By Cliff Mintz Ph.D.
Personalized or individualized medicine is the latest life sciences innovation that is poised to transform medicine and delivery of healthcare to patients. While some describe personalized medicine as a technology of the future, others contend that personalized medicine is already influencing and having an impact on the way patients are being treated today.
Generally speaking, most experts agree that the era of personalized medicine began in earnest in 2003 after sequencing of the human genome (and publication of a genetic map) was completed by the U.S. Department of Energy and the National Institutes of Health. Prior to 2003, physicians and healthcare providers primarily relied on patients’ memories and family histories to assess personal disease risks. Now, advances in genomics and bioinformatics are revolutionizing science and allowing consumers to acknowledge disease risk factors more accurately, pursue appropriate treatment options, and possibly maintain better health.
Access to the entire human DNA sequence has allowed investigators to begin to identify: 1) genetic defects and gene polymorphisms associated with disease initiation and progression, 2) effectiveness of specific treatment regimens, 3) predictions of patient drug responsiveness and clinical outcomes, 4) likelihood of adverse events and tolerability issues with certain drugs, and 5) fine tuning of dosing requirements. Activities linking the performance and pharmacology of drugs with genomics is collectively known as pharmacogenomics. Pharmacogenomics introduced the concept of using molecular markers (biomarkers) to assess drug efficacy and safety and the risk of disease — or its presence — before the appearance of clinical signs and symptoms.
While Ray Woosley, M.D., Ph.D., president and CEO of the Critical Path Institute, agrees that recent advances in pharmacogenomics may have accelerated interest in personalized medicine, he warns that patients’ needs — not science itself — should drive the adoption of personalized medicine. “There is no question that exciting changes are under way,” he said. However, he added, “I think the science is moving much faster than medical practice at this point. Personalized medicine isn’t going to happen overnight; we are currently experiencing a scientific logjam of sorts. I think a carefully planned scientific and regulatory-compliant approach is warranted before personalized medicine is fully embraced and adopted by the healthcare community.”
What Is Personalized Medicine?
The term personalized medicine is frequently bandied about in both scientific and lay literature, but its precise definition has been elusive. An April, 2008 article in the U.S. News and World Report defines personalized medicine as “a young but rapidly advancing field of healthcare that is informed by each person’s unique clinical, genetic, genomic and environmental information.” Similarly, a description of personalized medicine on the Personalized Medicine Coalition’s website suggests that it “uses new methods of molecular analysis to better manage a patient’s disease or predisposition to a disease.”
In contrast, Critical Path’s Woosley contends that while molecular testing and pharmacogenomic analyses may be important, they aren’t always the most critical aspects of personalized medicine. “High tech solutions aren’t always the answer. Sometimes the most important part of personalized medicine — the patient — may be overlooked or, in some instances, left out of the equation,” he said. “Integration of clinical findings and results from pharmacogenomic analyses will be required before the full benefits of personalized medicine will be realized.” Nevertheless, there is general consensus among scientists, healthcare providers, and patient advocacy groups that personalized medicine will help to improve patient health outcomes in the future. To that end, personalized medicine is likely to have a major impact in three primary areas: 1) determining the safety and efficacy of an experimental new drug prior to regulatory approval, 2) establishing an individual’s genetic predisposition to certain disease states, and 3) identifying possible adverse drug reactions and tolerability issues in large patient populations.
Despite some recent advances and early successes, the field of personalized medicine is still in its infancy. While most Americans have already heard about the promise of personalized medicines, there are only a handful of commercially available products on the market today. Nevertheless, Michael Cantor, director of healthcare informatics at Pfizer, and Cecilia Schott, personalized healthcare business development director at AstraZeneca, believe that personalized medicine will benefit physicians and patients alike. Some of the likely benefits include:
The therapeutic areas most likely to benefit from personalized medicine include oncology, cardiovascular disease, neurodegenerative disease, psychiatric disorders, and metabolic diseases such as diabetes and obesity. “Things are advancing most rapidly in cancer diagnostics and treatment option determinations,” said Pfizer’s Cantor. “The greatest challenge we face in personalized medicine is determining whether or not the tests we are developing will have a clinical impact or provide patients benefit,” he added.
AstraZeneca’s Schott agrees that the field of oncology will greatly benefit from personalized medicine. She also contends that infectious diseases are another area likely to benefit from advances in personalized medicine. For example, AstraZeneca is currently developing a diagnostic test to identify patients with bacterial infections who may be at risk for developing sepsis, a disease that has mortality rates approaching 90%.
In addition to potential medical and clinical benefits to patients, many drug makers believe personalized medicine will help expedite the time required and reduce the costs associated with new product development. Pfizer’s Cantor offered, “Many of our products in development have a biomarker strategy and plan associated with them. This is necessary because many new drugs in the future will likely be packaged with companion diagnostic tests to determine the safest and most effective treatment options and to optimize dosing.” AstraZeneca’s Schott concurs and suggested that many of her company’s oncology drugs in development will likely be commercialized with companion molecular diagnostic tests.
Recent reports estimate that, on average, newly approved drugs work for only 50% of the people who take them. By using pharmacogenomic data about a new molecular entity and corresponding information about how patients’ genes may affect drug responsiveness, drug makers may be able to identify subsets of clinical trial participants who are most likely to respond or least likely to experience side effects. This would likely reduce the number of patients required to conduct clinical trials, which in turn would reduce the time and costs associated with garnering regulatory approval. While this may be a boon to drug manufacturers, patient advocacy groups argue this approach may limit and hinder new drug development to only molecularly well-characterized diseases. “Not so,” said Pfizer’s Cantor. “In the not-so-distant future, personalized medicine will be necessary to differentiate one company’s product from another in smaller patient populations and markets. The ability to compete in smaller, competitive markets will likely, in turn, foster new drug development in specialty areas including orphan diseases. Also, personalized medicine will allow companies to demonstrate that the products they develop have a clear clinical impact on the patients who use them. This will be necessary to justify premium prices and reimbursement costs for news products.”
Moving Toward Commercialization
The results from the human genome project indicated that humans possess 20,000 to 25,000 genes. To date, over 1,500 disease-related genes have been discovered. At last count, an estimated 1,300 genetic tests exist for conditions ranging from hearing loss to sudden cardiac arrest.
A recent report by PricewaterhouseCoopers predicts that the personalized medicine market for pharmaceutical, medical devices, and diagnostic companies is expected to grow 10% annually and reach $42 billion by 2015. However, in the past five years, about 10 personalized medicine tests have won regulatory approval in the United States and elsewhere. Of interest, most of these tests were developed in the areas of oncology, cardiovascular, and infectious diseases.
Most experts agree that the “poster child” of personalized medicine is the HER-2 gene, which produces a protein that causes a form of breast cancer. If a woman tests positive for the HER-2 gene, she is a good candidate for treatment with Herceptin, a breast cancer drug developed by Genentech. Herceptin treatment has been shown to reduce the risk of recurrence of HER-2 positive breast cancer by almost 50%. Similar diagnostic tests used to determine the effectiveness of certain treatment regimens have been developed for other oncology drugs, including Gleevac (chronic myeloid leukemia), Iressa (nonsmall cell lung cancer), Rituxan (non-Hodgkins Lymphoma), and Camptostar (colorectal cancer). A new diagnostic test is also in the works for another colon cancer drug called Erbitux.
Researchers also have found that two genes can affect how patients respond to the widely used anticlotting drug warfarin. Determining the appropriate treatment dose of warfarin is extremely challenging, and the test was developed to help fine-tune dosing regimens. However, while the test may have helped to improve warfarin dosing in some cases, there is still limited data on whether or not it has led to improved safety and efficacy. And, perhaps more importantly, even with the test, about 45% of the variability in responsiveness to warfarin remains unexplained and is likely due to other factors, including diet, exercise, and patient compliance (taking the medication).
Roche Diagnostics recently developed an FDA-approved diagnostic that assesses the level of activity of a person’s drug-metabolizing cytochrome P450 (CYP450) enzyme system. CYP450 enzymatic activity is known to affect the effectiveness of certain medications, most notably, antidepressants and cardiovascular drugs. The test allows physicians to fine-tune drug dosing based on a person’s metabolism rather than cruder indicators such as body weight or body mass index. However, like the warfarin test, it isn’t clear whether or not the CYP450 diagnostic is any better than trial-and-error with regard to clinical utility. Another new molecular diagnostic test was developed for Ziagen (abacavir), a drug used to treat HIV infections.
Although abacavir is an effective treatment for HIV, one of its main drawbacks is the risk of a hypersensitivity reaction, which has been reported to be fatal in some instances. Recently, a predictive test, based on the relationship of abacavir sensitivity with the human leukocyte antigen allele HLA-B*5701, was developed to reduce the incidence and risk of adverse events among patients taking abacavir. This test is now widely used to determine whether or not abacavir should be used to treat individual HIV-infected patients.
Despite these early successes, Pfizer’s Cantor cautions that personalized medicine may not make sense for drugs in all therapeutic areas. “Only tests that are likely to have a clinical impact on prescribing habits, treatment selection, and patient safety ought to be developed,” he said. Cantor added, “I think it makes sense in the oncology area but do we really need a test to help to determine the correct dosage for a statin?” Critical Path’s Woosley echoed similar sentiments. “There is no question that some of the new biomarker tests are worthwhile,” he said. “But, much more work needs to be done to verify and validate the relationship with certain biomarkers and diseases before tests are ultimately commercialized and used in clinical settings.”
What’s In Your Genome?
Completion of the human genome project and advances in automated DNA sequencing and analysis have given rise to so-called personal genomics companies such as 23&Me and Complete Genomics. These companies provide direct-to-consumer (DTC) genetic analyses services to individuals interested in learning more about their genetic makeup or ancestry. While these companies — also known as personal genomics companies — currently don’t offer whole genome DNA sequencing services, many industry experts believe it is only a matter of time before they become available. To that end, Complete Genomics recently announced it expects to be able to sequence an entire human genome for $5,000 or less by the end of 2010!
Alan McHughen, Ph.D., a faculty member at the University of California-Irvine and personalized medicine advocate, has “no doubt that whole genome sequencing will be used and useful for people.” But he worries that lay consumers don’t truly understand the implications of the personal information contained in their DNA and is concerned about access and privacy issues for whole genome sequence data. “If I donate or pay to have my DNA sequenced, and the data is subsequently used for beneficial purposes, then I have no problem. However, if that data is inappropriately shared, misused, or stolen, there may be serious personal consequences for individuals who provided their DNA,” he warned. Others worry that the DTC genome analysis trend may lead to unnecessary medical interventions, possible false assurances, and missed diagnoses in patients. Because the clinical value of most personal genomics tests remains unproven, most personalized medicine experts agree that additional research will be necessary to assess their predictive value and potential to improve the use of clinically effective interventions and therapies.
The Five Challenges To Personalized Medicine
There is no question that personalized medicine has the potential to revolutionize medicine and transform healthcare. However, before the full potential of personalized medicine can be realized, there are several formidable challenges that must be overcome. First, while there is little doubt that some of the new molecular biomarker tests are worthwhile, many potential biomarkers have yet to be verified and qualified for use in personalized medicine products. According to some estimates, there currently may be as many as 200 molecular biomarkers in various stages of commercial development. Woosley and other experts believe the real challenge of personalized medicine is finding relevant biomarkers and then matching them with an actual medical condition of interest. To that end, the Critical Path Institute submitted and received FDA approval for use of seven biomarkers in a variety of therapeutic areas. Woosley indicated that the Institute will submit FDA applications for 18 new biomarkers (including several for Alzheimer’s disease) later this year. Nevertheless, other biomarker researchers contend that more than half of the published biomarker studies have been compromised by factors such as sex and age mismatches of sample donors and variations in the handling and storage of donor samples. “Despite the hype and all of the promises that have been made, much work needs to be done before personalized medicine can be fully realized,” said Woosley.
Second, despite approval of a handful of personalized medicine diagnostic tests, the FDA has yet to clearly define a regulatory approval pathway for this new class of products. Although the agency has been collecting biomarker data for the past five years or more, it has yet to issue useful guidance on the subject. This means that each regulatory submission for a personalized medicine product is handled on a case-by-case basis by regulators. This process is time-consuming, labor-intensive, and costly. Further, industry insiders and personalized medicine advocacy groups contend that FDA regulators lack the knowledge and training to critically evaluate prospective new personalized medicine tests. Further, many believe that the agency’s personalized medicine program is grossly underfunded and understaffed. According to Woosley, more than $1 billion has been budgeted for a personalized medicine program at the European Medicines Agency, whereas only $18 million was allocated for a similar program at the FDA.
Despite the problems at the FDA, several important regulatory questions pertaining to personalized medicine must be addressed in the near future. For example, a pressing question is how narrowly should clinical trials be designed to include/exclude trial participants based on the results of certain genetic screening tests? Another question pertains to whether drug efficacy and safety are defined in different ways for different genetic subgroups within patient populations. Finally, FDA regulators must craft a clearly defined and interpretable regulatory framework for the validation and verification of molecular biomarkers.
Third, the success of personalized medicine is contingent upon the ability of scientists and healthcare providers to capture, manage, store, and provide access to large amounts of data and medical information. This will require the use of high-speed computer networks and large databases composed of electronic health records (EHRs). At present, most medical records in the United States are almost exclusively paper-based. While billions of dollars of U.S. stimulus funds have been allocated to convert paper records into EHRs, no consensus has been reached on software standards that will be used to create, store, or share EHRs. Further, linking clinical data and genomic data sets is likely to present formidable integration challenges, and superimposing treatment algorithms on this data may be even more daunting. Consequently, it will be difficult to begin to practice personalized medicine on a large scale (despite a growing number of commercially available tests) until the software standards are adopted and the supporting IT infrastructure is better defined and constructed.
Fourth, in order for personalized medicine to succeed, healthcare providers, patients, and insurers must learn how it works. This will require substantial sums of money to develop instructional materials, continuing medical education programs, and public outreach campaigns. At present, it isn’t clear how these programs will be funded or whether or not government, medical organizations, private sector companies, or academic institutions will assume responsibility for training and educational initiatives.
Finally, and perhaps most importantly, there are many privacy, confidentiality, and fair-use concerns about personalized medicine. Mark Rothstein, J.D., at the University of Louisville Center for Health Policy and Bioethics, believes that the advent of personalized medicine coupled with the federal initiative to digitize healthcare records will invariably raise privacy issues. “For the first time, medical and genetic information about individual patients [collected and stored over long periods of time] will be linked and centrally located. This raises the likelihood of potential confidentiality, privacy, and access concerns,” he said. Rubenstein added, “The number one concern that individuals have today is that information about past health or prediction of future health based on genetic tests may be used by a health insurance company to increase rates or deny healthcare coverage. Also, people are concerned that employers might use genetic information to make decisions about hiring, firing, and job assignments.”
Personalized medicine advocates contend that the Genetic Information Nondiscrimination Act (GINA) enacted in May 2008 would shield patients from potential “genetic discrimination” by either health insurance companies or employers. While this may be true, GINA does not cover life, disability, or long-term care insurance, and the potential for genetic discrimination still exists in these areas. For example, a person at genetic risk for developing Alzheimer’s could be denied long-term healthcare insurance because Alzheimer’s patients have been known to live for long periods of time, and their care is costly.
Surprisingly, at present, it isn’t clear who owns or ultimately controls a person’s genetic information and DNA sequence data after it is generated. For example, it is likely (but not certain) that a consumer who purchases whole genome sequencing services from a personal genomics company owns and controls his/her sequence data. However, as whole genome sequencing continues to enter the mainstream, individuals will likely receive complete or partial genomic sequence information from a variety of sources. Ownership and control of the information isn’t likely to be straightforward or easily defined until rules and regulations are crafted to clarify how genomic information is owned, stored, and accessed by individuals and third parties.
Faster Drug Discovery, Less Cost
Personalized medicine has the potential to fundamentally change the way U.S. healthcare is practiced and delivered in the 21st century. While there is much work to be done, personalized medicine promises to expedite drug discovery, cut development costs, improve diagnoses, and provide patients with more effective and safer drug treatments. However, its success depends on the ability of drug and diagnostic manufacturers, healthcare providers, medical educators, information technology professionals, policy makers, and payors to work together to create an integrated framework that meets the healthcare needs of all Americans.