Clinical Trials in Rare Diseases

Brendan M. Buckley MD DPhil FRCPI

College of Medicine and Health

University College Cork

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

b.buckley@ucc.ie

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

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 the 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

MarketingAuthorizations

Number of

Products

Year

Source: EU Commission, Jan 2011

2010

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)

Product type Biotechnology 1.0

New ‘small molecule’

1.9 (0.5-7.7)

Existing ‘small molecule’

3.9 (0.9-16.6)

Heemstra H, et al.. Eur J Clin Pharmcol 2008; 64: 545-552

*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

AvicennaAbū ‘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 TrialA 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 Steps beforebefore doing a Clinical Trial 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

Regulators work

to protect the public health

• by assuring availability of medicines

• which are safe

• effective

• and of adequate quality.

Don’t Fear the Regulators (IMB / EMA) !

Steps in doing a clinical trial - 1Steps 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 - 2Steps 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 TrialsRecruitment to Clinical Trials

Everyone with the Disease

Everyone with the Diagnosis

Accessible patients

Suitable patients

Volunteers for Trial

Recruited to Trial

Recruited to Trial

Registers

Incidence -v- Prevalence

High Incidence with Short Survival

Low Incidence with Long Survival

Low Incidence with Short Survival

Easy to recruit Short time to outcomes

Difficult to recruitLong time to outcomes

V. Difficult to recruitShort time to outcomes

Common diseases may be rare !

e.g. primary adenocarcinoma of pancreas

‘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

Incidence -v- Prevalence

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_prevalence_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

Orphan medicine , ‘Carbaglu’, was licensed on the basis of a trial on 12 patients with retrospective data collected on 20 patients

in only 42 patients from 28 families, of whom 34 were definitely diagnosed as NAGS deficient, 8

siblings having died without precise diagnosis .

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 pre-synaptic membrane depolarization.

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

201-500

101-200

<100

0>500

Orphan drugs licensed in EUMainly 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

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

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.

Opening the Bottlenecks

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 organisationsSuccessful 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

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

b.buckley@ucc.ie