connecting the dots for fast-track approval for rare disease and orphan drug

FOCUSED. TRUSTED. GLOBAL.

Experts. Experience. Execution.

Connecting the Dots for Fast-Track Approval for Rare Disease and Orphan Drugs

June 17, 2015


AgendaUnique Methods for Site Selection and Feasibility

Successful Recruitment/Retention Approaches

Overview of Common Study Execution Needs

Optimal Training and Monitoring Strategies


What is a Rare Disease?

Any disease that affects a small % of the population

Estimated 350 million people worldwide suffer from rare disease


Definitions vary across governments

o US: FDA defines a rare disease or condition as one affecting

< 200,000 people in the US (defined in the Orphan Drug Act (ODA) of 1983 and Rare Disease Act of 2002)

o Europe: A life-threatening or chronically debilitating disease with

such low prevalence that special combined efforts are needed to address them • 1 in 2,000 people

o Japan: Disease affecting <50,000 people in Japan

• 1 in 2,500


Countries with Rare Disease Legislation

European Union Singapore Russia

United States Japan Australia

o Anticipated introduction of orphan legislation: Canada

Turkey China


Rare Doesn’t Have To Mean Unheard Of

Clinical Examples of Rare Disease

o Amyotrophic lateral sclerosis (ALS)o Cystic fibrosiso Progeriao Hemophiliao Homozygous familial hypercholesterolemia


A Focus in Pediatrics

Trials are often designed to include both pediatric and

adult populations

50%

Children

33%Treatments with

orphan designation are

for children

35%Deaths in first year of life

are attributed to rare diseases

• 30% will not live past 5th birthday

• Pediatric patients now surviving longer into adulthood


Where to start with orphan drug development

o Obtain designation as orphan medicinal product or orphan drug Applications required in each region (i.e. FDA,

EMA, etc.)

o Define strategy for development pathwayo Partner with advocacy groups o Review available natural history data o Identify key opinion leaders and/or establish

scientific advisory committees


Type Fast Track Breakthrough Therapy Accelerated Approval Priority Review

Program Nature

Designation Designation Approval Pathway Designation

Qualifying Criteria

Intended to treat a serious condition AND nonclinical or clinical data that demonstrate potential to address unmet need OR designated as a QIDP

Intended to treat serious condition AND early data suggests substantial improvement on a clinically significant endpoint(s) over available therapies

Treats a serious condition AND provides meaningful advantage AND demonstrates an effect on a surrogate endpoint likely to predict earlier benefit OR can be measured earlier

An application that treats a serious condition AND would provide significant improvement OR proposes a pediatric labelling change [505A] OR QIDP OR submitted with a PR voucher

Timing ofRequest

With IND or after; NLT pre-BLA or pre-NDA meeting

With IND or after; NLT EOP2 meeting

Discuss with review division during development,

With original BLA, NDA, or efficacy supplement

FDA ResponseTimelines

Within 60 calendar days of receipt of the request

Within 60 calendar days of receipt of the request

Not specified Within 60 calendar days of receipt of original submission

Features Actions to expedite development and review; rolling review

All FT features, plus Intensive guidance on efficient drug development; organizational commitment; rolling review; other actions to expedite review

Approval based on an effect on a surrogate endpoint or an intermediate clinical endpoint that is reasonably likely to predict a drug’s clinical benefit

Shorter clock for review of marketing application (6 months compared with the 10-month standard review)

AdditionalConsiderations

Designation may be rescinded if it no longer meets qualifying criteria for fast track

Designation may be rescinded if it no longer meets qualifying criteria for breakthrough therapy

Promotional materials; confirmatory trials to verify and describe the anticipated effect on IMM or other clinical benefit; subject to expedited withdrawal

Designation will be assigned at the time of original BLA, NDA, or efficacy supplement filing

References Section 506(b) of the FD&C Act, as added by section 112 of the FDAMA and amended by section 901 of FDASIA

Section 506(a) of the FD&C Act, as added by section 902 of FDASIA

21 CFR part 314, subpart H21 CFR part 601, subpart ESection 506(c) of the FD&C Act, as amended by section 901 of FDASIA

Prescription Drug User Fee Act of 1992

After: Guidance for Industry: Expedited Programs for Serious Conditions – Drugs and Biologics (US FDA; May 2014); by [email protected]


Growth in Rare Disease Pipeline

o Market growing at twice the rate of general R&D

o Special opportunity to make a truly meaningful, innovative contribution to the treatment of conditions with unmet medical needs

o Incentives to develop these compounds Extended patent protection

(7 year exclusivity - US, 10 year - EU)• Development timelines accelerated

Tax credits on clinical research costs Annual grant funding Waiver in PDUFA filing fees Premium pricing


Site Selection and Feasibility

o Key differences from typical trials: Pre-identified investigators

• Network at scientific meetings or partner with a KOL to identify sites

Site Qualification Visits • Conducted to identify issues and

solve challenges rather than evaluate site’s ability to participate

Registries/Advocacy Networks Scientific Meetings and Literature


Regulatory Submissions

Preferential pathways are

possible

Skewed country to site ratio• Many

countries with relatively few sites

• Majority local EC/IRB sites

• Multiple review committees due to patient age or novel therapy

Patients may request to travel to

existing site locations

across country borders


Country Transfer Considerations

Completed and approved pre-screening worksheet

Travel logistics ICF in referring language

CDA Medical record release

Patient items translated

CA/IRB/EC IP transport (temperature and customs considerations)

Translator on site

Consent from host site Financial costs overall IP label translation

Transfer patient expectations

Insurance requirements

Validated questionnaires/ PROs


Case study of US KOLPower of Motivated Investigator

Site w/ KOL

Site Average

0 20 40 60 80 100 120

Days to Start Up

Days to Start Up

• Pediatric orphan indication • Local IRB started up in 28 days • Investigator ensured staff finalized submission documentation

quickly• Investigator hand delivered contracts to signatory to accelerate

contracting• Used previously agreed upon key elements of contract and consent

language to improve turnaround timelines


Social Media

Recruitment

o Social media should be closely monitored Potential for unblinding Misinformation Boost awareness of trial

positively impacts recruitment Support Learning – important insights

can be gained


Recruitment

o Advocacy group interactions Participate in advocacy

events Regularly update

community Post information about

your trial

o Registry partnershipso Develop referral network

of investigators


Patient Recruitment and Retention

o Create a positive patient experienceo Minimize patient burden

Recommend a sequence of study procedures Tailor assessments to minimize patient discomfort Strategically plan a positive patient experience and

reduce patient and caretaker disruption


Patient Retention

o PI and CRC involvement and encouragement is critical Discuss study expectations and all

possible outcomes during the screening process

Engage subjects• Reminder calls of what to expect

o “Trial Fatigue” or “Clinical Trial Burnout” With limited patient populations in

rare disease, each data point is precious

Possible apathy or aversion to trials • Intensified by a negative experience


Common Study Execution Needs

Increased collaboration

between CRO and Sponsor

Frequently required vendors• Travel Centers • Patient costs, on-

site translators• Call center• Home healthcare

nurses• On demand

training services


Common Study Execution Needs

o Supply management of site equipment o Tailored training plan

PIs are indication experts, but may be industry sponsored research naïve

Novel endpoints

o Panel discussions with site staff to share study tips and discuss challenges


Monitoring Considerations

o Bolus recruitment is commonplace Dry runs may be necessary based on complexity of

protocol Increased monitoring visit frequency

o Complex medical histories with high volume of medical records

o Close oversight of investigational product accountability


Monitoring Considerations

Create a strong site support plan • CRC support tools/funding• Site specific recruitment plan based on database review • Individualized CRA-CRC interaction plan

• Maintain interest, discuss recruitment efforts, keep the relationship positive


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connecting the dots for fast-track approval for rare disease and orphan drug

Health & Medicine

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debilitating disease

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