5
Development of New Therapeutic Drugs and Biologics for Rare Diseases

When it is obvious that the goals cannot be reached, don’t adjust the goals, adjust the action steps.

Confucius


Once a potential therapeutic drug or biologic has been discovered, the process of developing the therapeutic for a particular disease, whether rare or not, begins with preclinical development and continues through increasingly complex and demanding phases of clinical testing to support approval for marketing. Much of what is done throughout the process of drug development is driven by necessary regulations that require the sponsor of a new drug to demonstrate its safety and efficacy. (Figure 5-1 depicts the process, in simplified form, from the earliest basic investigations through studies undertaken after a product has been approved for marketing.) Although public and nonprofit organizations have sometimes taken a product through this process, this work, which is expensive and risky, has traditionally been done within pharmaceutical and biotechnology companies. Approximately 10 percent of potential therapeutics that effectively pass preclinical development reach the market, and the cost for each is estimated to average from $100 million to more than $1 billion, depending on the disease and other factors and taking the cost of failed drugs into account (see, e.g., DiMasi et al., 2003; PhRMA, 2007; Gassman et al., 2008). According to one study of the 50 largest pharmaceutical firms, about one in six new drugs that entered clinical testing eventually received approval for marketing, but this rate varied widely by therapeutic class and was slightly higher for drugs licensed into a company than for drugs originated by the company (27 percent



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5 Development of New Therapeutic Drugs and Biologics for Rare Diseases When it is obvious that the goals cannot be reached, don’t adjust the goals, adjust the action steps. Confucius Once a potential therapeutic drug or biologic has been discovered, the process of developing the therapeutic for a particular disease, whether rare or not, begins with preclinical development and continues through increas- ingly complex and demanding phases of clinical testing to support approval for marketing. Much of what is done throughout the process of drug devel- opment is driven by necessary regulations that require the sponsor of a new drug to demonstrate its safety and efficacy. (Figure 5-1 depicts the process, in simplified form, from the earliest basic investigations through studies un- dertaken after a product has been approved for marketing.) Although pub- lic and nonprofit organizations have sometimes taken a product through this process, this work, which is expensive and risky, has traditionally been done within pharmaceutical and biotechnology companies. Approximately 10 percent of potential therapeutics that effectively pass preclinical develop- ment reach the market, and the cost for each is estimated to average from $100 million to more than $1 billion, depending on the disease and other factors and taking the cost of failed drugs into account (see, e.g., DiMasi et al., 2003; PhRMA, 2007; Gassman et al., 2008). According to one study of the 50 largest pharmaceutical firms, about one in six new drugs that entered clinical testing eventually received approval for marketing, but this rate varied widely by therapeutic class and was slightly higher for drugs licensed into a company than for drugs originated by the company (27 percent 

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 RARE DISEASES AND ORPHAN PRODUCTS IND NDA Basic research Therapeutic Preclinical Exploratory Advanced Long-term discovery development development development evaluation “The Idea” “The “The “Proof of “Regulatory “Postmarket” Compound” Medicine” Concept” Proof” (Phase IV (Phase I/II (Phase III trials) trials) trials) Universities Public/private research institutes Foundations, advocacy groups Medical centers, hospitals, clinics Large pharma and biotech companies 10-14 years FIGURE 5-1 Drug development: from idea to market and beyond. NOTES: IND = Investigational New Drug application; NDA = New Drug Applica- tion; Major emphasis = ; Secondary emphasis = . SOURCE: Adapted from Corr, 2008. FIGURE 5-1 versus 16 percent) (DiMasi et al., 2010). The proportion of orphan drug approvals accounted for by large pharmaceutical companies has grown in recent years (Tufts Center, 2010), but the committee found no analysis of the success rate specific to orphan drugs. Given the relatively low odds of success and the high costs of drug development, pharmaceutical and biotechnology companies usually focus on potential therapies with the highest likelihood of generating a good fi- nancial return—as is the case with virtually all companies in any field. This has meant that potential therapies for rare diseases, including therapies for life-threatening conditions, have often languished in the early development pipeline. Moreover, conventional approaches to drug development are often not feasible for rare diseases, which offer not only small markets but also small populations for participation in clinical trials. To paraphrase the ad- age of Confucius, to achieve the goals of developing effective treatments for rare diseases calls for an adjustment of the action steps. As described in Chapter 3, the Orphan Drug Act has provided incen- tives for the development of drugs for rare diseases, and the Food and Drug Administration (FDA) has approved more than 350 applications for

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 NEW THERAPEUTIC DRUGS AND BIOLOGICS the marketing of such drugs. Today, those incentives combined with the increasing expense and difficulty of developing blockbuster drugs have led some major pharmaceutical companies and biotechnology firms to an- nounce that they are launching or considering orphan drug development (Anand, 2005; Dimond, 2009; Pollock, 2009; Whalen, 2009). In addition, charitable foundations linked to advocacy groups have made significant progress during the past 15 years in strategically filling the investment gap for orphan products and in pushing therapies for rare diseases through the development pipeline. The National Institutes of Health (NIH) is also supporting programs to help translate research discoveries into success- ful products, and innovative strategies for the conduct and analysis of studies involving small populations are allowing sound research when conventional trials designs are not possible or not feasible. At FDA, the recently created position of Associate Director for Rare Diseases at the Center for Drug Evaluation and Research (CDER) is a positive step (see Chapter 3). This chapter begins with a description of the traditional approach to preclinical and clinical development as it applies to drug therapies for common or rare diseases. Later sections of this chapter examine the infra- structure for drug development (including biomarkers, patient registries, and clinical research training) and adjusted action steps such as alternative models of organizing and funding orphan product development. Some of these models build on public-private partnerships and other innovative strategies that have emerged from initiatives to speed the development of products for neglected tropical diseases. PRECLINICAL DEVELOPMENT Once a single promising compound is selected based on the kinds of basic research and therapeutic discovery reviewed in Chapter 4, companies initiate preclinical studies both in vitro and in animals to evaluate a drug’s safety and potential toxicity. These preclinical studies are also used to as- sess potential effectiveness. Sponsors design additional studies to provide convincing evidence that a drug is not mutagenic (i.e., it does not cause genetic alterations) or teratogenic (i.e., it does not cause fetal malforma- tions). Because a patient’s ability to excrete a drug can be just as important as the patient’s ability to absorb the drug, other preclinical studies focus in detail on those factors. The following discussion of therapeutics focuses on drugs but also notes certain special features of preclinical studies for biologics. As described ear- lier in this report, drugs are chemicals—small-molecule medicines that can be taken orally or that may be administered in various other forms, such as injection, infusion, transdermal patch, or dermal application. Biologics are

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0 RARE DISEASES AND ORPHAN PRODUCTS proteins, antibodies, peptides, and some vaccines that are usually injected or infused because they cannot be absorbed orally. For purposes of this discussion, they are usually encompassed under the term drug. The safety and other data from preclinical studies are crucial in deter- mining whether a drug will move on to studies in humans. Preclinical stud- ies also guide researchers in designing phase I clinical trials. For example, preclinical studies with animals help determine the range of dosing of a test drug to be evaluated in a phase I clinical trial. They also help to identify criteria for evaluating safety in humans, including signs and symptoms that should be monitored closely during early clinical trials. Unfortunately, preclinical studies in animals are not precise predictors of what will happen with humans. In addition, companies often must undertake carcinogenicity studies in animals to help assess whether a potential therapy might cause tumors. Be- cause carcinogenicity studies require considerable time and resources, FDA guidance advises that “they should be performed only when human expo- sure warrants the need for lifetime studies in animals” (FDA, 1996, p. 1; see also CDER, 2002). The guidance therefore recommends carcinogenicity studies for any pharmaceutical for which clinical use is expected to be con- tinuous over at least 6 months or to involve intermittent but frequent use in the treatment of chronic or recurring conditions (FDA, 1996). Long-term carcinogenicity studies might not be required when the potential therapy is intended for patient populations for whom life expectancy is predicted to be short (e.g., 2 to 3 years, as for some cancer therapies). FDA’s guidance on carcinogenicity studies also states that rodent car- cinogenicity studies usually are not required to be completed prior to con- ducting large clinical trials in humans, unless a special concern is identified. If studies are required, they ordinarily must be completed before a sponsor applies for marketing approval. However, for drugs intended to treat life- threatening or debilitating diseases, the guidance advises that carcinogenic - ity testing can be conducted after rather than before a drug is approved for marketing. Thus, FDA required a postmarketing carcinogenicity study for the orphan drug carglumic acid (Carbaglu), a drug that must be used long term (Beitz, 2010) (see also Box 3-3). In addition, the agency generally will not require carcinogenicity studies for endogenous substances such as en- zymes that are given as replacement therapy, particularly if previous clini- cal experience exists with similar products. Thus, FDA has not required pre- or postmarketing carcinogenicity studies for such orphan biologics as galsulfase (Naglazyme) (Weiss, 2005). In at least one case (pentosan poly- sulfate sodium [Elmiron], approved in 1996), FDA nominated an orphan drug for carcinogenicity testing by the National Toxicology Program (NTP, 2004). The test results allowed the drug’s label to be revised in 2006 to report no clear evidence of carcinogenic risk.

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 NEW THERAPEUTIC DRUGS AND BIOLOGICS One focus of the analysis of CDER reviews as recommended in Chapter 3 would be how the carcinogenicity guidance is being implemented for orphan drugs across FDA review divisions. Depending on the results of that analysis, CDER might develop additional guidance on this topic. Preclinical work generates a pharmacologic profile of a drug that will be beneficial long into the drug’s future. For example, researchers can use the profile to develop the initial manufacturing process and the pharmaceu- tical formulation to be used for testing with humans. Industry has particular strengths in these areas. Researchers can also use specifications assigned in the preclinical stage to evaluate the chemical quality and purity of the drug, its stability, and the reproducibility of the quality and purity during repeat manufacturing procedures. (This is sometimes referred to as “chemistry, manufacturing, and controls [CMC] information.” CMC requirements and CMC activities evolve during the entire development process.) The FDA repurposing initiative described below emphasizes the value of this preclinical work if sponsors see a possible new use of an already-approved drug for a rare disease. Preclinical studies, as well as manufacture of the drug at small scale, can be very expensive (several million dollars) and time-consuming (1 to 2 years). These studies also require specific expertise, both in the proper design and execution of the studies and in the proper interpretation of the results. Most studies need to be done under good laboratory practice (GLP) conditions to qualify for regulatory submission (21 CFR Part 58). GLP conditions apply not only to specified instrumentation, record keep- ing, and analysis, but also to specific laboratory conditions that, in most cases, require special facilities. More generally, meeting regulatory require- ments for the approval of a drug requires expert knowledge and meticulous documentation. At the stage of drug production, companies must conform to what FDA refers to as current good manufacturing practice, or cGMP, requirements (21 CFR 210, 211). For biologics (excluding vaccines) the development pathway is similar in many respects to that for small-molecule drugs. Two major differences stand out. First, the production of sufficient quantities of a biologic for preclinical and clinical development studies requires unique approaches for expression of the proteins and their purification to regulatory standards. As is the case for injected drugs, extensive studies are done to formulate the protein for injection under sterile conditions. Second, biologics can po- tentially elicit an immune response in the recipient. This response must be monitored very closely because it is not always predictable. Thus, biologics may present special issues to be addressed in preclinical studies, such as im- munogenicity (i.e., induction of an antibody response) and immunotoxicity (agents intended to stimulate or suppress the immune system may cause cell-mediated changes) (CDER-CBER, 1997).

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 RARE DISEASES AND ORPHAN PRODUCTS Preclinical development of biologics is also quite unpredictable. For example, experimental animals are very likely to develop endogenous antibodies against the human wild-type protein that could complicate interpretation of the results related to toxicology, distribution, and me- tabolism. In many cases, the ease of development of a biologic depends on whether it is a true “wild-type” (i.e., normal) human protein or whether it is a variant protein. As a general rule, the use of wild-type protein as a re- placement therapy for a particular rare disease simplifies preclinical as well as clinical development, but there are exceptions. For example, a patient who produces none of a normal human protein because of an underlying genetic defect might easily produce antibodies against replacement wild- type protein, whereas a second patient, who has a different genetic defect and produces low levels of the normal protein, would not recognize the biologic as “foreign” and usually would not mount an immune response to the protein. By their very nature, studies in preclinical development are major hurdles in the development of therapeutics for all diseases—but especially those that are rare. A later section of this chapter discusses ways in which these hurdles are being or might be addressed by NIH, FDA, companies, and advocacy groups. The next several sections of this chapter are organized around the clinical trial phases that are conventionally used to develop evidence of safety and efficacy for drugs intended for common conditions. For drugs intended for quite rare diseases, the delineation among phases I, II, and III trials is often not as clear. As discussed in Chapter 3, FDA may not require the usual sequence of trials. The agency strongly encourages sponsors of drugs for rare diseases to seek meetings with FDA to discuss development strategy prior to submission of an Investigational New Drug (IND) applica- tion (Pariser, 2010). PHASE I CLINICAL TRIALS: SAFETY Before clinical studies can begin, sponsors must submit an IND appli- cation to FDA. This application must include the results of the preclinical studies discussed above. Given the generally small numbers of patients available for the study of rare diseases, sponsors benefit particularly from regulatory guidance on the extent of phase I analysis that CDER considers sufficient prior to the start of phase II clinical trials. Phase I trials initiate the testing of drugs in humans. They often involve small numbers (20 to 100) of healthy volunteers but sometimes include research participants with a rare or other specific condition for which targeted pathways have been identified as potentially relevant to disease

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 NEW THERAPEUTIC DRUGS AND BIOLOGICS pathogenesis.1 A phase I study may last for several months. Drug doses usually start at very low levels, and research participants are monitored very carefully as the dose is escalated. In some circumstances and depend- ing on the study protocol, individual participants may receive only one dose. Phase I studies focus on the evaluation of a new drug’s safety, the de- termination of a safe dosage range, the understanding of the drug’s clinical pharmacology, the identification of side effects, and sometimes the detec- tion of early evidence of effectiveness if the drug is studied in patients with the target disease. From phase I clinical trials, researchers gain important information about • the drug’s effect; • the drug’s pharmacokinetics (absorption, distribution, metabolism, and excretion) to better understand a drug’s properties in the body; • the acceptability of the drug’s balance of potency, pharmacokinetic he properties, and toxicity or the specificity of the drug (i.e., its ability to hit its desired target without altering another biological process); and • the tolerated dose range of the drug. In January 2006, CDER issued guidance on exploratory IND studies (CDER, 2006). It defined such studies (which some refer to as phase 0 clinical studies) as occurring early in the initial phase of clinical studies, having no diagnostic or therapeutic purposes, and involving very limited exposure of humans to the investigational drug. The guidance urged spon- sors to consider exploratory IND studies, in particular, for drugs intended for patients with serious, life-threatening diseases, which is often the case for rare diseases. Such studies involve fewer resources than conventional approaches and thus allow sponsors to “move ahead efficiently with the development of promising candidates” (p. 2). For example, during such an exploratory study, sponsors can test one or more related compounds at very low doses that are sufficient to determine the half-life, absorption, metabolism, and excretion of a drug. Such testing is particularly useful in guiding the selection of one compound among several to take to a full phase I study and in providing more early information when concerns exist about the predictive value of preclinical data from animals. It may be particularly helpful in studies of rare diseases. 1 Among other provisions, government rules on the conduct of research involving human overnment participants require that studies including children either involve no more than minimal risk or have expected benefits that justify the risk involved (OHRP, 2008). Thus, healthy children would generally not be included in a phase I safety study.

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 RARE DISEASES AND ORPHAN PRODUCTS The guidance on exploratory IND studies is relatively recent. Such studies will occur long before an application for approval reaches FDA, so it will take time before the effect of this approach on product development for rare conditions can be assessed. In any case, exploratory studies appear a useful option for a company or other sponsor that is nearing the initiation of clinical research for a drug to treat a rare condition. PHASE II CLINICAL TRIALS: PROOF OF CONCEPT OR EFFICACY In conventional clinical trials for drugs for common conditions, phase II studies provide an investigational drug’s first test of efficacy in research participants who have the disease or the condition targeted by the medi- cation. Even if combined phase I-II trials are performed to obtain initial findings of safety and efficacy, larger phase II trials will normally be needed to determine optimal dosing to maximize efficacy and minimize adverse events. These studies may include up to several hundred participants and may last from several months to a few years. As described in Chapter 3, for drugs intended for rare conditions, FDA may accept studies involving smaller numbers of research participants than are required for more common conditions. It may also allow the use of historical controls (or possibly no controls) if the rare disease has a defined course in the absence of treatment that will permit comparisons with results for an investigational drug. Phase II studies help determine the correct dosage, identify common short-term side effects, and define the best regimen to be used in pivotal clinical trials. Conventionally, the initial step is usually a phase IIa clinical trial that is focused on an initial proof of concept. This step is to demon- strate that the drug did what it was intended to do: that is, it interacted correctly with its molecular target and, in turn, altered the disease. Phases I and IIa are sometimes referred to as “exploratory development.” Phase IIb trials are larger and may use comparator agents and broader dosages to obtain a much more robust proof of concept and additional guidance on dose selection. They are often done at a regulatory standard that requires conformance with good clinical practice principles and guidelines (see, e.g., CDER-CBER, 1996, and documents at http://www.fda.gov/Science Research/SpecialTopics/RunningClinicalTrials/default.htm). PHASE III CLINICAL TRIALS: REGULATORY PROOF Conventional phase III clinical trials are designed to evaluate a can- didate drug’s benefit in a carefully selected patient population with the disease. These trials are to confirm efficacy, further evaluate safety and

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 NEW THERAPEUTIC DRUGS AND BIOLOGICS monitor side effects, and sometimes compare the candidate drug to com- monly used treatments. They provide crucial evidence needed to satisfy regulators that the drug meets the legal requirements for marketing ap- proval and to provide necessary information for product labeling after approval of the drug. For common conditions, phase III studies are usually conducted with large populations consisting of several hundred to several thousand par- ticipants who have the disease or the condition of interest. Specific deci- sions about the size of the study group will depend on such factors as the magnitude of the effect of interest, characteristics of the study population, and study design. Phase III trials typically take place over several years and at multiple clinical centers around the world. The study drug may be compared with existing treatments or a placebo. Phase III trials are, ide- ally, double blinded; that is, neither the patient nor the investigator knows which participants are receiving the drug and which are receiving existing treatment or placebo during the course of the trial. FDA typically requires two phase III clinical trials for approval of a drug, but the law authorizes FDA to approve a drug based on one multi- center study in appropriate circumstances. Because the number of patients available to participate in a clinical trial involving a rare disease is often very small, FDA frequently approves orphan drugs with less extensive re- quirements for clinical studies (see Chapter 3). If clinical trials are successful, a New Drug Application (NDA) is sub- mitted to FDA for review. The review process usually takes 10 to 12 months and may include, at the discretion of FDA, an advisory committee review. Drugs for rare conditions may qualify for one of several options for speed- ing the path to approval (see Chapter 3). Phase II, and sometimes phase III, trials may fail due to the large het- erogeneity of the patient population being studied. As a result of genetic heterogeneity, some research participants may respond well and others may not respond at all to an investigational product. Increasingly, research is subdividing common diseases such as breast or lung cancer into many heterogeneous subtypes that may differ in their responsiveness to different treatments and that may qualify as rare in terms of the number of people who fit a particular subtype. Because most rare diseases have a more homogeneous genetic pattern than do common diseases and because they are often characterized by similar or identical genetic or epigenetic defects, patients with these diseases could be expected to have a more uniform response to a drug. This should reduce the size of phase II and III studies required to demonstrate efficacy. Indeed, in recognition of this relative homogeneity, CDER has accepted the use of historical controls in phase II trials for extremely rare diseases (see Chapter 3).

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 RARE DISEASES AND ORPHAN PRODUCTS PHASE IV POSTMARKETING STUDIES FDA will frequently specify postmarketing study (phase IV) require- ments to further evaluate an approved drug and obtain more information about safety or effectiveness or both. As described in Chapter 3, such stud- ies are required if the accelerated approval process is used. Approval for one drug (not for a rare disease) was recently rescinded based on postmarketing study results that indicated no benefit. Many of the approvals of drugs for rare diseases reviewed by the committee included provisions for various kinds of postmarketing studies. Responding to evidence of the agency’s lax monitoring of company ful- fillment of postmarketing study requirements, the FDA Modernization Act of 1997 (P.L. 105-115) required FDA to establish a system for monitoring and publicly reporting sponsor progress in fulfilling postmarketing study commitments and requirements. The agency published rules implementing the legislation in 2000 (65 Fed. Reg. 64607). Although study fulfillment is important, the committee was not able to investigate this outcome for orphan drugs. INFRASTRUCTURE FOR DRUG DEVELOPMENT The process of drug development, whether it involves a small molecule or a biologic, is expensive and time-consuming. Invariably, it takes not only expertise, but robust infrastructure and significant funds to bring a therapy to market. Almost 70 percent of the total spent in drug development is for failures at various stages of the drug development process. Although there are several streams of funding for drug development, the total amount is inadequate to support investigation of the thousands of rare diseases profiled earlier in this report—with significant conse- quences for affected patients, their families, and their communities. Clearly, innovation—on every level and by all stakeholders—is needed. This section expands on the discussion begun in Chapter 4 by describing elements of the infrastructure that are needed for clinical development of therapies, in- cluding biomarkers for use as surrogate endpoints in clinical trials, patient registries, clinical trial consortia, and clinical research training. Not included in the discussions below are many other infrastructure el- ements, information sharing initiatives, and collaborations. To cite one ex- ample, the Clinical Data Interchange Standards Consortium is a nonprofit organization to establish standards for acquiring, exchanging, submitting, and archiving clinical research data (see http://www.cdisc.org/). To cite another example, Tox21 is a new collaboration involving NIH, FDA, and the Environmental Protection Agency. It is intended to develop innovative methods to predict the toxicity of drugs and other chemicals in humans,

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 NEW THERAPEUTIC DRUGS AND BIOLOGICS speed the testing process by using robotic and informatics technologies to test compounds in cells, and establish priorities for chemicals that require further evaluation (Jones, 2010). Biomarkers One important avenue for speeding clinical studies of rare diseases in- volves the identification of biomarkers to monitor responses to therapy and guide dosing. Biomarkers have multiple uses. As described in a recent Insti- tute of Medicine (IOM) report, they are used “to describe risk, exposures, intermediate effects of treatment, and biologic mechanisms; as surrogate endpoints, biomarkers are used to predict health outcomes” (IOM, 2010a, p. 3). Biomarkers figure significantly in several of the innovative approaches to developing drugs for rare diseases as discussed below. Developing and validating biomarkers is not a trivial undertaking even for common conditions, but it is highly relevant for rare diseases and war- rants concerted attention. Box 5-1 summarizes the recommendations on biomarker evaluation in the IOM report (IOM, 2010a). The IOM report emphasized the importance of context—including disease prevalence and severity—in evaluating biomarkers. It observed that “an intervention meant to treat a rare but life-threatening disease may permit more tolerance of risk than an intervention meant to treat a more common but less serious disease” and that “it may be easier to defend use of a surrogate endpoint for trials of rare and life-threatening diseases than for trials of primary preven- tion interventions for common but less serious or life-threatening diseases” (IOM, 2010a, p. 113). For biomarkers as well as clinical trial strategies generally, it will be important to consider what constitutes reasonable flex- ibility in FDA assessments of biomarkers for rare conditions. Because a validated biomarker can serve as a surrogate endpoint in a clinical trial, this may allow sponsors to reduce the number of research par- ticipants and the time required for clinical trials. In addition, the accelerated approval pathway described in Chapter 3 allows FDA to approve a drug based on evidence involving surrogate endpoints that are not considered well established but that are determined to be reasonably likely to predict clinical benefit. FDA then requires postapproval studies to develop further evidence about benefits and risks based on clinical outcomes. (As discussed in Chapter 3, the Government Accountability Office recently expressed concern that FDA did not have an adequate process for monitoring the progress of these studies [GAO, 2009b].) The Biomarkers Consortium is a public-private partnership that is managed by the Foundation for the National Institutes of Health. It aims to develop biomarkers for use in research, therapeutic and diagnos- tic development, regulatory approval, and clinical practice (http://www.

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 RARE DISEASES AND ORPHAN PRODUCTS development research on a specific rare disease (see listings at http://www. accessdata.fda.gov/scripts/opdlisting/oopd/index.cfm). Competing companies may also combine insights and work together to solve a particular regulatory problem. A recent example is from the Critical Path Institute (C-Path), an independent, nonprofit organization that brings together FDA, pharmaceutical companies, and others to focus on drug de- velopment issues and to support FDA’s Critical Path Initiative (see Chapter 3). C-Path’s Predictive Safety Testing Consortium involves 16 companies. Recently, as a result of joint efforts across these companies, FDA and its European counterpart, the European Medicines Agency, have both agreed to a new standard for preclinical testing of drugs entering development to predict renal toxicity (C-Path, 2009b). The consortium is now working to qualify and validate new biomarkers in other areas. C-Path was also instru- mental in developing the Coalition Against Major Diseases. Advocacy Groups Given the challenges and expense that beset the traditional model of pharmaceutical research and development in bringing new drugs to market, developing treatments for rare diseases represents an opportunity to test new paradigms. Led by patients and families, disease-specific foundations have begun to do just that (IOM, 2008). As described in Chapter 4, the strategy includes “de-risking” early-stage research and development for promising products by providing philanthropic capital as well as research tools and access to patients. Although advocacy groups have traditionally provided support for basic discovery research, many of them have recently assumed a more active role in shepherding the drug development process in their areas of focus. Again, one objective is to minimize the risks associated with the early phases of therapeutic development. For example, building on the promising results of its basic research program, the Muscular Dystrophy Association now supports the preclinical work necessary for an IND application, as well as funding a national patient database, early clinical trials, and associ- ated research infrastructure costs (see information at http://www.mdausa. org/research). Appendix F includes other examples. These novel approaches have begun to bear fruit, increasing the number of promising therapies that proceed to later-stage clinical trials (IOM, 2008). Another Model: Public-Private Partnerships for Neglected Diseases Public-private partnerships have played an important role in advancing therapeutics for neglected diseases of the developing world. For example, as mentioned in Chapter 4, the Medicines for Malaria Venture is working with

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 NEW THERAPEUTIC DRUGS AND BIOLOGICS pharmaceutical companies and academic centers to discover promising new molecules; the Special Programme for Research and Training in Tropical Diseases is another example of a public-private partnership. At the end of 2004, about half of the public-private partnerships engaged in research and development for neglected diseases projects involved multinational corpora- tions doing so on a “no-profit, no-loss basis”; the other half involved often smaller firms that found commercial opportunity in these resource-limited markets (Moran, 2005). Similar kinds of partnerships could be used more effectively to develop therapies for rare diseases. For example, companies could undertake pre- clinical development activities for compounds entering development for a rare disease from NIH or academic institutions. Alternatively, a partnership could, through sheer volume, coordinate these preclinical development ac- tivities using specific contract research companies to complete the work at a regulatory standard and at a reduced price. One example is the Interna- tional Partnership for Microbicides. This approach uses royalty-free licenses for specific compounds from pharmaceutical and biotechnology companies to develop and distribute vaginal gels and other microbicide products to prevent HIV infection (Brooks et al., 2010). In the realm of clinical development, an example of public-private part- nership is the recently announced Critical Path to TB Drug Regimens (Fox, 2010). With C-Path coordinating, this entity will test promising new treat- ment regimens in collaboration with FDA scientists and 10 pharmaceutical companies. The same approach could be applied to specific rare diseases. National Institutes of Health Just as pharmaceutical companies have had reasons to innovate, NIH has, in recent years, been called upon to complement its support for ba- sic biomedical discovery by facilitating the translation of discoveries into therapies for both common and rare diseases. It too is building “innovation platforms” to support such translation. As part of its Roadmap initiative, NIH launched the Rapid Access to Interventional Development (RAID) program as a pilot activity in 2004. Not a grant program, RAID supports selected aspects of preclinical devel- opment, providing expertise and performing required studies at a regulatory level using existing NIH facilities and contract resources (http://nihroadmap. nih.gov/raid/). Academic investigators as well as qualified small businesses are eligible to use the resource. Although not explicitly targeted to rare diseases, the program is meant to facilitate access to preclinical resources for projects that are unlikely to attract private-sector investment. Approved projects have targeted some rare conditions, including beta-thalassemia and Friedreich’s ataxia. The online program description notes that several

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0 RARE DISEASES AND ORPHAN PRODUCTS individual NIH institutes offer similar support services. However, the diver- sity of opportunities and the relatively decentralized structure of NIH may make it difficult for potential grantees to identify the opportunities that best fit their circumstances (Cornetta and Carter, 2010). In 2006, in recognition of the need to integrate the translational re- search infrastructure within academic health centers, NIH launched its Clinical and Translational Science Awards (CTSA) program (http://www. ctsaweb.org/). The program now includes 55 institutions; ultimately, NIH plans approximately 60 CTSAs, with total funding of around $500 million per year. Individual CTSA programs are to coordinate clinical research resources within an institution to facilitate involvement in translational research by a greater number of investigators than have traditionally been engaged. The programs are also meant to provide a range of training oppor- tunities and integrate academic medical research with community health. Within the CTSA Child Health Consortium Oversight Committee, a rare diseases work group is seeking to identify gaps in rare diseases research and ways in which the consortium might help fill those gaps. The CTSA program is also intended to facilitate resource sharing and consortium-wide collaborations, including shared biorepositories and other resources. One example is the Pharmaceutical Assets Portal, which is spon- sored by the NIH National Center for Research Resources and Pfizer (http://www.ctsapharmaportal.org/). It allows investigators to learn about compounds that have already been evaluated for specific diseases and might be developed for other conditions. The networked structure of CTSA institutions would seem to be ideal for facilitating rare diseases research, in which multicenter clinical trials are the rule and investigators are scattered across several institutions. The CTSA program provides a coordinated infrastructure, but funding is still quite limited for the innovative projects it is meant to facilitate. In 2010, as part of the Patient Protection and Affordable Care Act (Section 10409 of P.L. 111-148), Congress took a significant step to fill the translational research funding gap when it authorized a new Cures Accelera- tion Network (CAN) to provide up to $500 million annually for conducting and supporting research to develop “high-need cures.” These are cures that the Director of NIH determines to be a priority and for which market incen- tives are not likely to support timely or sufficient development. The program would cover development of drugs, biologics, medical devices, diagnostics, and behavior therapies. One key feature is the provision of assistance to award recipients in devising research protocols so that they will comply with FDA standards throughout all stages of product development. The program can fund projects through three types of competitive awards, one of which requires the grantee to provide matching funds. Both

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 NEW THERAPEUTIC DRUGS AND BIOLOGICS public and private organizations (including pharmaceutical and biotechnol- ogy companies) are eligible for funding. Although not limited to rare diseases, the program, if funded to its full appropriation, will represent an unprecedented resource for the develop- ment of therapies for rare diseases and will offer an important complement to the infrastructure provided by the CTSA program. It is not, however, clear to what extent it will subsume or complement the existing Therapeu- tics for Rare and Neglected Diseases (discussed in Chapter 4) and RAID programs or whether its activities will be integrated with those of the NIH Office of Rare Diseases Research and the Rare Diseases Clinical Research Network. The existing infrastructure of rare diseases and translational research, although slight in relation to the need, is an important resource. Thus, a recommendation at the end of this chapter emphasizes the impor- tance of coordinating new and existing programs to speed the translation of research discoveries into safe and effective therapies, diagnostics, and preventive interventions for people with rare diseases. Food and Drug Administration Critical Path Initiative In addition to collaborating in some of the initiatives described above, FDA launched the Critical Path Initiative in 2004 to “to find fundamen- tally faster, more predictable, and less costly ways to turn good biomedical ideas into safe and effective treatments” (FDA, 2004, p. 30). The initiative is intended to help build partnerships involving industry, advocacy groups, and others to share information and expertise and to promote problem solving and innovation in a broad range of areas, including biomarker development, information technology, streamlining clinical trials, and clini- cal investigator training. The predictive safety effort described above is an example of one such collaborative effort. The 2009 report on the Critical Path Initiative does not cite any activi- ties focused specifically on orphan products. Nonetheless, a number of the activities should help improve the quality and efficiency of drug trials for rare as well as common conditions. For example, one of the collaborations seeks a better understanding of the genetics of drug-induced liver injury, including Stevens-Johnson syndrome, a serious rare disorder (CPI, 2010). Repurposing Existing Drugs In parallel to the concept of precompetitive sharing of compounds or data as discussed in Chapter 4, another avenue for innovation involves repurposing old drugs for potential treatments of rare diseases. That dis-

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 RARE DISEASES AND ORPHAN PRODUCTS cussion noted that the National Chemical Genome Center is developing a library of approved drugs so that they can be more easily screened for possible repurposing. Without the need to repeat toxicological or pharmacokinetic assess- ments, a considerable portion of the costs of bringing a drug through the re- search and development pipeline can be saved (Chong and Sullivan, 2007). Furthermore, population safety, dosing, and adverse events are already known. In addition, for drugs to treat rare diseases, the marketing protec- tions offered by the Orphan Drug Act provide an incentive to companies that might otherwise not be interested in further work on an old drug for which patent protection had expired. The Office of Orphan Products Development at FDA recently posted a database of products that already have an orphan drug designation for a rare disease and have been approved for the treatment of some other rare disease, for treatment of a common disease, or both. Such products have al- ready gone through preclinical testing and been judged to be pharmacologi- cally active, safe, and effective for some clinical condition (OOPD, 2010). The repurposing of existing drugs for rare diseases treatments may lead to higher pricing for existing, more common use of the drug. Although the example of colchicine discussed in Chapters 3 and 6 involves a previously unapproved but widely available drug, it may still be suggestive of one consequence of repurposing if patients with the common condition have limited alternatives.3 Use of Public and Philanthropic Funding to Reduce Overall Development Costs Public and philanthropic funding for drug development and clinical trials for rare diseases, particularly if directed toward nonprofit, patient- led consortia, reduces the need for a high rate of return for the commercial firms that ultimately manufacture and market a new drug. Such funding potentially could attract more industry investment in these therapies. For drugs whose profit margins might be slim or initially nil, public funding such as that proposed in the previously mentioned Cures Acceleration Net- 3 Internationally, pharmaceutical firms have offered preferential pricing for drugs in differ- ent countries and for drugs with multiple uses; in the latter situation, customers for one use of a drug pay a higher price so that customers for a different use, typically for a neglected disease, may have closer-to-marginal cost pricing or have access through company donations. The latter kind of dual market requires some serendipity. Examples include a treatment for sleeping sickness that has a secondary cosmetic indication for removing unwanted facial hair for women (eflornithine [brand name Vaniqa]) and a treatment for river blindness that has a lucrative veterinary market for treating heartworm in dogs (e.g., ivermectin [Mectizan]) (see, e.g., Collins, 2004; Torreele et al., 2004).

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 NEW THERAPEUTIC DRUGS AND BIOLOGICS work initiative may provide the necessary resources to bridge the “valley of death” from preclinical to clinical phases of testing and then fund pivotal clinical trials. One difference between this program and the NIH Small Business Innovation Research program is that the latter excludes nonprofit entities whereas the former extends eligibility to nonprofit research enter- prises, such as patient groups that may be particularly effective in recruiting participants for clinical trials. Examples involving resource sharing arrangements and public and voluntary funding for the development of treatments for neglected diseases offer possible models for rare diseases. One approach involves humanitar- ian access licensing by universities that offer publicly funded inventions royalty-free in exchange for commitments from companies to produce the drug at no profit or close to marginal cost for those in need in the devel- oping world. For example, the University of California, Berkeley, struck such an arrangement with the Institute for OneWorld Health and Amyris Biotechnologies (see IOM, 2008; and, generally, So and Stewart, 2009). In exchange for a co-exclusive, royalty-free license from the university, Amy- ris Biotechnologies pledged to use the microbial process of synthesizing artemisinin and to produce the antimalarial at no profit for the developing world. With the support of a $42 million Gates Foundation grant, all three parties benefited (IOWH, 2004). Notably, Amyris Biotechnologies was able to pursue proof-of-concept testing of this technology without diluting shareholder equity. When a company involved in this kind of arrangement seeks to raise second-round venture capital, equity in the firm will be more valuable with this kind of groundwork in establishing proof of concept of the technology. RECOMMENDATIONS Chapter 3 includes a number of recommendations for actions by FDA to identify and reduce problems related either to its own performance or to the performance of sponsors of new drugs that may slow or discourage the development of drugs for rare diseases. These recommendations call on FDA to identify areas of inappropriate inconsistency across CDER units in their review of orphan drug applications, develop related guidance on cri- teria for approval of orphan drugs based on differences in candidate drugs or the associated rare diseases, continue work to expand understanding and appropriate use of small clinical trial designs, and collaborate with NIH to ensure that NIH-funded product development research meets regulatory standards. The recommendations in this chapter focus primarily on steps that NIH can take in collaboration with industry and advocacy groups to further accelerate development of safe and effective products for people with rare

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 RARE DISEASES AND ORPHAN PRODUCTS diseases. The first recommendation focuses on the preclinical stage of drug development. The objective is to expand the resources and options for ac- celerating drug development, including the options available to investiga- tors funded by rare diseases advocacy groups. RECOMMENDATION 5-1: NIH should create a centralized preclini- cal development service that is dedicated to rare diseases and available to all nonprofit entities. The creation of this service could be accomplished through several dif- ferent models. Within NIH, one possibility would be to expand the capacity of the RAID program, which, although not dedicated to rare diseases, does include them in its project portfolio. Similarly, the TRND program cur- rently overseen by the Office of Rare Diseases Research could be expanded not only in terms of the number of awards but also to provide coverage of preclinical development projects such as the selection and arranging of testing of promising compounds. Alternatively, to leverage involvement and additional funding from companies and philanthropic organizations, a preclinical development ser- vice could be based in an entity such as the Foundation for NIH. This foundation was established specifically to support NIH collaboration with academic institutions, industry, and nonprofit groups without certain con- straints that apply to NIH itself (FNIH, 2010). The Biomarkers Consor- tium is an example of this kind of collaboration. A different and possibly complementary approach would be to establish a consortium of pharma- ceutical and biotechnology companies through which selected preclinical development projects would be carried out using the resources provided by consortium members or by individual companies. As emphasized in this chapter, the development and validation of bio- markers for use as surrogate endpoints in clinical studies of drugs for rare diseases will speed such studies and should reduce their costs. Another IOM committee has recommended a Department of Health and Human Services- wide effort to encourage the collection and sharing of data about biomark- ers for drugs, biologics, devices, and foods (IOM, 2010a). In addition, the establishment of clearly defined standards for biomarker validation and application in clinical trials for rare disorders will reduce the possibility that FDA will reject applications for the approval of an orphan drug based on inadequate biomarker validation, a problem noted in Chapter 3. RECOMMENDATION 5-2: In collaboration with industry, academic re- searchers, NIH and FDA scientists, and patient organizations, FDA should expand its Critical Path Initiative to define criteria for the evaluation of surrogate endpoints for use in trials of products for rare conditions.

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 NEW THERAPEUTIC DRUGS AND BIOLOGICS In addition to agreement on criteria for the evaluation of surrogate endpoints for clinical trials, the expansion and improvement of patient registries and biorepositories are other important elements in a strategy to accelerate rare diseases research and product development. Today, an uncounted number of organizations and researchers in this country and around the world maintain rare diseases registries and specimen collections in some form, sometimes for the same condition. No uniform, accepted standards govern the collection, organization, or availability of these re- sources. An increase in the use of registries and biorepositories and a more systematic approach to their creation, maintenance, and accessibility are needed on a national and global basis. Building on work already begun, NIH can take a lead role in working with industry and private partners to make the creation and maintenance of registries and biorepositories easier and less expensive, to expand information sharing, and to promote stan- dards and processes that yield high-quality data and specimens and protect patients or research participants. RECOMMENDATION 5-3: NIH should support a collaborative public- private partnership to develop and manage a freely available platform for creating or restructuring patient registries and biorepositories for rare diseases and for sharing de-identified data. The platform should include mechanisms to create standards for data collection, specimen storage, and informed consent by patients or research participants. For example, features of a systematic, coordinated approach to patient registries for rare diseases would include agreement on minimum common data elements, definitions, and coding protocols and also uniform and widely accepted mechanisms for patient or research participant consent. Partners would have easy access to a common central resource or platform for creating or reconfiguring registries. In clinical trials, the latter might involve a biomarker substudy protocol available with the main study proto- col. Study participants would then be asked for consent related to the larger clinical trial and for consent related to future biomarker studies. These features would not only make the creation or revision of existing registries easier (especially for groups or researchers with limited funds), but also facilitate data sharing and pooling. Given the limited resources of many organizations and researchers working on rare diseases, the goal would be for the system to evolve into a self-sustaining, public-private partnership. The committee understands that this would be a complicated undertaking at all stages. In the realm of clinical research, the Rare Diseases Clinical Research Network is a valuable resource but one with a relatively limited and pre- determined scope that constrains its ability to take advantage of unantici-

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 RARE DISEASES AND ORPHAN PRODUCTS pated opportunities presented by scientific discoveries. In some cases, other research networks have greater flexibility as in the Marfan example cited above. These other networks, however, lack a specific focus on rare dis- eases. The committee believes that it is desirable to enhance existing clinical research activities focused on rare diseases. This enhancement should in- clude a program or programs that are not strictly organized around specific disease areas but rather have the flexibility to partner with or recruit other existing networks or sites to rapidly capitalize on research advances and to achieve common and broadly defined goals in rare diseases research. RECOMMENDATION 5-4: NIH should increase its capacity and flex- ibility to support all phases of clinical research related to rare diseases, including clinical trials of new and repurposed therapeutic agents. Op- portunities to be explored include • expanding the Rare Diseases Clinical Research Network to address opportunities for diagnostic and therapeutic advances for a greater number of rare diseases; • setting priorities for rare diseases research within other NIH clinical trials networks; • creating a study group approach to rare diseases, modeled after the Children's Oncology Group; and • building additional capability for rare diseases clinical research within the Clinical and Translational Science Awards program. In addition, although the Cures Acceleration Network will not focus exclusively on rare diseases research, such research falls well within the program’s intended scope and should benefit from it if appropriations for the network support the goals set for it. For the program to target resources effectively, it is important that it be coordinated with the Office of Rare Diseases Research and that the selection process for network projects in- clude individuals with expertise in rare diseases and the science of small clinical trials. RECOMMENDATION 5-5: NIH should establish procedures to ensure coordination of the activities of the Cures Acceleration Network with those of the Office of Rare Diseases Research, FDA’s orphan products grants program, and other existing initiatives to promote and facilitate the translation of basic science discoveries into effective treatments for rare diseases. It should build on existing resources when appropriate, avoid creating duplicative research infrastructure, and engage advocacy groups in its work.

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 NEW THERAPEUTIC DRUGS AND BIOLOGICS A precondition for the network to achieve its goals is the appropriation by Congress of adequate resources. In addition, requiring clinical studies funded through the Cures Acceleration Network to disclose both positive and negative results will underscore the importance of sharing data in ac- celerating progress toward high-need cures. The recommendations in this chapter and the preceding one focus on strategies that may directly expand and improve the quantity, quality, and efficiency of rare diseases research and orphan product development. The next chapter turns to a quite different set of considerations that may influ- ence company decisions about research and development activities, that is, health plan policies and practices related to drugs and biologics for rare diseases.

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