Disclaimer: Presentation slides from the Rare Disease Workshop - - PowerPoint PPT Presentation

Disclaimer:

Presentation slides from the Rare Disease Workshop Series are posted by the EveryLife Foundation for Rare Diseases for educational purposes only. They are for use by drug development professionals and statisticians, and are not to be used to guide the prescribing or use of any of the drugs mentioned in the slides. To obtain information on a particular drug, refer to the drug labeling. Do not reproduce or distribute the slides (full set or any portion of) without the permission of the author.

Rare Disease Workshop 4: Developing Guidance and Policy Recommendation for Accelerated Approval in Rare Diseases

November 15, 2012 Larry Bell, M.D. Regulatory, Prosensa

 Orphan Drug Act

• Signed into law in 1983
• As of September 2010 360 approved products
• Approx. 1/3 of NME approvals are Orphan Products
• Much more needs to be done

 More than 6,000 rare diseases affecting more than 25 million Americans,  Approx. 200 of these have approved therapies

 Office of Rare Diseases established in 2010

 History of Retroviral approvals

• Demonstrates a successful record for use of accelerated

approvals and FDA, Sponsor flexibility

• AIDS crisis ushered in ‘trial and error’ process of

approvals followed by ‘rule making’

 Regulations codified in 1992

• Largely in response to AIDS epidemic

 Since inception of program, of the more than 80

products made available, approx. 40% (32) were to treat HIV

 HIV drug approval history has at least two

distinctive phases

• 1987-1996 (Endpoint studies required for full approval)
• 1997-present (HIV-RNA considered validated endpoint)

 CD4 and viral load, while not perfect, were most

promising markers among others (e.g. B2-

microglobulin, cytokines, HIV p24 core antigen)

 No single marker fully explains varying clinical

effects with therapeutic interventions

• Use of available markers at the time allowed for

earlier access to Rx therapy

CD-4 lymphocyte level in blood is associated with severity

• f AIDS so change in CD-4 concentration considered as

an indicator of disease status

• Clinical trials found: slower decline in CD-4 count but no

effect on death rate; early rise in CD-4 count but no long- term benefit

• CD-4 count positive in several trials in which clinical
• utcomes positive, and also in several trials where clinical
• utcomes were not effected
• CD-4 counts, while not perfect

 Allowed earlier access to patients  Allowed opportunity to investigate combination therapy and define HART protocol, and evolve knowledge of disease process

 Clinical Endpoint studies became increasingly

difficult to conduct

• Real-time viral load monitoring
• With HART, Physicians and Patients unwilling to stay
• n randomized treatment after viral rebound

 FDA, NIH, Sponsors worked collaboratively

• 1996 Surrogate Marker Working Group
• Analyzed large dataset

 Correlations between viral load and clinical outcome, and viral load suppression and durability of response

 1997 Antiviral Advisory Committee conclusions

• HIV RNA is a suitable endpoint for:

 Accelerated Approval (24 weeks) and  Regular Approval (48 weeks)

• General concordance with other markers, (e.g. CD4)

 Accelerated Approval process worked well for

antiretrovirals

• All drugs eventually received regular approval
• Viral load is a good surrogate that correlates with

disease progression across the spectrum of drugs

• Early and late viral load changes are highly correlated

 Reasonable Biological model with viable

surrogate markers

 Strong collaborative effort  Flexibility on use of available regulations and

guidance to meet an unmet medical need

 Accelerated approval pathway provided for earlier

treatment options for patients

• Use of available, evolving and best available surrogate

markers allowed for knowledge and data to evolve

• ‘Trial and Error’ type approach worked well

 Large extensive database

• Useful but not always available in all rare diseases
• Need new methodology for linking information from

short-term studies

 Particularly when clinical endpoint studies are not feasible

 Capitalize on the successes achieved

• Work collaboratively on Accelerated Guidance for

Rare Disease Drugs

• Advance Regulatory Science, Policies and Decision

Making to expedite drug development

 Better methods for design, conduct and analysis for small trials, and meta-analysis  More guidance on emerging science for biomarkers and pharmacogenomics

 Work collaboratively to develop a better

benefit/risk qualitative framework

• Incorporate Analysis of Condition and Unmet

Medical need information

• Incorporate this information into entire

development process

 Incorporate patient perspective and patient-

focused information into drug development

• Obtain patient (family as appropriate) perspective
• n disease severity or unmet medical need
• More use when appropriate of PROs

 For diseases which are (ultra) rare, serious

and/or life-threatening and where there are no alternative options:

• There is an urgency to make new

medicines available which may require unconventional approaches to development

• Global development harmonization is key

 Increasingly rare patient populations with

different exons skipped

 Highly variable standards of care further

impact ability to recruit patients into trials

• Not possible to power study in traditional ways
• Need for creative study design
• Need to develop novel biomarker and/or surrogate

markers

• Create risk/benefit framework in context of limited

number of patients

 Once relationship has been established for

surrogate marker (e.g. dystrophin) and clinical

• utcome
• surrogate should be acceptable as primary outcome,

placebo should not need to be re-established

 Groups of exon ‘skippable’ patient populations

• overlap enables learning's from one program to another

 Oligonucleotides have same chemical backbone

with predictable pharmacology

• enabling learnings across preclinical studies

Concept of extrapolated efficacy Within indication

Compound A

Demonstrated safety and efficacy (dystrophin; 6 mwt, 2nd functional

• utcomes)

AMBULANTS Compound A

Demonstrated safety and efficacy (dystrophin, 2nd motor skill functions)

NON-AMBULANTS

Demonstrated safety and efficacy Comparable efficacy or better Extrapolated safety and efficacy

14

Compound B

Demonstrated safety and efficacy (dystrophin; trend 6mwt)

AMBULANTS Compound A

Demonstrated safety and efficacy (dystrophin, 2nd motor skill functions)

UNDER 5’S Compound B

safety and extrapolated efficacy

UNDER 5’S Compound B

safety and extrapolated efficacy

NON-AMBULANTS