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A Working Paper of the 21st century
FDA Task Force

June 2006

Prescription for Progress: The Critical Path To Drug Development

Robert Goldberg, Ph.D. and Peter Pitts

Executive Summary

The biopharmaceutical industry can bring new medicines to market in a faster, safer, and less expensive way than current government and industry policy allows. Recognizing this reality, the U.S. Food and Drug Administration (FDA) has taken a dramatic step to streamline drug development by incorporating new technologies. The FDA's Critical Path Initiative, announced in March 2004, has recommended evaluation of new ways to use genetic tools, faster computers, new imaging techniques, and electronic medical records in the drug evaluation process.[1] This ongoing project, while still in its infancy, holds the potential to break down barriers between regulators and industry and to expedite the often complicated journeys of lifesaving medical innovations from researchers to regulators to patients.[2]

In support of the Critical Path Initiative, the Center for Medical Progress at the Manhattan Institute convened 25 experts from industry, government, and the scientific community in a task force on the 21st century FDA. In spirited and wide-ranging discussions, participants considered how advances in genomics and other disciplines might be used to optimize the drug approval process. This working paper distills the problems, principles, and proposals that surfaced during that dialogue.

In our discussions, a general consensus emerged that FDA, scientific researchers, and pharmaceutical companies can collaborate to:

  • Integrate biomarker validation into every stage of the regulatory review for drug, diagnostic, and biologic applications.
  • Improve clinical trials by creating one standard for collecting and using data from electronic medical records.
  • Utilize validated biomarker-based studies to assess the safety and effectiveness of specific drugs for specific subpopulations at specific doses.
  • Articulate the importance of congressional appropriations sufficient to implement the FDA’s Critical Path activities, as well as providing the $5.9 million earmarked for Critical Path purposes in the FDA’s 2007 budget proposed by President George W. Bush.

This working paper is intended not as the final word on the Critical Path but as a springboard to continuing discussion and debate. Although this paper focuses on drug development, participants in the task force's discussions recognize that the FDA has vital responsibilities in other areas, such as bioterrorism and food safety. Nevertheless, the authors of this report believe that the Critical Path Initiative should be a priority within the FDA and within government. By steering us toward a drug approval process that is driven more by science and restricted less by regulation—by unleashing the powers of American enterprise and pathbreaking science—the Critical Path Initiative can improve health and save lives.


The Critical Path to Personalized Medicine

The biopharmaceutical industry has the means to bring revolutionary new medicines to market faster, more safely, and less expensively than current industry or government policy allows. Yet the FDA, drug developers, and scientific researchers have only begun to evaluate the new technologies that may optimize testing-and-approval of new drugs.

We are living in a period of enormous innovation in the biological sciences. New fields like genomics, proteomics, and other "-omics" sciences are being linked to powerful new computers and statistical modeling that allow researchers an unprecedented view into the inner workings of human biology.[3]

Biopharmaceutical companies have embraced this knowledge and are rushing to translate new discoveries into powerful, safer, and more effective therapies that can treat diseases based on their underlying genetic roots, hastening the day when patients will, as a matter of course, receive individualized or targeted drug therapies.

The scientific challenges facing the development of personalized medicine are considerable. The current system of drug development and approval is outdated, inefficient, and expensive. It often uses technological standards developed in the 1960s to evaluate drug candidates identified using the latest advances in basic science. Under the FDA’s current framework, the development of personalized therapies remains more expensive and less efficient than it could be, slowing the translation of new knowledge into new treatments.

The current regulatory and industry approach is focused on ensuring that every product is safe and effective for the general population. At a presentation on drug safety convened at the Institute of Medicine, senior FDA staffers remarked that current drug development technologies are "largely empirical in nature" and that "this tradition focuses on population means and observations of outliers" that result in "trial and error" clinical medicine.[4]

The FDA and its stakeholders recognize that this approach makes failure likely for products that otherwise might be safe and effective for specific subpopulations or individuals. The challenge facing industry and regulators is to develop valid standards for identifying these "high responders" at earlier stages in the drug development process. The goal is to speed development of important new drugs to market and ensure that people receive the medicines that are best for them.

To its great credit, the FDA is taking a dramatic step to catalyze the use of new technologies to focus and streamline drug development. The FDA’s Critical Path Initiative, announced in March 2004, aims to use genetic tools, faster computers, new imaging techniques, and electronic medical records in the drug evaluation process.[5] This report breaks new ground by bringing together the analyses and ideas of experts and stakeholders to identify serious challenges to the Critical Path and to suggest solutions for those challenges.

Many task-force participants believe that the media creates a false dichotomy between "bad" drugs (which reach the market, but shouldn't have) and "good" drugs (which are, at least in the public’s mind, "safe"). In truth, "bad" drugs with unacceptable safety profiles are usually weeded out by the development process before they reach market. It is true, however, that the development process focuses on a new drug’s broad-based safety and efficacy profile. Consequently, drugs that have bad effects on small subsets of patients may slip through these screens.

In fact, physicians need better knowledge about how to use medicines safely and effectively in individuals and subpopulations. Some drugs, such as Vioxx, may cause problems for a small subset of people. Others drugs, such as thalidomide, may beintolerable for broad populations but useful in subpopulations; thalidomide has been widely used to treat certain cancers. Instead of taking "'bad" drugs off the market, or plastering them with interminable warning labels, regulators and industry should work together to develop personalized medicines that can better ensure that people who can safely benefit from these drugs get them and that those who are at risk avoid them.

The hope is that scientific advances will eventually enable pharmaceutical companies to use genomic screening techniques linked to biomarkers early in the drug development process to identify drugs likely to cause serious side effects in a substantial number of people.[6] FDA and industry can facilitate this goal by working together to create standards for biomarker validation that can be used in clinical testing to screen for rare, but unavoidable, side effects such as liver, kidney, and heart damage. This technology is not currently available, although these side effects are often the reason that medicines do not reach the market or are withdrawn from the market. A more targeted approach to drug development and evaluation would make medicines more effective and safer. The first step is to find and validate likely biomarkers.

Biomarkers are measures of disease progression, pharmacology, or safety that can identify unique disease mechanisms or responses to medicines. FDA guidelines can specify how biomarker-based tools and alternative drug evaluation techniques can be used for drugs, biologics, and diagnostics as well as a combination of medicines and tests.

Because of advances in our understanding of how genetic variations shape response to medicines and disease, researchers have reason to hope that biomarkers can become an important new tool for the personalization of medicine. But validating these biomarkers will require an unprecedented degree of collaboration and cooperation among many stakeholders in the biopharmaceutical community.

Figure 1. Innovation Gap

© 2004 Burrill & Company. Confidential and Proprietary

How can the FDA, working with industry and other partners, best promote and advance personalized medicine? That is the vital question confronting policymakers, industry leaders, the scientific community, and the FDA itself.

Public Health and the Critical Path

The drive to streamline the drug development and approval process through biomarkers, better animal models, improved surrogate end points, and innovative clinical trial designs has important public health implications, especially for the development of new vaccines and an antibiotics.[9] The markets for these drugs are often smaller and much less reliable sources of industry revenue than for chronic ailments like heart disease and cancer. As a result, lengthy and expensive regulatory requirements can act as powerful disincentives for companies to invest in research for these vital public health tools.

Public health officials actively discourage physicians from prescribing new antibiotics, hoping to delay the evolution of drug-resistant pathogens. This practice may be prudent medically, but it has the side effect of reducing industry revenue for investing in the next generation of antibiotics. Vaccines, on the other hand, can be subject to government price con controls trols[10] and are administered to targeted populations at infrequent intervals. As a result, the annual U.S. sales for a single statin drug, Lipitor, are greater than those of the entire global vaccine industry. Since companies view these products as finan financially unattractive, the pipeline for new vaccines vaccines[11] and antibiotics antibiotics[12] to combat resistant pathogens, emerging diseases, and potential bioterror attacks has grown worryingly thin. Streamlining the drug development process and lowering de de-velopment costs should spur additional research into these product areas.


Shortcomings of the Current Drug Development and Approval Process

In the last decade, U.S. pharmaceutical research and development expenditures have risen 250 percent, and from 1999 to 2003 the National Institutes of Health (NIH) budget for biomedical research doubled, from approximately $13 billion to over $27 billion.[7] Although these expenditures have led to many advances in basic biomedical science, the number of new drug and biologic applications per year submitted for FDA approval over this period has declined.

Figure 2. 10-Year Trends in Major Drug and Biological Product Submissions to FDA

Source: FDA

The Tufts Center for the Study of Drug Development estimates that the industry must spend $800 million to $1.7 billion and 12 to 15 years of research and development on average to bring a product to market.[8] These costs must be recouped predominantly during a limited period of patent protection or marketing exclusivity if drug development is to remain financially viable. With such great amounts to recoup in such a limited time, the drug industry is forced to charge increasingly higher prices. Because of rapidly escalating prices for branded prescription medications, national drug policies and price controls are being considered, which would threaten the future of the research-based pharmaceutical industry in the United States. Higher development costs also limit accessibility of medications and discourage development of medications for orphan diseases and diseases that affect primarily low-income populations.

Individual companies have devoted enormous resources to identifying potential biomarkers that would help streamline the development and approval process. To date, however, critical improvements have proved elusive. Many biomarkers have been discovered, but the task of validating them is laborious, and many do not prove reliable in the validation process. For instance, there is still no biomarker to predict hepatic injury (liver damage), nor is there a good animal model available. Achieving even one of these goals would represent a major breakthrough.

The FDA has concluded an analysis of the causes for the delays in drug development and has called for collaborative research to develop and validate new tools and methods for testing new medicines. The FDA is confident that this research and the resulting new tools will enable more rapid and informative drug development, such as occurred for AIDS drugs in the 1980s and 1990s. In response to the AIDS crisis, the FDA worked closely with the pharmaceutical industry to develop innovative methods for the rapid development of new drugs for AIDS and HIV[13], resulting in development times as short as two years for these drugs. During the same period, the average development time for all drugs slowed to less than twelve years. This experience clearly demonstrates that it is feasible to accelerate drug development without taking unnecessary and dangerous shortcuts.

It is clear that FDA leadership is committed to the Critical Path Initiative. It is increasing the number of training sessions for reviewers on new statistical and drug study methods. The Interdisciplinary Pharmacogenomics Review Group (IPRG) advises and educates reviewers on how drug evaluation can utilize pharmacogenomics (the study of how variations in the human genome affect the response to medications).

But the agency needs new organizational mechanisms and additional resources to implement the Critical Path Initiative fully and to ensure that drug advisory committees utilize its tools. While the amount of this additional funding should be determined through consultation with the FDA, Congress, and FDA stakeholders, there is a glaring need for additional funding. The FDA is unable to routinely send staff to important collaborative scientific activities in such areas as bioinformatics, biomarker development, nanotechnology, clinical trial design, and imaging. For example, a recent meeting on storing, collecting, and analyzing tissue samples drew scientists and managers from the National Cancer Institute, the army, CDC, private companies, and academia, but no one from the FDA attended, despite the fact that the agency will be one of the single biggest repositories of genetic samples in the world. Similarly, there is no FDA office responsible for ensuring that companies adopt Critical Path Initiatives.

Bioinformatics is a branch of clinical research that analyzes biological information using computers and statistical techniques. An ever-growing discipline, it includes analyzing data from drug studies, evalu evaluating and mining clinical data of patients in the real world, collecting and storing genetic material, and combing patient health records to develop predictive models of health care.

Promoting Collaboration

The FDA's senior management has collaborated with industry, other government agencies, community-based research, and academia to develop new ways to evaluate drugs during and after the development process. The Critical Path process will be most successful, however, when collaboration expands beyond senior management and FDA reviewers are comfortable using validated Critical Path tools.Medical reviewers, for example, within drug divisions could actually begin to use non-frequentist trial designs (such as Bayesian models) or virtual clinical trials for diseases where small treatment populations make traditional clinical trials extremely time-consuming or expensive. Although the agency is developing guidances that implement new sciencebased standards, industry can do much more to share the clinical data necessary to validate the standards. Safety biomarkers, for example, have the potential to expedite the creation of new guidances.

Through conferences, consortia, and other means, the Critical Path Initiative has encouraged collaborative efforts in the following areas:

  • Testing and development of molecular and imaging biomarkers for regulatory approval and use
  • Specific directions for use of biomarkers in clinical trials during drug development (a clear regulatory framework for evaluation)
  • Collection and evaluation of genomic and molecular information to develop assays for predicting the toxicity of drugs at given doses and identifying who benefits most from which treatments
  • Evaluation of the impact of drugs in the real world through the use of electronic patient records

Bayesian analysis

Bayesian analysis is an important statistical tool for confirming that smaller groups of patients are benefiting from new drugs and devices and identifying the connection between how a product works and clinical outcome.

When comparing two hypotheses using the same information, traditional statistical methods would typically result in the rejection or non-rejection of the original hypothesis with a particu particular degree of confidence, while Bayesian methods would yield statements that one hypothesis was more probable than the other. Rather than assuming that we know nothing prior to con conducting an experiment and then conducting an experiment to see if a cause and an effect (drug and clinical outcome) happen so frequently that it is most likely not a matter of chance, Bayesian analysis presumes that we have knowledge about other causes and effects and uses that knowledge to shape the experiment and come up with an estimate of whether the cause and effect are the result of chance. Such estimates and experiments are continually updated in light of new knowledge.

The FDA recognizes that Bayesian computations can be used in combination with these two forms of data. The FDA has used Bayesian statistics to accelerate the approval and improve the safety of coronary stents. Harvard statisticians used Bayesian statistics to analyze seven ran randomized trials of FDA-approved stents involving 5,806 patients stored at the Harvard Clinical Research Institute (HCRI) to develop an “objective performance criterion” for medical device clinical trial. [15]

With input from stakeholders, the FDA is working to clarify standards and guidelines for the application of these new tools in the regulatory process. In that spirit, the FDA and stakeholders can continue to employ statistical measures that identify smaller groups of patients more likely to benefit from a product compared with those less likely to do so.

Such approaches incorporate the sort of confirmatory evidence encouraged and allowed under the FDA Modernization Act of 1997.14 The act allows drugs to be approved with data from one adequate and well-controlled clinical trial investigation and with confirmatory evidence to establish effectiveness for risk/benefit assessment. Under this model, validated biomarkers will be combined, as reliable data emerge, with existing studies to speed up drug development and narrow the group of patients for whom a medicine works best.

In the past, when the FDA granted "accelerated approval" of a drug, it was based on the results of one or more adequate and well-controlled studies establishing that the drug has an effect on a surrogate end point that is reasonably likely to predict clinical benefit. Thereafter, the FDA requires studies, once the drugs are available, to re-establish clinical benefit. The Critical Path Initiative accelerates approval and, in theory, makes it available to drugs and diagnostics or a combination of the two. Combining a genetic test that identifies who responds best to a drug could become more widespread as collaborative efforts identify benchmarks that can accelerate the development of products targeted to particular populations.

Recommendations for Promoting Collaboration

  • A new cross-centers products task force can, in collaboration with relevant review communities within the Center for Devices and Radiological Health (CDRH), the Center for Biologics Evaluation and Research (CBER), and the Center for Drug Evaluation and Research (CDER), review the agenda of advisory committees for biomarkerbased diagnostics, biologics, and drugs.
  • The Interdisciplinary Pharmacogenomics Review Group can develop guidelines for the use of biomarkers in combination with small and adaptive trial designs. It should develop specific training, recruitment, and reorganization goals to be funded through the Prescription Drug User Fee Act (PDUFA) budget increases.
  • Standards can be set for small and adaptive trial design and promoted throughout the divisions to replace, where appropriate, Phase 3 pivotal trials.
  • The agency can separately build upon the exploratory IND (investigational new drug) guidelines and work with consortia, such as the Critical Path Institute’s biomarker safety consortium, to improve and increase computerized simulations of drugs to complement Phase 1 human testing. Consistent with the rationale of the exploratory IND, the FDA can collaborate to develop guidelines for the use of these computerized models. An organization such as the Critical Path Institute could sponsor meetings to help the FDA develop methods for doing so. Such a program would allow reviewers to work more closely with their scientific peers outside the agency.
  • To encourage familiarity with Critical Path tools throughout the FDA's rank and file, FDA senior leadership can make knowledge of the Critical Path an integral part of performance and incentive reviews. Without this performance review, there may be wide variance in the use of Critical Path tools among different product reviewers, even within the same center.

Genomics and Postmarket Drug Safety

The fast moving field of genomics can also impact drugs on the market now, which may not have benefited from the use of validated biomarkers during their development and regulatory approval. Novel DNA markers may provide an important contribution to postmarket drug safety by helping to quantify an individual’s risk of suffering an adverse events from the use of currently approved medications. Yet research into this field also raises questions on how to apply genomic phar pharmacosurveillance data to drug labeling. It also raises questions about how to best coordinate the roles of the pharmaceuti pharmaceutical industry, the research community, and insurance providers in dealing with novel diagnostic tests that may be developed post approval for marketed drugs.

Eploratory INDS and Validating Biomarkers

The FDA and industry share responsibility for developing better tools for clinical evaluation. To that end, early in 2006, the FDA announced a new method for early stage pharmacokinetics (drug metabolism over time) and pharmacodynamics (the effect that the drug is having over time) clinical testing. This new approach, called the exploratory IND, was developed by the Interagency Oncology Task Force (IOTF). An exploratory IND study, sometimes called a "Phase 0 trial," involves "very limited" human exposure to a compound and has no therapeutic or diagnostic intent. The exploratory IND process increases the number of potential drugs that can be tested in micro-doses in small numbers of patients instead of testing pill-size quantities in large clinical trials. While unexpected and serious adverse reactions may still arise, the IND process may allow companies to identify promising drugs—or reject drugs with poor safety or efficacy profiles—before entering into a Phase 1 clinical trial.

As FDA Deputy Commissioner Dr. Woodcock has noted, "The purpose of an exploratory IND [study] is to learn about new discoveries before embarking on extensive human trials... Thus, we think eventually not only will this lead to new knowledge about many new discoveries, it will save people from being exposed to higher doses of compounds that ultimately turn out not to be useful."[16]

Many companies, in association with the FDA, are seeking to identify and validate potential biomarkers. For example, the FDA and BG Medicine, a Massachusetts-based biotechnology research company, are seeking to validate biomarkers to discern signs of human liver toxicity in the beginning of the drug development process.[18]

The NIH, CDC, FDA, National Institute of Technology Standards, Department of Energy, companies, and Department of Defense are working independently of one another and are not sharing information with nonprofit centers and companies.

The FDA currently lacks the resources to be a full partner in these important activities. There is not enough staff to be part of all the relevant committees or the meetings and scientific programs within government or the scientific community as a whole.

Absent FDA leadership, the various federal agencies involved in genomic research sometimes find it difficult to work together. For example, the NIH, CDC, FDA, and companies have been meeting about the development of a biomarker for a rare drug side effect called QT prolongation that causes heart failure.[19]

But the FDA currently lacks the resources to send the relevant medical reviewers to these meetings. In this case, Duke University would like EKG data to identify genetic variations linked to the heart problem. Companies are ready to share EKG data, but the absence of the FDA is stalling progress.[20] Similarly, the FDA's Clinical Pharmacology and Biopharmaceutics office, which is responsible for receiving genomic data, and scientists who review drug and diagnostic applications are unable to fully participate in collaborative efforts to create genomic analysis platforms and to evaluate pharmacogenomic data.

Recommendation for Validating Biomarkers

  • The FDA should be given additional funds sufficient to sustain its Critical Path activities, particularly for maintaining a leadership role in biomarker development and use.

The Critical Path Institute is a nonprofit organization[17] created in 2005 to support the FDA in its effort to implement the Critical Path Initiative. Based in Tucson, Arizona, the C-Path Institute has been given $10 million in public and private seed funding for five years. The institute is working with the FDA, drug companies, and other scientific stakeholders to collab collaborate on a variety of biomarker activities:

  • The Cardiovascular Safety Biomarkers Initiative will develop tools for assess assess ing and preventing idiosyncratic adverse cardiac events.
  • A QT biomarker initiative aims to assist the FDA in accelerating approval by in increasing the likelihood of effective safety screens and risk management programs.
  • The Toxicogenomic Biomarkers Initia Initiative will explore ways to incorporate new technology into methodologies for evaluating general toxicity related to the drug development process.

Post-Market Drug Evaluation

The FDA and the entire biomedical community recognize that prior to marketing, with current tools and technology, there is no way to detect rare, unexpected side effects short of performing studies with sample sizes that exceed tens of thousands of patients. Such massive clinical trials are not practical or sustainable and would bring drug development to a halt. Nor does it make sense to rely on doctors and patients to submit reports of possible problems when information technology permits real time and continuous reporting of such events.

Rather, as the Critical Path report notes, "[S]afety issues should be detected as early as possible, and ways to distinguish potential from actual safety problems should be available. Unfortunately, in part because of limitations of current methods, safety problems are often uncovered only during clinical trials or, occasionally, after marketing."[21]

The goal of post-market drug evaluation need not be limited to safety but can also include the ability of doctors and patients to choose medicines and treatments that are best. Further, computerized analysis of clinical data can help pinpoint which patient subgroups will be more likely to benefit from one medicine or avoid side effects from another. In short, post-market data can be the source of information to develop faster studies that more accurately predict and measure safety and benefits.

To achieve this goal, the FDA, consumers, health plans, and companies must use disease registries, biobanks, and electronic patient records to coordinate medical information that can be used to further personalize medicine (see sidebars). Several agencies are already banking DNA samples using various approaches and standards. The FDA is cooperating with the National Cancer Institute to adopt NCI standards for DNA submissions. Such collaboration is critical to create a common platform for the evaluation of genetic materials and for the establishment of best practices in the future. At present, the FDA's participation in the creation of this important source of post-market information is limited by resource constraints. Congressional approval of the FDA's requested $4.7 million for drug safety evaluation would facilitate the agency's participation in these collaborative efforts.

Biobanks are "actual repositories of collected human tissue—blood, bone, serum, or sometimes just individuals' DNA. But they become … valuable because of the clinical … information captured about the patient and the molecular data generated from the sample. When this data is integrated in a robust, secure fashion—or a clinical genomics environment—researchers can use biobanks for many different purposes, such as hunting for reasons for the underlying genetic processes that cause different diseases or identifying molecular markers that may provide early warning signs."[23] Larger health plans and hospitals, as well as the Medicare program, are switching to electronic patient records that contain information on many individuals' characteristics, their medical diagnoses, the medicines they took, and how they fared. The health systems of the Mayo Clinic, Kaiser Permanente of Northern California, and several disease-specific patient registries together comprise millions of patients' records with information that can be useful for proactive post-market drug evaluation.

The Mayo Clinic used electronic patient records earlier than many large health systems did. It has a base of 4.4 million electronic records that can generate outcome data using standardized entry criteria. Mayo has a full-scale program for the development of biomarkers in adjusting drug dosing and safety profiling. With the help of IBM, Mayo will be able to link its outcomes data to very large external sources of genomic and proteomic data such as the National Cancer Institute. Mayo is also generating its own genomic data by collecting genetic samples and integrating with outcome data. These efforts provide a promising model for the future use of medical records in post-market surveillance.[24]

Use of these data sources—with appropriate safeguards to protect patient privacy and prevent the abuse of medical information—holds great promise for improving drug safety, health outcomes, and the reliability of drug development studies.[25] If a safety problem emerges, it will be more precisely identified in terms of patient characteristics, dosing, and genetic variations. Such information can be used to update and further refine medical treatments to avoid safety problems as well as to maximize benefit.

The next step is to use electronic medical record systems to mine patient data in new ways and to compare outcomes among patients with similar disease characteristics and genomic makeup. Because researchers can look at dozens of patient characteristics and hundreds of treatment steps, observational studies designed to detect individual differences in response to medicine or other treatments can be fairly small but still yield powerful conclusions. Studies have found that carefully designed post-market trials have the same explanatory power as randomized, controlled trials.[26]


Disease registries have become a powerful tool to identify populations of patients most ap appropriate for a given clinical trial. Disease registries are computerized systems that capture and track key patient information. They are longitudinal, ongoing databases that collect and maintain information on patients with specific diseases. Registries keep track of patients' signs and symptoms, what medications they may be using, various alternative therapies that they may have tried, and such issues as psychosocial aspects of the disease and functional status. All data are collected from physician visits or encounters with the health system.

Each patient's privacy is maintained by coding his or her history. Many registries are simply lists of patients with the disease or disorder, and some provide enough clinical data to provide a "snapshot" of the characteristics of the clinical expression of the disease. Few registries actually provide an up-to-date assessment of the natural history of the disease needed for the design of prospective clinical trials, most likely because of the difficulty in obtaining the required clinical data on an ongoing basis.

One example of a comprehensive approach to patient registries is the C-Path Institute’s Orphan Drug Registry, which will create an electronic medical record (EMR) with additional specific modules for each disease. The EMR will automatically be updated from the medical-care pro providers and include a portal for patients or their families to submit their own data on the course of the disease and how it is being managed. It will identify the standards for accurate diagnosis and characterization of these and other rare diseases. It will also identify a population of patients who are readily available for participation in clinical trials, and it will provide a basis from which to conduct post-market safety surveillance. [22]

The FDA, however, must weigh the need for a complete overhaul of its bioinformatics operation against other pressing agency priorities. For now, it is seeking to create standards that make FDA data easily available to researchers outside the agency and to establish common formats that allow the sharing and pooling of data from registries and electronical medical records systems.

In addition to better data, researchers and the agency must work with other organizations in an open way to develop terminology standards and interoperability standards for use in animal and human studies. The FDA is part of the Clinical Data Interchange Standards Consortium (CDISC) HL7 (standards for electronic interchange of clinical, financial, and administrative information among health-care computer systems) to ensure that FDA bioinformatic activities are consistent with those in the private sector. The National Cancer Bioinformatics Grid, Centers for Medicare and Medicaid Services, FDA, and Centers for Education and Research on Therapeutics (CERTS, a program of the Agency for Health Quality Research in the Department of Health and Human Services) have taken important strides toward data sharing but do not work together on a regular basis.

Recommendations for Preclinical and Post-Market Drug Evaluation

  • Create a Center for Clinical Bioinformatics within the FDA and a corresponding Bioinformatics Interagency Task Force. This center could allow stakeholders to create a single standard for collecting and using information from electronic patient records, which would improve medicines and clinical trials. This could include companies, Medicare, health plans, employers, NIH, and CERTS.
  • The FDA should become a full participant along with NIH and NCI as part of the NCI’s Biospecimen Coordinating Committee and NCI's Wide Repository Committee.
  • Companies submitting genomic data should establish specific protocols for the collection, storage, and sharing of tissue samples and serums from which genomic, protein, and metabolic profiles information is generated. One approach that should be considered is the forthcoming NCI best-practice standards. The FDA can require companies to contribute all relevant clinical trial data and biospecimens in standard format by a date set by the agency. The Center for Clinical Bioinformatics can develop partnerships with large health systems such as the Mayo Clinic and integrate its post-market program with larger efforts to mine data for genetic and clinical patterns. If this is implemented, there must be changes in the legal and intellectual property infrastructure to allow the FDA to share data among pharmaceutical companies, and pharmaceutical companies must agree on which data can be shared and which are proprietary.

A practical driver for personalized medicine and the study of drug response variation is the realization that extremely rare and catastrophic side effects that require drug withdrawals from the market may be trac tractable for formal study. The process would include monitoring the epidemiological occurrence of adverse events and corre corre- lating the cases with a higher frequency of certain genetic markers, which result from genome screens. The utilization of genomic data for surveillance constitutes a powerful application of personalized medicine, which is now feasible with the advent of array diagnostic technologies. By focusing on both common and rare side effects, the practice of personalized medicine should accept the challenge of drug safety and in the process could re relieve some of that burden from the clinical trial process.

Accelerating Approval

It is important to let the public know what personalized medicine would look like from the standpoint of the Critical Path Initiative. These new tools could accelerate approval for a wide range of drugs, diagnostics, and devices targeted to specific subpopulations.

Critical Path activities and tools leading to targeted approval of a drug could go through a process such as the following:

  1. An exploratory and confirmatory phase (up to targeted approval) to determine the safety and effectiveness of a drug for a specific group of patients at a specific dose. This would occur in Phase 2 testing and would include biomarker-based studies to identify how specific groups of people respond to medicines. Tools used to develop targeted subgroups would include gene-expression profiling, gene sequencing, proteomics, and molecular imaging.
  2. At this point, a medicine could be granted targeted approval. Access could be limited to the specific subpopulation to control early market access.
  3. Drug safety and effectiveness could be monitored in a registry-type setting or in cooperation with the NIH, academic medical centers, or health plans with acceptable EPR systems.
  4. Companies could replace direct-to-consumer advertising with a communications plan designed to improve prescriber and individual knowledge of the relative risks and benefits of the product for that defined patient population while prospective and confirmatory trials were conducted.
  5. Expanded approval could be given to other patients after updated safety assessment and clinical outcome. Any uses for broader patient groups could be applied through a streamlined process similar to the drug's original targeted approval mechanism.

Recommendations for Accelerated Approval

  • Companies that rely upon validated biomarkers in Phase 2 testing to identify drugs that work for subpopulations with increased benefit and smaller risk or provide an unmet medical need should be able to make their medicines available to people who meet the pharmacogenomic criteria of their clinical trials on the basis of one study with convincing proof of efficacy in the relevant population.
  • Companies can participate in registries or in postmarket monitoring of their products within a national interoperable electronic medical records program also used by the FDA.


The key to making medicines safer and more effective is to make them more personalized and targeted. Moreover, the way to personalize medicine is to transform the FDA from an organization of rulebased regulators to a public health–focused agency staffed with 21st century science-based standard setters. By collaborating with academic institutions, private companies, and other government agencies, the FDA can utilize genetic information and better bioinformatics to create a template that will allow us to move from trial and error or one size fits all medicine to predictive and ersonalized care.

Much of 21st century health care might be shaped by policies and actions that are outside the realm of science. If we are not vigilant, third-party payers and the tort system could force drug companies and the FDA to shift investment away from personalized medicine. We recognizes the scientific and regulatory challenges, as well as the impact, that personalized medicine will have on the manufacturing and marketing of medicines. Steering drug development to smaller, even orphan markers will require a significant investment on the part of companies, without a certain return for their efforts. The marketing methods of the past, geared to broad populations and after the fact detection of safety problems, will give way to informing and educating small groups of patients and physicians whose understanding of the mechanisms of new medicines and participation in data collection will be critical. To the extent that the FDA evolves into a science-based standard setter for translating genetic knowledge into medicines, great progress is possible.

The task force strongly commends the FDA's Critical Path Initiative and the scientists in government, academic, and private settings whose insights made it possible. We share their commitment to personalized medicine as a template for both drug development and public health in the twenty-first century. These reforms will help promote a future where treatment is predictive, rather than haphazard and empirical. They will help usher in an era in which drugs are targeted by biomarkers and diagnostics rather than marketed to large, and perhaps inappropriate, populations.

The sequencing of the genome has made possible a revolution in human health. Personalized medicine is a possibility that depends ultimately on our ability to create the tools and marshal the will to make its many benefits a reality. The recommendations of the task force are intended to promote the Critical Path with a positive discussion of the specific resources and actions needed to achieve this goal. We look forward to making them, and the vision they seek to sustain, a reality in the years ahead.

Appendixes >>



  1. In March 2004, the FDA released a white paper entitled "Innovation or Stagnation?: Challenge and Opportunity on the Critical Path to New Medical Products," available online at: This report is often termed the "Critical Path Initiative."
  2. The FDA's basic statutory authority rests on the Food Drug and Cosmetic Act of 1938 (U.S.C. Title 21, Chapter 9). The FDA's mission statement describes the agency's broad mandate: "The FDA is responsible for protecting the public health by assuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation's food supply, cosmetics, and products that emit radiation. The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate, science-based information they need to use medicines and foods to improve their health." The purpose of this paper is to examine and recommend ways to improve a small, but vitally important, part of the FDA's mission: the regulation and approval of new medicines to treat human disease and disability.
  3. On December 23, 2004, for instance, the FDA approved a genetic test called the Roche AmpliChip, which may help doctors determine which drugs will have fewer side effects and work better for people. The FDA noted:
    [T]this system uses DNA extracted from a patient’s blood to detect certain common genetic mutations that alter the body's ability to break down (metabolize) specific types of drugs. The enzyme produced from the gene that is tested, called cytochrome P4502D6 (CYP4502D6), is active in metabolizing many types of drugs including antidepressants, antipsychotics, beta-blockers, and some chemotherapy drugs. Variations in this gene can cause a patient to metabolize these drugs abnormally fast, abnormally slow, or not at all. For example, the same dose that is safe for a patient with one variation might be too high (and therefore toxic) to a patient with a different variation who cannot metabolize the drug.
    Center for Devices and Radiological Health (CDRH) Consumer Information, available online at:
  4. The National Academies Institute of Medicine, Committee on the Assessment of the U.S. Drug Safety System, June 8, 2005. Powerpoint presentation by Janet Woodcock and Steve Galson, Acting Director of the Center for Drug Evaluation and Research. Available online at
  5. "Innovation or Stagnation?"(see n. 1 above).
  6. This is the goal of the FDA's Predictive Safety Testing Public/Private Consortium. Members of the consortium include the FDA and the Critical Path (C-Path) Institute, along with other representatives from government, academia, and industry.
  7. "Innovation or Stagnation?" (see n. 1 above).
  8. Tufts Center for the Study of Drug Development, "Backgrounder: How New Drugs Move Through the Development and Approval Process," November 2001; and J. Gilbert, P. Henske, and A. Singh, "Rebuilding Big Pharma's Business Model,” InVivo: The Business & Medicine Report 21, no. 10 (November 2003), Windhover Information.
  9. In its recently released Critical Path Opportunities Report (March 2006), the FDA stated: "There is urgent need for successive generations of antibiotics and evolving medical countermeasures (including new vaccines and improved tests for screening donor blood and tissues) against emerging infections and bioterror attacks. Although multiple hurdles to innovation exist, modernizing the Critical Path sciences could play a significant role in solving public health needs."
  10. As in the federal Vaccines for Children program.
  11. Paul Offit, chief of the Division of Infectious Diseases and director of the Vaccine Education Center at the Children's Hospital of Philadelphia has stated:

    The cost to develop and make many vaccines is greater than that to make most drugs, because products given to healthy people are often held to higher standards of safety than those given to people who are sick. In 1998 the FDA licensed a vaccine to prevent rotavirus, a common cause of fever, vomiting, and diarrhea in young children. After the vaccine had been on the market for one year—and was given to about one million children—the CDC detected a rare adverse event: About one of every 10,000 children who received the vaccine developed intussusception, a blockage of the intestine. As a consequence, the rotavirus vaccine was withdrawn.

    Before it was licensed, the rotavirus vaccine had been given to about 11,000 children in placebocontrolled prospective studies. Because intussusception was very rare, studies performed prior to licensure were not big enough to determine that rotavirus vaccine caused the condition. Following the withdrawal of the rotavirus vaccine in 1999, children have continued to be hospitalized for and killed by rotavirus. Although many more children would have been helped by a rotavirus vaccine than hurt by it, the current culture does not allow for any serious side effects from a vaccine. As a consequence, pharmaceutical companies are now asked to disprove even very rare adverse effects prior to licensure. Two companies, Merck and GlaxoSmithKline, are now testing rotavirus vaccines in pre-licensure trials that include more than 140,000 children. The cost of these two large trials is about $400 million. The added financial burden of now disproving rare adverse events before licensure is another disincentive to making vaccines.

    "Why Are Pharmaceutical Companies Gradually Abandoning Vaccines?" Health Affairs 24, no. 3 (2005): 622–30.
  12. See also "Bad Bugs, No Drugs: As Antibiotic Discovery Stagnates . . . A Public Health Crisis Brews," from the Infectious Diseases Society of America (July 2004), available online at:
  13. Christopher Adams and Van Brantner, "New Drug Development," Bureau of Economics, Federal Trade Commission, July 7, 2003.
  14. 14 Food and Drug Administration Modernization Act of 1997, Public Law 105-115, 105th Congress.
  15. Carole Cruzan Morton, Focus, "Statistical Approach Speeds Up Stent Trials", February 7, 2003. Available online at:
  16. "FDA Exempts Phase-I Drugs from Strict Manufacturing," American Society of Health System Pharmacists, January 12, 2006. Available online at
  17. According to its website, the Critical Path Institute "is an independent, publicly funded, non-profit organization dedicated to the critical path initiative. C-Path fosters research and educational programs intended to enable the pharmaceutical industry to safely accelerate the development of new medications." The C-Path Institute was jointly founded by the University of Arizona, the FDA, and SRI International.
  18. Michelle Meadows, "Why Drugs Get Pulled off the Market—Pharmaceuticals," FDA Consumer, January–February 2002.
  19. The QT interval is a measurement on an electrocardiogram; QT prolongation is a biomarker for sudden cardiac arrest that is associated with drug treatment.
  20. Patrick Clinton and Jill Wechsler, "What Ever Happened to Critical Path," Pharmaceutical Executive, p. 4, available online at:
  21. FDA Critical Path Report, July 2004.
  22. "Orphan Disease Registries." The Critical Path Institute. April 3, 2006.
  23. Brett J. Davis, "BioBanking 101: Accelerating Personalized Medicine," available online at:
  24. "Mayo Clinic 2004 Highlights." The Mayo Clinic.
  25. For instance, electronic health records could be mined to produce routine adverse event reports scrubbed of personally identifiable information.
  26. J. Concato, N. Shah, and R. Horwitz, "Randomized, Controlled Trials, Observational Studies, and the Hierarchy of Research Designs," New England Journal of Medicine 342, no. 25 (June 22, 2000): 1887–92.
  27. The following information (unless noted otherwise) is adapted from the FDA's "History of the FDA," by John P. Swann, Ph.D., FDA History Office (adapted from George Kurian, ed., A Historical Guide to the U.S. Government (New York: Oxford University Press, 1998), available online at:
  28. The distinction between prescription drugs (requiring prior physician approval) and over-the-counter drugs was added by the Durham Humphrey Amendment in 1951.
  29. Medical devices follow a different regulatory track. Swann: "The legislation having failed to develop, the Secretary of HEW commissioned the Study Group on Medical Devices, which recommended in 1970 that medical devices be classified according to their comparative risk, and regulated accordingly. The 1976 Medical Device Amendments, coming on the heels of a therapeutic disaster in which thousands of women were injured by the Dalkon Shield intrauterine device, provided for three classes of medical devices, each requiring a different level of regulatory scrutiny—up to pre-market approval."
  30. 21USC393, available online at: 4489608+0+0+0&WAISaction=retrieve.

Center for Medical Progress.


Download PDF (2.86 MB)


FDA Chief Speaks at Critical Path Conference Pharma Marketletter, 6-13-06

FDA Trying to Shift Approach to Encourage Personalized Drugs FDA Week (Vol. 12, No. 23), 6-9-06



The Critical Path to Personalized Medicine

Public Health and the Critical Pat

Shortcomings of the Current Drug Development and Approval Process

Promoting Collaboration

Bayesian Analysis

Genomics and Postmarket Drug Safety

Eploratory INDS and Validating Biomarkers

Post-Market Drug Evaluation


Accelerating Approval




FDA Task Force Members

Manhattan Institute 21st Century FDA Task Force.

Prescription for Progress:
The Critical Path for Drug Development



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