giuliano 4th ss 2016.ppt [modalit compatibilit...

4th International Summer School on Rare Disease and Orphan Drug Registries

The PillarsDefining the scientific aims

Organised by Istituto Superiore di Sanità

Rome (Italy), September 26-28, 2016





Joseph GiulianoGlobal Medical Affairs

Amicus Therapeutics

Princeton, NJ USA

Presentation agenda

1. What are the PILLARS?

2. Role of scientific observation and aims of a

registry (Huntington disease)

3. Clear aims have impact – the registry’s




purpose

4. Registry adaptability

2

Registries defined

• “a file of documents containing uniform information about individual persons, collected in a systematic and comprehensive way, in order to serve a predetermined purpose.” 1

• “an organized system for the collection, storage, retrieval, analysis, and dissemination of information on individual persons who have either a particular



on individual persons who have either a particular disease, a condition (e.g., a risk factor) that predisposes [them] to the occurrence of a health-related event, or prior exposure to substances (or circumstances) known or suspected to cause adverse health effects.” 2

1 Brooke EM. The current and future use of registers in health information systems. Geneva: World Health Organization; 1974. Publication No. 82 National Committee on Vital and Health Statistics. Frequently Asked Questions About Medical and Public Health Registries. [August 14, 2012]

The Pillars of a successful registry

AimsPatients

Families, Carers

STAKEHOLDERS

Investigators/HCPsAcademia, Hospitals, Community



Sustainability

Governance

4

Academia, Hospitals, Community

ResearchersBasic, Translational, Public Health

GovernmentPublic Health, Payers, Regulators

IndustryPharma/Biotech, CROs

Aims

The overall purpose of the registry,

clearly defined, aligned with

important questions and other

objectives stakeholders want to

achieve

Sustainability

The continuation of a registry’s





efforts to meet current needs and

deliver its desired outcomes to the

community of stakeholders.

Governance

The processes of governing:

Policies, monitoring progress,

scientific integrity, ethical oversight

Presentation agenda








purpose


6

Always begin with observation



The original observations of George Huntington

The hereditary chorea, as I shallcall it, is confined to certain andfortunately a few families, and hasbeen transmitted to them… hardlyever manifesting itself until adultor middle life, and then coming ongradually but surely, increasing by



gradually but surely, increasing bydegrees, and often occupying yearsin its development, until thehapless sufferer is but a quiveringwreck of his former self.

"On Chorea," by George Huntington, M.D., The

Medical and Surgical Reporter: A Weekly Journal,

(Philadelphia: S.W. Butler), vol. 26, no. 15 (April 13,

1872), pp. 317-321.

The original observations of George Huntington- 2



"On Chorea," by George Huntington, M.D., The

Medical and Surgical Reporter: A Weekly Journal,

(Philadelphia: S.W. Butler), vol. 26, no. 15 (April 13,

1872), pp. 317-321.

There are three marked peculiarities in this disease:

1. Its hereditary nature.

2. A tendency to insanity and suicide.

3. Its manifesting itself as a grave disease only in adult life.

Scientific aims

• Understand the phenotype as it evolves over time

• Differences between prodromal and manifest disease

• Patterns of symptom onset: age, family history, gender

• Treatment effects on different symptoms



• Treatment effects on different symptoms

• Prevalence and risk factors for suicide

The HD mutation

180 kb DNA

CAG CAG CAG CAG+n

> 40

> ~70

unaffected

adult onset HD

juvenile onset HD

36-39

6-35

incomplete penetrance

Short Arm of Chromosome 4

(4p16.3)

Htt

The Huntington's Disease

Collaborative Research Group

(1993) Cell 72, 971-83





180 kb DNA

66 67321

≤ 35 CAG - unaffected

≥ 40 CAG – causes disease within normal lifespan

≥ 70 CAG – causes childhood onset

36 - 39 CAG – increased likelihood of developing HD

A single mutation with an expanded tri-nucleotide repeat

40

60

80

Ag

e a

t N

eu

rolo

gic

On

se

t



Normal alleles HD alleles

J. Gusella, Harvard/MGH

0 10 20 30 40 50 60 70 80 90 100 110 120

Number of CAG Repeat Units

0

20

Ag

e a

t N

eu

rolo

gic

On

se

t

HD Degeneration

NormalNormal HDHD

Cortical

Thinning



Basal Ganglia

Degeneration

Ventricular

Enlargement

Scientific Aims

• Neuronal/structural correlates of disease

symptoms

• CAG-length relationship to structural

changes and neuronal dysfunction



changes and neuronal dysfunction

• Genetic modifiers of disease onset –

GWAS

The three main aims for Enroll-HD



Landwehrmeyer, B., et.al, (2016) Movement Disorders- Clinical Practice

Registry scope

• What data will be collected?

– Characterization of the phenotype

– Natural history, symptom progression

– Disease sub-types

• Sample collections?



• Sample collections?

– DNA

– Plasma, lymphocytes

• Tissue donations?

– Biopsies

– Target organs

16

Presentation agenda








purpose


17

Clinical Observatio

n

Natural History

Etiology

Interventions

Public Health

New TxDevelopme

nt

Natural history Disease characteristics (S&S)

Disease progression

Outcomes

Etiology Environmental exposure

Genetics

Interventions Clinical effectiveness

Cost effectiveness





Cost effectiveness

Safety/harm

Public health Disease surveillance

Public policy

New treatment

development

Recruitment in CTs

Feasibility

Protocol design

Presentation agenda








purpose


19

Why do registries need to be adaptable?

Adaptability – able to adjust the registry readily

to changing conditions

• Changes in science and medicine (new observations)Changes in science and medicine (new observations)Changes in science and medicine (new observations)Changes in science and medicine (new observations)

• Changes in personnel and leadershipChanges in personnel and leadershipChanges in personnel and leadershipChanges in personnel and leadership



• Patient reported outcomes (PRO): testing, validating Patient reported outcomes (PRO): testing, validating Patient reported outcomes (PRO): testing, validating Patient reported outcomes (PRO): testing, validating and adoptingand adoptingand adoptingand adopting– Include new measures to replace oldInclude new measures to replace oldInclude new measures to replace oldInclude new measures to replace old

• Important for sustainabilityImportant for sustainabilityImportant for sustainabilityImportant for sustainability

• Align technology for adaptabilityAlign technology for adaptabilityAlign technology for adaptabilityAlign technology for adaptability

• Align governance for adaptabilityAlign governance for adaptabilityAlign governance for adaptabilityAlign governance for adaptability

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