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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

Orphan Product Development

Focus Group Research - Final Report

May 2010

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

  • Introduction
  • Key Findings
    • Academic Medical Researchers
    • Patient Advocates
    • Investment Community
    • Pharma/Biotech Executives
  • Summary & Considerations
study background
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
research objectives
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
data collection
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
  • Introduction
  • Key Findings
    • Academic Medical Researchers
    • Patient Advocates
    • Investment Community
    • Pharma/Biotech Executives
  • Summary & Considerations
key findings academic medical researchers
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
key findings academic medical researchers8
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
key findings academic medical researchers9
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
key findings academic medical researchers10
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
key findings academic medical researchers11
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
key findings academic medical researchers12
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
key findings academic medical researchers13
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)
key findings academic medical researchers14
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
key findings academic medical researchers15
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
  • Introduction
  • Key Findings
    • Academic Medical Researchers
    • Patient Advocates
    • Investment Community
    • Pharma/Biotech Executives
  • Summary & Considerations
key findings patient advocates
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
key findings patient advocates18
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
key findings patient advocates19
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?
key findings patient advocates20
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
key findings patient advocates21
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
  • Introduction
  • Key Findings
    • Academic Medical Researchers
    • Patient Advocates
    • Investment Community
    • Pharma/Biotech Executives
  • Summary & Considerations
key findings investment community
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
key findings investment community24
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
key findings investment community25
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)
key findings investment community26
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
key findings investment community27
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
key findings investment community28
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
key findings investment community29
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
key findings investment community30
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
key findings investment community31
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
  • Introduction
  • Key Findings
    • Academic Medical Researchers
    • Patient Advocates
    • Investment Community
    • Pharma/Biotech Executives
  • Summary & Considerations
key findings pharma biotech execs
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
key findings pharma biotech execs34
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
key findings pharma biotech execs35
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
key findings pharma biotech execs36
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)
key findings pharma biotech execs37
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
key findings pharma biotech execs38
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
key findings pharma biotech execs39
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
key findings pharma biotech execs40
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
  • Introduction
  • Key Findings
    • Academic Medical Researchers
    • Patient Advocates
    • Investment Community
    • Pharma/Biotech Executives
  • Summary & Considerations
  • 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”
  • 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
  • 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
  • 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