Rare Diseases and Orphan Products Accelerating Research and Development (2010) / Chapter Skim
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5 Development of New Therapeutic Drugs and Biologics for Rare Diseases
5 Development of New Therapeutic Drugs and Biologics for Rare Diseases
Pages 147-178
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From page 147... ...
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)
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From page 148... ...
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.
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From page 149... ...
Later sections of this chapter examine the infrastructure 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.
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From page 150... ...
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.
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From page 151... ...
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)
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From page 152... ...
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.
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From page 153... ...
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)
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From page 154... ...
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.
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From page 155... ...
Phase III trials are, ideally, 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 multicenter study in appropriate circumstances.
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From page 156... ...
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, including biomarkers for use as surrogate endpoints in clinical trials, patient registries, clinical trial consortia, and clinical research training.
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From page 157... ...
Because a validated biomarker can serve as a surrogate endpoint in a clinical trial, this may allow sponsors to reduce the number of research participants 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.
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From page 158... ...
. An example of a generally accepted biomarker for a rare condition is blood phenylalanine level for the rare disease phenylketonuria.
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From page 159... ...
A second way that registries can help is when the information collected includes biological specimens or links to specimen data. Such information has the potential to reveal biochemical, histologic, or other markers that may be found to be suitable as surrogate endpoints in clinical trials and that, in turn, can reduce the time required for clinical trials used to support FDA approval, particularly for long-term chronic conditions.
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From page 160... ...
In 2010, the Office of Rare Diseases Research at NIH sponsored a workshop on the intersection of patient registries, biospecimen repositories, and clinical data (see Rubenstein et al., 2010)
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From page 161... ...
One potentially comprehensive approach would be for funding agencies to widely advertise the anticipated launch of clinical trials for rare disorders, to request proposals for and prioritize ancillary studies, and to mandate the establishment of or participation by grantees in standardized patient registries and biorepositories. This would depend on a coordinated intellectual, financial, and physical infrastructure (probably including international acceptance and participation)
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From page 162... ...
. The RDCRN cannot carry out clinical trials for diseases that fall outside the scope of the funded consortia.
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From page 163... ...
Chapter 3 discusses the joint education programs of FDA and NIH to familiarize both agency staff and others with these designs. It recommends that the agencies evaluate the extent to which studies submitted in support of orphan drugs are consistent with advances in the science of small clinical trials and associated analytic methods and develop responses based on the findings.
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From page 164... ...
Access to Information on Negative Findings and Decisions Traditionally, information about failed clinical trials and negative FDA decisions has been limited. With few exceptions, FDA regulations generally prohibit the release of information from or about an IND, NDA, or Biologic Licensing Application (BLA)
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From page 165... ...
In recent years, government, medical journals, advocacy groups, trade associations, and others have taken steps to increase the availability of information about successful and unsuccessful clinical trials. Box 5-2 summarizes some of these.
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From page 166... ...
As discussed in Chapter 4 in the context of discovery research, such collaboration might involve several aspects, including that competitors share the costs of early-stage research in rare diseases and also share expertise and findings. Another element might involve cooperation on the development of biomarkers that could be used to monitor therapies for specific diseases and that might ultimately be used as surrogate endpoints
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From page 167... ...
It has announced a public-private initiative to support the development of better treatments for Alzheimer disease and Parkinson disease. In addition to the sharing of information on failed and successful trials, this collaboration among pharmaceutical companies, patient advocacy groups, voluntary health associations, and government agencies will include the development of disease progression models to improve the design of clinical trials to meet FDA standards (CPath, 2009a)
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From page 168... ...
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 associated research infrastructure costs (see information at http://www.mdausa. org/research)
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From page 169... ...
For example, companies could undertake preclinical 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 activities using specific contract research companies to complete the work at a regulatory standard and at a reduced price.
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From page 170... ...
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.
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From page 171... ...
. 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 clinical investigator training.
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From page 172... ...
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, patientled 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.
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From page 173... ...
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 criteria 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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From page 174... ...
. 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.
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From page 175... ...
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 protocol.
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From page 176... ...
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 include 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.
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From page 177... ...
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 influence 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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