connecting the dots for rare disease studies

FOCUSED. TRUSTED. GLOBAL.

Discovery Series: Connecting the

Dots for Accelerated Rare Disease

Studies

Pirouz Shamszad, MD

Alexander Artyomenko MD, PhD

Derenda Nichols


Introduction to Rare Disease

Pirouz Shamszad, MD


Pirouz Shamszad, MD, FAAP

o Board-certified in cardiology and pediatrics

o Clinical expertise treating children with rare cardiac

disease and research experience utilizing registries

and databases to better describe the epidemiology,

safety, and outcomes of patients with rare disease


Overview

o Introduction to Rare Disease

Definitions and Epidemiology

o Regulatory basics

FDA and Pathways

o Clinical Trials in Rare Disease

Challenges and considerations to trial design

Ethical considerations

Pediatric considerations


A Field of Zebras

“When you hear hoof beats, think horses, not zebras.”


Definition

What is Rare Disease?

o There is no single, widely-accepted

definition for rare disease

o Current definitions are prevalence-based

and vary by geography and local

governing regulatory bodies


Countries with Rare Disease Legislation

United States

Japan

Australia

European Union

Singapore

Russia

o Anticipated introduction of orphan legislation:

Canada

Turkey

China


Definition - USA


o In the US, rare disease status is defined by

designations set forth in the Orphan Drug Act

(ODA) of 1983 and Rare Disease Act of 2002

o Defined as any disease:

Affecting < 200,000 people in the US

• ~1 in 1,500 people

Affecting >200,000 in the US and no expectation that

drug development costs for such disease will be

recovered from sales in the US of such drug


Europe and Japan


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


Not quite the same

Orphan Diseases

o Rare Diseases are sometimes referred to as

Orphan Diseases

o Not necessarily the same

Orphan diseases can encompass other diseases that:

• Are “neglected” with regards to treatment options or

availability of treatment

• More common in developing countries



Clinical Examples and Epidemiology of

Rare Disease


Rare Doesn’t Have To Mean Unheard Of

Clinical Examples of Rare Disease

o Amyotrophic lateral sclerosis (ALS)

o Cystic fibrosis

o Progeria

o Hemophilia

o Homozygous familial hypercholesterolemia


Clinical Examples of Rare Disease

o Metachromatic leukodystrophy

o Fibrodysplasia ossificans progressiva (Stoneman)

o Glomuvenous malformations plaque type

Rare Can Be Quite Rare


Rare Disease – The Numbers

Once diagnosed with a rare

disease, it’s not so “rare”

anymore


Rare Disease – The NumbersNot as Rare As One May Think


A Special Focus

Children with Rare Disease

o 50% affected by Rare Diseases are children

Responsible for 35% of deaths in first year

30% will not live past 5 years of age

o 33% of treatments with orphan designation

are developed for children


Regulatory Basics


An Important Effort

Treating Rare Disease

o Continual need for therapies among Rare

Diseases

Opportunity to make meaningful, innovative

contributions

Must balance against financial concerns

o Market for Rare Disease compounds is growing

at twice the rate of the balance of R&D

Driven by development incentives


Orphan Drug Designation

Treating Rare Disease

o FDA Office of Orphan Products Development (OOPD) established in 1983 via ODA

o Orphan Drug Designation program provides orphan status and associated incentives

o Mission: Advance the evaluation and development of

products that demonstrate promise for the diagnosis and/or treatment of rare diseases or conditions

Provides incentives for sponsors to develop products for rare diseases


Essential Concepts

Expedited Pathways

o Serious Condition

Morbidity impacting day-to-day functioning

Typically progressive

o Available Therapy

FDA approved/licensed product for same

indication or relevant to current SOC

o Unmet Medical Need

Treatment not addressed by available therapy


Designed for Serious Conditions

Expedited Development Pathways

1. Fast Track

2. Breakthrough Therapy

3. Accelerated Approval

4. Priority Review


Accelerate Development for Serious Disease


o Fast Track:

Preclinical/clinical data demonstrate potential to fill

unmet medical need

Rolling review

o Breakthrough Therapy:

Preliminary clinical data demonstrate improvement

over available therapy

Fast Track provisions plus intensive guidance


Accelerate Development for Serious Disease


o Priority Review: Application providing significant advancement OR

proposes a pediatric labelling change

FDA makes this designation at time of application

Application is reviewed in ~6 months vs. ~10 months

o Accelerated Approval: Provides meaningful therapeutic advantage AND

demonstrates effect on a surrogate endpoint predicting earlier benefit

Eligibility assessed early in development by FDA

Requires post-market study to verify and describe clinical benefit or effect on irreversible morbidity or mortality


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 of

Request

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 Response

Timelines

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)

Additional

Considerations

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 H

21 CFR part 601, subpart E

Section 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]


Successes

OOPD Orphan Drug Designation

o Since 1983: Successfully enabled the development and marketing of

more than 3,000 products, including 460 drugs, and 500 clinical trials resulting in 50 approvals

• <10 products supported by industry betwen1973 – 1983

o In 2013 alone: Approved 33 orphan drugs

Approved 27 new molecular entities:

• 9 were for orphan products and approved after 1 review

• 2 used the breakthrough therapy pathway

• 5 used fast track pathway

• 4 used the priority approval pathway


Clinical Trial Design in Rare Disease


The Basics Are The Same

Clinical Trial Design

o Clinical trials in Rare Disease have similar

requirements to those of general clinical trials:

Study design (sample size, endpoints)

Regulatory submissions

Site selection

Patient recruitment

Data collection/measurements

Allotted funds and study personnel


The Execution is Challenging

Clinical Trial Design in Rare Disease

Despite similar requirements to general clinical

trials, clinical trials in rare disease are complicated

by small sample size


Challenges – Small Sample Size

Clinical Trials in Rare Disease

o Patient populations will be limited in Rare

Disease clinical trials

Variable disease sub-types

Varying presentation and progression

High inter-subject variability (heterogeneity)

o Limited number of sites and investigators

Consolidated to large academic centers


Considerations – Mitigating Small Sample Size


o Utilize alternative trial designs and statistical techniques

that maximize data from a small, heterogeneous group

Examples: Crossover, n-of-1, Adaptive, Historical control

FDA has greater risk tolerance with existing precedent for

approval of orphan dugs based on NON-randomized,

placebo-controlled, or double blind trials

o Capitalize on resources:

OOPD Small Clinical Trials course

Direct pre-IND guidance from FDA about design and

outcomes

Protocol working groups (disease-specific working groups)


Considerations – Mitigating Sample Size (cont.)


o Possible “all-inclusive” strategies

Companion or extension protocols

Expanded access programs

• For excluded patients that may benefit from use

o Enrichment strategies (using genetic subtyping)

May make results less generalizable


Challenges – Lack of Outcome Assessment


o Natural history and clinical features of Rare

Disease are not always understood

o Challenge in determining outcome assessment

Endpoints and biomarkers difficult to identify

o Duration of trial difficult to determine

Especially true for chronic disease that cross from

childhood to adulthood


Considerations– Mitigating Lack of Assessment


o Current push to better understand natural histories and clinical features of these disease

o Expand foundational science (pre-clinical) Aid in identifying biomarker profiles and describing natural

history of disease

o Endpoint identification Capture patient recorded outcomes utilizing patient

advocacy/support groups

Adapt Phase 2a designs to test endpoints

Development of global patient registries


Challenges – Ethics


o Higher risk tolerance due to these life-

threatening illnesses or lack of current therapies

Both from patients and FDA

o Limited patient population contributes to

significant “trial fatigue”

Burden on patients looking for treatment options

Burden on study teams working for each data point


Challenges – Ethics of Controls


o Controls strengthen trial design by addressing

variability

o In the setting of life-threatening or shortening

disease, the ethics of a control arms are

heightened

Patients or parents of patients may be reluctant to

receive control or there may be no

Greater urgency to receive active treatment, before

therapeutic window is lost


Considerations– Ethics


o For any given product, the following must be weighed: Desired clinical benefit

Risk to benefit probability

Amount of tolerable uncertainty

o In situations where no preclinical or clinical data is available, “… it is important for FDA and sponsors to partner early in the product development process and reach agreement on potential paths forward” (FDA, 2014)


Considerations– Ethics


o Incorporation of an open-label extension and

use of rescue medications can be used to help

justify placebo-controlled designs

Add-on to standard of care therapies

o Stabilization may be seen as a reasonable

benefit

Risks for harms may be acceptable given the

potential for slowed progression of the disease versus

absolute cure


Challenges – Research Involving Children


o 50% of rare diseases affect children usually due to genetic etiology of most rare diseases Children represent a small percentage of the overall general

population, adding to recruiting difficulty

o Evolving approach to pediatric research from a “vulnerable” population in the 1970’s to our “moral imperative” in the 2010’s

o Children are not little adults If adult data exist, may not apply to children

o Pediatric institutions generally have less developed research infrastructure than adult counterparts


Considerations – Research Involving Children


o Support the family decision to include (or exclude) their child in a clinical trial Acknowledge the disruption to daily life

Facilitate travel/lost work

o Address safety and benefits of a trial vs. standard of care or no therapy Full disclosure/transparency; Assent

o Provide patient support systems /team relationships geared to the child


Success Lies In A Team Approach

Clinical Trial Execution in Rare Disease

Medpace Rare Disease Team

A team of dedicated individuals across all functional

areas contributing to a collective experience

Disease/trial specific insights and lessons learned from

past trials to foster creative strategies

Internal/External Rare Disease Training Programs

Strong partnership and collaboration with Sponsor,

Investigators, and Patient Groups


Resources

o FDA OOPD

o NIH Office of Rare Diseases

o National Organization of Rare Diseases (NORD)

o European Organization for Rare Diseases

(EURODIS)

http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/OfficeofScienceandHealthCoordination/ucm2018190.htm

http://rarediseases.info.nih.gov/

https://www.rarediseases.org/

http://www.eurordis.org/



Real-World Evidence

in Rare Diseases

Alexander Artyomenko MD, PhD

Webinar Spotlight:


Alexander Artyomenko, MD, PhD

o Cardiologist with > 13 years of experience in Late

Phase clinical research

o Unique background encompassing medicine, clinical

trials and project management, with a highly

successful track record in developing strategies and

executing global phase IIIb-IV and observational

studies


Alone we are rare…together we are strong!


o “Data used for

decision-making that

are not collected in

conventional RCTs…”

o i.e., collected in an

observational, non-

controlled, non-

experimental setting

What is Real-World Evidence?

Garrison,L.P.,et al,(2007).Using RWD for coverage and payment decisions: the ISPOR RWD task force report. InternationalSociety for Pharmacoeconomics and Outcomes Research(ISPOR), Value in Health,Vol10,No5.


Real-World Evidence

Outcomes research

Resource use and

treatment options analysis

Patient experience, compliance

and preferences

evaluation

Effectiveness and benefits review across

treatment options


Why we need RWE in rare diseases?

o Address research questions

Natural history of the disease/condition

Influence of lifestyle, environment, genetics

RCTs may not always be feasible for very

rare diseases

o Support the market access and pricing

strategy

Healthcare resources and product utilization

o Further research on safety and

comparative effectiveness of the

product

Support treatment decisions


Aligning the Stakeholder Needs

Pharma

• Address data gaps

• Feedback from payers and patients

Providers

• Maximum treatment safety and effectiveness

• Reduced treatment costs

Payers

• Evidence of positive clinical, humanistic and economic outcomes

Patients

• Minimal side effects

• Cure the disease

• Improve quality of life

• Affordable care


Patient-Reported Outcomes in Rare Diseases

o Out of 69 orphan medicines approved by

EMA as of Nov 2013, 20.3% had a PRO claim

o Various PRO concepts were assessed (i.e.,

symptoms, function, and QOL), with QOL

representing almost 30% of the PRO claims

Patient-reported outcome (PRO) claims in products indicated for the treatment of rare diseases and approved by the European Medicines Agency (EMA). Laure-Lou Perrier, Catherine Acquadro, Benoit Arnould, ISPOR May 2014


Health Economics in Rare Diseases

o The National Institutes of Health reports that about 6,000 rare diseases affect approximately 30 million Americans each year

o Even at a modest annual estimate of $15,000 per person for biologics targeting rare diseases, the annual bill for rare diseases would amount to $450 billion, nearly half of the global pharmaceutical market of $990 billion in 2012

http://rarediseases.info.nih.gov/files/Rare_Diseases_FAQs.pdf

IMS Health, IMAP


Recent EU changes in evidence requirements for the

reimbursement of orphan drugs

Country Major changes

United Kingdom • New responsibility for assessment of ultra orphan drugs for NICE (1st of April 2013)

• New appraisal mechanism developed by NICE for ultra orphan drugs (1st of April 2013)

• Value-based pricing system (1st of January 2014)

France • Economic evaluation in national reimbursement assessment (Autumn 2013)

• Early dialogue pilot system

Germany • AMNOG (1st of January 2011)• Responsibility for assessment of orphan drugs passed from IQWIG

to the G-BA – No clinical added benefit assessment• Threshold reduction for annual budget from 50 million to 30 million

Euro

Belgium • Discussion about appropriate study designs for orphan drug assessment

• Orphan drugs will be subject to contract negotiations• Discussion guided by ethical arguments

Austria • Transparency directive changes• Current Austrian health reform

An European overview of the future changes in evidence requirements for the reimbursement of orphan drugs

A stakeholder analysis. Lisa J. Krüger, Johannes J Tamminga, Ben F.M. Wijnen, Mickael Hiligsmann, Silvia M.A.A. Evers, accessed via http://www.ispor.org/research_pdfs/46/pdffiles/PSY72.pdf

http://www.ispor.org/research_pdfs/46/pdffiles/PSY72.pdf


The Varied Sources of RWE

•Routinely Collected Primary and Secondary Care Datasets

•Retrospective Chart Review Datasets

•Medical Claims Datasets

•Electronic Medical Records

Retrospectively collected data

•Prospective chart review datasets

•Large pragmatic trials

•Patient and population surveys

•Registries

Prospectively collected data


Retrospectively Collected Data


o Routinely Collected Primary and Secondary

Care Datasets

Explore evidence of safety, effectiveness and health

outcomes improvement and support clinical

innovation efforts

No international standard approach to coding and

classification

Examples:

• US: Veterans Health Administration database

• UK: Clinical Practice Research Datalink


Retrospectively collected data


o Retrospective Chart Review

Information not originally

collected for research purposes

Well-defined research questions, inclusion/exclusion criteria, CRF

and data collection procedure

Training and monitoring for data

abstractors

Should address inter-rater and

intra-rater reliability, confidentiality and ethical

considerations




o Medical Claims Datasets

Initially created for financial administrative purposes

Patient-level information on diagnosis, treatment

types, providers and costs

Standardly coded

Examples

• PharMetrics®

• Medicaid

• Truven Health MarketScan




o Electronic Medical Records

More comprehensive clinical data

Includes info on non-prescription drugs

Additional healthcare info (labs, risk

factors, nurses etc.)

Not limited to insured only population

Not widely adopted


US

PharMetrics

LabRx

MarketScan

WellPoint

Medicare

HRTX/DoD

AustraliaGPRN

TaiwanNational Health

Insurance Research

Database

ItalyHealthSearch

Pedianet

France

In Fine PHARMA

EGB / SNIIR-AM

Canada

RAM-Q

SWO

Saskatchewan

Europe

IMS Disease Analyser (AT, DE, FR, UK)

PharmAccess (FR, GE, IT, UK) Denmark

ODS

OPED

PDNJ

Sweden

Swedish

registriesFinland

Finnish

registries

UK

GPRD

THIN

MEMO

Netherlands

Pharmo

ICPI

• Electronic Health Records

• Pharmacy Databases

• Medical Claims Databases

• National Registries


Prospectively Collected Data


o Prospective Chart Review Datasets

Robust site feasibility is essential

Protocol, CRF and training required

o Large Pragmatic Trials

Interventional trials

Relaxed eligibility criteria

Closest to the standard of care


Natural History Studies

o The natural course of the disease from the time

immediately 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 external intervention

Posada de la Paz M, Groft SC. 2010. Rare diseases epidemiology. Vol. 686


NH Study Types

o Retrospective chart review

o Prospective cross-sectional

o Prospective longitudinal


NH Study Goals

o Define the disease

o Identify knowledge gaps

o Understand patients needs

o Improve diagnosis

o Identify potential biomarkers and outcome

measures

o Develop centres of expertise

o Raise disease awareness


Patient and Population Surveys

o Primarily used for epidemiological information

o Should be well designed, structured standardized and validated Satisfaction and experience type surveys

o May have questionable validity and generalizability of the results Population sampling

Voluntary response bias

Convenience sampling

Length and structure

Are patient surveys valuable as a service improvement tool in health services? An overview. A. Patwardhan, C. Spencer, Journal of Healthcare Leadership, May 2012.


One of the most widely used data sources

Registry

o …a patient registry is an organized system that

uses observational study methods to collect

uniform data (clinical and other) to evaluate

specified outcomes for a population defined by

a particular disease, condition, or exposure,

and that serves one or more predetermined

scientific, clinical, or policy purposes.

Gliklich RE, Dreyer NA, eds. Registries for Evaluating Patient Outcomes: A User’s Guide. 2nd ed.Agency for Healthcare Research and Quality. September 2010.


Types of Registries

o Disease/condition

registry

Research the natural

history of the disease

Study treatment

patterns

o Product registry

Follow up long terms

outcomes for patients

using a new therapy

Pregnancy registries


A total of 641 registries*

Geographical coverage of rare disease

registries

Orphanet database, January 2014 report

European,

6.2%

Global,

11.5%

National,

69.6%

Regional,

12.0%

Undefined,

0.6%


Addressing Scientific and Commercial Objectives

Registries

o To understand clinical practice, identify unmet clinical need, disease natural history and treatment.

o To evaluate the effectiveness of treatments, meet post-marketing commitments in terms of quantification and characterization of safety endpoints

o To generate supportive data for new indications, product position, label extension and reimbursement

o To demonstrate the economic value, quality of life benefits of a particular treatment/product

o To develop positive relationships with clinicians / patients and develop product advocacy

o To obtain relevant information on prescribing (i.e. physician behaviour and patterns)


Registries

Main Strengths

• Flexible design and lower cost

• Information on normal clinical

care

• Information on long term

outcomes

• Good for hypothesis generation

• High external validity when

appropriately designed

• Feasible for broader range of

practice environments

Main Weaknesses

• Confounding and other forms of bias

are common features

• Recruitment challenges due to larger

sample sizes

• Weaker causal inference as regards

effectiveness and safety assessments

• Physician motivation and patient

retention can be challenging

• Possibility of variable data quality

• Absence of threshold for defining good

practice standard


The Future: RWE stakeholders meet Big Data

o Increasing volume of patient-level information and our ability to analyze it EMRs, claims data

Patient communities, social media

Individual sensors and wearables

Medication compliance, behaviours, functional parameters (respiratory, cardiovascular, metabolic etc.)



Executing Rare Disease Studies

Derenda Nichols


Derenda Nichols

o > 24 years experience in the CRO industry with 13

years in post marketing and peri-approval research

o Successfully participated in planning and execution of

large, multi-country projects in a variety of

therapeutics areas


(A few) Operational Considerations

o Multiple stakeholders with differing interests

o Limited numbers of patients

o Scant knowledge about the pathophysiology or

natural history of the disease

o Few investigators who typically are experts in

their field, but may be naïve in conducting

industry sponsored research

o Pediatric population may need to be followed

to and beyond age of consent

o Little data to support study design decisions


Aligning Stakeholder Understanding

o Identify all stakeholders

o Delineate objective(s) and scope at the earliest

planning stages

o Consider national / regional interests

o Define operational roles / responsibilities

o Communicate frequently and transparently

o Make no assumptions


Registry

•“Real world”

•Observational

•Hypothesis generating

•Large “N”

•Flexible

•GCP “light”/GRACE

•Relatively long duration

Clinical Trial

•Randomized

•Selective entry

•Hypothesis driven

•Small “N”

•Powered

•GCP required

•Typically short duration

Registry ≠ Clinical Trial


Differences Between Registries and RCTs

Activity Registries RCT

Sites May include research naive sites Experienced sites

Site visits Variable Yes

Site honoraria Variable Substantial

Case report forms Usually simpler, shorter Complex, extensive

Protocol Simple, straightforward Comprehensive

Duration Long term Short term

Sample sizeVariable

Relatively small based on

disease under study

Investigator agreement Simple Complex

Investigator motivation

Scientific or clinical practice

valueScientific value

Patient motivation

Scientific or clinical practice

valueScientific value

Patient consent Usually Yes

Data quality control Variable Comprehensive

Outcomes Final Intermediate

Statistical analysis Usually descriptive Hypothesis testing

Design Observational Structured


Why include Registries In Rare Disease Drug

Development?

o Increases the likelihood for developing a treatment

for the disease in question

o Establishes a standard of care

o Improves patient outcomes and life expectancy

o Provide insights to potential clinical endpoints and

variability in clinical progression among subsets of

patients

Orphanet. Report on Rare Disease Research, Its Determinants In Europe and The Way Forward, May 2011

ll


Getting It Right The First Time . . .

o Registry studies need careful planning Expensive to conduct

Often long in duration (5, 10, 15+ years)

Regional regulatory requirements can differ substantially (e.g. data protection laws, EC submission process)

Clinical development may drives natural history registry timelines

Marketing approvals / insurance reimbursement drive timelines for product registries

Sites are managed remotely

Need to balance simplicity with adequate data capture/integrity

Sites/patients need to stay interested and motivated

o Poor planning in year 0 can haunt you in year 5, 10…


Registries - “Monitoring” from a Distance

o Risk-based, centralized monitoring is the norm

o Routine field monitoring is not typical for

registries

o Site performance can be evaluated using a

standardised checklist reviewed in regular calls

with sites

o Pre-defined triggers for escalated on-site

monitoring


Triggers for Registry On-site Monitoring

o Triggers that may justify on-site monitoring: Failure of the site to obtain appropriate Patient

Informed Consent

Suspected data integrity issues

Sites enrolling greater than a pre-determined number of patients

Excessive staff turnover

Unresolved/excessive outstanding data queries

Lack of understanding and/or non-compliance of study procedures by site staff

Non-compliance with safety reporting procedures (e.g. delayed or incomplete SAE/AEI reporting)


Lessons Learned



Common Study Execution Needs

o Increased collaboration between Sponsor and

selected vendors and partners

o Frequently required vendors

Travel Centers – Colpitts, NORD

• Patient costs, on-site translators

Call center

Home healthcare nurses

On demand training services


Common Study Execution Needs

o Supply management of site equipment for

novel endpoints

o Training on novel endpoints

o PIs typically experts in their field, but industry

sponsored research naïve

Tailor a training plan for good clinical practice, good

documentation practice and basic adverse event

reporting


Site Selection and Feasibility

o Differences between typical site selection and

feasibility:

Sponsors usually have pre-selected investigators

Registries are often the key to understanding where

population is treated along with identifying and

tracking key inclusion/exclusion data


Site Selection and Feasibility

o QVs are conducted to identify issues and solve

these challenges rather than evaluating site’s

ability to participate

o Highly motivated but very busy - study-specific

tools, training, and monitoring support are vital

Reminders/refreshers regarding GCP/GDP

o Varying requirements for navigating IRB/EC

approval, contracting, etc.

Leverage past experience and PI commitment to

reduce timelines


Regulatory Submissions

o Ratio of countries to number of sites is skewed

Many countries and relatively few sites

Nearly all sites are local EC/IRB sites

Multiple review committees are common due to

patient age or novel therapy

o Patients may request to travel to existing site

locations across country borders

Establish process/checklist to ensure necessary

resources and documentation are in place


Regulatory Submissions

o Lower the risk of lengthy back and forth

Review past experiences with each site

Discuss the EC/IRB review process and expectations

with each Investigator prior to submission

Complete ICF Preparation Early

• Identify types of ICFs/Patient Information (according to

age groups) needed for each site

• Tailor ICFs to IRB/EC mandatory expectations based on

previous experience

Investigator involvement in the process is key


Conditional Marketing Approval

o Authorization may be granted if certain specific

obligations, are met and approved annually by the

Agency for the following:

Seriously debilitating or life-threatening diseases

Emergency threats (WHO, EU Commission)

Orphan medicinal products

o Granted when all requirements are met:

Benefit/Risk balance is positive

It is likely that comprehensive clinical data will be provided

Unmet medical needs will be fulfilled

Benefit to public health of immediate availability outweighs

risks that additional data are still required


Recruitment Strategies

o Generate excitement about your trial

Presence at scientific meetings

Engage the PIs and CRCs in the study through

strategic outreach/team building

Utilize registries to understand what sites to target for

referrals and participation in the study

Collaborate with advocacy groups

• Significantly improves study and medication awareness

and further enhance site and patient

interest/enthusiasm


Patient Retention

o PI and CRC involvement and encouragement is

critical for patient retention in this study

o Request that the PI discuss study expectations

and all possible outcomes with

patient/guardians during the screening process

o Engage subjects

o Reminders (phone calls, text messages or

emails) about what to expect


Social Media

o Social media can have many positive

and negative effects on your trial

Potential for unblinding

Misinformation

Boosted awareness of trial positively impact

recruitment

Support

Advocacy

Learning – important insights

can be gained


Monitoring Strategies

o Create a strong site support plan

Bolus recruitment is commonplace

• Dry runs may be necessary based on complexity of

protocol

• Increased monitoring visit frequency

CRC support tools/funding; CRCs in hospitals are

overworked

Site specific recruitment plan for patients based on in-

house database review

Individualized CRA-CRC interaction plan – maintain

interest, discuss recruitment efforts, keep the

relationship positive


Ensuring Data Integrity - Monitoring

o Strategies for conducting on-site monitoring

may include:

Selecting a pre-determined number of patients for full

clinical monitoring

Performing Source Document Verification for all

patients on critical data fields

• Patient demographics

• SAE information

• Adverse events of interest data

• Concomitant medications


Safety Monitoring

o Unique anatomy/physiology

Typical physiology and effects on safety assessments

(labs, ECGs, radiographic studies, etc) may be largely

unknown or poorly characterized

Safety assessments may be significantly abnormal at

baseline, making detection/interpretation of changes

more challenging

• Consider how safety signals may be uniquely

manifested in the patient population

• Define safety flags in the context of the disease (ex: LFT increases in patients with myopathy)

• Tailor safety monitoring algorithms


Factors for Success

o Strong, inclusive planning effort

o Collaborative team (sponsor, partners, other stakeholders) sharing common vision

o Well-defined processes and communication pathways

o Knowing the “ins and outs” of FDA approval requirements

o Engaged Investigators

o Motivated Patients

o Proactive assessment of study performance and risks


THANK YOU!

connecting the dots for rare disease studies

Health & Medicine