• 11/23/2004
  • R&D Directions Staff
  • Pharmalive (www.pharmalive.com)

A new term has entered the pharmaceutical developer’s glossary: theranostics. This word, created by the diagnostics company Pharma­Netics, defines the development of diagnostic tests that can identify which patients are most suited for a drug and provide feedback on how well the drug is working. The demand for theranostics is substantial, and the companies that produce these tests are reporting high-growth revenue rates. These companies tout the benefits of theranostic products: Patients get optimal treatment and excessive health-care expenditures can be reduced. These products will become more important in the coming years as health-care resources become even more limited, experts predict.

Theranostics are a rapidly evolving group of specialized molecular diagnostic tests that are viewed as improving the real-time treatment of disease, making treatment more cost-effective, and adding value to the drug-development process. The concept of combining a drug with a diagnostic is also known as predictive medicine, personalized medicine, integrated medicine, pharmacodiagnostics, and Dx/Rx partnering.

Theranostics go beyond traditional diagnostic products that only screen or confirm the presence of a disease. Theranostics can predict risks of disease, diagnose disease, stratify patients, and monitor therapeutic response. Theranostic products can provide physicians with information that enables them to individualize and optimize the therapeutic regimen of the patient. The physician may make better-informed decisions on timing, quantity, type of drugs, and choice of treatment procedure based on the relevant information provided by these tests.

Recent advances in the understanding of the molecular pathways of disease have been a catalyst for the dynamic interplay between medical diagnostics and therapeutic drug treatment. Medical diagnostics can confirm gene expression and protein expression and their interactions. Medical diagnostics can be used to guide and monitor therapy based on the interaction of biologicals and pharmaceuticals with target proteins. More specifically, protein biomarkers and corresponding tests can be used to predict and monitor drug response. This enables the stratification of patients into groups that are most likely to respond to a certain drug treatment regimen with minimal side effects.

A diagnostic test that can increase the clinical utility of a drug and reduce the risks and costs associated with developing and marketing that drug creates synergy, which leads to improved disease management, experts say.

Diagnostic companies are positioning themselves to offer theranostic tools by widening the application of in vitro diagnostic technologies to include more than just disease detection. According to the business-information company Decision Resources (dresources.com), these companies are developing theranostics for two applications: genetic testing, which seeks to identify patients who have inherited predispositions for various disorders; and therapeutic monitoring, in which diagnostic tools are used after a treatment regimen to monitor the therapeutic progress of the selected drug, and to help physicians decide whether to modify the prescribed therapy on an individual patient basis.

The best examples of theranostics application are the genetic testing that takes place before Genentech’s Herceptin and Novartis’ Gleevec are administered. Herceptin would not have reached the market without an accompanying diagnostic test that helps physicians identify patients whose cancer cells express the protein HER2, making them eligible for therapy. Gleevec reached the market without its test, but in August, a test was approved to detect a protein that is present in the tumors Gleevec is approved to treat.

Herceptin, approved in September 1998, is the first humanized antibody approved for the treatment of HER2-positive metastatic breast cancer. Herceptin is designed to target and block the function of HER2 protein overexpression.

Herceptin is a humanized monoclonal antibody that targets the HER2 protein in metastatic breast cancer patients and inhibits the proliferation of tumor cells that overexpress HER2 protein. Herceptin, when used alone and in combination with chemotherapy, significantly delays disease progression among many patients with metastatic breast cancer. HercepTest, a diagnostic test for the assessment of HER2 overexpression, aids in the assessment of patients for whom Herceptin treatment is being considered. The test was developed for Genentech Inc. by DakoCytomation AS (dakocytomation.com), a cancer-diagnostics company with a focus on personalized medicine that has its headquarters in Copenhagen, Denmark. Herceptin, and the diagnostics associated with it, demonstrate the ultimate synergy between a therapeutic and a diagnostic: The drug and the diagnostic come to market at the same time and the drug’s labeling includes the diagnostic.

In early 1998, DakoCytomation was approached by Genentech to develop a diagnostic assay to select patients for treatment with Herceptin. The active chemical in Herceptin, trastuzumab, is an antibody belonging to a new class of biological agents known as targeted therapies, which are named for their ability to bind specific molecules found on cancer cells. Research had demonstrated that tumors that responded best to the drug had high levels of a specific protein targeted by Herceptin on their surface. This finding ultimately led to the development of HercepTest, which identifies this specific overexpressed protein in breast tumors, with the purpose of selecting the patients who would benefit from Herceptin treatment.

In September 1998, FDA granted approval for Herceptin and HercepTest for the treatment of metastatic breast cancer. This joint approval, the first of its kind for an oncology drug and associated pathology test, marked the beginning of a new era for cancer-disease management. In addition to HercepTest, the labeling of Herceptin includes the application of another assay, PathVysion, as being appropriate assays to aid in the selection of patients for Herceptin therapy. PathVysion is a fluorescence in situ hybridization assay used to detect gene amplification. HercepTest, along with another test, Pathway, are immunohistochemistry test kits for the selection of Herceptin patients.

PathVysion was developed and is made available by Abbott Laboratories. Abbott (abbott.com) gained the assay when the company acquired Vysis Inc. in October 2001 for $355 million. Vysis, which is operating as a subsidiary of Abbott, is a genomic-disease-management company that develops and markets clinical-laboratory products. These products provide information critical to the evaluation and management of cancer, prenatal disorders, and other genetic diseases.

In January 2002, FDA granted Abbott approval to include Herceptin in PathVysion’s label, making it the only HER-2 product to have three claims: prognosis, adriamycin-based therapy selection, and Herceptin therapy selection.

Net sales of Herceptin were $425 million in 2003, a 10% increase from 2002. The success of Herceptin and HercepTest heralded the resurgence in the development of antibodies and other targeted therapies for the treatment of cancer. The fact that the drug’s success was tied to a diagnostic test, in turn, led to a new awareness of the potential value of diagnostic assays that identify the specific molecules targeted by new therapies.

“The utilization of diagnostic assays that go alongside treatment with Herceptin represents a dramatic success story in the area of pharmacogenetics and gives us some idea of what the process of parallel development of diagnostic assays and drugs will look like down the road,” says Oren Cohen, M.D., chief medical and scientific officer, Quintiles Transnational Corp. (quintiles.com), a company that provides a range of professional services, information, and partnering solutions to the pharmaceutical and biotechnology industries.

DakoCytomation’s next product development effort in this field is for an assay to detect an equally important growth factor receptor called EGFR, or epidermal growth factor receptor. A multitude of biopharmaceutical companies are developing EGFR-targeted drugs, but the catalyst for DakoCytomation’s development of an EGFR test came from ImClone Systems Inc. (imclone.com). In 1999, ImClone was in the advanced stages of testing Erbitux, its first potential cancer drug and an antibody against EGFR. Shortly after this, DakoCytomation began to work with ImClone to develop a diagnostic test to select patients for treatment with Erbitux. The outcome of this development effort, the EGFR pharmDx test, is used in clinical trials to qualify patients for treatment with Erbitux. The clinical trials are evaluating the effectiveness of the drug in combination with conventional therapies, such as radiation and chemotherapy, in patients with various stages of colorectal, lung, pancreatic, and head and neck cancer.

Erbitux was approved in February 2004 in the United States, in combination with irinotecan, in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are refractory to irinotecan-based chemotherapy and for use as a single agent in the treatment of patients with EGFR-expressing, metastatic colorectal cancer who are intolerant to irinotecan-based chemotherapy.

Gleevec was first approved in 2001 by FDA for use with chronic myeloid leukemia patients. The drug’s labeling was extended in February 2002 for the treatment of patients with c-Kit positive inoperable and/or metastatic malignant gastrointestinal stromal tumors. Gleevec was the first signal-transduction inhibitor approved for marketing in the United States. The product is marketed by Novartis (novartis.com). In 2003, global sales of Gleevec were $1.13 billion, up 68% from 2002.

In August 2004, Ventana Medical Systems Inc. (ventanamed.com) received approval for its VentanaDx c-Kit rabbit monoclonal antibody diagnostic kit. This is the first FDA-approved diagnostic kit using a rabbit monoclonal antibody. The approved diagnostic kit allows physicians to detect the presence of the c-Kit protein in gastrointestinal stromal tumors. Although not the sole basis for making a diagnosis of gastrointestinal stromal tumors, c-Kit will be an asset in the selection of patients who may be eligible for treatment with Gleevec.

C-Kit is the second targeted diagnostic kit developed by Ventana, The company markets a Pathway Her-2/neu diagnostic kit. Ventana develops, manufactures, and markets instrument and reagent systems that automate tissue preparation and slide staining in clinical histology and drug-discovery laboratories.

The force driving the development of companion diagnostics is the enhanced understanding of the molecular basis of disease. Scientists know that certain patients respond better to certain drugs than others. The opportunity and the challenge for drug companies lie in identifying the responders, those patients who are likely to respond well to the drug. This identification will require specific diagnostic tools.

Experts say other forces that will drive personalized medicine are regulatory pressure and more drugs such as Herceptin and Gleevec, which have demonstrated that targeted therapy can be profitable therapy.

Although the development of personalized medicine is still in its beginnings, experts predict that all pharmaceutical companies will eventually head down that path. Experts say companion diagnostics are a critical part to the commercialization of personalized medicines.

In understanding the molecular level of an individual’s disease, drug companies can target one or two drugs that will be the most effective in an individual. Companion diagnostics could determine the best therapeutic option for that patient.

“If we are going to personalize medicine, we need to know who is potentially in need of or responsive to a given pharmacological agent,” says Michael Evelegh, Ph.D., executive VP, clinical and regulatory affairs, and founder of International Medical Innovations (imimedical.com), which acquires technologies that have undergone initial successful proof-of-principle tests. The company develops these technologies into predictive medicines that address medical needs and that can be used as front-line screening tests. The company markets Prevu Skin Sterol Test, a noninvasive skin cholesterol test for assessing the risk of coronary artery disease.

According to International Medical Innovations executives, there is an essential need to develop easy, noninvasive, nonexpensive methods of identifying potential responders and target populations. If this method cannot be developed, personalized medicine is just a pipe dream, they say.

Theranostics are key to the success of personalized medicine. Adverse drug events and drugs that do not work result in a tremendous cost burden on the health-care system. Personalized medicines that enhance efficacy in patients and reduce the risk of adverse events will be a tremendous gain for health care, experts say.

Most theranostic applications are focused on the field of anticancer and antiviral drugs. The potential exists for companion diagnostics to be used with drugs that treat metabolic, central nervous system, cardiovascular, and inflammatory diseases.

“Oncology has some advantages and some real pressing needs for companion diagnostics,” says Andrew Dorner, Ph.D., senior director, molecular profiling and biomarker discovery, Wyeth Research (wyeth.com), which is focusing on delivering biomarkers that could become companion diagnostics for its oncology drugs. “Obviously, cancer patients don’t have a lot of time to try multiple drugs to see which one works. The ability to identify the weak link in a cancer patient’s disease and have the appropriate drug to target would be of an immense value to the patient.

“From a mechanistic standpoint, it is possible to look for underlying genetic mutations that might be causing the cancer and that would be a possible target that we could go after with the therapy,” Dr. Dorner says. “Some information that we’re seeing with mutations in the epidermal growth factor receptor indicating sensitivity or resistance to drugs exemplifies that this type of genotyping is coming into play to identify which patients will most respond to the drug.”

One of Wyeth’s programs targets specific cell surface markers on cancer cells with a very cytotoxic drug, calicheamicin. Normally, this compound cannot be administered as a chemotherapeutic agent because of its extreme toxicity. Wyeth has been attaching calicheamicin to an antibody, which serves as a warhead to deliver the cytotoxic drug to cancer cells that express on their surface a protein that is unique to these cells. The antibody attaches to the protein on the cancer cells and gets the calicheamicin into the cells to kill them. In this instance, the companion diagnostic being developed is for the expression of the targeted protein on the cell surface, Dr. Dorner says.

Calicheamicin is a potent antitumor antibiotic isolated by Wyeth researchers from a bacterium in a caliche clay soil sample from Texas. The antitumor antibiotic is linked with Wyeth’s Mylotarg, a recombinant humanized antibody cleared by the U.S. Food and Drug Administration in March 2000 under accelerated approval for the treatment of patients with CD33-positive acute myeloid leukemia in first relapse who are 60 years old or older and who are not considered candidates for other cytotoxic chemotherapy. Mylotarg is a significant advance in the treatment of acute myeloid leukemia and was the first drug specifically approved to treat relapsed acute myeloid leukemia patients.

The antibody portion of Mylotarg binds specifically to the CD33 antigen, a glycoprotein commonly expressed by myeloid leukemic cells. This antigen is also found on other bone-marrow hematopoietic cells, but not on pluripotent progenitor cells. This antibody was developed by Fred Hutchinson Cancer Research Center in Seattle, and subsequently licensed to Wyeth. Under an agreement with Wyeth, CellTech Group humanized the anti-CD33 antibody and jointly developed the chemical linker between the antibody and calicheamicin.

Wyeth is working with Celltech to develop another compound linked to calicheamicin: CMC-544. A humanized anti-CD22 monoclonal antibody, CMC-544 is being assessed in a Phase I study in patients with non-Hodgkin lymphoma by Wyeth.

The idea of using antibodies to deliver targeted chemotherapy to specific cell populations in the treatment of cancer, such as acute myeloid leukemia, has significant potential. Wyeth has a significant in-house effort to discover and develop companion diagnostics. Wyeth executives believe that companion diagnostics can add value to drugs and provide extra benefit to patients.

Early in their pharmacogenomics programs, Wyeth scientists accepted the importance of biomarkers in developing a theranostic. “One of the things that Wyeth has realized fairly early on in the various ongoing pharmacogenomics programs is that the concept of biomarkers is very important,” Dr. Dorner told R&D Directions. “[It is important to have] the ability to identify patients most likely to respond to a drug, and to identify patients who might be at risk for an adverse event. [It is important to be able to have] biomarkers that show that our drugs are hitting their targets appropriately as we go through our preclinical development work, ultimately leading to our first in-man studies. [It is important to have] the ability to understand molecular mechanism, to have biomarkers that are associated with drug effect and, hopefully, predictive of response is a key emerging field for the pharmaceutical industry.”

Wyeth’s translational medicine initiative ties scientists conducting the molecular profiling and biomarker discovery with experimental clinical groups and early-phase clinical trials groups to have a smooth discovery, development, and clinical application of biomarkers that would ultimately lead to the association of a companion diagnostic test with a drug. The mission of Wyeth’s translational medicine group is to look at every drug that is in the company’s pipeline and to determine whether possible to develop a biomarker for the drug.

“Putting together this translational medicine group uniting scientists with the clinic is probably the way that R&D needs to be restructured in the future to tackle these questions,” Dr. Dorner says. “Our program of biomarkers within the translational medicine program is going to be very extensive in that every program moving forward through its discovery phase will be examined for the need for biomarkers, and we will develop specific biomarker discovery development plans where warranted. That’s the significance that Wyeth attaches to this.”

The vision of translational medicine is one where genomic discoveries can be rapidly translated to the diagnosis and treatment of disease in a manner tailored to the individual. The increased understanding of molecular medicine will shift clinical practice from treatment based on symptoms to treatment based on the underlying causes of disease. Physicians will be prescribing drugs that are designed more intelligently, work more effectively, and have fewer toxic side effects.

The mapping of the human genome is only the first step. Researchers have yet to translate the variations in human genes that explain disease progression and resistance to therapy and why some individuals encounter debilitating diseases and others live healthy lives. Although all the puzzle pieces of the genetic make-up have been identified, scientists and clinicians now have the formidable task of interpreting how they fit together to apply the genome map to patient care.

The success of monoclonal antibody therapeutics directed toward specific molecular targets in tumors should help to accelerate the development of companion diagnostic tests to support the selection of therapeutic agents and monitoring of treatment.

According to Roche executives, the therapeutic area where companion diagnostics have been demonstrated to work the best, where they are most widely used, and where there is a clear rationale for their use is in virology and antivirals. The use of companion diagnostics in the antiviral field is different from how companion diagnostics are being used with oncology drugs. Whereas oncology drugs are designated to include the use of a particular diagnostic on the labeling and are tied to the drug, antiviral drugs are used independently.

“HIV and hepatitis C treatment have a relatively extensive use of diagnostic tools, which first diagnose a disease and second are used to choose treatment and to monitor patient response to treatment,” says Tom Metcalfe, head of Roche’s biomarker program. “There are a couple of other areas where we see that the evidence is perhaps less strong but that the potential is large, and that’s in metabolic disease in general and in inflammatory disease. We believe that there will be extensive use of companion diagnostics in the future.”

Roche (roche.com) operates two core businesses, pharmaceuticals and diagnostics, which provide innovative products and services that address prevention, diagnosis, and treatment of diseases. Roche’s Diagnostics Division, the world leader in in vitro diagnostics with a broad product portfolio, supplies a wide array of innovative testing products and services used by researchers, physicians, patients, hospitals, and laboratories worldwide.

For many of the therapeutic areas that Roche scientists are researching, they are developing assays that allow them to understand the molecular phenotype. “Time and our clinical experience will tell whether or not these are going to be useful as practical companion diagnostics,” Mr. Metcalfe told R&D Directions. “We’re certainly committed to this approach and we have a lot of experience now in development with applying this approach. We can’t predict yet whether or not a drug and a companion diagnostic will result out of our own pipeline, but we’re certainly preparing for the eventuality that we will require one.”

Roche seems to be ahead of its pharmaceutical competitors when it comes to developing companion diagnostics. One of the reasons is that Roche has operated a diagnostics division for a long time, whereas most other pharmaceutical companies have not.

“One of the reasons we think our approach will have success is because we understand clinical diagnostics intimately, and obviously, we understand drug development very well,” Mr. Metcalfe says. “We have a better understanding than most of the interplay between these two approaches. As a result, we have a more efficient and effective approach, and perhaps a better-informed strategy.”

Although Roche plans to rigorously apply biomarker thinking throughout its development process, research and development executives understand that the result may not be a companion diagnostic. “There is an importance to apply this in what we are doing,” Mr. Metcalfe says. “With targeted drugs in oncology, there’s a very strong rationale for applying this, and that more of these drugs will require companion diagnostics. And this is mostly to do with the heterogeneity of cancer. There is no one single approach that we believe will be successful in cancer and it’s very important for us to understand what the nature of the patient’s cancer is to choose the right treatment.”

More drugs are expected to be developed that will be packaged with companion tests to identify responders. More than 400 molecularly targeted therapeutics are in late-stage development. This new class of therapeutics requires a companion diagnostic to guide therapy.

The market for theranostic products is creating opportunities for pharmaceutical and diagnostic companies. Market analysts say the potential market for theranostics is enormous. Neither diagnostics nor pharmaceutical companies can afford to ignore this new science.

Most pharmaceutical companies are concerned that targeted medicines will mean reduced market size and the end of billion-dollar drugs. But the more visionary pharmaceutical R&D executives see this as an opportunity. Whereas the traditional blockbuster drug is created because millions of patients take it, the new blockbuster drugs will be created because a few hundred thousand patients get tremendous value from it. “The potential for translational medicine to provide extraordinary value by targeting patients is going to be a new blockbuster model,” Dr. Dorner told R&D Directions.

Market analysts say if a diagnostic improves the chances of getting a drug through development so that its development costs are lower, and improves its performance so that more doctors are willing to prescribe the drug, it may not be necessary to have huge drug sales to have a profitable drug. According to the analysts, the targeted therapy may command a premium price.

Theranostic tests and data are increasingly required by pharmaceutical companies to help ensure successful completion of clinical trials, receive FDA approval, and guide physicians in subsequent patient care. Many of these tests will be so intimately linked to safety and efficacy of a therapeutic drug that the drug is unlikely to be prescribed without them. This link offers advantages to both the pharmaceutical company and its diagnostic partner. For the drug company, the link can provide a strategic advantage and a barrier to entry for competing products; an expensive drug supported by a rapid, easy-to-use theranostic can be safer and more cost-effective than a drug without such a link. For the diagnostic company, the close link to cost-effective therapy will allow premium pricing of the high-value theranostic test.

“There is some concern that this would segment the market,” Dr. Cohen says. “The drug would only be available to a smaller percentage of the population compared with the blockbuster drugs that we’re used to in the current environment that generate so much revenue for the industry and are prescribed so very often.

“But there’s a general recognition that we are heading into a new era of drug development that will be less predominated by blockbusters and we will have many more of these targeted medications that will go hand-in-hand with pharmacogenetic testing. The combination is healthy. Ultimately, what we’re trying to do is to improve the drug-development process to make it a better and safer endeavor for patients.”

Only a few companies are paying attention to the development of theranostics. Abbott, Novartis, and Roche, in addition to Wyeth, are among the handful of pharmaceutical companies investing in this dynamic sector. Among diagnostic companies, PharmaNetics (pharmanetics.com) is working hard to establish itself in the emerging field of theranostics, or rapid near-patient testing, in which the diagnostic results may influence treatment decisions. The company’s tests can be used in the treatment of angina, heart attack, stroke, deep-vein thrombosis, and pulmonary and arterial emboli.

PharmaNetics was the company that conceived the term “theranostics,” defining the emerging field of medicine that enables physicians to monitor the effect of antithrombotic agents in patients being treated for angina, myocardial infarction, stroke, and pulmonary and arterial emboli. The company has developed, manufactured, and marketed rapid turnaround diagnostics to assess blood-clot formation and dissolution. PharmaNetics tests are based on its proprietary, dry-chemistry Thrombolytic Assessment System. The company’s principal target market is the management of powerful new drug compounds, some of which may have narrow therapeutic ranges, as well as monitoring routine anticoagulants.

The diagnostic industry is working independently of pharmaceutical companies to bring theranostics to market. Emerging pharmacogenomics technologies are presenting drug-discovery and development companies with the promise of targeted therapies and potential new revenue streams and are creating new opportunities for diagnostic companies to develop tests that can be used to determine patient response to a drug and screen out inappropriate candidates. The increasing interest in theranostics is likely to prompt more pharmaceutical companies to develop diagnostics divisions or acquire diagnostic companies. Future progress in theranostics will draw on developments in pharmacogenomics.

“There’s not an extreme urgency to develop companion diagnostics,” Dr. Dorner says. “This has to be done in the next year or so and we have to hurry up and get something on the market. The whole pharmaceutical industry at this point is asking not how urgent is the need but that the need is there. Everyone believes that this is the future for the pharmaceutical industry and the questions are, ‘How can it be practically implemented? What are the technologies, and what are the time lines within the drug development pathway for accomplishing this?’ As health-care costs continue to escalate, as our drugs become more sophisticated and targeted to specific populations of patients, the need for companion diagnostics to direct therapy will become greater and greater.”

FDA’s guidance on pharmacogenomic data submission will accelerate the development of theranostics. The guidance specifies when to submit pharmacogenomic data to the agency, what data to submit, and how to submit the data. These data must be focused on diagnostic tests used in conjunction with drugs and show how responses to the drug vary from person to person.

In November 2003, FDA issued a draft guidance to the pharmaceutical industry advising the companies about when to submit pharmacogenomic data to the agency during the drug’s development and review process, what formats may be used for submissions, and how the data will be used in regulatory decision making. The guidance defines pharmacogenomics as the use of a pharmacogenomic test in conjunction with therapy — an assay intended to study interindividual variations in whole-genomic or candidate gene single-nucleotide polymorphism maps, haplotype markers, and alterations in gene expression or inactivation that may be correlated with pharmacological function and therapeutic response.

The regulatory agency acknowledges that the promise of pharmacogenomics lies in its potential to individualize therapy, making it more effective while reducing its risk. FDA says the pharmacogenomic field is in its early-development stage and pharmaceutical companies are reluctant to conduct pharmacogenomic testing during the drug-development stages because they do not know how the agency will use these data in drug-application review process. The guidance was written to clarify the agency’s policy.

FDA envisions that pharmaceutical companies will begin to use pharmacogenomic tests to support drug development and/or to guide therapy. Most pharmacogenomic data are of an exploratory or research nature and are not required to be submitted. Although the submission of pharmacogenomic data is not required under FDA regulations, the agency is encouraging the voluntary submission of these data. The data can be submitted to an investigational drug application, a new drug application, or a biologics drug application. The data can be submitted to support scientific content related to dosing, safety, or efficacy. The agency will not use the information submitted for regulatory decision making but only for scientific and informational purposes.

The agency recommends joint development of the pharmacogenomic tests and the drug, and submission of complete information on the test to the agency. The agency plans to issue another guidances on joint development of pharmacogenomic tests and drugs in the near future.

Many pharmaceutical companies are using biomarkers during Phase I and Phase IIa clinical studies to predict and monitor safety and efficacy outcomes. Few pharmaceutical companies have the core capabilities, however, that would allow the development of those biomarkers into clinically validated and regulator-acceptable surrogate markers of disease outcomes, thus time and costs savings are not yet realized in Phase IIb and Phase III registration studies. Pharmaceutical companies, with their access to large numbers of patients who have undergone therapy with proprietary medicines, represent a resource that can be used to validate biomarkers. In collaboration with a medical-diagnostics company, they can jointly develop these validated biomarkers into a medical-diagnostic test.

Right now, only a few pharmacogenomic tests for certain drug-metabolizing enzymes are considered valid biomarkers in humans. FDA is encouraging pharmaceutical companies to develop pharmacogenomic tests that predict which subpopulations will have a positive response to therapy. Regulators point to the trend that has emerged in the past few years of drug labels becoming more narrow in their indications. The shift has become apparent in the HIV-drug-therapy field, which evolved from broad indications to narrow indications when the drug-resistance tests became available.

The agency is particularly interested in receiving pharmacogenomic data that distinguish patients at greater risk for a serious adverse event, and exploring the correlation in the appropriate populations. For pharmaceutical companies interested in developing the drug solely for populations that exclude the high-risk patients based on pharmacogenomic testing, the agency recommends that the company jointly develop a diagnostic and the drug because the agency would be unable to prove a drug for which the safety profile was predicated on a pharmacogenomic test that was unavailable.

FDA envisions that in the future, pharma-cogenomic markers that predict drug toxicity will be identified and developed on a parallel path with overall drug development. The medicine would be developed in a conventional manner with a parallel effort to identify appropriate predictors of toxicity. If the drug’s risk-benefit profile were acceptable, the drug could be approved before the completion of efforts to refine and develop the relevant pharmacogenomic tests. When the predictive value of a diagnostic test is to be established and the test is to become commercially available, the drug label could be changed to reflect the data.

FDA is countering the perception that pharmacogenomic testing is likely to give very definitive answers about safety and effectiveness in subpopulations. This may happen sometimes, as it happens in oncology, and in these cases the rapid development of a diagnostic test is highly encouraged. This is unlikely, the agency says, to be the ordinary case. In most instances, the gene expression profile is likely to be one of a number of factors.

“FDA had a workshop in March on the concept of how to codevelop a diagnostic assay for pharmacogenomics or pharmaco-
genetics data and a drug and a companion diagnostic should be developed simultaneously, but I am not sure that is possible,” Dr. Dorner says. “In most cases, biomarkers for the diagnostic will be identified or will be discovered in a Phase II clinical trial because many times the Phase I clinical trial is healthy volunteers and it isn’t always a diseased population that is going to be targeting in the later-stage trials. In many cases, we will be discovering biomarkers in Phase II to put together an assay to be validated in Phase III and then go to the FDA for registration of the drug as well as some information on what the companion diagnostic should be.

“At this point, we are going to have to develop, perhaps, new paradigms of how to jointly develop a diagnostic that can be used in the label to determine patient-therapeutic options. That is something that FDA is very interested in, understanding how to do this.”

Industry observers say the era of the blockbuster market is over. Although there will be more blockbusters, there are not enough blockbusters left to fuel the entire pharmaceutical industry. The innovation in the industry has been more and more in targeted therapies.

“This is a good trend,” Dr. Cohen says. “Targeted therapies will allow for many indications and will allow us as physicians to offer better and safer medications over time. We will not have personalized medicine tomorrow, but during the next decade there will be an explosion in the number of drug-development programs that utilize pharmacogenetic-companion tests. This is a natural evolution of molecular medicine.” R&D