The Need for, and Application of, Natural History Data in Orphan Disease Medical Product Development

Transcription

1 The Need for, and Application of, Natural History Data in Orphan Disease Medical Product Development Haley J Kaplowitz, PhD Executive Director, Safety, Epidemiology, Registries & Risk Management United BioSource Corporation 1

2 Rare or Orphan Disease Any disease that affects a small percentage of the population Most rare diseases are genetic and present throughout a person's entire life The impact on the patient, family and caregivers can be particularly burdensome Individually rare, collectively common 6,000 to 7,000 rare diseases ~30 million (US), ~30 million (EU), ~350 million people affected globally 2

3 Orphan Drug Designation An orphan drug is a pharmaceutical agent that has been developed specifically to treat an orphan disease In the last 30+ years efforts have been made to encourage companies to develop orphan drugs The Orphan Drug Act in the USA (1983); Japan (1985), Australia (1997), and the EU (2000) ACA, FDASIA 3

4 Incentives for Orphan Drug Development Tax credits Research aid/grants Extended market exclusivity Waiver of user fees Shorter approval times Simplification of marketing authorization procedures, e.g.: Smaller trials Alternative designs to RCTs 4

5 Incentives for Orphan Drug Development 1.89 times ROI vs. non-orphans Global sales of orphan drugs may reach $176 billion by 2020 Orphan drug sales in the US, Europe or Japan will grow at nearly 11% per year through 2020, compared to only about 4% for drugs treating larger populations - EvaluatePharma 2014 By 2012, the orphan drug market was worth USD$637 million vs. USD$638 million for a matched control group of nonorpha drugs. - Thomson Reuters 2012 The re e ue-generating potential of orphan drugs [was] as great as for non-orphan drugs, even though patient populations for rare diseases are significantly smaller. " - Gaze and Breen 5

6 Orphan Drug Application (US/EU) Requirements: Prevalence below the statutory threshold Potential for lack of return on investment/no reasonable expectation of cost recovery Rationale for the use of the medicinal product for the rare disease or condition in question. Medical plausibility, if used only in sub-populations 6

7 Regulatory Definitions of Rare Country Prevalence* United States <200,000 European Union <5 in 10,000 Japan <50,000 Australia <2,000 * Number of people currently living with the disease 7

8 Increasing Investment in Orphan Drug Development 8

9 Opportunities, Yes! But Also Some Unique Challenges Difficulties in disease diagnosis Limited knowledge base (e.g. patient journey, disease epidemiology, regulatory pathway) Need to educate investigators, regulators 9

10 Opportunities, Yes! But Also Some Unique Challenges Clinical trial design and operations Limited number of experts/thought leaders Need for alternative designs to the traditional RCT Sensitive outcome measures to quantify disease Finding and recruiting patients from a small pool Identifying viable clinical sites, qualified investigators Greater e phasis o patie t role patie t- e tri Greater impact of language, cultural variability Impact of eligibility criteria on trial feasibility/success Care coordination across specialties 10

11 Disease Natural History The atural ourse of a disease fro the ti e i ediatel prior to its inception, progressing through its presymptomatic phase and different clinical stages to the point where it has ended and the patient is either cured, chronically disabled or dead without e ter al i ter e tio -Posada de la Paz M; Groft SC Rare diseases epidemiology. Vol. 686 Treated natural history: includes data on how the disease is treated if treatment is available. 11

12 Disease Natural History Data is Critical to successful product development & marketing, especially in rare disease Establish/Quantify unmet medical need Understand diagnosis challenges Understand patient geographic distribution Understand clinical characteristics, genotypes, phenotypes, heterogeneity Understand burden of disease Identify treating HCPs Provide data for required regulatory/payer documents (e.g. ODA) 12

13 Disease Natural History Data is Critical to successful product development & marketing, especially in rare disease Prepare for clinical trials (e.g. registering patients; patie t/other stakeholder oi e Inform drug development: regulatory pathway, clinical trial design (e.g. outcomes versus endpoints, disease stage and progression) Comparison data to assist interpretation of clinical trial results as well as real-world experience post-approval Meet regulatory requirements (e.g. safety, risk management) Demonstrate commitment to patients/disease space 13

14 Disease Epidemiology/Natural History Frequency of disease (incidence, prevalence) Track course of disease over time Identification of genotypic and phenotypic subpopulations Development and/or validation of clinical outcome measures, biomarkers and/or companion diagnostics Identify demographic, genetic, phenotypic, environmental & other characteristics that correlate with disease & outcomes Disease stage Disease progression and rates Outcomes (clinical, HRQoL/PROs, HCU) Treat e t path a s, utilizatio i the a se e of the investigational product 14

15 Methodological Approaches to Disease Epidemiology/Natural History Data Published research Healthcare database studies Retrospective chart review May not be viable/adequate in rare disease Original epidemiology (observational) studies (cross-sectional, prospective/longitudinal) 15

16 Strategic Approaches to Disease Epidemiology/Natural History Data Original epi (observational) studies/registries Concurrent with clinical trials Post-approval Prior to clinical trials (late phase) Inform clinical trial design/avoid costly mistakes, assumptions May not be viable/adequate in rare disease Provide historical information/historical controls (maybe even patient as own control) Engage stakeholders early Prospective/longitudinal NH studies are typically the most valuable design for depth and strength of knowledge to apply to clinical trial issues 16

17 Rare Diseases: Common Issues in Drug Development Guidance for Industry August 2015 FDA advises sponsors to evaluate the depth and quality of existing natural history knowledge early in drug development, when knowledge about the disease is insufficient to guide clinical development In-depth understanding of the disease helps sponsors avoid mistakes that may be costly in time and resources. Efficient study of the small number of affected patients may be guided better by greater understanding of the disease. 17

18 Rare Diseases: Common Issues in Drug Development Guidance for Industry K o ledge a out the disease s atural histor a i for important aspects of drug development including: Defining the disease population, including a description of the full range of disease manifestations and identification of important disease subtypes Understanding and implementation of critical elements in clinical study design, such as study duration and choice of subpopulations Developing and selecting outcome measures that are more specific or sensitive to changes in the manifestations of the disease or more quickly demonstrate safety or efficacy than existing measures. Developing new or optimized biomarkers that may provide proof-ofconcept (POC) information, guide dose selection, allow early recognition of safety concerns, or provide supportive evidence of efficacy. In some cases, biomarkers can be used for surrogate endpoints. 18

19 In Summary Disease natural history data are critical to rare disease medical product development where information may be severely limited** Required/encouraged by regulators (e.g. ODAs, CT design and interpretation) May help avoid costly mistakes during clinical development by informing clinical trial design Can help with interpretation of CTs (e.g. underpowered, uncontrolled) Can help with interpretation of real-world experience postapproval (e.g. safety) ** These points also apply to more common diseases where knowledge is limited (e.g. BPH, Alzhei er s 19

20 Natural History Data Informs More Than Clinical Development Application of data across the company serves multiple purposes and increases the ROI: Clinical Development/Operations Discovery Research Safety/Pharmacovigilance/Risk Management Regulatory Medical Affairs Marketing/Market Research 20