Clinical Trials in Rare Diseases
Brendan M. Buckley
MD DPhil FRCPI
College of Medicine and Health
University College Cork
b.buckley@ucc.ie
Insights into Successful Research in Rare Disease:
Dublin : 26 March 2012
Disclaimer
The views expressed are solely those of
the author and do not necessarily reflect
positions or policies of the organisations
to which he is affiliated.
No conflicts of interest potentially affect
this presentation
Insights into Successful Research in Rare Disease:
Dublin : 26 March 2012
Rare Diseases in the EU
EU defines ‘Rare Disease’ based on prevalence of < 5 per 10,000 of the population
Total EU population is about 500 x 106
Maximum number of people with any specific rare disease is about 250,000
However, the large number of diseases fitting the definition means that an estimated 29
Million EU citizens are potentially affected by a rare disease
Source: Eurostat
http://epp.eurostat.ec.europa.eu
Rare Diseases in Ireland
29 Million EU citizens
of whom
250,000 are Irish citizens
are potentially affected by a rare disease
Annual Numbers of Orphan Designations and Marketing
Authorizations in the EU
Orphan
Designations
Number
of
Products
Marketing
Authorizations
2010
Year
Source: EU Commission, Jan 2011
Annual Numbers of EMA Marketing Authorizations
Data: EU Register of designated orphan medicinal products (as of March 2012)
Orphan medicinal products on the market
from: Dr Jordi Llinares, EMA, 2011
Orphan drugs licensed in EU
Predictors of Success in Applications for Authorization
Predictor
Value
Odds Ratio* (95% CI)
Other orphan drug approved for
Indication
No
1.0
Yes
17.3 (5.6-53.1)
Biotechnology
1.0
New ‘small
molecule’
1.9 (0.5-7.7)
Existing ‘small
molecule’
3.9 (0.9-16.6)
Product type
*Multivariate analysis
Heemstra H, et al.. Eur J Clin Pharmcol 2008; 64: 545-552
Orphan medicinal products marketed
60 unique orphan designated products authorized to May 2011
51% of these for diseases affecting less than 1/10,000 patients
Average time OD to MA is 3 years
Authorizations
• 38% under exceptional circumstances
• 6% conditional approval
from: Dr Jordi Llinares, EMA, 2011
Clinical Development of Orphan Medicines
Patients with rare diseases need medicines that are
•as safe
•as effective
•of the same quality
as any commonly used medicine
Clinical trials
Avicenna
Abū ‘Alī al-Ḥusayn ibn ‘Abd Allāh ibn Sīnā'
The effect of the drug must be seen to occur constantly or in many
cases, for if this did not happen, it was an accidental effect."
from:
Kitāb al-Qānūn fī al-ṭibb
The Canon of Medicine (1025)
‘Avicenna’
A Clinical Trial
A Prospective study of an intervention
Designed to measure the impact of a treatment
Compared with a control treatment
On a future possible outcome.
Steps before doing a Clinical Trial

Validate a good relevant non-human in vivo model

Obtain proof of principle

Work towards GMP production of the medicinal product

Apply for orphan status and avail of the incentives

Raise the money

Interest partners
Don’t Fear the Regulators (IMB / EMA) !
Regulators work
to protect the public health
•
by assuring availability of medicines
•
which are safe
•
effective
•
and of adequate quality.
Steps in doing a clinical trial - 1

Design a workable protocol

Focus on the hypothesis; avoid unnecessary, ‘interesting’, questions

Obtain protocol assistance and scientific advice from EMA

Obtain adequate funding

Recruit the right investigators

Obtain prompt regulatory and ethical approval to proceed

Recruit sufficient subjects

Recruit the right subjects
Steps in doing a clinical trial - 2

Conduct the study to highest standards of Good Clinical Practice

Monitor (quality assure) the study efficiently

Collect the data

Process the data

Report the data

Communicate the data

Use the data
Recruitment to Clinical Trials
Everyone with the Disease
Everyone with the Diagnosis
Accessible patients
Suitable
patients
Recruited to Trial
Volunteers for Trial
Incidence -v- Prevalence
Common diseases may be rare !
e.g. primary adenocarcinoma of pancreas
High Incidence with Short Survival
Easy to recruit
Short time to outcomes
Low Incidence with Long Survival
Difficult to recruit
Long time to outcomes
Low Incidence with Short Survival
V. Difficult to recruit
Short time to outcomes
Incidence -v- Prevalence
‘Rare diseases’ that are quite common !
•
primary adenocarcinoma of pancreas
•
renal cell carcinoma
•
Barrett’s oesophagus high-grade dysplasia
•
malignant glioma
•
multiple myeloma
•
hepatocellular carcinoma
Great majority of
diseases listed have a
prevalence < 1x 10-6
25,000 cases
each in EU
November 2009. Orphanet Report Series. Prevalence of Rare Diseases,
Bibliographic data.
http://www.orpha.net/orphacom/cahiers/docs/GB/Prevalence_of_rare_diseases_by_decreasing_prevale
nce_or_cases.pdf
A Pivotal Trial using just One Patient
Before insulin
After insulin
Small numbers may adequate if treatment effect is large
Orphan drugs can’t always get big trials
Some rare diseases affect fewer than 100 accessible patients in the EU.
Hyperammonaemia associated with N-acetylglutamate synthase (NAGS) deficiency
was identified over 20 years from 1980 to 2001
in only 42 patients from 28 families, of whom 34 were
definitely diagnosed as NAGS deficient, 8
siblings having died without precise diagnosis .
Orphan medicine , ‘Carbaglu’, was licensed on the basis of a trial on 12 patients with
retrospective data collected on 20 patients
Orphan drugs don’t always get big trials
Eaton-Lambert Myasthenic Syndrome
Prevalence in EU:
0.1 per 10 000
(45,000 individuals in EU)
Zenas® (amifampridine) blocks voltage-dependent K+ channels to prolong
synaptic membrane depolarization.
pre-
Authorization based on a mixed application, and pivotal efficacy data were based on
published studies.
Four randomized placebo-controlled studies & one active controlled study published
and Cochrane reviewed. Two studies were considered as pivotal.
Total number
of participants in both: 38.
Other controlled trials published in abstract form or as a short book article considered
as supportive. Also, some reports of uncontrolled investigations and case reports
which provided supportive information on efficacy.
EU M.A. 23/12/2009
Orphan drugs don’t always get big trials
Eaton-Lambert Myasthenic Syndrome
Prevalence in EU:
0.1 per 10 000
(45,000 individuals in EU)
Zenas® (3,4-diaminopyridine phosphate: amifampridine)
“ The CHMP recommended granting marketing authorization for Zenas under
exceptional circumstances, because the indication for which this product is intended
is encountered so rarely that the applicant cannot reasonably be expected to provide
comprehensive evidence. Therefore the applicant has agreed to provide further evidence
as specific obligations relating in particular to the safety and efficacy of Zenas including a
risk management plan.... including a registry to be established to monitor patients
undergoing treatment “
Doc. Ref.: EMEA/793638/2009
ASSESSMENT REPORT FOR Zenas
International Nonproprietary Name: amifampridine
Procedure No.: EMEA/H/C/001032
Orphan drugs licensed in EU
Numbers of participants in clinical trials
0
>500
<100
201-500
101-200
Orphan drugs licensed in EU
Mainly based on bibliographic / historic information
Drug
Indication
Date Marketing
Authorization (EU)
Evidence base
Carglumic acid
Hyperammonaemia due to N-acetyl
glutamate synthase deficiency
Jan /2003
Pharmacokinetic (12), retrospective
patient data (20)
Mitotane
Advanced adrenal cell carcinoma
Apr /2004
Bibliographic data only. No trials
Anagrelide
Essential thrombocythaemia
Nov /2004
Uncontrolled and compassionate use
(1446 patients evaluable for efficacy)
Nitisinone
Hereditary tyrosinaemia type 1
Feb /2005
Compassionate use (212)
Betaine
Homocystinuria
Feb /2007
Spontaneous literature reports (202)
Hydroxycarbamide Sickle cell disease
Jun /2007
Bibliographic and registries
Caffeine citrate
Primary apnea of prematurity
Jul /2009
Bibliographic data only. No trials
Thiotepa
Conditioning before haematopoietic
Mar/2010
Bibliographic data only. No trials
stem cell transplantation
Helping to buck the numbers for orphan trials
•
Pick a treatment with a big effect on outcome !
•
Optimize design, availing of Regulator’s scientific advice process
•
Maximize recruitment: patient organizations can really help
•
Keep long trials simple, so that participants don’t drop out
Helping to buck the numbers for orphan trials
•
Formally identify components of variance and minimize them
-
diagnostic criteria, control matching
-
outcome measures
•
Train investigators to competently and rigorously apply the protocol
•
Quality assure the trial in real time and take firm corrective action
Investigator incompetence kills medicines !
Through:
Poor detailed understanding of protocol (and GCP)
Compassionate pressures to stretch inclusion / exclusion criteria
Misunderstandings on adverse effects and efficacy measures
Failure to react to changes in critical observations on participants
Slow entry of data to study database
Barriers to Developing Orphan Medicines in Ireland
•
Lack of expertise in translation from bench to patient
•
Academic promotional systems
•
Access to funding of required scale
•
Access to potential trial participants
Opening the Bottlenecks
Roles for Patient Organisations

Encourage the development of Pan-European Centers of Excellence

Lobby for easier trans-national patient access to them

Support patients who travel from abroad to them
Opening the Bottlenecks
Roles for Patient Organisations
Act as True Stakeholders in the Clinical Trial Process:

Help formulate the questions to be answered by trials

Give ethical guidance to Ethics Committees

Promote recruitment to good trials

Discourage recruitment to poor trials

Ensure publication of trial results
Opening the Bottlenecks
Patient Organisations can help
Maximise effectiveness of rare disease trials

Effective multinational recruitment

Efficient use of scarce patient resources

Coordination of multiple study designs to facilitate meta-analyses

Long term open-label extension studies and structured postmarketing surveillance

Coordinated biobank use.
Successful patient organisations
Have a few clear research goals

Based on excellent scientific / medical advice

Verified by committed expert members
Pursue their research agenda carefully

Fund research to fulfill that agenda

Manage the different agendas of researchers

Require practical results from researchers whom they fund

Are not easily deflected by ‘novelty’ into new projects
Successful patient organisations
Commission research

rather than invite research proposals
Have a clear roadmap for the clinical development of any promising
treatment

Non-clinical studies in animal models

First-in man clinical studies

Further human studies
Have a clear view of funding needs for clinical development

A business plan to achieve necessary funding.

Ownership of intellectual property.
Ireland and Orphan Drugs Research
Success depends on virtuous integration between:
•
Higher Education
•
Patient Organisations
•
Government
-
state funding agencies
-
EI and IDA
•
EU agencies
•
Capital
Thank You !
Brendan M. Buckley
MD DPhil FRCPI
College of Medicine and Health
University College Cork
b.buckley@ucc.ie
Insights into Successful Research in Rare Disease:
Dublin : 26 March 2012