Clinical Trials in Rare Diseases

Brendan M. Buckley MD DPhil FRCPI College of Medicine and Health University College Cork

[email protected]

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 10 6 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 Year 2010

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

Other orphan drug approved for Indication

Value

No Yes

Odds Ratio* (95% CI)

1.0

17.3 (5.6-53.1)

Product type

Biotechnology New ‘small molecule’ Existing ‘small molecule’ Heemstra H, et al.. Eur J Clin Pharmcol 2008;

64

: 545-552 1.0

1.9 (0.5-7.7) 3.9 (0.9-16.6)

*Multivariate analysis

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 ṭ ibb 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 Low Incidence with Long Survival Low Incidence with Short Survival Easy to recruit Short time to outcomes Difficult to recruit Long time to outcomes 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

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

25,000 cases each in EU

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 synaptic membrane depolarization.

+ channels to prolong 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.

of participants in both: 38.

Total number

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

Carglumic acid Mitotane

Indication

Hyperammonaemia due to N-acetyl glutamate synthase deficiency Advanced adrenal cell carcinoma

Date Marketing Authorization (EU)

Jan /2003

Evidence base

Pharmacokinetic (12), retrospective patient data (20) Apr /2004 Bibliographic data only. No trials Anagrelide Essential thrombocythaemia Nitisinone Betaine Hydroxycarbamide Sickle cell disease Caffeine citrate Hereditary tyrosinaemia type 1 Homocystinuria Primary apnea of prematurity Nov /2004 Feb /2005 Feb /2007 Jun /2007 Jul /2009 Uncontrolled and compassionate use (1446 patients evaluable for efficacy) Compassionate use (212) Spontaneous literature reports (202) Bibliographic and registries Bibliographic data only. No trials Thiotepa Conditioning before haematopoietic stem cell transplantation Mar/2010 Bibliographic data only. No trials

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 post marketing 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

[email protected]

Insights into Successful Research in Rare Disease: Dublin : 26 March 2012