E
The Pathway from Idea to Regulatory Approval: Examples for Drug Development

Peter Corr and David Williams*

IN BRIEF: FROM IDEA TO MARKET AND CLINICAL PRACTICE

For small-molecule drugs, the path to a marketed drug involves a long and exhaustive journey through basic research, discovery of the medicine, preclinical development tests, increasingly complicated clinical trials with humans, and regulatory approval by the Food and Drug Administration (FDA). Several years—usually 10 to 15—and hundreds of millions of dollars later, under the best of circumstances, a new drug will be approved for marketing. Because of its complexity, drug discovery and development is widely recognized as one of the most financially risky endeavors in all of science and a major challenge for the biomedical industry. Much of this cost comes from failures, which account for 75 percent of the total research and development costs. Although these failures are disappointing and costly, they still contribute to the body of knowledge on disease processes. Academic health centers and research institutions play major roles in defining the targets applicable for small molecules and carrying out the clinical trials that are needed. The discovery and development process for therapeutic proteins or biologics is similarly long and difficult, and success is far from certain. Biologics are derived from living sources, including humans, other animals, bacteria, and viruses. From these sources come products such as vaccines and monoclonal antibodies, which also are regulated by the FDA. Academic health centers and research institutions have led the development of many biological agents, many of which have been successfully codeveloped with pharmaceutical and biotechnology companies.

*

Peter B. Corr, Ph.D., and David A. Williams, M.D., are members of the Committee on Conflict of Interest in Medical Research, Education, and Practice.



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E The Pathway from Idea to Regulatory Approval: Examples for Drug Development Peter Corr and Daid Williams*∗ IN BRIEF: FROM IDEA TO MARKET AND CLINICAL PRACTICE For small-molecule drugs, the path to a marketed drug involves a long and exhaustive journey through basic research, discovery of the medicine, preclinical development tests, increasingly complicated clinical trials with humans, and regulatory approval by the Food and Drug Administration (FDA). Several years—usually 10 to 15—and hundreds of millions of dol- lars later, under the best of circumstances, a new drug will be approved for marketing. Because of its complexity, drug discovery and development is widely recognized as one of the most financially risky endeavors in all of science and a major challenge for the biomedical industry. Much of this cost comes from failures, which account for 75 percent of the total research and development costs. Although these failures are disappointing and costly, they still contribute to the body of knowledge on disease processes. Aca- demic health centers and research institutions play major roles in defining the targets applicable for small molecules and carrying out the clinical trials that are needed. The discovery and development process for therapeutic proteins or biologics is similarly long and difficult, and success is far from certain. Biologics are derived from living sources, including humans, other animals, bacteria, and viruses. From these sources come products such as vaccines and monoclonal antibodies, which also are regulated by the FDA. Academic health centers and research institutions have led the development of many biological agents, many of which have been successfully codevel- oped with pharmaceutical and biotechnology companies. * Peter B. Corr, Ph.D., and David A. Williams, M.D., are members of the Committee on Conflict of Interest in Medical Research, Education, and Practice. 

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6 CONFLICT OF INTEREST Medical devices include a range of technologies, from surgical gloves, syringes, and thermometers to sophisticated prosthetics, imaging equip- ment, artificial heart valves, and electronic neurostimulators. Reflecting this diversity, the path from idea to product development for medical devices can be quite variable and quite different from that for drugs and biologics. The same is true for the extent of collaboration among academic, indus- try, and government researchers. Before they can market complex devices, device manufacturers must seek either premarket clearance (which is most common and which generally does not require clinical data) or premarket approval (which is required for only a small number of devices—often im- planted devices—and which does require clinical data) from the FDA. As is the case for drugs, obtaining premarket approval is a complicated process that can take many years. For complex medical devices, the research team may include physicists, materials scientists, engineers, and mathematicians, as well as biologists and physiologists. Physicians often play a critical role in defining the needs for devices and the initial testing of prototypes in human clinical trials. In some cases, the basic idea for important medical devices can come from individuals who are not involved in basic or clinical research. For example, the idea (and crude first model) for a device to drain the buildup of cerebrospinal fluid in individuals with hydrocephalus came from a self-described mechanic who was the parent of an affected infant (Baru et al., 2001). The following sections briefly describe the sequence of events for small- molecule drugs from concept to a marketed product. Figure E-1 (developed by the authors) depicts the process in graphic form for each of the following seven sections. (A more thorough review of the research and development process for small molecules, therapeutic proteins, vaccines, medical devices, and diagnostics can be found at www.rdguide.org.) BASIC RESEARCH: THE IDEA Long before a new drug can even be imagined, scientists are working to gain a basic understanding of a disease or of specific normal chemical pathways that are subverted in an abnormal cell. This research might be conducted in academic laboratories and research institutes around the world, and some of it is paid for by industry. Industry also plays a large role in the development of novel technologies, such as new approaches to sequencing of the human genome. Along the road toward developing new medications, researchers have to acquire a basic understanding of bacterial, animal, and human genomes. They study which genes are involved in specific diseases. They also look at how gene products—or proteins—contribute to the derailments in cellular processes that result in the initiation or maintenance of a disease.

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IND POC NDA Therapeutic Preclinical Exploratory Advanced Approval and Basic Research Discovery Development Development Development Development Postmarket Initial - Robust “ The Idea” “The Compound” “The Medicine ” “ Proof of Concept” “Regulatory Proof ” “Medical Marketing” Biotechs and Universities Emerging Institutes Pharma Governments Institutes Foundations Companies Universities Associations Academic Medical Centers, Hospitals, Clinics 10 to 14 years Pharmaceutical Companies and Large Biotech Companies FIGURE E-1 Defining biomedical research from idea to market. IND = Investigational New Drug application; POC = proof of concept; NDA = New Drug Application; Pharma = pharmaceutical companies. SOURCE: Adapted from Corr, 2008.  E-1 broadside

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 CONFLICT OF INTEREST In a kind of medical reconnaissance mission, biologists seek out and identify targets that might be attacked with a new drug. These targets are proteins, as well as the genes that define how those proteins are structured. Either may play a role in the onset or progression of a particular disease. Until recently, researchers were limited to studying the biology (the function or the structure of molecules and cells) of only about 500 target proteins or genes. Now, with scientific advances, such as knowledge of the sequence of the human genome, the number of available biological targets has soared. Despite these gains, however, researchers still know very little about the role that many of these new targets play in causing or maintain- ing diseases. Once researchers have identified a target, they then validate them by determining whether the target is relevant to the disease that they are study- ing. They must then determine if a drug could affect the target enough to alter the course of the disease. To do this, they use biochemical, cellular, or animal models to validate the biological mechanism of the target gene or protein. Box E-1 summarizes an example of successful, extended, and complex collaboration that involved scientists from the National Institutes of Health as well as academic and industry scientists. Chapter 4 of the committee report cites additional examples. Searching for Compounds When a potentially relevant target for an identified disease is validated, chemists then mount a massive search for chemicals that might modify the target or targets. They screen vast compound libraries to develop a list of potential chemicals that might some day become a new medicine. This so- phisticated process can be divided into three distinct steps: (1) development and maintenance of large compound libraries, (2) specific assay develop- ment, and (3) high-throughput screening. Assays are analyses that quantify the interaction of the biological target and the compound that the researchers are investigating. They also might measure how the presence of the compound changes the way in which the biological target behaves. The chemical compounds tested in these assays are maintained in large compound libraries, some of which contain more than 5 million chemi- cals. Products from natural sources like plants, fungi, bacteria, and sea organisms can be integrated within compound libraries. Most compounds, though, are derived through the use of chemical synthesis techniques, in which researchers create chemical compounds by manipulating chemicals. They might also use combinatorial chemistry, in which researchers create

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 APPENDIX E BOX E-1 Case Example of Successful Collaboration in Drug Discovery and Development In 2002, the biotechnology company Sugen and the Salk Institute published the human kinome, a subset of the human genome (Manning et al., 2002). K inases regulate proteins and, in turn, have multiple functions in cells in both the normal and the disease states. On the basis of that work, scientists now know that there are 518 kinases in humans. These findings have revolutionized the approach to the inhibition of these kinases by drugs used to treat cancer and other diseases and that are currently on the market. Elsewhere, researchers knowledgeable about patients with severe combined immunodeficiency disease (popularly referred to as the “bubble boy syndrome”) had identified these patients as having mutations within the JAK-3 kinase, which suggested that a possible mechanism for affecting the deficiency of the immune system could be achieved through a JAK-3 inhibitor (Russell et al., 1995). This research was done at the National Institutes of Health. Industry scientists at Pfizer spent several years discovering a compound that is active against JAK-3. The goal was to find a compound that would not block JAK-1 or JAK-2 kinase but that would be effective as an immunosuppressant by specifically and partially blocking JAK-3 without causing severe side effects. Pfizer focused first on the drug’s role as a potential antirejection drug for p atients who have received an organ transplant. It collaborated with the transplant center at Stanford University to conduct studies with primates, with promising r esults (see, e.g., Borie et al. [2004]). The drug is being tested with human trans- plant recipients. It is also being investigated as a treatment for rheumatoid arthritis (see, e.g., Changelian et al. [2008] and Stanczyk et al. [2008]). new chemical compounds in large masses and test them rapidly for desir- able properties. Testing of the expanding number of available biological targets against millions of chemical entities requires some highly sophisticated screening methods. Researchers use robotics, for example, to simultaneously test thousands of distinct chemical compounds in functional and binding assays. Many times, academic researchers with expert knowledge of specific path- ways may guide the development of assays in collaboration with industry. The chemical compounds identified through this kind of screening can provide powerful research tools that help provide a better understanding of biological processes. This, in turn, may lead to new targets for potential drug discoveries.

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0 CONFLICT OF INTEREST The purpose of this chemistry stage is to refine the compound. Hun- dreds and possibly thousands of related compounds may be tested to determine if they have greater effectiveness, less toxicity, or improved pharmacological behavior, such as better absorption after a patient takes the drug orally. To optimize the molecules being investigated, scientists use computers to model the structure of the lead compounds and how they link to the target protein. This approach to structure-based design is known as in silico modeling (the word “silico” refers to the silicon technology that powers computers). This kind of structural information gives chemists a chance to modify the molecules or compounds selected in a more rational way. Lead optimization produces a drug candidate that has promising biological and chemical properties for the treatment of a disease. The drug candidate is then tested for its pharmacokinetic behavior in animals, including its gastrointestinal absorption, body distribution, me- tabolism, and excretion. It is also tested for its pharmacodynamics, which refers to the relative effectiveness of the molecule. Preclinical Studies: The Medicine Once a single compound is selected, preclinical studies are performed to evaluate a drug’s safety, efficacy, and potential toxicity in animal models. These studies are also designed to prove that a drug is not carcinogenic (i.e., it does not cause cancer when it is used at therapeutic doses, even over long treatment intervals), mutagenic (i.e., it does not cause genetic altera- tions), or teratogenic (i.e., it does not cause fetal malformations). Because a patient’s ability to excrete a drug can be just as important as the patient’s ability to absorb the drug, both of these factors are studied in detail at this stage of preclinical development. Preclinical studies also help researchers design proposed Phase I stud- ies to be conducted with human. For example, preclinical studies with animals help determine the initial dose to be evaluated in the clinical trial and help identify safety evaluation criteria. The latter include factors such as patient signs and symptoms that should be monitored closely during clinical trials. The result of work at this stage is a pharmacological profile of the drug that will be beneficial long into the drug’s future. Researchers can use the profile to develop the initial manufacturing process and pharmaceutical formulation to be used for testing with humans. Industry has particular strengths in these areas, and most development efforts at this stage are based in biotechnology or pharmaceutical companies. They can also use specifications assigned in this stage to evaluate the chemical quality and purity of the drug, its stability, and the reproducibility of the quality and

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 APPENDIX E purity during repeat manufacturing procedures. At this stage, and before testing with humans begins, an Investigational New Drug (IND) applica- tion is filed with the FDA. If the IND application is approved, then clinical trials can begin. Phase I Clinical Trials: Safety Phase I trials are the first time that a drug is tested in humans. These trials may involve small numbers (20 to 100) of healthy volunteers, or they may include patients with specific conditions for which targeted pathways have been identified as potentially relevant to the disease under study. A Phase I study may last for several months. The focus of a Phase I study is the evaluation of a new drug’s safety, the determination of a safe dosage range, the identification of side effects, and the detection of early evidence of effectiveness if the drug is studied in patients with disease, for example in patients with cancer. From Phase I clinical trials, researchers gain important information about • the drug’s effect when it is administered with another drug (the effect is often unpredictable and sometimes results in an increase in the ac- tion of either substance or creates an entirely new adverse effect not usually associated with either drug when it is used alone); • the drug’s pharmacokinetics (absorption, distribution, metabolism, and excretion) to better understand a drug’s actions in the body; • the acceptability of the drug’s balance of potency, pharmacokinetic he properties, and toxicity or the ability of the drug to zero in on its target and not another biological process; and • the tolerated dose range of the drug to minimize its possible side effects. Phase II Clinical Trials: Proof of Concept In Phase II clinical trials, the study drug is tested for the first time for its efficacy in patients with the disease or the condition targeted by the medica- tion. These studies may have up to several hundred patients and may last from several months to a few years. They help determine the correct dosage, common short-term side effects and the best regimen to be used in larger clinical trials. This usually begins with Phase IIa clinical trials, in which the goal is to obtain an initial proof of concept (POC). The POC demonstrates that the drug did what it was intended to do, that is, interacted correctly with its molecular target and, in turn, altered the disease. Phases I and IIa are sometimes referred to as “exploratory development.” The Phase IIb

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 CONFLICT OF INTEREST trials are larger and may use comparator agents and broader dosages to obtain a much more robust POC. Phase III Clinical Trials: Regulatory Proof Phase III clinical trials are designed to prove the candidate drug’s benefit in a large targeted patient population with the disease. These trials confirm efficacy, monitor side effects, and sometimes compare the drug candidate to commonly used treatments. Researchers also use these clinical trials to collect additional information on the overall risk-benefit relationship of the drug and to provide an adequate basis for labeling after successful approval of the drug. Phase III studies are conducted with large populations consisting of several hundred to several thousand patients with the disease or the condi- tion of interest. They typically take place over several years and at multiple clinical centers around the world. These studies provide the proof needed to satisfy regulators that the medicine meets the legal requirements needed to be approved for marketing. The study drug may be compared with existing treatments or a placebo. Phase III trials are, ideally, double blinded; that is, neither the patient nor the researcher knows which patients are receiving the drug and which patients are receiving placebos during the course of the trial. Phase III trials are usually required for FDA approval of the drug. If the trials are successful, then a New Drug Application is submitted to the FDA. The process of review usually takes 10 to 12 months and may include an advisory committee review, but such a review is at the discretion of the FDA. Phase IV Clinical Trials: Marketing and Safety Monitoring Phase IV trials are studies conducted after a drug receives regulatory approval from the FDA. They may be used primarily for medical marketing. In some cases, the FDA may require or companies may voluntarily under- take postapproval studies to generate additional information about a drug’s long-term safety and efficacy, including its risks, benefits, and optimal use. These studies may take a variety of forms, including studies that use data from the administrative databases of health plans as well as observational studies and additional clinical trials. Postapproval trials may also be designed to test the drug with ad- ditional patient populations (e.g., with children), in new delivery modes (e.g., as a timed-release capsule), or for new uses or indications (i.e., for the treatment of a different medical condition). Because these postapproval trials are intended to provide the basis for FDA approval of further uses or

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 APPENDIX E delivery modes, they must meet the same standards as the Phase III trials conducted for initial approval. REFERENCES Baru, J. S., D. A. Bloom, K. Muraszko, and C. E. Koop. 2001. John Holter’s shunt. Journal of the American College of Surgeons 192(1):79-85. Borie, D. C., J. J. O’Shea, and P. S. Changelian. 2004. JAK3 inhibition, a viable new modal- ity of immunosuppression for solid organ transplants. Trends in Molecular Medicine 10(11):532-541. Changelian, P. S., D. Moshinsky, C. F. Kuhn, M. E. Flanagan, M. J. Munchhof, T. M. Harris, J. L. Doty, et al. 2008. The specificity of JAK3 kinase inhibitors. Blood 111(4):2155-2157. IOM (Institute of Medicine). 2009. Breakthrough Business Models: Drug Deelopment for Rare and Neglected Diseases and Indiidualized Therapies. Washington, DC: The Na- tional Academies Press. Manning, G., D. B. Whyte, R. Martinez, T. Hunter, and S. Sudarsanam. 2002. The protein kinase complement of the human genome. Science 298(5600):1912-1934. Russell, S. M., N. Tayebi, H. Nakajima, M. C. Riedy, J. L. Roberts, M. J. Aman, T. S. Migone, et al. 1995. Mutation of Jak3 in a patient with SCID: Essential role of Jak3 in lymphoid development. Science 270(5237):797-800. Stanczyk, J., C. Ospelt, and S. Gay. 2008. Is there a future for small molecule drugs in the treatment of rheumatic diseases? Current Opinion in Rheumatology 20(3):257-262.