genetic data have not brought many significant achievements. Pharmaceutical companies, biotech firms and government researchers are very inspired by the prospects of personalized medicine, but the time to switch to new approaches to treatment is still being postponed.
Currently, personalized medicine occupies only a thin layer in the structure of the healthcare sector, where most diseases are still treated with blockbuster drugs, the sale of each of which brings at least a billion US dollars a year. The transition to personalized drugs designed to treat much smaller populations of patients is impossible without changing the fundamental principles of the work of pharmaceutical companies.
Changes in healthcare – an industry dependent on a multitude of regulatory documents and complex health insurance schemes – are taking place very slowly. The U.S. Food and Drug Administration and insurance companies are looking for new methods to evaluate the effectiveness of highly specific diagnostic techniques and treatments. At the same time, chemists and biologists are paying more and more attention to research devoted to the introduction of the results of studying the molecular biological characteristics of diseases into the clinic, and they are particularly closely studying biomarkers - molecular indicators of the effectiveness of drugs.
In the medical community, personalized medicine is considered either as a fundamentally new approach to medical practice, or as a continuation of the traditional principle of "treating not the disease, but the patient" using more advanced equipment and more information. In fact, cancer treatment has been partially personalized for some time thanks to the accumulated data that allows classifying tumors based on anatomical and visual characteristics.
However, with the decoding of the genome, practical medicine has a new dimension at its disposal – the opportunity to dig deeper than the study of anatomical and structural features, and turn to the molecular mechanisms of disease development.
The biological features of breast tumors and leukemias, as well as patients with such diagnoses, are classified to facilitate the selection of optimal treatment methods. For example, hormonal drugs have been successfully used for more than 20 years to treat breast cancer expressing an estrogen receptor. The next stage was the appearance of the drug Herceptin, which selectively acts on tumors expressing the HER2 receptor and is one of the first sensational representatives of medicines for personalized treatment.
Another celebrity is Gleevec, a drug for the treatment of chronic myeloid leukemia characterized by the presence of a chromosomal anomaly called the Philadelphia chromosome. Currently, Glivec is used to treat some other diseases associated with certain mutations.
According to Dr. Gordon B. Mills, head of the Faculty of Systems Biology at the M.D. Anderson Cancer Center, part of the University of Texas, a real breakthrough has occurred in the field of personalized medicine over the past five years. Scientists have begun to really understand the real value of the data obtained as a result of decoding the human genome. Currently, they are developing drugs, devices and approaches to test their hypotheses.
All this happens at a time when less than 10% of the drugs approved for clinical trials enter the market. Despite all the knowledge acquired in recent years, this indicator is much worse than 15 years ago. In addition, 50% of failures occur in phase 3 clinical trials, which maximizes financial losses. Experts believe that genetic research can help solve this problem by changing approaches to conducting clinical trials.
The optimal solution to this issue implies compliance with the following sequential steps: identification of the target, creation of a drug selectively acting on it and identification of patients responding to it.
Currently, this approach is being tested as part of a one–year pilot program of clinical trials of lung cancer treatment conducted by the MD Anderson Cancer Center called "BATTLE" - Biomarker-Integrated Approaches of Targeted Therapy for Lung Cancer Elimination, Biomarker-Integrated approaches to targeted therapy aimed at eliminating lung cancer. Trials involving patients who do not respond to traditional lung cancer treatments involve a cycle of biopsies and a gradual selection of the optimal treatment method for each patient. The goal of the program is to create a protocol for the treatment of lung cancer in accordance with the detected tumor biomarkers, which will be based on the results of studying the molecular mechanisms of response and resistance to certain selectively acting agents.
According to Roy S. Herbst, one of the leaders of BATTLE, head of the Department of thoracic Oncology, scientists have developed a huge number of new experimental drugs with pronounced pharmacological activity, however, in order to obtain positive results, each of the patients needs to choose the "right" drug, which is quite a difficult task.
The development of diagnostic techniques for describing the characteristics of pathologically altered tissues has also become the main activity of some biopharmaceutical companies. Celera, famous for decoding the human genome, has shifted its priorities towards the development of clinical techniques for personalized medicine.
Vice President of the company John Sninsky also holds the opinion that such techniques, in fact, are a continuation of traditional medical approaches. He notes that personalized treatment has existed for a long time, but until now, specialists have not been able to use the molecular information that appeared due to the sequencing of the human genome and the study of its transcription.
A new aspect is the shift in approaches to the treatment of complex pathologies, such as cardiovascular diseases, Alzheimer's disease, rheumatoid arthritis and cancer. Diseases of each of these groups have similar manifestations, however, a detailed study reveals that the physiological mechanisms underlying the development of equally manifesting diseases can be radically different. Currently, specialists have the opportunity to use molecular information for more detailed classification of diseases within traditional categories.
Constantly emerging new information greatly changes the state of affairs. Previously, people spent their whole lives studying one gene, whereas today it is possible to study up to 25,000 genes in parallel. And existing methods of analyzing gene expression by evaluating the synthesis of RNA and proteins allow us to study their role in the development of diseases instead of studying the gene itself.
The growing amount of information needed for the development of medicines stimulates the development of a multifaceted pharmaceutical industry. As a result, chemists and biologists working in this industry will need to work closely with specialists in computational biology and bioinformatics to develop treatment methods based on the biological characteristics of the disease and subsequent planning of clinical trials based on data on the biological characteristics of patients. In 2001, John Sninski left Roche, where he headed the research conducted by Roche Molecular Systems, and devoted his activities to the introduction of new genomics methods in the development of selectively acting personalized medicine drugs.
The chief executive officer of Nodality, David R. Parkinson, a former vice president of the Department of clinical research in oncology at Novartis, who also worked for Amgen and Biogen Idec, also left Big Pharma in order to develop the direction of biologically oriented diagnostics.
There are pessimists who consider conversations about personalized medicine to be empty words, or who claim that its introduction is not economically justified. However, according to Parkinson, many do not understand that the revolution is not over yet and specialists have yet to significantly change their views on the classification and treatment of malignant neoplasms and other diseases.
At the moment, drug developers have achieved great success in creating agents that selectively act on various tumor molecular targets. However, there is still no significant progress in predicting the effects of such selectively acting drugs on different tumors of the same type. In part, this inefficiency is due to the lack of a close relationship between biology in its traditional sense and the clinical classification of tumors. Personalized medicine begins with changing this situation.
Bridging the gap between biology and clinical medicine implies achieving a better definition of the biological characteristics of diseases. The concept is that a detailed study of the biological aspects of the effect of a particular drug on a particular patient with a disease will improve our understanding of the mechanisms of development of this disease.
Based on the work of Dr. Gary Nolan from Stanford University, who studies the signaling mechanisms used by lymphocytes and malignant cells, Nodality has developed a flow cytometry method that allows determining the biochemical and physiological characteristics of individual cells.
The principle of the method is that cells labeled with fluorescent antibodies to specific phosphoproteins that perform important intracellular signaling functions are passed through a laser beam of light, upon contact with which cells containing the desired protein begin to glow. The technique allows us to estimate the number of phosphoproteins in individual cells, including tumor cells, which is an indicator of the activity of a particular signaling mechanism.
Nodality plans to develop standard tests for selecting optimal treatment methods for patients. This work touches on many aspects of personalized medicine, including the transfer of laboratory data to the clinic. In addition, it raises questions about how the use of such tests will be regulated and who will pay for them. She also emphasizes the need for coordinated joint activities of the industrial and scientific sectors, which will accelerate the development of affordable diagnostic tests.
Most of the largest pharmaceutical companies have already begun to implement the principles of personalized medicine, primarily the use of biomarkers. Some of them reorganize the structure of research units in order to speed up the development process. However, some analysts are skeptical that large companies that for a long time specialized in the production of widely used blockbuster drugs that annually bring billions of dollars in profits are really interested in developing drugs of highly specialized action.
It is obvious that in reality, the principles of production of "blockbusters" are unsuitable for large companies that are developing personalized medicine approaches. Personalized medicine requires a change in the "blockbuster" mentality, because a blockbuster drug should help a large number of patients, and if a new drug is effective only in treating 10% of patients with, for example, lung cancer, it can no longer be called a blockbuster and earn huge profits from its sale.
The head of AstraZeneca's external relations department, Wayne Rosenkrantz, claims that large pharmaceutical companies object to such statements. Based on the information he knows about the work being carried out not only by AstraZeneca, but also by such major manufacturers as GlaxoSmithKline and Genentech, he predicts the appearance of the first personalized drug developed by one of the concerns of Big Pharma based on genetic research data within 3-5 years, followed by an acceleration of the pace of work in this direction.
According to Rosenkrantz, the increase in the level of understanding of the molecular foundations of the drugs being developed contributes to the development of understanding of the mechanisms of their action, and the more data available on their impact on the human body, the more the situation changes. The information obtained should be used in the development of diagnostic methods, but at the present stage all these mechanisms are still under study.
Roche adheres to a similar philosophy with regard to the decentralized research program launched a year ago, within which five separate research and commercial organizations working in various therapeutic areas are organized. In addition to specialists in search, development and business planning, each research group includes a specialist in clinical research and exploratory development (CRED).
Andreas Wallnoefer, Head of the Roche CRED Initiative Explains that the task of CRED is to focus on biomarker identification strategies and direct efforts to study diseases and underlying molecular mechanisms. The ultimate goal is to position personalized medicine as a fundamental principle of all aspects of work.
The concept of biomarkers is not new to Roche, but their use has not been evenly distributed across all areas of research. When developing drugs, the company's specialists have always used pharmacogenomics approaches and surrogate markers. However, at the present stage of development, given the increased attention to the convergence of the clinic and research work and active work to improve the understanding of the mechanisms of disease development based on methods of systems biology, there is a need for more systematic approaches.
The company decided that all drug development programs should be based on a biomarker strategy that will not only accelerate the personalization of medical care, but also facilitate the decision-making mechanism at the early stages of drug development. This strategy will help the company to increase the productivity of research work (by selecting the most promising programs) and at the same time increase the effectiveness of drugs while reducing the risk of side effects.
One of Roche's most innovative programs for the introduction of personalized medicine is a collaboration with Plexxikon, which aims to test an experimental antitumor drug that selectively inhibits the activity of a mutant variant of the BRAF kinase enzyme gene involved in several mechanisms of the formation of malignant tumors.
James A. Williams, head of the Department of molecular Medicine, working within the framework of Pfizer's antiangiogenic drug development programs, is of the opinion that such changes are not so much a revolution as a stage of evolution.
Like most pharmaceutical companies, Pfizer adheres to the tradition of introducing new technologies for conducting exploratory research. For example, cholesterol has long been considered a biomarker of cardiovascular diseases, the prognostic role of biomarkers in the diagnosis of cancer has also been studied for years. According to Williams, Pfizer has been investing in personalized medicine for a very long time, but until recently, a different terminology was used in relation to this area.
Pfizer integrates personalized medicine into drug development, including in collaboration with other companies. For example, the company recently announced a joint work with Source MDx to develop and evaluate the effectiveness of pharmacodynamic and prognostic biomarkers based on RNA, carried out as part of Pfizer's programs to develop methods of antitumor and anti-inflammatory therapy.
Specialists of large pharmaceutical companies claim that increasing the level of understanding of the mechanisms of disease development at the molecular level is an exciting process, along the way of which a number of scientific problems arise. They also point to the existence of regulatory obstacles and the question of how it is necessary to change the healthcare infrastructure in order to introduce personalized medicine into clinical practice and organize its financing system.
At the moment, the US Food and Drug Administration (FDA) has not yet developed a strategy for regulating these issues, and companies are working blindly, because it is not known what requirements the FDA and payers will impose on evidence of the medical value of new diagnostic and treatment methods. Due to the existing uncertainty, companies are faced with the question of the expediency of following the course of transition to personalized medicine, but the final answer to this question is an unequivocal "yes", since otherwise the creation of new drugs will become impossible at all.
According to Steven I. Gutman, director of the FDA's Laboratory Diagnostics Effectiveness and Safety Assessment Service, the responsibility for developing a personalized medicine infrastructure largely falls on the shoulders of researchers engaged in obtaining evidence of the analytical feasibility and clinical significance of new diagnostic tests.
Confirmation of the analytical effectiveness of such tests is sometimes quite time-consuming, but absolutely necessary. Gutman believes that the existing regulatory infrastructure can be upgraded to control new methods. He is of the opinion that changes in research approaches do not require radical changes in the system of functioning of the FDA.
The basic requirements of the FDA for the functionality and effectiveness of new diagnostic methods are very clear. Regarding each of the tests, the management asks the same questions to which the developer cannot help but have answers, such as: "Is the test so accurate and reproducible?" and "What effect does taking medications have on the test results?"
Gutman also notes that the US National Institutes of Health are monitoring developments in the field of personalized medicine. A recent report by the Advisory Committee on Genetics, Health and Society at the National Institutes of Health (Advisory Committee on Genetics, Health & Society at NIH), for example, noted the existence of weaknesses in the system of control over genetic testing, as well as a call for joint work of the public and private sectors to assess and eliminate existing shortcomings.
Another intractable issue is the need to restructure the insurance compensation system for personalized medicine services. Experts emphasize the irony of the situation, since it turns out that at the dawn of the era of personalized medicine, the relationship between doctors and patients is characterized by minimal personality. Doctors are paid for their work depending on the number of patients they examined, and not depending on the time spent on selecting an individual treatment protocol or on its results.
One of the first companies trying to change the insurance system is IBM. According to Paul Grundy, head of the company's initiatives on health protection, technology and strategy, IBM management is not satisfied with the modern insurance system, within which it is possible to pay for episodic procedures or processes and it is impossible to pay for a comprehensive health protection scheme that includes full–fledged interaction between a doctor and a patient. For example, it is possible to pay for the amputation of a limb to a diabetic patient, but it is impossible to pay for such a level of relationship between a doctor and a patient that would avoid amputation.
Grandi also directs the Association of Individually Selected Primary Care (Patient-Centered Primary Care Collaborative) – consisting of 107 members of the coalition of public and private consumers of health insurance, public health services and large insurance companies. The coalition is exploring the possibilities of creating new health insurance structures that will allow paying for diagnostic-based preventive medicine and other opportunities provided by personalized medicine. Currently, the coalition coordinates at least six comprehensive pilot projects to provide medical care in various US institutions.
According to Kathryn A. Phillips, professor of medicine and economics at the University of California, it is quite difficult to reach an agreement on the payment system for medical care. The reason lies in the fact that at the moment payers (insurance companies) do not seek to take the initiative, as they do not see enough convincing evidence of the value of personalized medicine.
At the heart of this problem is the lack of results of processing clinical data and economic assessments, as well as the weak activity of the industry to provide adequate information necessary for making decisions about insurance payments. It is necessary to develop a manual on technical cost assessment and a risk allocation scheme. Thus, Professor Philips' opinion echoes the previously mentioned call for joint work of the public and private sectors to assess and eliminate the existing shortcomings of regulatory control.
However, the public does not want to wait. Awareness of personalized medicine is growing with the publication of reports on methods of early diagnosis of cancer and the identification of genetic predisposition to diseases. Currently, a number of kits for self-genetic testing are already available, and private companies offer paid genome screening services. For example, Navigenics, a California-based genomic testing company, offers an initial genome scan and specialist consultation for $2,500. Those interested can continue to cooperate with the company and, as the results of new scientific research become available, receive updated information about their genome for just $ 250 per year.
Mari Baker, Chief Executive Officer of Navigenics, is confident that public interest in using the capabilities of genomic technologies will grow, which will lead to a reduction in the cost of work and increase their availability. The possibility of using genetic data for early diagnosis and treatment will promote the adoption of personalized medicine, gradually pushing aside concerns about the possibility of misuse of genetic information. Moreover, President George W. Bush announced that in the near future he will sign a bill already under consideration by the US Congress prohibiting the use of genetic information by employers and insurance companies.
Perhaps one of the most compelling commercial arguments in favor of personalized medicine is the prospect of cost reduction. Experts believe that the main incentive encouraging insurance companies to work together with researchers and medical communities to introduce personalized and preventive medicine into the healthcare system is a potential increase in the efficiency of medical care.
Meanwhile, new participants are joining the work. For example, Genomic Health has developed the Oncotype DX diagnostic kit, which currently covers 30% of the testing market for estrogen receptor-positive breast cancer without lymph node damage, accounting for approximately 50% of all breast cancer cases.
According to Randal W. Scott, Chief Executive Officer of Genomic Health, it is very difficult to get insurance coverage for such tests, but this test meets all the clinical criteria of the American Community of Clinical Oncology and the National Unified Oncology Network, which led to the participation of all major payers, including Medicare and United Healthcare.
The mechanism of action of Oncotype DX is based on a method for analyzing the gene expression of cells of biopsy tumor material, similar to reverse transcriptase polymerase chain reaction (RT-PCR), which is the main method for assessing viral load in HIV-infected people. The company adapts the methodology to work with other types of cancer, including colon, lung and prostate cancer. The completion of work on the test for the diagnosis of prostate cancer is scheduled for next year, and the appearance of the product on the market – in 2009.
Scott believes that medicine is in a state of revolution driven by technology. He compares the progress being made with Gordon Moore's law relating to the electronics industry, which states that the number of transistors in integrated circuits of computers doubles every two years. The productivity of new technologies is rapidly increasing, and over time they will significantly affect the principles of the use of medicines. A very important point in all that is happening is to ensure the rapid and adequate transfer of preclinical data into clinical ones.
Evgeniya Ryabtseva
Portal "Eternal youth" www.vechnayamolodost.ru
based on the article by Rick Mullin "Personalized Medicine", published in the journal Chemical & Engineering News on February 11, 2008.
14.03.2008