Challenges in clinical trials in small populations

Violeta Stoyanova, MD, PhD, MPH

Chair COMP at EMA

April 2019

The Committee for Orphan Medicinal Products

Main items on the COMP agenda

Orphan designation

Protocol assistance

Orphan status at time of marketing authorization

Advising the EC on the establishment and development of a policy on OMP in

the EU:

- developing and establishing an EU-wide policy;

- detailed guidelines;

- liaising internationally;

- Involvement with patient and consumers, academia, industry

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Applications for orphan medicinal product designation

0

50

100

150

200

250

300

350

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

submitted positive opinions negative opinions withdrawals during assessment EC Designations

The orphan designation is the appellation given to certain medicinal products under development that are intended to diagnose, prevent or treat rare conditions when they meet a pre-defined set of criteria foreseen in the legislation. Medicinal products which get the orphan status benefit from several incentives (fee reductions for regulatory procedures (including protocol assistance), national incentives for research and development, 10-year market exclusivity) aiming at stimulating the development and availability of treatments for patients suffering from rare diseases.Orphan Designations are granted by Decisions of the European Commission based on opinions from the COMP. Orphan designated medicinal products are entered in the Community Register of Orphan Medicinal Products.

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At the time of marketing authorisation, the COMP will check if all criteria for orphan designation are still met. The designated orphan medicinal product should be removed from the Community Register of Orphan Medicinal Products if it is established that the criteria laid down in the legislation are no longer met.

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Chart includes:15 authorised extensions of indication18 withdrawals from the register of orphan medicinal products (including 6 ext. of indication)5 withdrawals from register medicinal products human use40 removals of initial MAA from register after expire of the market exclusivity period & 1 ext of indication

164 initial orphan marketing authorisations and 22 extension of

indication granted to date

Number of conditions: 124

Active orphan MA: 107

Active extension of indication: 15

A Alimentary tract and metabolism

B Haematology

C Cardiovascular system

H Systemic hormonal

J Anti-infectives for systemic use

L Immunology

L Antineoplastic

M Musculo-skeletal system

N Nervous system

R Respiratory system

S Sensory organs

V Various

A19%

B8%

C5%

H3%

L- immuno3%

L-onco41%

M1%

N8%

R4%

S2%

V3%

J3%

A B C H L- immuno L-onco M N R S V J

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New orphan conditions designated

64

4955

73

8880

98

73

106

128

107

148

136

187 190

209

147

169

78% 51% 44% 42% 39% 33% 21% 23% 16% 26% 14% 28% 25% 18% 18% 18% 14% 9%0

50

100

150

200

250

2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

TOTAL DESIGNATIONS (2121) NEW CONDITIONS (524) - 25%

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Defining the orphan condition

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Distribution of orphan designations adult/paediatric use

Adult32%

Paediatric13%

Both55%

Period 2000 – 2017Total designations 1952

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Distribution of orphan designations adult/paediatric use

2 104 5 8 6

133 6

313 15

62

19 25 22 20 12

9

30 28

17 2239

33

49

43 7661

51

44

70113 113

155 114

3

24 17

33 4343

34 46

2427

54 4142

4749 55

34 21

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017

Nu

mb

er o

f d

esig

nati

on

s

Medical conditions affecting children only

Medical conditions affecting both children and adults

Medical conditions affecting adults only

Period 2000 – 2017Total designations 1952

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Prevalence for designated orphan conditions

less than 1 in 10,000

40%

between 1 and 3 in 10,000

49%

more than 3 in 10,000

11%

Period 2000 – 2017Total designations 1952

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Orphans designations based on significant benefit

50%56%

69%

89%

70%

53%

70%76% 77% 81%

47%

67% 66%57%

64% 59% 59%67%

56%

0

50

100

150

200

250

2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018

Designations Percentage based on SB

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The challenges in drug development

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Define the orphan condition

Adults and/or Pediatric?

Which patients to include in the trial?

Which endpoints are clinically relevant?

Which outcome measures?

Need for a significant benefit argumentation

Direct comparisons

Indirect comparisons

Historical control data

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The IRDiRC SPCT Task Force met in March 2016

• different study methods/designs

their relation to different characteristics of medical conditions;

• adequate safety data;

• multi-arm trial designs;

• decision analytic approaches and rational approaches to adjusting levels of evidence;

• extrapolation;

• patients’ engagement in study design;

Innovative/non-traditional methodologies

• Adaptive trial designs

• Bayesian methods

• EMA guidelines on trials in small populations / Asterix project*

• Real World Evidence, Artificial Intelligence, Machine Learning

• New endpoints, that no one has used before

• Data collection in compassionate use programmes…

• Regulatory science constantly evolves

*Advances in Small Trials dEsign for Regulatory Innovation and eXcellencehttp://www.asterix-fp7.eu/

• Acceptance of novel methods within the whole EU regulatory network?

• Their use by the pharmaceutical industry?

• How patients and clinicians understand them?

• HTA experts: synergy EMA / HTA (working group in the HTA Network)

HTA members attending EMA scientific workshops

Guidelines are developed in consultation between parties, e.g. on registries

HTA experts in Scientific Advice / COMP / CHMP discussions?

Collignon et al. Trials (2018) 19:642

Big data

EMA/HMA joint task force on Big Data (2017)

• Map relevant sources;

• Define the main format in which they are expected to exist

• Identify the usability or applicability of big data

• Describe the current and future state, challenges

• Need for regulatory expertise and competences the need to specify

legislation and guidelines

• Need for data analyzing tools and systems

• Responsibility of regulators' vs sponsor's

• Design and create a roadmap

• Generate a list of recommendations

• Collaborate with other worldwide regulatory authorities and partners

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Big data

EMA/HMA joint task force on Big Data (2017)

• complex, multi-dimensional, unstructured, heterogeneous,

• accumulating rapidly;

• might be analysed computationally to reveal patterns, trends, associations;

• require advanced or specialized methods to provide a reliable answer

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Thank you!