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Orphan Product Development. Focus Group Research - Final Report May 2010 Conducted on Behalf of the National Organization for Rare Disorders (NORD) by Gen., LLC. Contents. Introduction Key Findings Academic Medical Researchers Patient Advocates Investment Community

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Orphan Product Development

Focus Group Research - Final Report

May 2010

Conducted on Behalf of the National Organization for Rare Disorders (NORD) by Gen., LLC


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Contents

  • Introduction

  • Key Findings

    • Academic Medical Researchers

    • Patient Advocates

    • Investment Community

    • Pharma/Biotech Executives

  • Summary & Considerations


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Study Background

  • NORD has convened a task force on orphan product development to comprehensively examine the policies and processes applicable to orphan product development – from discovery to approval and availability

  • As part of addressing these objectives, NORD commissioned a qualitative focus group research study to gain a better understanding of key stakeholders’ understanding of and perspectives on the orphan product development process


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Research Objectives

  • Explore stakeholders’ current perspectives on the orphan product development process

  • Identify stakeholders’ perceptions of the key challenges in the process of orphan product development

  • Produce a list of proposed solutions to address the challenges in the process of orphan product development


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Data Collection

  • To address these objectives, NORD sponsored four (4) focus groups with representatives of groups and companies involved in the development of orphan products:

    • Academic medical researchers

    • Patient advocates

    • Investors/venture capitalists (VCs)

    • Pharmaceutical/biotechnology industry executives

  • Following are focus group logistics:

    • Each group lasted approximately 1.5 hours in duration

    • Focus groups were conducted in April 2010

    • All study participants were recruited by NORD


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Contents

  • Introduction

  • Key Findings

    • Academic Medical Researchers

    • Patient Advocates

    • Investment Community

    • Pharma/Biotech Executives

  • Summary & Considerations


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Key FindingsAcademic Medical Researchers

  • Experiences with & overall perspectives on orphan product development

    • Varying degrees of experience with the drug development / orphan product development process

    • Different areas of therapeutic focus: medical genetics, neurological disorders, pregnancy disorders, and cardiovascular diseases (i.e., vulnerable plaque)

    • Initial comment was that challenges often arise for orphan medications as a result of a lack of resources at all major junctures, especially the pharmacology/toxicology stage

    • Throughout the discussion, study participants underscored the need for more information about what regulators and industry are looking for with respect to preclinical study design


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Key FindingsAcademic Medical Researchers

  • Key challenges in orphan product development identified by academic medical researchers fall into 6 general categories:

    • Pre-clinical challenges

    • Clinical-trial related

    • Endpoints

    • Investigator-related

    • Resources

    • Regulatory


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Key FindingsAcademic Medical Researchers

  • Respondents identified several pre-clinical development challenges:

    • Lack of data on quantitative natural history data on rare diseases

    • Lack of availability of relevant and validated animal models

    • Early studies within a rare disorder often conducted by inexperienced researchers

      • May result in the unfortunate termination of a project in its nascent stages

      • Would stymie corporate interest & uptake of a given project


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Key FindingsAcademic Medical Researchers

  • Numerous challenges were noted in clinical trial design and execution:

    • Relative lack of knowledgeable & experienced investigators

    • Statistical issues posed by dealing with small sample sizes

    • Design of clinical trials for multi-system disorders

      • Controlling for concomitant disorders and concomitant medications

    • Patient identification and recruiting challenges exist

      • Reaching and recruiting the correct patents


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Key FindingsAcademic Medical Researchers

  • ENDPOINTS was first major challenge:identification of clinical endpoints and concurrence with regulators on clinical endpoints for the evaluation of orphan products

    • Need to “guess” which clinical endpoints are important, necessitating multiple trials

    • Attaining agreement with regulators about appropriate clinical endpoints

    • Discrepancy between endpoints selected by study investigators and those considered of importance to regulators

      • May result from investigators not consulting FDA prior to initiating study

      • Instances of investigators gaining advance agreement on endpoints which are later rejected by regulators

    • Medical / scientific / investigator community forms own consensus on endpoints but does not involve regulators in the process

      • May leads to decisions which are later rejected by regulators


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Key FindingsAcademic Medical Researchers

  • The second major challenge pertains to investigators’ expertise and interest

    • Investigators possess varying expertise in finding a partner to help develop a new entity, and/or to sell this entity to potential investors (often contingent on tech transfer capability)

    • Young investigators who are junior faculty often do not venture into rare diseases because it may prove a career “dead end”

      • Rare diseases may not afford near-term publication opportunities

    • Investigators may have low familiarity with IP considerations

      • Lack of knowledge of the IP process may lead to an entity’s not having sufficient protection to foster industry interest

      • Need for improved IP education for academic investigators, especially junior faculty, as well as university tech transfer groups


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Key FindingsAcademic Medical Researchers

  • A third challenge identified pertains to resource availability, acquisition and utilization

    • Overall dearth of funding for orphan medications

      • Perception is that there is only $14 million provided by the Federal government for orphan drug research

    • Investigators may have varying degrees of ability to acquire and efficiently deploy resources during the pre-clinical development process

      • Funding often may not be available to conduct pharmacology / toxicology experiments (which is often where development of a candidate is halted)


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Key FindingsAcademic Medical Researchers

  • Lastly, respondents identified several key regulatory challenges

    • First is that reviewers within FDA may not have commensurate expertise in treatment area as does the investigator

    • Second, current guidelines for development of orphan medications (i.e., ICH guidelines) may not be helpful to investigators

    • One point raised: need for FDA guidance on qualifying surrogate endpoints


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Key FindingsAcademic Medical Researchers

  • Potential solutions proposed academic medical researchers include:

    • Federally-funded trust to support research and investigation into natural history of and medications for rare disorders

    • More FDA guidance on qualification of surrogate endpoints

    • A handbook to provide guidance to academic investigators on development of medications for rare diseases

    • Some modality to stimulate/spur more young investigators to get involved in rare diseases (as opposed to viewing orphan product development as “career suicide”)

    • Establishment of a working group to determine which clinical trials processes and statistical approaches are most appropriate for orphan medications

    • Development of a national clearinghouse of information to accumulate / aggregate information on natural history of rare diseases

    • Greater public awareness of rare diseases


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Contents

  • Introduction

  • Key Findings

    • Academic Medical Researchers

    • Patient Advocates

    • Investment Community

    • Pharma/Biotech Executives

  • Summary & Considerations


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Key FindingsPatient Advocates

  • Participant backgrounds

    • Patient advocates represent a wide range of rare diseases and exhibit a range of familiarity with the orphan medication development processes

    • Most of the participants got involved in rare disorders as a result of a child or other loved one being impacted by the condition in question – a few come from a non-profit or clinical research background

    • The organizations represented in the focus group generally saw their overall role as advocating for / providing a voice to the people affected by these conditions, as well as keeping those individuals well-informed


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Key FindingsPatient Advocates

  • From the very outset, patient advocates expressed a range of frustrations with orphan product development:

    • Overall dearth of treatment options

    • Lack of commercial interest to pursue development of orphan medications

    • Dearth of awareness of rare diseases on the part of physicians

    • Lack of credible information on rare diseases to disseminate to the general public

    • Overall lack of public awareness about the importance of rare diseases

    • Process of developing medications takes a long time

    • Disconnect among physicians, patients & investigators evaluating new products

    • Effective medications are available overseas but not approved in the U.S.

    • Reimbursement challenges once medications for rare diseases do get approved

    • Effective medications may be discarded from consideration due to disagreement over which endpoints and changes in those endpoints are meaningful

    • Perceived lack of harmonization in the orphan product approval process between the US FDA and European Union/EMEA

    • Patients can get “discarded” from clinical trials if they have a co-morbid illness


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Key FindingsPatient Advocates

  • Topics patient advocates would like to better understand about the orphan product development process:

    • Timetable/schedule of typical FDA approval process (vs. process of orphan drug development)

    • The costs associated with developing an orphan medication, especially from the standpoint of a major pharmaceutical company

    • How one moves a product from off-label usage to on-label approval

    • How does the EMEA (and parallel regulatory bodies from other markets, e.g., Australia) operate differently than FDA in terms of orphan medications

      • More specifically, how EMEA and other regulatory bodies weigh and evaluate adverse events

      • How do both FDA and EMEA evaluate the risk threshold for medications, esp. treatments for rare diseases?

    • What are the clinical trials requirements or standards for orphan medications?


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Key FindingsPatient Advocates

  • Perceived challenges identified by patient advocates:

    • Lack of awareness among bench researchers looking at new medication targets of applicability to rare diseases (and/or potential therapeutic value)

    • Dearth of studies conducted on the natural history of rare diseases, hence lack of natural history data, and the lack of known / well-defined clinical endpoints

      • Due to a lack of natural history data, finding an endpoint is more the result of “luck” than a systematic process

    • The current drug approval process is geared towards large populations, not small/rare disorders

      • Applying statistical/research standards to small sample sizes is a challenge

    • Several financial challenges were noted

      • Uncertainty around whether the investigator can obtain the grant funding

      • Large cost of the clinical trials to the pharmaceutical company (creating risk aversion)

    • Perceived lack of ROI

    • Possible reimbursement challenges once a medication is available

    • Companies pursuing similar targets may not share information

    • Physicians often are unwilling to report writing medications off-label


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Key FindingsPatient Advocates

  • Patient advocates offered a range of potential solutions:

    • The first proposed solution entails a redefining what constitutes a rare disease as far as number of patients (i.e., “Orphan Drug Act 2.0”)

      • Redefine a rare disease as a condition affecting a population smaller than 200,000

      • Process similar to the EMEA model of “exceptional approval”

    • Establishment of an on-line, centralized clearinghouse of data pertaining to rare diseases

      • Natural history and other information of use to investigators, investors and other parties

    • Convening of a working group to evaluate a new set of research standards for very small study populations

    • Helping academic researchers become more familiar with the FDA approval process, e.g., internships within CBER/CDER

    • Modifying or enhancing the system of incentives within the research community to promote more:

      • Basic/bench research into rare diseases (in order to make it more high-priority)

      • Natural history studies of rare diseases

      • Studies to establish what constitutes “steady state” within a given disease category

      • Collaboration between academia and pharmaceutical industry

    • Need to considerably augment awareness among the public as well as treating physicians about rare diseases


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Contents

  • Introduction

  • Key Findings

    • Academic Medical Researchers

    • Patient Advocates

    • Investment Community

    • Pharma/Biotech Executives

  • Summary & Considerations


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Key FindingsInvestment Community

  • Current environment for investing in the orphan drug space:

    • VCs are still investing in companies that have growth potential

    • Recent liquidity crisis has limited number of companies investing and the amount of capital to invest

    • Uncertainty about the operability of capital markets

      • Whether private companies can be taken public is in question

    • Uncertainty as to how the impact of the recently-promulgated Federal health reform initiative

    • Large pharmaceutical companies such as Pfizer and GSK have recently started investing in the orphan drug space


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Key FindingsInvestment Community

  • Elements of the process by which investors de-risk projects in the orphan product space:

    • Evaluate MOA

    • Determine whether animal models are robust and demonstrate efficacy

    • Quantify the number of patients affected by a condition

    • Assess managers & management track record

    • Assess both the FDA documents related to future approval

    • Perform due diligence as to whether there is sufficient IP protection

    • Confirm there will be mechanisms in place for eventual reimbursement of the product in question


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Key FindingsInvestment Community

  • Main perceived challenges that exist in orphan product development:

    • The first challenge that was raised is the difficulty of clinical development as a function of several factors:

      • Small populations mean that it is difficult to reach and recruit participants for clinical trials

      • Identification of relevant and approvable clinical endpoints

      • The fact that there is less of a “track record” with rare diseases vs. larger / established disease states

      • Clinical trials are a challenge to conduct due to statistical constraints in evaluating small populations with (that potentially have co-morbid conditions)


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Key FindingsInvestment Community

  • Several aspects of the regulatory evaluation process for orphan products were noted as challenges:

    • Ensuring that the reviewers within FDA possess familiarity with the treatment area in question

    • Transparency of FDA decision-making – specifically, public investors would like better understanding of how FDA plans to evaluate a compound and what the FDA is communicating to the company

      • Specifically, investors requested a public record of the precise criteria that FDA communicated to the company a given orphan product to attain approval

    • Desire for increased flexibility around endpoints required for approval of an orphan product

    • A further challenge raised is the perceived degree of concordance in agency policy at highest levels vs. among those actually reviewing new medications

    • Interest in risk-benefit considerations that are taking into consideration during the developmental process being carried forward into manufacturing

      • At present, investors perceive that there is no tolerance for risk in CMC


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Key FindingsInvestment Community

  • A third area of challenge that was identified by investors is evaluative challenges in assessing the potential opportunity for a company or a product in question

    • First, it is difficult to obtain accurate information on number of patients with rare diseases in order to determine the market size and potential

    • Additionally, it is difficult to ascertain the market structure in evaluating the opportunity

    • It was noted later in the discussion that current repositories of patient information for rare diseases are decentralized

    • Further, one investor remarked that there is a lack of literature on the natural history or clinical course of the disease


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Key FindingsInvestment Community

  • A fourth are of possible challenge is the recently promulgated health care reform bill, the effect of which respondents generally feel is uncertain

    • Notably, any possibility for future pricing pressure is seen as a major potential challenge that could prove devastating to investment in the orphan product space


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Key FindingsInvestment Community

  • Potential solutions proposed by investors:

    • First, investors spoke of a “well-defined pathway” for the approval of orphan medications, one that is:

      • Transparent /publicly available communication between the FDA and the company

      • This would need to be rooted in a published or agreed-to guideline

    • Next, investors are seeking reliable sources of rare disease patient information

      • More specifically, a centralized repository of epidemiological data so that they can evaluate the structure of the market (i.e., how a condition is currently treated) as well as potential market size

    • A third item noted is that investors require confidence in the maintenance of favorable pricing and reimbursement conditions

    • The need protect payment mechanisms and the 7-year orphan product protection statute were underscored by all investor participants

    • A fifth area of discussion spoke to flexibility around CMC requirements

    • Another area of focus is the need for reviewers within FDA who are very familiar with the disease state in question

    • Lastly, a solution that was forwarded is to create a fund that would support early research efforts in the orphan disease space


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Key FindingsInvestment Community

  • Following are investors’ perceptions of the role (and potential role) of NIH in the process of developing orphan medications:

    • NIH is perceived as primary source of grant funding to sponsor bench science/new discoveries

    • NIH is regarded as funding early-stage clinical pathway development/medical knowledge and translational research

  • When asked as to what NIH could potentially do differently, following were some of the suggestions raised:

    • Conduct more translational research on existing products (vs. more bench research)

    • Help to fund small companies in the orphan drug space (since these companies are less able to raise money in the private markets

    • Additionally, NIH may be able to help harness and guide the investment of wealthy individuals into rare diseases


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Key FindingsInvestment Community

  • Towards the end of the discussion, investors raised a potential warning flag about the future development of orphan medications

    • It was noted that due to the aforementioned challenges, especially the monetary constraints in the wake of the credit crunch, there is a dearth of private investment in early-stage orphan research programs

    • As a result, there may be fewer compounds moving from discovery into pre-clinical development, which could lead to a future shortage of medication candidates 6-7 years down the road

    • It was noted that an opportunity for NIH is to step into the breach and help to move development projects from the discover into the pre-clinical stage


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Contents

  • Introduction

  • Key Findings

    • Academic Medical Researchers

    • Patient Advocates

    • Investment Community

    • Pharma/Biotech Executives

  • Summary & Considerations


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Key FindingsPharma/Biotech Execs

  • Industry executives characterized the current challenges they face in developing orphan medications

    • The first challenge that was described resides in companies’ ability to quantify the unmet need & the opportunity within a rare disease treatment area

      • Dearth of natural history data

      • Lack of market data

    • Pharmaceutical / biotechnology executives pointed to several clinical development challenges

      • Small populations of patients

      • Identifying and connecting with patients


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Key FindingsPharma/Biotech Execs

  • Industry executives characterized the current challenges they face in developing orphan medications (cont.)

    • Several comments were made about the current regulatory environment for developing orphan products

      • Respondents pointed to be need for better clarity/consistency in the regulatory process and what is expected

        • Respondents spoke of Companies often have to face “unexpected hoops” leading to additional investment in the clinical development process

      • It was felt that the agency needs a better understanding of the cost/investment that is required to bring orphan medications to market

      • Further, executives spoke of the need for increased harmonization of U.S. & EU regulatory procedures for orphan medications

      • One respondent referred to an “asymmetry of knowledge” between investigators, including those working on behalf of the company, and the FDA reviewers looking at the product


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Key FindingsPharma/Biotech Execs

  • Industry executives characterized the current challenges they face in developing orphan medications (cont.)

    • The next overall set of challenges pertain to manufacturing

      • First, it was mentioned that it is difficult to scale up manufacturing of a rare disease entity due to unique processes

      • Additionally, manufacturing represents a major aspect of the investment in rare diseases

    • Respondents pointed to challenges in working with key opinion leaders (KOLs) in rare diseases

      • First, there are a limited number of KOLs within a given treatment area

      • Secondly, these KOLs often are prevented from consulting with government since they are consulting with industry – this is seen as part of what contributes to the asymmetry of expertise between industry and regulators


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Key FindingsPharma/Biotech Execs

  • Industry executives characterized the current challenges they face in developing orphan medications (cont.)

    • There are also a number of more generalized risks involved in the orphan drug space:

      • One, the current situation in the financial sector, i.e., the recent crisis in the credit markets

      • Secondly, the impact of the recently promulgated health care reform bill remains unknown 

        • A few respondents note that the elimination of lifetime caps and the negation of restrictions on pre-existing conditions are encouraging vis-à-vis rare diseases)


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Key FindingsPharma/Biotech Execs

  • Industry executives proposed a series of potential solutions to these perceived challenges:

    • Global multidisciplinary forum that would incorporate industry, regulators, NIH, academia and patient advocate groups

    • Need for assurances of pricing protection, especially in light of the newly-promulgated National health care legislation

    • There is a need for solutions vis-à-vis the regulatory process

      • More clarity of requirements for approval

      • More flexibility, i.e., a greater threshold for risk tasking in rare diseases and more flexibility around surrogate endpoints

      • Greater recognition that no one knows about the disease, hence more need to educate reviewers on the realities of orphan diseases


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Key FindingsPharma/Biotech Execs

  • Industry executives proposed a series of potential solutions to these perceived challenges (cont.):

    • More time, i.e., longer meetings, to permit more dialogue/conversation between the company and regulators

      • The need for more time was attributed to the common lack of knowledge and experience within a given rare disorder, necessitating more dialogue about the best way to evaluate the disorder

      • These longer dialogues would allow for more extensive information sharing and to ensure a common knowledge base, including regulators attaining a better grasp for the company's decision making process

      • Additionally, executives are seeking more time for experts to provide education to FDA reviewers looking at rare diseases


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Key FindingsPharma/Biotech Execs

  • Industry executives proposed a series of potential solutions to these perceived challenges (cont.):

    • Look at ways to resolve the FDA/EMEA inconsistency, i.e., greater US/EU regulatory harmonization

    • Create incentives for the re-purposing/re-tasking of existing medications (since ownership of older molecules could present an IP challenge)

    • Screening solutions (i.e., identification of affected population)

      • For example, genetic screening of newborns


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Key FindingsPharma/Biotech Execs

  • At the end of the meeting, pharmaceutical/biotechnology industry executives were queried as to their perceptions of the role (and potential role) of NIH:

    • NIH is perceived to support innovation and translational medication

    • Secondly, it is perceived to provide funding grants to support the development of orphan medications

    • However, the main challenge is perceived to be the small size of funding for rare diseases


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Contents

  • Introduction

  • Key Findings

    • Academic Medical Researchers

    • Patient Advocates

    • Investment Community

    • Pharma/Biotech Executives

  • Summary & Considerations


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Summary

  • There exist a number of shared / common challenges which are perceived to exist in the development of orphan products:

    • There are important pre-clinical development challenges, which have implications for researchers and corporations

      • There is a general lack of natural history data on rare diseases

      • There is a lack of validated animal models in rare diseases

      • There is a lack of centralized prevalence/ incidence data on rare diseases, making it difficult to assess the extent of the disease (as well as the commercial opportunity)

    • Important clinical development challenges were identified as well

      • First, the ability to identify, reach and enroll patients for clinical trials is difficult due to small numbers of patients

      • Secondly, several groups pointed out that there are statistical challenges when dealing with an ultra-small group of patients (especially who may have concomitant conditions and/or who are polypharmacy)

      • Third, identifying knowledgeable pool of investigators to conduct the clinical trials is a challenge

    • Orphan/rare disease viewed as a career path with less potential for success than working on established diseases – in other words, “career suicide”


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Summary

  • Several important challenges pertaining to the regulatory aspects of orphan product development were noted across groups:

    • Identification and concordance on clinical endpoints and surrogate markers for approval

    • Transparency of the entire regulatory/approval process (particularly the public availability of communication between FDA and companies)

    • Perceived asymmetry of expertise between investigators and companies and regulators/reviewers

  • Potential future reimbursement challenges

    • The possibility of the recent Federal health care reform program mandating price controls and/or curtailing reimbursement


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Conclusions

  • Several potential solutions were put forth by focus group participants, which include:

    • A global forum on orphan product development which would encompass the key constituencies: industry, regulators, NIH, academia and patient advocates

    • A Federal fund to support development of natural history data for rare diseases, which could be managed under the auspices of NIH

    • A handbook on orphan product development that would be applicable to a broad audience: researchers / academics, patient advocates, industry and investors

      • This handbook would set forth key expectations/guidelines at the various stages of orphan product development

    • Establishment of a centralized clearinghouse of data on rare diseases, encompassing natural history, epidemiology, incidence / prevalence both in the US and globally


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Conclusions

  • Other solutions include:

    • Programs & resources to encourage young investigators to focus on orphan product development as a career path

    • An increased amount of education for academic researchers and clinical investigators on rare diseases

      • Education on the regulatory process/pathway for investigators

      • Education (esp. junior faculty and university technology transfer groups) on IP requirements that favor future commercial development


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