Enhancing Rare Enhancing Rare Diseases Research Diseases Research

Efforts:Efforts:

Fostering Development Fostering Development of Collaborative of Collaborative Research TeamsResearch Teams

11stst International Conference on International Conference on Rare Diseases and Orphan DrugsRare Diseases and Orphan Drugs

February 14-16, 2005February 14-16, 2005 Stockholm, Sweden Stockholm, Sweden

Giovanna Spinella, MD., CDR, PHS Giovanna Spinella, MD., CDR, PHS Extramural Program Director, ORD, NIH Extramural Program Director, ORD, NIH

The Promise of Rare Diseases The Promise of Rare Diseases ResearchResearch

Rare diseases research can provide Rare diseases research can provide novel discovery and medical novel discovery and medical breakthroughs in development of new breakthroughs in development of new treatments for people afflicted by treatments for people afflicted by these conditions and has the potential these conditions and has the potential applicability to more common medical applicability to more common medical conditions in our societyconditions in our society

Rare diseases research may hold the Rare diseases research may hold the keys for understanding the keys for understanding the complexities of both normal abnormal complexities of both normal abnormal disease physiologydisease physiology

Relevant Issues for Rare Diseases Relevant Issues for Rare Diseases Research:Research:

Small populations dispersed over wide geographic Small populations dispersed over wide geographic areasareas

Heterogeneous expression of diseaseHeterogeneous expression of disease Variable diagnostic criteria and assessment Variable diagnostic criteria and assessment

measuresmeasures Limited Laboratory Scientists and Clinician Limited Laboratory Scientists and Clinician

Expertise and ExperienceExpertise and Experience Limited Access to Research ResourcesLimited Access to Research Resources

Pockets of genetic, clinical, laboratory, Pockets of genetic, clinical, laboratory, pathological materialspathological materials

Restrictions to animal and other disease models, Restrictions to animal and other disease models, reagents.reagents.

Limited Foreseeable Profits/Financial IncentivesLimited Foreseeable Profits/Financial Incentives Drug/therapeutic agent development costs Drug/therapeutic agent development costs

compared to marketcompared to market Industry greater dependency on clinical and Industry greater dependency on clinical and

laboratory scientist collaboration-requires laboratory scientist collaboration-requires negotiations of IP issues, etc. negotiations of IP issues, etc.

Facilitating Rare Diseases Facilitating Rare Diseases ResearchResearch

Systematic collection of clinical informationSystematic collection of clinical information Standard Protocols-agreement across clinical sites on Standard Protocols-agreement across clinical sites on

minimum elements to be collected on all patients; minimum elements to be collected on all patients; identified research questions to be answered; focus on identified research questions to be answered; focus on developing measures/markers of developing measures/markers of disease/assessment/disease course/outcomesdisease/assessment/disease course/outcomes

Partnerships and CollaborationsPartnerships and Collaborations Developing an international research community. Developing an international research community.

Commitment to working across varying policies and Commitment to working across varying policies and regulations to facilitate collaborative research.regulations to facilitate collaborative research.

International coordination of patient disease International coordination of patient disease organizations/foundations-help bridge the patient organizations/foundations-help bridge the patient populations and cultures; address mutual needs.populations and cultures; address mutual needs.

Industry/other organizations-the coordination of the Industry/other organizations-the coordination of the scientists and patient support organizations within a scientists and patient support organizations within a rare disease population –an asset for partnerships and rare disease population –an asset for partnerships and bringing new treatments to the clinic and interfacing bringing new treatments to the clinic and interfacing government/regulatory agencies.government/regulatory agencies.

Exploit Technology to Enhance Communication Exploit Technology to Enhance Communication Systems/Data Accrual and Management/Access Across Systems/Data Accrual and Management/Access Across NationsNations Coordinated data management systems for Coordinated data management systems for

communication and sharing, collection, storage and communication and sharing, collection, storage and analysis of data from multiple clinical sitesanalysis of data from multiple clinical sites

Provide an internationally accessible resource pliable for Provide an internationally accessible resource pliable for public information and education as well as a research public information and education as well as a research resourceresource

Exploit Opportunities to Nurture New Investigators Exploit Opportunities to Nurture New Investigators Trained in Rare Diseases Research, Identify Areas Trained in Rare Diseases Research, Identify Areas Where Specialized Training is Needed and Provide Where Specialized Training is Needed and Provide AccessAccess Developing collaborative research teams generates a Developing collaborative research teams generates a

research environment for training of new investigators research environment for training of new investigators and exposes rare disease scientists to new technologies, and exposes rare disease scientists to new technologies, methodologies that can be applied to rare diseases methodologies that can be applied to rare diseases research investigations.research investigations.

Current ORD Activities Towards Current ORD Activities Towards Building Collaborative Research Building Collaborative Research

TeamsTeams Rare Disease Clinical Research Network

10 clinical research consortia comprising 10 clinical research consortia comprising 55 medical institutions (over 300 55 medical institutions (over 300 investigators) within the United States and investigators) within the United States and 7 countries; 7 countries;

34 patient advocacy groups representing 34 patient advocacy groups representing over 40 rare diseases (Coalition for Patient over 40 rare diseases (Coalition for Patient Advocacy Groups)Advocacy Groups)

Data and Technology Coordinating CenterData and Technology Coordinating Center Broad NIH sponsorship and participation: 5 Broad NIH sponsorship and participation: 5

NIH Institutes; 1 NIH Center (NCRR) and NIH Institutes; 1 NIH Center (NCRR) and ORD, NIH.ORD, NIH.

Rare Diseases Clinical Rare Diseases Clinical Research Network Research Network

Consortia Consortia Angelman, Rett, Prader-Willi Syndromes – A. BeaudetAngelman, Rett, Prader-Willi Syndromes – A. Beaudet

Bone Marrow Failure Disease – J. MaciejewskiBone Marrow Failure Disease – J. Maciejewski

Genetic Diseases of Mucociliary Clearance – M. KnowlesGenetic Diseases of Mucociliary Clearance – M. Knowles

Genetic Steroid Disorders – M. NewGenetic Steroid Disorders – M. New

Nervous System Channelopathies – R. GriggsNervous System Channelopathies – R. Griggs

Cholestatic Liver Disease – R. SokolCholestatic Liver Disease – R. Sokol

Rare Lung Disease – B. TrapnellRare Lung Disease – B. Trapnell

Rare Thrombotic Disorders – T. OrtelRare Thrombotic Disorders – T. Ortel

Urea Cycle Disorders – M. BatshawUrea Cycle Disorders – M. Batshaw

Vasculitis Clinical Research – P. MerkelVasculitis Clinical Research – P. Merkel

Data and Technology Coordinating Center (DTCC) – J. Data and Technology Coordinating Center (DTCC) – J. KrischerKrischer

Rare Diseases Clinical Rare Diseases Clinical Research Network – Goals Research Network – Goals

http://www.rarediseasesnetwork.org/http://www.rarediseasesnetwork.org/

Facilitate Clinical Research in Rare Diseases Facilitate Clinical Research in Rare Diseases Training of Clinical Investigators in Rare Diseases Training of Clinical Investigators in Rare Diseases

ResearchResearch Centralized Data and Technology Coordinating CenterCentralized Data and Technology Coordinating Center

to assist into assist in design of clinical protocols, data collection, design of clinical protocols, data collection, storage and analysis from multiple diseases and storage and analysis from multiple diseases and multiple clinical sitesmultiple clinical sites

Develop tools for web based recruitment and referral, Develop tools for web based recruitment and referral, cross disease data miningcross disease data mining

Support Collaborative Clinical ResearchSupport Collaborative Clinical Research Longitudinal Studies of Patients with Rare Diseases Longitudinal Studies of Patients with Rare Diseases

(Including Natural History Studies)(Including Natural History Studies) Clinical Proof of Concept or Demonstration ProjectsClinical Proof of Concept or Demonstration Projects

Rare Diseases Clinical Research NetworkRare Diseases Clinical Research Network Rare Diseases Clinical Research Center Rare Diseases Clinical Research Center

(Consortium) Key Features:(Consortium) Key Features: Concept: Concept:

Consortium of Investigators, Institutions, and Organizations, Consortium of Investigators, Institutions, and Organizations, including Partnership with Patient Advocacy Organizations; including Partnership with Patient Advocacy Organizations; encourage partnership with industryencourage partnership with industry

Sub-Grouping of Rare DiseasesSub-Grouping of Rare Diseases Clinical Research Studies with Longitudinal Clinical Research Studies with Longitudinal

ComponentComponent Includes Human Laboratory Work; Pilot Studies/Phase I/II Includes Human Laboratory Work; Pilot Studies/Phase I/II

TrialsTrials Utilizes Institutional GCRCs across the Center Consortium Utilizes Institutional GCRCs across the Center Consortium

(coordination of GCRCs across the rare diseases consortium). (coordination of GCRCs across the rare diseases consortium). Training of New Rare Diseases InvestigatorsTraining of New Rare Diseases Investigators Public Resource and EducationPublic Resource and Education Commitment of Each Rare Disease Clinical Commitment of Each Rare Disease Clinical

Center to Collaboration with other Clinical Center to Collaboration with other Clinical Centers and the DTCC within the NetworkCenters and the DTCC within the Network

Current ORD Activities Towards Current ORD Activities Towards Building Collaborative Research Building Collaborative Research

TeamsTeams Rare Disease Clinical Research Rare Disease Clinical Research

NetworkNetwork Networking Meetings: Special

workshops focused to fostering coordination and collaboration, bringing potential partners together towards addressing key next steps in moving research in a rare disease forward.

Networking Meetings always include Networking Meetings always include patient advocacy group(s) and potential patient advocacy group(s) and potential funding sources for activities generated funding sources for activities generated by the discussion.by the discussion.

Possible Content of Meeting include:Possible Content of Meeting include: Develop clinical research consensus on key Develop clinical research consensus on key

questions and measures for developing questions and measures for developing clinical research protocols; form new clinical research protocols; form new collaborationscollaborations

Assess various models of disease, assays, Assess various models of disease, assays, etc., tools for uncovering drug or other etc., tools for uncovering drug or other discoveries for rare disease therapeutics-discoveries for rare disease therapeutics-develop strategy for moving forward.develop strategy for moving forward.

Current ORD Activities Towards Current ORD Activities Towards Building Collaborative Research Building Collaborative Research

TeamsTeams Rare Disease Clinical Research Rare Disease Clinical Research

NetworkNetwork Networking Meetings: Networking Meetings: Quality genetic testing: Working

across government agencies within the United States towards quality diagnostic testing (genetic and biochemical testing) for rare diseases with goal of integrating efforts internationally

Promoting Quality Laboratory Testing for Rare Diseases: Keys to Ensuring Quality Genetic Testing" Conference, Atlanta,

May 2004• Participants include more than 50 experts

from government, academic institutions, professional organizations, laboratories, industry, healthcare payers, and patient advocacy groups.

• Goals: Assure access to quality laboratory testingAssure access to quality laboratory testing

Research laboratories providing patient testingResearch laboratories providing patient testing Expedite translation of gene findings into Expedite translation of gene findings into

clinical and public health practiceclinical and public health practice Identify data and education needsIdentify data and education needs Promote collaboration, cooperation, Promote collaboration, cooperation,

partnership, and community involvementpartnership, and community involvement

• Recommendations:• Education- to promote quality translation of research

findings into clinical testing and to advance understanding of quality standards for patient testing research community( institutional review boards (IRBs), providers and users of laboratory services, healthcare payers, patients, research participants, and advocacy groups, to minimize adverse impact on access to testing

• Guidance, strategies, and criteria- how rare disease tests should be validated, and how analytic validity, clinical validity, and clinical utility should be established for rare disease tests

• Quality assurance strategies-Quality assurance strategies- for clinical genetic for clinical genetic testing for rare diseases. testing for rare diseases.

• Quality data collection- Quality data collection- Mechanisms and strategies Mechanisms and strategies during each step of test development through clinical during each step of test development through clinical application application

• Partnership and networks-Partnership and networks- to improve and facilitate to improve and facilitate research translation, data sharing, clinical availability, and research translation, data sharing, clinical availability, and quality assurance.quality assurance.

• Infrastructure-Infrastructure- to provide momentum and enable to provide momentum and enable development of activities needed, including facilitating the development of activities needed, including facilitating the translation process, assuring the quality of testing services, translation process, assuring the quality of testing services, and improving access to testing. and improving access to testing.

Issues Identified with Regards to Test Referral to Issues Identified with Regards to Test Referral to Non-US laboratoriesNon-US laboratories

US dependency for rare diseases diagnostic testing-US dependency for rare diseases diagnostic testing-roughly 22% genetic tests are available only from non-roughly 22% genetic tests are available only from non-US laboratories.US laboratories.

standards are needed both for specimen shipping and standards are needed both for specimen shipping and tracking documentation and for the validity and quality tracking documentation and for the validity and quality of the testing. of the testing.

CLIA requirements, US and international privacy CLIA requirements, US and international privacy regulations, and other requirements may impose regulations, and other requirements may impose restrictions both on cross-border test referrals and on restrictions both on cross-border test referrals and on obtaining information necessary for test selection, obtaining information necessary for test selection, result interpretation and reporting. result interpretation and reporting.

““Borderless" laboratories may be able to facilitate Borderless" laboratories may be able to facilitate sending specimens and test results across borders and sending specimens and test results across borders and may provide a model for addressing trans-border may provide a model for addressing trans-border testing; however, the use of these laboratories can be testing; however, the use of these laboratories can be problematic when contact information for the testing problematic when contact information for the testing laboratory is not provided and test results are laboratory is not provided and test results are transcribed or edited on the report issued to the transcribed or edited on the report issued to the referring institution. referring institution.

NNATIONALATIONAL LLABORATORYABORATORY NNETWORKETWORK

RRAREARE DDISEASEISEASE GGENETICENETIC TTESTINGESTINGforfor

A family of laboratories for orphan disease diagnostics.

Six laboratories formed the NLN in May 2004 and agreed to share a commitment to ensure that quality, affordable genetic testing services are accessible to all. Visit the Rare Disease Conference website for additional information: http://www.phppo.cdc.gov/dls/genetics/Rare Disease Conf.aspx

Visit the NLN website soon at: www.rarediseasetesting.org

The six charter laboratories:

Medical Genetics Laboratories at Baylor College of Medicine, Houston, TX

Genetics Laboratory at Emory University School of Medicine, Atlanta, GA

GeneDx, Inc., Gaithersburg, MD Molecular Genetics Laboratory at Hospital

for Sick Children, Toronto, Canada Orphan Disease Testing Center at University

of California at Los Angeles, CA University of Chicago Genetics Services

Laboratories, Chicago, IL

:

Current ORD Activities Towards Current ORD Activities Towards Building Collaborative Research Building Collaborative Research

TeamsTeams Rare Disease Clinical Research Rare Disease Clinical Research

NetworkNetwork Networking MeetingsNetworking Meetings Quality Genetic Testing Quality Genetic Testing Education and Information

Resources for Patient Advocacy Organizations and Research Investigators

ORD Seminar Series: ORD Seminar Series: Gaining Access to Research Resources Gaining Access to Research Resources

Regional Training Workshop for National Regional Training Workshop for National Patient Support OrganizationsPatient Support Organizations

NIH Extramural Research Funding StructureNIH Extramural Research Funding Structure NIH Rare Diseases Intramural Research NIH Rare Diseases Intramural Research

Program and Patient Recruitment and Referral Program and Patient Recruitment and Referral The FDA: Orphan Designation and Drug The FDA: Orphan Designation and Drug

Evaluation for Rare DiseasesEvaluation for Rare Diseases Patenting/Cross Licensing of Genetic Materials Patenting/Cross Licensing of Genetic Materials Ensuring Ethical Research Ensuring Ethical Research What Information You Need and Where To Find What Information You Need and Where To Find

It! It! Implications in Genetic Testing: Genetic Implications in Genetic Testing: Genetic

Counseling Counseling IRB/Human Subjects Protection /Vulnerable IRB/Human Subjects Protection /Vulnerable

Populations Populations

Trans-NIH Working Group Trans-NIH Working Group on Rare Diseases Research on Rare Diseases Research

IssuesIssues Development of Diagnostic Genetic Development of Diagnostic Genetic

TestsTests Collection, Storage, and Distribution Collection, Storage, and Distribution

of Biomaterials for Researchof Biomaterials for Research Research Models for Rare DiseasesResearch Models for Rare Diseases Sources of Rare Diseases Information Sources of Rare Diseases Information Training – Intramural and ExtramuralTraining – Intramural and Extramural

Web-based inventory of bio-specimen Web-based inventory of bio-specimen repositories?repositories? Maintained and updated site with information to include:Maintained and updated site with information to include:

extent of collection,extent of collection, specimen types collected,specimen types collected, donation policies and requirements,donation policies and requirements, preparation and collection procedures,preparation and collection procedures, location of repositories,location of repositories, contact information, contact information, sources of support, andsources of support, and limitations to access.limitations to access.

In addition, consideration for:In addition, consideration for: an educational component to guide researchers in areas such as an educational component to guide researchers in areas such as

collecting samples, and human subject privacy and informed collecting samples, and human subject privacy and informed consent; consent;

methods that repositories can use to assess their success in methods that repositories can use to assess their success in fulfilling requests and ways for them to identify and solve problems fulfilling requests and ways for them to identify and solve problems that arise;that arise;

methods ORD/NIH can use, independent of the repositories, to methods ORD/NIH can use, independent of the repositories, to query investigators on their success in obtaining needed samples; query investigators on their success in obtaining needed samples; and and

a way to identify a repository’s responsiveness to investigator a way to identify a repository’s responsiveness to investigator requests for new tissue types. requests for new tissue types.

Broadening EffortsBroadening Efforts How Can We Work More Effectively How Can We Work More Effectively

Together to Meet the Challenges of Together to Meet the Challenges of Rare Diseases Research?Rare Diseases Research?

Can We Develop an International Can We Develop an International Collaboration and Coordination of Rare Collaboration and Coordination of Rare Diseases Research to Benefit the Diseases Research to Benefit the People With Rare Diseases?People With Rare Diseases? What Form Would It Take? What Form Would It Take? International Teams to Work on specific International Teams to Work on specific

Areas and Issues to bring suggestions, Areas and Issues to bring suggestions, recommendations and solutions? to recommendations and solutions? to interact with the various government interact with the various government agencies and programs?agencies and programs?