7th Workshop Eurordis Round Table of Companies December 14th, 2008 Paris, France La Maison des Arts et Métiers
“Proof of Concept and Level of Evidence in Orphan Drug Development"
Introduction Concept Paper Programme List of Participants Presentations and biographies
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
ʺProof of Concept and Level of Evidence in Orphan Drug Developmentʺ
INTRODUCTION
It is my pleasure to introduce the proceedings of the 7th Workshop of the Eurordis Round Table of Companies (ERTC) “ Proof of Concept and Level of Evidence in Orphan Drug Development” held on 14 December 2007 at la Maison des Arts et Métiers, Paris, France. Despite the technical topic, this workshop was well-attended by 60 participants, including 30 companies, representatives from the US, UK and French regulatory agencies and also from patient organisations. Defining the term “Proof of Concept” sparked a lively discussion and although, as expected, no real consensus could be reached, the participants were confronted with different views and therefore able to obtain a richer understanding of this term and its issues. Most participants agreed that, in the case of orphan drugs, the demonstration of the proof of concept represents a green light to move forward to the next milestones. Thus, as Dr Kerstin Westermark indicated in the conclusion of her presentation, it would probably be more appropriate to talk about “proofs of concept”, rather than “proof of concept”, depending on the type of test done: from molecular, to mice, to man. Thank you again for participating and contributing to this workshop.
Yann Le Cam Chief Executive Officer
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
CONCEPT PAPER
According to our experience and to a recent preliminary survey we conducted with the different stakeholders involved in drug development, there is no agreed upon understanding of the term “proof-of-concept”. In addition to the lack of consensus on the definition of this adaptable term, there is, in our opinion, the need to define what use has been made of this concept in the drug development area to date. In the case of orphan drugs in particular, the demonstration of proof of concept can represent a green light to move forward to the next milestones: the passage from pre-clinical to first-in-man studies, the minimum amount of data or demonstrations necessary to convince decisions makers or investors at company level to start or continue investing financially or to convince regulators to grant an orphan drug designation, and later, a market authorisation. Are these steps completed in a different manner and with a different level of proof of concept? We can assume that because of their specificities such as the small size of the total patient population and the high level of innovation of some products, the required level of proof of concept could be different for orphan drugs. Is this really the case? This 7th ERTC workshop will first aim to clarify the term “proof of concept” to hopefully reach a consensus on the language and thus improve the quality of communication between stakeholders. The analysis of the experiences at the COMP and CHMP level in the designation and marketing authorisation processes for orphan drugs will help acquire more accurate knowledge of how regulators evaluate the different levels of proof of concept presented by the sponsors and how this has an impact on the levels of evidence presented in the central marketing applications. In the afternoon session, representatives of all stakeholders- industry, regulatory authorities, patients and academics- will present real-life cases of how the demonstration of the different proofs of concept are applied differently and explain how this impacts all aspects of their work.
A large amount of time will be left to the panellists and the attendees for an in-depth discussion on the complex puzzle created by this versatile term “proof-of-concept”.
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
PROGRAMME 8:30 Welcome & coffee MORNING - 9:00 - 12:30 Chairpersons: Eric Abadie (Chair of the CHMP) – Kerstin Westermark (Chair of the COMP) 9:00 - 9:15 Welcome address (Yann Le Cam, Eurordis) Same language but different definitions of “proof-of-concept” 9:15 - 9:35 “Proof-of-Concept: Univocal Concept or Shared Ambiguity?” (Rembert Elbers, COMP member nominated by Germany) Learning from experience: analysis of the levels of evidence in the US and European designation and marketing authorization processes: 9:35 -10:00 “Proof-of-Concept in the European Orphan Drug Designation Process” (Fabrizia Bignami, Eurordis) 10:00 -10:25 “Proof-of-Concept in the US Orphan Drug Designation Process” (Tan Nguyen, FDA) 10:30 – 11: 00 – COFFEE BREAK 11:00 - 11:25 “From Proof-of-Concept to Evidence-based Marketing Authorisation” (Marco Cavaleri, EMEA, SAWP) 11:25 – 11:40 “From Proof-of-Concept to Evidence-based Marketing Authorisation, the CHMP Perspective” (Pierre Demolis, AFFSSaPS, CHMP) 11:40 – 12:30 Discussion (50’)
12:30 -13:45 – LUNCH AFTERNOON - 13:45 -16:30 Chairpersons: Tan Nguyen (OOPD -FDA) – Josep Torrent-Farnell (COMP member)
13:45 -14:25 “Proof-of -Concept as a Green Light for Further Development” (Detlef Niese, Novartis Pharma AG and Louis-Christian Clauss, Baxter) 14:25 -14:45 “Proof- of -Concept as a Green Light for Regulators” (Kerstin Westermark, Chair of the COMP) 14:45 -15:15 “Proof- of- Concept as a Green Light for Ethics” (Olivia Niclas, patient representative AFDE and Jean-Claude Ameisen, Inserm) 15:15 -15:45 “Case Studies” by 2 industry representatives (Bonnie Mills, IDM Pharma, Inc. and Andreas Orfanos, Neurochem, Inc.) 15:45 -16:30 Discussion with panel and all participants (45’) Panel members: afternoon speakers 16:30
End of Workshop
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
LIST OF PARTICIPANTS
Name
Affiliation
Country
Abadie, Eric
Afssaps, DEMEB & CHMP, EMEA
France
Aiach, Karen
Alliance SANFILIPPO
France
Ameisen, Jean-Claude
INSERM
France
Benichou, Bernard
Genzyme Europe
France
Bignami, Fabrizia
Eurordis
France
Blumer, Karin
Novartis International AG
Swizterland
Bodin, Anne-Mary
Eurordis
France
Caizergues, Didier
Généthon
France
Cavaleri, Marco
EMEA - SAWP
UK
Chaubourt, Emmanuel
Association Française contre les Myopathies (AFM)
France
Clauss, Louis-Christian
Baxter S.A.
France
Cuervo-Alvarez, Virginia
Pharma Mar, S.A.
Spain
Demolis, Pierre
Unité PTC4/DEMEB, AFSSAPS & CHMP, EMEA
France
Denèfle, Patrice
Généthon
France
Dohin, Elisabeth
Pharmion France
France
Dortok, Aydin
Novartis Oncology
Italy
Dubosq, Annick
Orphanet Inserm SC11
France
Ducruet, Catherine
Les Echos
France
Dufour, Franck
Vaincre La Mucoviscidose
France
Duguet, Corinne
ERYtech Pharma
France
Dupuy, Patrick
Orfagen
France
Elbers, Rembert
COMP - Federal Institute for Drugs and Medicinal Devices Germany
Elefant, Elisabeth
Centre de Référence sur les Agents Tératogènes (CRAT)
France
Emmanuel, Florence
ERA-NET Coordination Action “PrioMedChild” – Inserm
France
Ewen, Colin
Pfizer Ltd.
UK
Faurisson, François
Eurordis
France
Forget, Sylvain
Swedish Orphan International SARL
France
Fortun, Marie-Christine
Orphan Europe
France
Galen, Michele
Novartis Oncology
USA
Golub, David
Mark Krueger & Associates, Inc.
USA
Haviland, Kate
PTC Therapeutics
USA
Hughes-Wilson, Wills
Genzyme
Belgium
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Name
Affiliation
Country
Irwin, Joseph
Jennifer Trust for Spinal Muscular Atrophy
UK
Kelly, Samar
Actelion Pharmaceuticals Ltd.
Switzerland
Krueger, Mark
Mark Krueger & Associates, Inc.
USA
Le Cam, Yann
Eurordis
France
Leto di Priolo, Susanna
Novartis Oncology
Italy
Lipucci di Paola, Michele
AVLT/Eurordis ( Thalassemia)
Italy
Lorence, Annie
AFSSAPS-DEMEB
France
Maruzzi, Mario
Chiesi Farmaceutici S.p.A
Italy
Mathivet, Laurence
Association Française contre les Myopathies (AFM)
France
Mavris, Maria
Eurordis
France
Metz, Rob
IDM Pharma, Inc.
USA
Mills, Bonnie
IDM Pharma, Inc.
USA
Murphy, Lise
Svenska Marfanföreningen
Sweden
Niclas, Olivia
French Organization for Etodermal Dysplasia (AFDE)
France
Niese, Detlef
Novartis Pharma AG
Swizterland
Orfanos, Andreas
Neurochem Inc.
Canada
Ouary, Stéphane
Association Française contre les Myopathies (AFM)
France
Patel, Jatin
GlaxoSmithKline R&D Ltd.
UK
Quartel, Adrian
BioMarin Europe Ltd.
UK
Rahajarizafy, Annie
Eurordis
France
Rinaldi, Alain
Alexion Europe
France
Spain, Helen
Pfizer Ltd.
UK
Stanescu, Angela
ZKS-Center of clinical trials, University Hospital Freiburg
Germany
Tejada, Paloma
Eurordis
France
Thomas, Matthew
OOPD - FDA
USA
Topini, Thomas
Chiesi Farmaceutici S.p.A
Italy
Torrent-Farnell, Josep
COMP - Fundació Doctor Robert
Spain
Westermark, Kerstin
COMP - Medical Products Agency
Sweden
Wheeler, Colin
Celgene Limited
UK
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Presentations
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Prof. Rembert ELBERS COMP member nominated by Germany Prof. Elbers studied Human Medicine at the Ludwig-Maximillians Universität Munich (LMU) and holds a Medical Diploma and a Doctorate. He holds additional qualifications in biochemistry and pharmacology. Prof. Elbers has been a member of the COMP since 2001. He is also a member of several working parties: − Scientific Advice Working Party − Member COMP Working Group with Interested Parties − Various small Ad Hoc Groups, e.g. Ad Hoc Group on Clinical Trials in Small Populations He has been Head of BfArM oncology unit since 2000. Contact details: Prof. Rembert Elbers Federal Institute for Drugs and Medicinal Devices Pharmacovigilance Department Kurt-Georg-Kiesinger-Allee 3 53175 Bonn, Germany
[email protected] Tel.+ 49 228 207 34 49
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Bundesinstitut für Arzneimittel und Medizinprodukte
Same Same language language but but different different definitions definitions of of “proof-of-concept”: “proof-of-concept”:
Proof-of-concept - Univocal Concept or Shared Ambiguity? 7th Workshop Eurordis Round Table of Companies
"Proof of Concept and Level of Evidence in Orphan Drug Development" December 14th, 2007 La Maison des Arts & Métiers, Paris, France
Dr. Rembert Elbers, BfArM, Germany With the help of the Eurordis-Team
Bundesinstitut für Arzneimittel und Medizinprodukte
Proof of Concept Survey - Question
The question: Without consulting any reference text or any of your colleagues, give us your own definition of “proof of concept” in few lines.
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Bundesinstitut für Arzneimittel und Medizinprodukte
Proof of Concept Survey - Responders 78 Responders:
• • • •
30 Academics
• • •
8 physicians 20 scientists 2 ethicists
17 Industry 6 Patients’ Organisations 25 Regulators
• • •
COMP members National Agencies Industry
Bundesinstitut für Arzneimittel und Medizinprodukte
Proof of Concept Survey - Methods
• First reading • Determination of fields • Qualitative content of PoC • PoC in drug development • PoC in Scientific process • Quantification
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Bundesinstitut für Arzneimittel und Medizinprodukte
Should I stop my Talk here? Proof of concept (Wikipedia): PoC is a short and/or incomplete realization of a certain method or idea(s) to demonstrate its feasibility, or a demonstration in principle, whose purpose is to verify that some concept or theory is probably capable of exploitation in a useful manner… Proof of Concept (Scientist):
Don't know!
Bundesinstitut für Arzneimittel und Medizinprodukte
A universal concept, but…
•
8 responders “don't know” or give a tautological definition
• •
6 academics 2 regulators
•
Qualitative content
•
Quantitative content
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Bundesinstitut für Arzneimittel und Medizinprodukte
Hard or Soft Proof •
Statistical proof (with regard to efficacy) are cited 12 times
• •
•
7 times positively (need of statistical proof for a PoC)
• • •
3 industry 1 scientist 3 regulatory
5 times negatively (PoC prior to a statistical proof)
• • • •
2 scientists 1 physician 1 PO 1 regulatory
PoC is based on surrogate endpoints, biomarkers
•
5 times
• • •
2 industry 2 physicians 1 scientist
Bundesinstitut für Arzneimittel und Medizinprodukte
Qualitative content
• Safety , 3 times
• 1 from industry (6%) • 2 scientists (10%)
• Methodology, level of confidence 5 times • 1 physician • 2 scientists • 1 PO • 1 regulatory
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Bundesinstitut für Arzneimittel und Medizinprodukte
PoC in drug development 4 fields
• Preclinical non animal data • Mechanism of action, pharmacodynamics, physiopathology Animal model Efficacy in patients, clinical feasibility, clinical studies
• •
Bundesinstitut für Arzneimittel und Medizinprodukte
PoC in drug development % of responders mentioning this topics
60 50 academics patients org regulatory industry
40 30 20 10 0 in vitro
mechanism, PD
animal mod.
clinical studies
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Bundesinstitut für Arzneimittel und Medizinprodukte
PoC in drug development % of responders mentioning this field
45 40 35 30 25 20 15 10 5 0
physicians scientists
in vitro
mechanism, PD
animal mod.
clinical studies
Bundesinstitut für Arzneimittel und Medizinprodukte
PoC in scientific development % of responders mentioning this field
80 70 60 50 40 30 20 10 0 Green light for human use
GL for development
preliminary
academics patients org regulatory industry
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Bundesinstitut für Arzneimittel und Medizinprodukte
Still confused…but on a higher level?
(COMP): Proof of concept is a complex idea which is incapable of being encompassed by a simple definition. However, the most important element is that there will be a continuous range of situations which will require different levels of evidence….
Bundesinstitut für Arzneimittel und Medizinprodukte
PoC – What is this? PoC is clearly not an univocal concept, not even the ambiguities of this term are shared. Any useful definition will depend on what type of “concept” is considered and what level of “proof” is expected, e.g.:
• • • •
PoC for early drug development PoC for “first in men” use PoC for Orphan Designation PoC for full clinical development
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Bundesinstitut für Arzneimittel und Medizinprodukte
PoC – Spectrum of Views (Scientist): …proof based on theory (no experimental validation) which may be established by analogy using structure or functional parameters…
Bundesinstitut für Arzneimittel und Medizinprodukte
PoC – Spectrum of Views (Scientist): … Compliance with stringent efficacy and safety criteria evaluated in an experimental animal model accurately reflecting the human disease…
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Bundesinstitut für Arzneimittel und Medizinprodukte
PoC – Spectrum of Views (Industry): Evidence of clinical activity (e.g. Efficacy) with favourable benefit and risk of a drug or biologic in a Phase 1 or 2 study that requires confirmation in a later stage.
Bundesinstitut für Arzneimittel und Medizinprodukte
PoC – Spectrum of Views (Industry): ... means that a given pharmacological compound or other therapeutic method has shown significantly efficacy in the way that was originally claimed in a randomized double blind, placebo controlled study. The proof of concept need to be performed in a way that presents an approach than can be used as a therapy and should therefore in most cases consist in a systemic application of the potential therapeutic…
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Bundesinstitut für Arzneimittel und Medizinprodukte
PoC - My own definition (Assuming that there is a strong hypothesis - based on animal results or, in rare cases, even on “in vitro” data - with regard to the question how a new OMP should be effective or provide benefit to patients) In this case proof of concept would consist of results from a few patients with regard to an endpoint which has the potential to falsify the underlying hypothesis by making testable, discriminatory outcome predictions. I would consider proof-of concept to be established if experiment fails to falsify the hypothesis and if all further observations are also within reasonable agreement with predictions derived from the hypothesis. In my view PoC is much more about failing to verify a hypothesis than about confirming something.
Bundesinstitut für Arzneimittel und Medizinprodukte
Thank You for Your Attention! - Everything is up for Discussion -
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia BIGNAMI, PhD. Director for Therapeutic Development, Eurordis, France Dr Fabrizia BIGNAMI holds a PhD in Cellular and Developmental Biology from the Department of Cellular Biology at La Sapienza University- Rome, Italy Since 2002, she has worked as Director for Therapeutic Development at Eurordis, in charge of all activities relating to research and medicinal products for rare diseases in Europe, mainly: - Permanent observer and patient representatives’ supporter at the Committee for Orphan Medicinal Products (COMP), European Medicines Agency (EMEA) London, UK. - Responsible for the Eurordis Round Table of Companies (ERTC) program. Prior to this she worked as Project Manager for cellular therapies at the Scientific Department of the French Association against Myopathies (Association Française contre les Myopathies, AFM-Téléthon). Contact details: Dr Fabrizia Bignami EURORDIS Plateforme Maladies Rares 102, rue Didot 75014 Paris France
[email protected] Tel. +33 (0)1 56 53 52 64
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
www.eurordis.org
Proof-of-Concept in the European Orphan Drug Designation Process Fabrizia BIGNAMI, PhD Eurordis’ Director of Therapeutic Development
7th Eurordis Round Table of Companies Workshop Paris December 2007
Proof of Concept and Level of Evidence in Orphan Drug Development
Orphan Drug Designation Criteria in Europe EC Regulation 141/2000:
• Prevalence < 5/ 10 000 (or unlikely to generate a sufficient return on investment)
• Life threatening or chronically debilitating condition + Medical plausibility
• Significant benefit (or no other treatments available)
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
Objectives of the analysis
•To study which level of evidence is provided by the sponsors at the time of the application for orphan drug designation.
•To identify any possible relationship between the types of data provided and the success rate in designation.
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Methodology • Applications submitted to the COMP in the year 2006 and 2007 that received an opinion or were voluntarily withdrawn by the sponsor.
• Please note: the year taken into account is the year of submission, not the year of the opinion/withdrawal: 102
for 2006 77 for 2007
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
Data: categories for codification
1. In vitro (biochemical, cells, organs) 2. Efficacy in animal models
Data from literature were not considered Data concerning other drugs of the same class, were not considered
3. PharmacoKinetics in animals 4. Toxicity in animals 5. Phase I in healthy volunteers 6. Phase I in patients
In case of composite phase (e.g. I/II), the latest phase was considered
7. Phase II 8. Phase III (same indication)
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Percentage of applications including specific data in vitro efficacy
Animal Studies
PK Tox Ph. I H.V. Ph. I Ptt
Human Studies
Ph. II Ph. III 0
20
40
60
80
% 6
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
Stage of development and Designation Rate (DR)
DR DR
73% DR
60%
82%
cl i
on ly
on ly
pr e
in
cli n
ni ca l
i ca l
vi tr o
DR
88%
al l
200 180 160 140 120 100 80 60 40 20 0
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Percentage of applications including specific data
in vitro
in vitro
efficacy animal
efficacy animal
PK animal
PK animal
Tox animal
Tox animal
Phase I H.V.
Phase I H.V. Phase I Ptt
Phase I Ptt
Phase II
Phase II
Phase III
Phase III 0
20
40
60
80
%
2006 n= 102
0
20
40
60
80
%
2007 n= 77*
*Applications evaluated by November 2007 8
"Proof of Concept and Level of Evidence in Orphan Drug Development"
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
Submitted data and designation rate
0
38%
59%
89%
79%
91%
2006 n= 102
87%
l l a
20
0
l a c i n i l c
40
20
l a c i n i l c e r p
60
40
o r t i v n i
60
l l a
80
l a c i n i l c
100
80
l a c i n i l c e r p
120
100
o r t i v n i
120
87%
87%
2007 n= 77*
*Applications evaluated by November 2007 9
Percentage of applications including specific data
in vitro
in vitro
efficacy animal
efficacy animal
PK animal
PK animal
Tox animal
Tox animal
Phase I H.V.
Phase I H.V.
Phase I Ptt
Phase I Ptt
Phase II
Phase II
Phase III
Phase III 0
20
40
60
%
Biotech products n= 47
80
0
20
40
60
80
%
Other products n= 132
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
Percentage of applications including specific data
in vitro
in vitro
efficacy animal
efficacy animal PK animal
PK animal
Tox animal
Tox animal
Phase I H.V.
Phase I H.V.
Phase I Ptt
Phase I Ptt
Phase II
Phase II
Phase III
Phase III 0
20
40
60
0
80
20
40
60
80
%
%
Non advanced Biotech n= 29
Advanced Therapies n= 18
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Submitted data and designation rate
30
0
0
38%
71%
81%
77%
Biotech products n= 47
68%
90%
81%
l l a
10
l a c i n i l c
60
l a c i n i l c e r p
90
20
o r t i v n i
30
l l a
120
l a c i n i l c
40
l a c i n i l c e r p
150
o r t i v n i
50
85%
Other products n= 132
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
Submitted data and designation rate
30
20
25
16
20 12 15 8 10 4
5
Non advanced Biotech n= 29
67%
88%
70%
l l a
76%
l a c i n i l c
88%
l a c i n i l c e r p
l l a
61%
0
o r t i v n i
l a c i n i l c
20%
l a c i n i l c e r p
o r t i v n i
0
78%
Advanced Therapies n= 18
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Summary BT and NBT:
Less clinical data for the Biotech applications than for the non Biotech.
Within the BT group this is even more accentuated than in the ATMP, where phase II is predominant.
The global reduced success rate of BT products (77%) compared to the NBT products (85%)
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
Percentage of applications including specific data
in vitro
in vitro
efficacy animal
efficacy animal
PK animal
PK animal
Tox animal
Tox animal
Phase I H.V.
Phase I H.V.
Phase I Ptt
Phase I Ptt
Phase II
Phase II
Phase III
Phase III 0
20
40
60
80
0
20
%
40
60
80
%
Oncology n= 73
Metabolic diseases n= 20
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Submitted data and designation rate
25
80
20 60 15 40 10 20
70%
80%
l l a
60%
l a c i n i l c
Cancer n= 73
89%
l a c i n i l c e r p
98%
l l a
67%
l a c i n i l c
l a c i n i l c e r p
60%
o r t i v n i
0
o r t i v n i
0
5
75%
Metabolic diseases n= 20
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
Submitted data and designation rate
80
25
80
20
60
60
15 40
40 10
20
20
5
l l a
l a c i n i l c
l a c i n i l c e r p
60% 70% 80% 75%
0
o r t i v n i
l l a
l a c i n i l c
Oncology n= 73
l a c i n i l c e r p
60% 67% 98% 89%
0
o r t i v n i
l l a
l a c i n i l c
l a c i n i l c e r p
o r t i v n i
0
58% 77% 81% 80%
Metabolic diseases n= 20
Others n= 88
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Summary Oncology versus other medical areas:
Larger amount of clinical data in the oncology group
The higher success rate of oncology applications with clinical data (98%) results in the overall higher success rate of this group (89%)
While lower success rate for applications presenting preclinical data only do not differ across the categories
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
Percentage of applications including specific data
In vitro
In vitro
Efficacy animal
Efficacy animal
PK animal
PK animal
Tox animal
Tox animal
Phase I H.V.
Phase I H.V.
Phase I Ptt
Phase I Ptt
Phase II
Phase II
Phase III
Phase III 0
20
40
60
80
0
20
%
40
60
80
%
Prevalence ≤1 /10 000 n= 76
Prevalence >1/10 000 n= 73
19
Submitted data designation submitted dataand and designation rate rate
0
0
77%
77%
93%
87%
Prevalence ≤1/10 000 n= 76
83%
95%
88%
l l a
20
l a c i n i l c
20
l a c i n i l c e r p
40
o r t i v n i
40
l l a
60
l a c i n i l c
60
l a c i n i l c e r p
80
o r t i v n i
80
89%
Prevalence >1/10 000 n= 73
20
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
Percentage of applications including specific data
In vitro
In vitro
Efficacy animal
Efficacy animal
PK animal
PK animal
Tox animal
Tox animal
Phase I H.V.
Phase I H.V.
Phase I Ptt
Phase I Ptt
Phase II
Phase II
Phase III
Phase III 0
20
40
60
0
80
20
40
60
80
%
%
Without M.A. n= 107
With M.A. (other form or other indication)
n= 52 21
Submitted data designation submitted dataand and designation rate rate
120
60
100
50
80
40
60
30
40
20
20
10
82%
l l a
79%
l a c i n i l c
67%
l a c i n i l c e r p
Without M.A. n= 107
84%
0
o r t i v n i
90%
l l a
78%
l a c i n i l c
8O%
l a c i n i l c e r p
o r t i v n i
0
81%
With M.A. (other form or other indication)
n= 52 22
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
Summary
• There is no difference in the type of data provided for conditions with a prevalence below or above 1/ 10 000. This translates in a same overall success rate.
• Applications for products that already have a Marketing Authorisation (other forms or indications) contain more clinical data (arrive at a later development stage) But This does not translate into a better overall success rate. 23
Studies in animal (efficacy, PK or Tox) according to the outcome 90% 80% 70% 60% 50% 40% 30% 20% 10% 0%
designated withdrawn
t ra m
se ou
it bb ra
g do m
ke on
y
r he ot m
ifi od
ed
Designated applications: 2.58 animal models Withdrawn applications: 1.51 animal models 24
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
Clinical studies % of applications including specific data
40 35 30 25
Designated Withdrawn
20 15 10 5
Phase I healthy vol.
Phase I patients
Ef fic ac To y le ra nc e Do sa ge
L TO
PK
L TO
PK
0
Phase II
25
CONCLUSIONS (I/III) Those applications including clinical « proof » have a better designation rates (88% vs 73%) But 45/62 (73%) applications with only preclinical data obtain the designation This represents more than 1/3 of all designations for the period 2006-07, And this group includes 16/27 (60%) applications containing in vitro results only
26
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
CONCLUSIONS (II/III)
Oncology applications WITH clinical « proof » have a 98% success rate! Overall, no influence of prevalence except for applications without clinical data in low prevalence conditions: less convincing. Overall NBT drugs more successful than BT. this difference is due to the low results of BT with only preclinical data (63% vs 90%) +++ if only in vitro (38% BT vs 68% NBT)
27
CONCLUSIONS (III/III) A COMP designation acts like a PoC: • To obtain it, there is no preferential stage in the development process
• There is no standard content of a designated application (This is dramatically different from a Marketing Authorisation)
• The designation is more a cut-off point that marks a “before” and an “after” (confidential → public, choice of condition)
• It has an operational value (green light): gives an official qualitative value to the content of the file (the couple drug + condition and the quality of the data submitted and, to some extent, of the development plan) → access to incentives and induced benefits 28
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Dr Fabrizia Bignami - Eurordis : Proof of Concept in the European Orphan Drug Designation
Thank You! Dr François Faurisson Clinical Research Advisor
[email protected] Dr Fabrizia Bignami Director of Therapeutic Development
[email protected]
29
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Tan NGUYEN, (replaced by Dr Mathew Thomas) Medical Officer, OOPD/OC/FDA HF-35 Dr NGUYEN has been serving as a medical officer in the FDA Office of Orphan Products Development for 6 years, and previously served as a medical reviewer in the Division of Antiviral Drug Products. He has reviewed over 200 orphan drug designation requests, and was responsible for approvals of several anti-HIV and anti-hepatitis drugs. He is also a practicing pathologist at Walter Reed Army Medical Center in Washington DC, and an Associate Professor of Pathology at the Uniformed Services University in Bethesda, Maryland Contact details: Dr Tan Nguyen Medical Officer Office of Orphan Products Development HF-35-FDA Parklawn Building, Room 6A55 MD 20857 Rockville USA
Dr Mathew T. THOMAS Health Science Administrator, Designations Reviewer and Grants Project Officer, OOPD/OC/FDA HF-35 Since October 2007, Dr. Thomas works in the Office of Orphan Products Development as a Health Science Administrator and is responsible for designation reviews and functions as a grants project officer. Since 1989, Dr. Thomas has worked in the Center for Drug Evaluation and Research (CDER) of the FDA. He joined CDER as a medical reviewer in the Division of Metabolism and Endocrine Drug Products. From January 1995 to October 2007, Dr. Thomas worked as a Pharmacologist/Scientific Reviewer in the Division of Scientific Investigations (DSI) and has an extensive experience in Clinical Bioresearch Monitoring (BIMO). He has participated in numerous domestic and international BIMO inspections and was the Project Officer for the development of DSI's web site, DSI's Electronic Complaint Form, and DSI's activities pertaining to the evaluation of the validity of electronic clinical trial data. Dr. Thomas serves as an FDA speaker at many national and international conferences and workshops. Contact details: Dr Mathew T.Thomas Health Science Administrator, Designations Reviewer and Grants Project Officer Office of Orphan Products Development/HF-35 Office of Science and Health Coordination Office of the Commissioner U.S. Food and Drug Administration 5600 Fishers Lane, Room 6A-55 Rockville, Maryland 20857, USA
[email protected] Tel.+1 301-827-0993
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Proof of Concept in the FDA OrphanDrug Designation Process 7th Workshop of the EURORDIS Round Table of Companies: Proof of Concept and Level of Evidence in Orphan Drug Development Mathew T. Thomas, MD Tan Nguyen, MD, PhD FDA Office of Orphan Products Development http://www.fda.gov/orphan/
Regulatory Bases for “Proof of Concept” in Orphan-Drug Designation • Orphan Drug Act incentives are intended for the development of “promising orphan drugs.”1 • Orphan Drug Regulations: • “A description of the drug and a discussion of the scientific rationale for the use of the drug in the rare disease or condition…” must be included in the designation request.2 • A request may be denied if “there exists insufficient information…to establish a medically plausible basis for expecting the drug to be effective…”3 1
Pub. L. No. 97-414 (1983) as amended 21 CFR 316.20(b)(4) 3 21 CFR 316.25(a)(2) 2
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Why “Proof of Concept” is Necessary in Orphan-Drug Designation • It is not in the public interest to provide substantial incentives to develop a drug that has no plausible prospect for success. • The orphan disease community should have the “right to know” if an experimental drug may be potentially beneficial. • The community, however, has no access to trade secret and confidential information about the drug. • A designation may be perceived by the community (and various stakeholders) as an objective and independent “vote of confidence” in the drug’s potential benefit.
Methods for Reviewing Adequacy of Evidentiary “Proof of Concept” • We conducted a survey to determine: • the existence of an IND • the stage of drug development • the availability of in vitro, in vivo, and clinical information (“proof-of-concept” evidence) to support the drug’s medical plausibility at the time the sponsor filed the orphan designation request
• The survey included: • 63 drugs designated in 2007 to date • 17 drugs not designated in 2006 due to inadequate scientific rationale
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Stages of Drug Development: Working Definitions • Preclinical stage: in vitro and/or in vivo testing • Clinical stages: • Phase 1: initial administration of the drug into humans (safety, tolerability, pharmacokinetic & pharmacodynamic properties, and early activity) • Phase 2: studies to explore the drug’s efficacy profile (dosage, target population, and endpoints for Phase 3 investigation) • Phase 3: “pivotal” studies to demonstrate or confirm the drug’s clinical benefit
Existence of an IND for the Orphan Indication Designated Drugs
Not Designated Drugs
35%
41% 59%
65%
IND exists for the orphan indication No IND
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Stage of Drug Development Designated Drugs 7% 2%
Not Designated Drugs
15%
24%
52%
32% 12%
44%
12%
Preclinical Phase 2 Undetermined
Phase 1 Phase 3
Availability of Supportive in vitro and/or in vivo Data Designated Drugs
Not Designated Drugs
10% 29%
35%
36% 25%
29%
in vitro data only Both
12%
24%
in vivo data only Neither
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Availability of Supportive Clinical Data Designated Drugs
Not Designated Drugs
16%
24%
76%
84%
Clinical data available
Clinical data not available
Reasons for Inadequate Evidentiary “Proof of Concept”
6% 6% 11%
No preclinical model studies
38%
Irrelevant preclinical models Anecdotal data only Over-interpretation of data
17%
Submission of incomplete data
22%
Equivocal clinical data
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How High Is the Bar for “Proof of Concept” in Orphan Designation? • A scientific concept alone, unless otherwise supported, is often insufficient. • Experimental data in preclinical model(s) are necessary in most cases. • Model(s) should be relevant to the disease. • The drug should be evaluated in in vivo model(s) if such is/are available. • Prior experiences with a similar drug per se may not be sufficient. • Comparative data to other drug(s) known to be active are desirable.
How High Is the Bar for “Proof of Concept” in Orphan Designation? • In the absence of convincing preclinical model information, data from clinical experiences with the drug are often necessary. • Data should be obtained from patients with the disease of interest. • Persuasive data from a “proof-of-concept” study, not necessarily statistically significant, are often sufficient.
• Anecdotal case reports, unless clearly compelling or otherwise supported, may not be adequate. • Important to submit complete data for review!
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Conclusions • FDA has not issued a Guidance on the quantity and quality of “proof-of-concept” data necessary for orphan-drug designation.1 • How much evidentiary data is adequate is determined on a case-by-case basis.
• There exists a reasonably consistent and uniform approach to this issue in most cases: • At the minimum: valid in vitro experimental data • At the maximum: compelling clinical experiences • ☺ medium: somewhere in between! 1
EMEA has issued a draft Guideline on this subject (EMEA/COMP/66972/2004).
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7th Workshop of the Eurordis Round Table of Companies - December 14th, 2007
Dr Marco CAVALERI, Scientific Administrator in the Scientific Advice and Orphan Drugs Sector, SAWP, EMEA Marco Cavaleri graduated in pharmaceutical sciences and holds a PhD in experimental pharmacology from the University of Milano. He spent several years in industry covering various roles within preclinical and clinical development especially in the area of antiinfectives. Approximately 2 years ago, he joined the EMEA as Scientific Administrator in the Scientific Advice and Orphan Drugs Sector. His main tasks being in support of the Scientific Advice Working Party (SAWP) activities. Contact details: Dr Marco Cavaleri EMEA Scientific Advice and Orphan Drugs Pre-Authorisation Human Unit 7, Westferry Circus Canary Wharf
[email protected] London E14 4HB Tel. (44-20) 7418 8531 UK
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From ProofProof-ofof-concept to evidenceevidence-based marketing authorisation M. Cavaleri EMEA 7th ERTC Workshop December 2007, Paris
14th
Status of Orphan Applications 2000
2001
2002
2003
2004
2005
2006
2007
Total
No. of applications submitted
72
83
80
87
108
118
104
117
769
Positive COMP Opinions
26
64
43
54
75
88
81
92
523
Commission Decisions
14
64
49
55
72
88
80
70
492
Final Negative COMP Opinions
0
1
3
1
4
0
2
1
12
Withdrawals
6
27
30
41
22
30
20
16
192
Update 29 November 2007
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Adult/Paediatric Use
Both 45%
Adult 45%
Paediatric 10%
Update 29 November 2007
Distribution of opinions musculoskeletal and nervous system 11%
other 6%
immunology 11%
metabolism 10%
antiinfectious 4% oncology 47% cardiovascular and respiratory 11%
immunology cardiovascular and respiratory metabolism other
oncology antiinfectious musculoskeletal and nervous system
Update 29 November 2007
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Status of Orphan Marketing Authorisation Applications 44 authorisations granted to date Fabrazyme for Fabry disease
Replagal for Fabry disease Glivec for chronic myeloid leukaemia, ALL, GIST, DFSP, MDS/MPD and HES/CEL Tracleer for pulmonary arterial hypertension, systemic scleroris Trisenox for acute promyelocytic leukaemia Somavert for acromegaly Zavesca for Gaucher disease Carbaglu for N-acetylglutamate synthetase deficiency
Update 29 November 2007
Status of Orphan Marketing Authorisation Applications cont’d Aldurazyme for Mucopolysaccharidosis type I Busilvex for haematopoietic progenitor cell transplantation Ventavis for pulmonary arterial hypertension Onsenal for Familial Adenomatous Polyposis Litak for indolent non-Hodgkin’s lymphoma Lysodren for adrenal cortical carcinoma Pedea for Patent Ductus Arteriosus Photobarr for Barret’s oesophagus Wilzin for Wilson's disease Xagrid for Thrombocythaemia
Update 29 November 2007
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Status of Orphan Marketing Authorisation Applications cont’d Orfadin for tyrosinemia type 1 Prialt for chronic pain requiring intraspinal analgesia Xyrem for narcolepsy Revatio for pulmonary arterial hypertension Naglazyme for Mucopolysaccharidosis VI or Maroteaux-Lamy syndrome Myozyme for Glycogen Storage Disease type II (Pompe’s disease) Evoltra for acute lymphoblastic leukaemia
Update 29 November 2007
Status of Orphan Marketing Authorisation Applications cont’d Nexavar for renal cell carcinoma Sutent for gastrointestinal stromal tumour and renal cell carcinoma Savene for anthracycline extravasation Thelin pulmonary arterial hypertension Exjade for chronic iron overload requiring chelation theraphy Sprycel for chronic myeloid leukaemia and acute lymphoblastic leukaemia Inovelon for epilepsy
Update 29 November 2007
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Status of Orphan Marketing Authorisation Applications cont’d Cystadane for homocystinuria
Elaprase for mucopolysaccharidosis Diacomit for myoclonic epilepsy in infancy Revlimid for multiple myeloma Soliris for paroxysmal nocturnal haemoglobinuria Siklos for sickle cell syndrome Atriance for acute lymphoblastic leukaemia Increlex for growth failure Gliolan for glioma Yondelis for soft tissue sarcoma Tasigna for chronic myelogenous leukaemia Torisel for renal cell carcinoma Nexavar for hepatocellular carcinoma
Update 29 November 2007
Status of Orphan Marketing Authorisation Applications 17 centralised applications in review process In 2006-2007, 5 Approvals under “Exceptional Circumstances” and 2 with “Conditional Marketing Authorization” Update 29 November 2007
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Status of Orphan Marketing Authorisation Applications Variations / Line Extensions in review process • Evoltra for acute myeloid leukaemia • Zavesca for Niemann-Pick type C disease
Update 29 November 2007
Negative outcomes for orphan MAA 22 applications for MA withdrawn 3 negative decisions/refusals
Update 29 November 2007
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Distribution of orphan MAAs 44 orphan authorised by centralised MA
5%
9%
34%
11%
14%
27%
Ant ineoplast ic and immunomodulat ing agent s blood cardiovascular
met abolism musculoskelet al and ner vous syst em ot hers
Update 29 November 2007
Orphan CHMP Opinions over time 20 18 16 14 12 10 8 6 4 2 0 2001
2002
2003
positive opinions
2004
2005
2006
2007
negative/withdrawals
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Overview clinical studies in positive opinions (up to 2004)
22% RCT 45%
Non controlled trials Case reports / bibliographical
33%
Overview clinical studies in positive opinions (2006(2006-2007) 7%
RCT 33% 60%
Non controlled trials Case reports / bibliographical
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Overview clinical studies in positive opinions (2006(2006-2007) Main (n)
Phase
Myozyme
1
II
O, NR, NC, MC
Evoltra
1
II
O, NR, NC, MC
1+Biblio 1+4 1+Biblio 1+Biblio
II III +II II II
Sutent GIST Sutent MRCC Sutent RCC 1st line
1 1 1
III II III
DB, R, Pbo, Mc O, NR, NC, Mc O, R, AC, Mc
Nexavar RCC Nexavar HCC
1 1
III III
R, Pbo, Mc DB, R, Pbo, Mc
Glivec DFSP Glivec Ph+ALL Glivec MDS/MPD Glivec CEL/HES
Design
O, NR, NC, Mc O, C, Mc + O, NC, NR, Mc O, NR, NC, Mc O, NR, NC, Mc
Savene
2
II,II/III
O, NR, NC, Mc
Thelin
3
III
DB, R, Pbo, Mc
Exjade
1+2
III+II
O, R, AC, Mc
Diacomit
2
II
DB, R, Pbo, Mc
Sprycel CML/ALL
5
II
O, NR/R, NC/C, Mc
Overview clinical studies in positive opinions (2006(2006-2007) Elaprase Inovelon
main (n)
Phase
2
II, II/III
DB, R, Pbo, Mc
Design
1
III
DB, R, Pbo, Mc
Biblio
--
--
Atriance
2
II
O, NR, NC, Mc
Gliolan
1
III
O, R, Pbo, Mc
Increlex
1+2
III
1: O, R, Pbo, CO
Revlimid
2
III
DB, R, Pbo, Mc
Siklos
Biblio /
--
--
Soliris
1
III
DB, R, Pbo, Mc
Torisel
1
III
O, R, AC, Mc
Tasigna
2
II
O, NR, NC, Mc
Yondelis
1
II
O, R, NC, Mc
Cystadane
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Overview clinical studies in negative opinions (up to 2004)
25% RCT 50%
Non controlled trials Case reports / bibliographical
25%
Overview clinical studies in negative opinions (2006(2006-2007) 10%
RCT 50% 40%
Non controlled trials Case reports / bibliographical
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Overview clinical studies in negative/withdrawals (2006(2006-2007) Main (n)
Phase
Surfaxin T RDS Surfaxin P RDS
1 2
Ib III
O, NR, NC, Mc O, R, AC, Mc
Design
Orathecin
2
II
O, R, AC, Mc
Riquent
2
III
DB, R, Pbo, Mc
Glivec Mastocytosis
1
II
O, NR, NC, Mc
Cerepro
2
I,II
O, R, C, Sc
Iplex
1
II
O, NR, NC, Mc
Retisert
2
II/III
Voraxase
2
Compassionate
Mycograb
1
III
DB, R, C, Mc (1) -DB, R, Pbo, Mc
Is the condition determining the type of study and the amount/quality of data? 12 10
10 8 6
5 4
4 2 0
other II III
3 2 1
1 0
CVR
0
1 0
GI
3
3
2
0
haem met
1 00
CNS
11 0
onc other
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Is the condition determining the type of study and the amount/quality of data? 12 10
10 8 6
double blind open other
5 4
4
33 3
3
22
2
2
1 1
0
ot he r
m
et
00
on c
0
G I ha em
C VR
00
C N S
0
0
2 1
Is the condition determining the type of study and the amount/quality of data? 14
13
12 10 controlled non controlled other
8 6
2
1 0
2
1 00
0
1 00
0
0
on c ot he r
C VR
0
1
m et C N S
2
3 22
G I ha em
4
55 4
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Significant Benefit in OMPs
- 66% products required demonstration of significant benefit, 14 with prevalence below 1 in 10,000
Data submitted for SB at the time of marketing authorisation sb 10%
6%
14%
17%
17%
non satisfactory methods
42%
met onc cvr haem cns
19% 50% 6%
met onc gi haem other
19%
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Data submitted for SB at the time of marketing authorisation study phase
14%
44%
Phase II Phase III Other
42%
Data submitted for SB at the time of marketing authorisation allocation 2%
48%
non randomised randomised
50% other
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Data submitted for SB at the time of marketing authorisation blinding
14% 40%
open double blind other
46%
Data submitted for SB at the time of marketing authorisation control group 2%
45%
53%
non controlled controlled other
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Data submitted for SB at the time of marketing authorisation overall sb
overall non satisfactory methods
3 characteristics 2 characteristics 1 or less
43% 54%
42% 50%
3%
3 characterisitcs 2 characteristics 1 or less
8%
Impact of Protocol Assistance on CHMP opinion 80.00%
75.00%
70.00% 60.00%
56.82%
50.00% 43.18% Positive opinion
40.00%
Negative opinion
30.00%
25.00%
20.00% 10.00% 0.00% Without SA
With SA
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Adherence to PA by OMPs with an outcome 100% 90%
91%
88%
83%
80% 75% 70%
67%
60% 50%
50%
50%
Posit ive Opinion
50% 43%
40%
Negat ive Opinion
30% 20% 10% 0%
0% Primary
Choice of
endpoint
comp.
Durat ion
St at ist ics
t ot al
Summary - 41 different orphan conditions with authorised OMP - 31 / 41 (76%) conditions have prevalence ≤1 / 10.000 - About 50% of pivotal trials for OMPs are RCT with a tendency in the last years towards an increase in the evidence provided at time of MAA - Protocol Assistance is a potentially effective tool for helping Sponsors with the planning of the studies facilitating an “agreed” transition from proof-of concept to evidence-based marketing authorization
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Pierre DEMOLIS, MD, PhD AFSSAPS, SAWP, CHMP Pierre Demolis is an MD, specialized in cardiology, and PhD, senior registrar (clinical pharmacology). He joined the AFSSaPS four years ago to manage a clinical assessment team specially involved in European procedures with, as main topics, metabolic orphan diseases, cancer and haematology. He has been working as a member of the Scientific Advisory Working Party for more than two years and was appointed last June to be the French representative for the CHMP. Contact details: Dr Pierre Demolis AFSSAPS Unité PTC4/DEMEB, AFSSAPS & CHMP, EMEA Chef de l'unité PTC4 (Produit de Thérapie Cellulaire) 143-147, boulevard Anatole France 93285 Saint Denis France
[email protected] Tel. 01.55.87.34.66
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From Proof-of-Concept to Evidence-Based Marketing Authorisation, the CHMP Perspective
P Démolis ERTC 12/07
What Does ‘Proof of Concept’ Mean ?
•
EMEA documents : search in http://www.emea.europa.eu :
• 30 documents, most of them refer to pre-clinical setting, no guidance paper in human…
•
Pubmed : proof of concept (limits: in title, human, English language)
• 131 references • 'Proof of concept' (PoC) trials often are carried out to determine if a treatment is biologically active or inactive’(1).
• One discussion paper on sample size calculation for PoC trails as opposed to pivotal efficacy trials (2)
• Most references deal with one particular setting/trial
2
1.
Lawrence Gould A. Timing of futility analyses for 'proof of concept' trials. Stat Med. 2005 Jun 30;24(12):1815-35.
2.
Yin Y.Sample size calculation for a proof of concept study.J Biopharm Stat. 2002 May;12(2):267-76
11/01/2008 – ERTC P Démolis
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No Accepted Definition
•
However…
• PoC trials evidence effects that could be logically related to the expected clinical benefit (e.g., tumour shrinkage in cancer)
• Might be used to quantitatively evaluate this effect (activity e.g. response rate)
• Validate mechanistic hypotheses formulated a priori for drug development
• Inform (indirectly ?) (reliably ?) on the expected size and likelihood of a clinical beneficial outcome (e.g., delayed progression, prolonged survival, i.e., efficacy).
• •
Is (human) activity an acceptable surrogate for efficacy ? Is (human) PoC an acceptable basis for full or conditional MA ?
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One Working Example
•
Clofarabine Original application for ALL after at least two prior treatments and AML 2d line.
•
CLO-212 in ALL : 40 patients, then updated with longer term follow-up in 61 pts
•
CLO-222 in AML : 42 pts
Both studies were single-arm
•
Initial results in CLO-212 (in 40 pts 2 to 6 prior lines) 11/40 at least partial response, 7 of them in remission NOT CONSIDERED AS A CLINICAL BENEFIT BY CHMP
•
Prolonged follow-up 18/61 at least PR, 12 in remission… AND 10 children underwent HSCT (8 responders) Survival 18 weeks (9-10 weeks in registries) more than 1 year in responders
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One Working Example
•
Clofarabine Original application for ALL after at least two prior treatments and AML 2d line.
•
CLO-212 in ALL : 40 patients, then updated with longer term follow-up in 61 pts
•
CLO-222 in AML : 42 pts
PoC (activity) Both studies were single-arm
•
Initial results in CLO-212 (in 40 pts 2 to 6 prior lines) 11/40 at least partial response, 7 of them in remission NOT CONSIDERED AS A CLINICAL BENEFIT BY CHMP
•
Prolonged follow-up 18/61 at least PR, 12 in remission… AND 10 children underwent HSCT (8 responders) Survival 18 weeks (9-10 weeks in registries) more than 1 year in responders
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One Working Example
•
Clofarabine Original application for ALL after at least two prior treatments and AML 2d line.
•
CLO-212 in ALL : 40 patients, then updated with longer term follow-up in 61 pts
•
CLO-222 in AML : 42 pts
Both studies were single-arm
Benefit (efficacy) •
Initial results in CLO-212 (in 40 pts 2 to 6 prior lines) 11/40 at least partial response, 7 of them in remission NOT CONSIDERED AS A CLINICAL BENEFIT BY CHMP
•
Prolonged follow-up 18/61 at least PR, 12 in remission… AND 10 children underwent HSCT (8 responders) Survival 18 weeks (9-10 weeks in registries) more than 1 year in responders
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Orphans and PoC
•
A positive R/B balance must be a basis for an approval (even conditional)
For orphan products as well !
•
NfG Clinical Trials in Small Populations CHMP/EWP/83561/05
http://www.emea.europa.eu/pdfs/human/ewp/8356105en.pdf
• • • •
7
Substitution studies (OK when symptoms are well known, within patients comparisons acceptable. In other situations, comparative data needed/expected Dose response relationship, pharmacodynamic studies (PoC ?) supportive Discussion on surrogate endpoints
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GUIDELINE ON CLINICAL TRIALS IN SMALL POPULATIONS http://www.emea.europa.eu/pdfs/human/ewp/8356105en.pdf
In the context of rare disorders for a given clinical endpoint or validated surrogate endpoint recruitment of a sufficient number of patients would be difficult or demonstration of this endpoint would take an unreasonable length of time. Then use of other surrogate markers as substitutes for a clinical endpoint may be considered. The term ‘surrogate endpoint’ should only be used for biomarkers, which have been validated. However, selection of a surrogate marker as study endpoint requires it to be reasonably likely – based on epidemiologic, pathophysiologic, or other evidence – to predict benefit. Prediction in itself may not be sufficient to establish efficacy. Considerations should include: • How closely changes in the surrogate endpoint are causally linked to changes in a clinical endpoint or symptom. • How much risk is associated with the therapy • What other therapies (if any) are available for the same condition. …/… A risk–benefit assessment may become very difficult, since the size of benefit may be impossible to determine based on a surrogate endpoint. Also it has to be pointed out that surrogate markers cannot serve as final proof of clinical efficacy or long-term benefit. If they are intended to be the basis for regulatory review and approval then, unless they are properly validated, there should be a predetermined plan to supplement such studies with further evidence to support clinical benefit, safety and risk/benefit assessment. Also it has to be pointed out that surrogate markers cannot serve as final proof of clinical efficacy or long-term benefit. If they are intended to be the basis for regulatory review and approval then, unless they are properly validated, there should be a predetermined plan to supplement such studies with further evidence to support clinical benefit, safety and risk/benefit assessment. 8
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Dr Detlef NIESE, Head External Affairs in Clinical Development & Medical Affairs, Novartis Detlef Niese is head of External Affairs in Clinical Development and Medical Affairs, at Novartis Pharma in Basel. He is a licensed pharmacist and board certified internist with specialization in clinical immunology / rheumatology. He received a doctoral degree in immunogenetics from the faculty of Medicine in Bonn Germany. Since 1990, Dr. Niese has been a member of the Faculty of Medicine of the University of Bonn, Germany, teaching Internal Medicine and Clinical Immunology. Before leaving academia in 1992, he headed Clinical Immunology and Clinical Pathology at the department of Internal Medicine at the University of Bonn, Germany. After joining Clinical Research and Development of Sandoz AG which later became Novartis AG he worked on development projects in the areas of organ transplantation, xenotransplantation, clinical immunology, tropical medicine and tissue engineering. Since 2001, Dr.Niese has been a member of the management team in Clinical Development at Novartis. Contact details: Dr Detlef Niese Head External Affairs Novartis Pharma AG Postfach 4002 Basel Switzerland
[email protected] Tel.+ 41-6132 47249
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Proof of Concept in Drug Development and Rare Diseases A perspective from Industry Detlef Niese M.D., Novartis Pharma Development
Agenda
Proof of Concept: What is it and why do we need it? Rare Diseases: Models and &Targets Conclusions
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Developing New Medicines Not a Linear Process… Genetics/ Genomics Proteomics Models
Understand Disease
Find Target
Learn for next Generation/ New indication Develop
Select best Compound
In Man
Design trials demonstrate safety efficacy and value
High Throughput Screening Funct. Genomics
Prove Concept in Man
Close Cooperation R&D
Translational Medicine
3 | Proof of Concept in Rare Disease: Industry | D Niese | December 14, 2007 |Eurordis Round Table, Paris |
New Drug Development Today Typical issues
Most development projects fail during the clinical phase • Exposure of patients or volunteers to risks of clinical research without benefit to anyone • Delayed availability of innovative medicines to patients • Lost time, money, resources
Decisions to advance development projects to next phase are often based on insufficient information (e.g. animal data) There is a need for rational, early decisions based on relevant data in man Studies generating such data are called “proof of concept studies”
4 | Proof of Concept in Rare Disease: Industry | D Niese | December 14, 2007 |Eurordis Round Table, Paris |
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Biomarkers Bringing Proof of Concept Studies to Life
Biomarkers are biological parameters (laboratory, imaging) which may correlate with • Disease pathways • Pathology, Pharmacology • Mode of action of drug candidate • Clinical Effect (“surrogate markers”) 5 | Proof of Concept in Rare Disease: Industry | D Niese | December 14, 2007 |Eurordis Round Table, Paris |
Biomarkers Bringing Proof of Concept Studies to Life
Validated Biomarkers can be used • To define patient populations likely to benefit from new treatment • Serve as trial endpoint in clinical trials (e.g. proof of concept)
6 | Proof of Concept in Rare Disease: Industry | D Niese | December 14, 2007 |Eurordis Round Table, Paris |
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Proof of Concept (PoC) Studies Powerful Tools to Rationalize Decisions in Drug Development
Objective Reduce attrition in clinical development phases Speed-up development and patient access to safe, effective treatment Strategies for PoC Identify short term, low risk endpoints highly predictive for safety and efficacy of new medicine in patients • Use of validated biomarkers (biologic markers, imaging) • Conduct trial in other disease with same mechanism of disease but easier to study • Genetic disorders with well understood disease pathways
Conduct PoC trials in human subjects as early as possible Advance development to next stage only after positive proof of concept
7 | Proof of Concept in Rare Disease: Industry | D Niese | December 14, 2007 |Eurordis Round Table, Paris |
Proof of Concept Studies The optimal indication for PoC Studies
Mechanism of disease well defined and closely linked to drug target (e.g. genetic disorders) Disease mechanism relevant for other diseases Endpoint easy to capture Fast response to treatment Positive risk-benefit
Examples Disease
Mechanism relevant for
• • • • •
Transplantation Other autoinflammatory disorders Other sensitive tumors other autoimmune disorders mTOR dependent tumors
Psoriasis Muckle Wells Syndrome CLL (bcr/abl translocation) Systemic Lupus Graft rejection
8 | Proof of Concept in Rare Disease: Industry | D Niese | December 14, 2007 |Eurordis Round Table, Paris |
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Proof of Concept Studies Requirements for Endpoints
Directly linked to mechanism of action, mechanism of disease or drug target Need for small sample size and short treatment duration Fast readout Positive risk-benefit Highly predictive for final clinical outcome Examples: • • • •
PET for tumor response Topical application of immunosuppressant Suppression of expression of disease related gene products Blockade of effector molecule (e.g. cytokine, hormone)
9 | Proof of Concept in Rare Disease: Industry | D Niese | December 14, 2007 |Eurordis Round Table, Paris |
Case Studies
Use of PET Scan in a rare tumor Muckle Wells Syndrome as model for IL1-mediated inflammation
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Proof of Concept in Rare Diseases: Proof of Concept in Target Indication Example of a Proof of Concept Study using PET Scan as a Biomarker for efficacy
* FDG PET studies before (A) and after 4 weeks of treatment (B) with a new medicine in a patient with a rare tumor 11 | Proof of Concept in Rare Disease: Industry | D Niese | December 14, 2007 |Eurordis Round Table, Paris |
Muckle-Wells Syndrome1 A Rare Inflammatory Disease mediated by Interleukin 1 beta
Muckle Wells Syndrome is a very rare, autosomal dominant, monogenetic disorder • Urticaria, deafness, amyloidosis
MW is caused by mutation of the NALP3/CIAS1 gene on chromosome 1q44 and overexpression of cryopyrin The mutation results in spontaneous release of IL1-beta. Other mutations at this locus are associated with other familial inflammatory disorders: Familial Mediterranean Fever, cold autoinflammatory syndrome and chronic infantile neurological cutaneous and articular syndrome Response to anakinra, a recombinant IL-1 beta receptor antagonist was described2 1
Grateau G, Muckle-Wells syndrome, Orphanet encyclopedia, June 2003 1 Hawkins PN, LachmannHJ, McDermott MF N Engl J Med 2003;348:2583-4
2
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Muckle-Wells Syndrome A Proof of Concept Study in MWS patients
Four adult MWS patients in Royal Free Hospital London Rapid, complete clinical and laboratory remission in all four patients following single dose of ACZ885, a fully human anti IL-1 beta monoclonal antibody (canakinumab) Response occurred within 2 days and remission lasted more than 155 days up to 203 days Study supports assumed mechanism of disease Data justify decision to move into further development in MWS and in other indications ACZ is currently in phase II/III in different indications as Rheumatoid Arthritis and patients with different NALP3/CIAS1 mutations Source:
Lachmann HJ, Jung T, Bobadilla M et al. Ann Euro Congr Rheumatol (EULAR) 2006 Abst OP0073
13 | Proof of Concept in Rare Disease: Industry | D Niese | December 14, 2007 |Eurordis Round Table, Paris |
Conclusions Proof of concept studies are small studies in patients or healthy volunteers which confirm that a new drug is active in man PoC studies are conducted to make early and rational decisions on advancing a development project to the next clinical phase Rare, monogenetic disorders with well understood mechanism of disease may provide the optimal condition to achieve two objectives: • Achieve Proof of concept for a new medicine targeting a specific disease mechanism, which may be relevant for other more frequent disorders • Develop treatment for patients suffering from the rare disorder under study 14 | Proof of Concept in Rare Disease: Industry | D Niese | December 14, 2007 |Eurordis Round Table, Paris |
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Thank You
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Dr Louis-Christian CLAUSS, Director, Global Regulatory Affairs, NPD, Baxter Dr Clauss is the Global Director Regulatory Affairs New Product Development, BioScience, at Baxter World Trade, France. He graduated both in Sciences and Business with a Master in Bio-Pharmacy and a PhD in Pharmacy and a degree in Business administration (IAE). He was a resident biologist in public hospitals before moving into the Multinational Health Care Industry, both in the Medical Devices and the Pharmaceutical fields (Mérieux, Dow Corning, Boston Scientific, Clintec, B.D®, Baxter) and has more than 20 years experience in International Marketing, Product development and Regulatory Affairs. He has led the development of numerous products including drugs, devices and Biologics including BioSimilar. He is a Member of numerous Professional Societies e.g DIA, RAPS (past General secretary, RACS,), EUCOMED (past chairman of the FRG), APIMCA (past President elected), etc…. He has published more than 60 papers and has spoken at numerous conferences (Scientific, Regulatory and Reimbursement subjects). Contact details: Dr Louis-Christian Clauss Director – Global Regulatory Affairs, New Product Development, BioScience Baxter S.A. 6, avenue Louis-Pasteur-B.P. 56 78311 Maurepas Cedex France
[email protected] Tel. +33 (0)1 34 61 50 51
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Importance of Proof of concept in the Technical Assessment process for licensing in or/and funding future development for the drugs Industry
Louis-Christian Clauss
Cautions
presentation is purely personal and should not in anyway be understood as representing Baxter position or any association I am member of
• This
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“Proof of Concept” Personal definition or regulatory ones ??
Biotechnology products / Orphan drugs Proof of Concept Role of Technical Assessment Team Due Diligence and Technical Assessment process in the word of Biotechnologies Lessons learned from Technical Assessment and Due diligence regarding Proof of concept Examples Therapeutic vaccine Blood coagulation factors Can we draw any conclusions? 11-Jan-08
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Due Diligence and Technical Assessment process in the word of Biotechnologies
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Screening Criteria Used to Identify and Prioritize Candidates of Interest CUSTOMER Unmet need Size/growth of patient population
COMPANY R&D capabilities Mfg capabilities Strategic fit
Prioritize Candidates
COMPOUND COMPOUND Proteins Proteinspeptides peptides Monoclonal Monoclonalantibody antibody Clinical Clinicalstage stage Non-partnered Non-partnered Non-small Non-smallmolecules molecules
CHANNEL Specialty physician
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A Typical BD Process Solicited/Unsolicited Opportunities Search Activities
Preliminary Screen Assessment
Target Lists
Opportunity Evaluation Legal Analysis Due Diligence
Market Analysis
Unsolicited Offers
TAT Analysis
Negotiate
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Any opportunity Business Development Marketing Technical assessment
Initial screen According to specific agreed upon criteria
No/YES Steering committee: Priority list - R&D - Marketing - BD
Reject - communication to stakeholders - potential reevaluation
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Opportunity assessment by the in-licensing team: • Technical assessment
Opportunity assessment file
• Marketing
Final assessment: • In-licensing team • Relevant function heads Pre-clinical Clinical Regulatory PD/PM IP • Internal experts • (External experts)
• Business development
Yes NO - archive - watch list
PSD
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R&D Council
SMT 9
Technical Assessment Team Members Technical Lead (M. S)
List of internal technical experts
Senior Analyst (A. B)
Project coordinator (100%)
Analyst (100%)
Pre-clinical (D.M) Clinical (C.M) IP (K. Z) Regulatory member (L.C.C) Process development, up-scaling (P.G) Project management (M.R) 10
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Screening and Selection Criteria Databases reviewed: • IMS-Health R &D Focus, ADIS R& D Insight, Investigational Drug Insight, Pharma Projects • Companies‘ web-sites • Business Development information
1280 candidates identified
320 candidates for the indications of:
Selection / exclusion criteria: •Exclusion criteria: & developments discontinued - about 830 records were excluded
Autoimmune / Inflammation / Infectious Disease / Etc……. were identified in all stages from discovery to marketed
Categorization criteria: • Stage of Development: Discovery, PreClinical, Phase I, Phase II, Phase III, Pre-Registration, Marketed • Developments originated by larger companies or partnered to big players 11-Jan-08
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Screening Overview- Sources Screen for MABs available for licensing
16 Phase I and Phase II developments identified for licensing
6 identified with potential interest
5 selected for technical assessment
5 assessed with no go recommendation
IMS Health R&D Focus database was screened for compounds indicated to be available for partnering / licensing
413 compounds screened (Phase II + III, marketed, (pre)-registration)
Available compounds left after exclusion of indications such as cancer,
Phase II • Phase III • (Pre)-registration • Marketed 11-Jan-08
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Screening Overview- Statistics 70
60
50
40
30
20
10
0
Preclinical
Stage Preclinical Phase I Phase II Phase III Preregistration Market
Phase I
Phase II
Total 55 22 63 18 1 4
Phase III
Preregistration
Rejected* 25 15 51 12 1 4
Market
On hold 18 4 3 3
Active 12 3 9 3
*Small molecules, transgenic expression, therapeutic field not within interest, data not convincing, too early stage
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Screen Overview - Therapeutic Field Distribution of screened opportunities Thrombotic Disorder 19%
Autoimmune / Inflammation 30%
Others 4% Renal 1% Infection Disease 16%
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Woundhealing 2%
Haemophilia 9%
Genetic disease 19%
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Prioritization of Projects
Input on prioritization Prioritization of projects – according to Therapeutic Field (in descending order) Hemophilia Thrombotic Disorders Rare Diseases (Cystic Fibrosis etc…..) Infectious Diseases Others
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Proof of concept •Best demonstration of Proof of concept •Phase II with appropriate comparators I.e Recognised Standard of care and if NO treatment exists use of placebo – Dose /response relationship is a very important element in the demonstration of “proof of concept” Use of adaptative clinical trial design when appropriate Use of Surrogate Marker (validated when possible)
When Phase II is not possible or Validated pre-clinical models exist Use of pre-clinical In Vivo / In Vitro models when human clinical relevance is demonstrated – e.g Coagulation Factor Proof of Concept can be demonstrated using knock out mouse models 11-Jan-08
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RAD Therapeutic vaccine Production of recombinant viral vector MVA encoding h5T4 (Published in 2006) MVA-h5T4= recombinant MVA encoding h5T4 and a LacZ marker gene were inserted into deletion region II Trovax= a transfer vector pTrV1b is constructed with the h5T4 coding sequence under the control of the modified H5 promotor and inserted into deletion region III in the plasmid pNEB 193
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Case study Therapeutic vaccine Oncology (1) • Clearly there is
an unmet medical need for the treatment of Clear Cell Renal Cancer and positive result will be welcomed by the medical community. • Very encouraging investigator feedback regarding anecdotic case report • The concept of a vaccine against 5TA antigen is very attractive •· RAD safety and tolerability have been well demonstrated when given at different doses and frequency to patients with clear cell renal cancer (RCC) and colon cancer (CRC) · > 95% of patients immunized demonstrated a positive response (either humoral and/or cellular). One might expect the cellular response to be more effective, especially in humans, but certainly cannot assume them to be the same; there is therefore a need to correlate immune reaction with clinical efficacy. ·
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Case study Therapeutic vaccine (2) No conditional approval following an appropriate Phase II is possible (all the trials designated as Phase II by RAD are in fact Phase Ib) 2. There is no clinical proof of concept, i.e. no proof of clinical Pharmacological activity/efficacy as no appropriate controlled (phase II) trials were conducted. The trials designated Phase II by RAD are in reality Phase Ib. No control study (even against historical data) has been conducted. 1. Using historic controls is not recommended only used to try to find some benchmark during protocols development
1.
·
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Case study Therapeutic vaccine (2) There is encouraging post-hoc analyses with suggested correlation between clinical efficacy and level of immunization, suggesting a trend in prolongation of Time To Progress in association with the level of immunological response. 2. Had these data been generated in a controlled study with an appropriate management of the intention to treat and the level of patient loss; those finding would have been enough to seek conditional approval. However, these are unplanned analyses of uncontrolled open label data, not designed into original protocols which could only be considered encouraging and can be used to support the design of appropriate subsequent Phase II a / b trials.
1.
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Pre-clinical In Vivo / In Vitro models when human clinical relevance is demonstrated •A hemophilia A mouse model was generated using gene targeting by Bi et al, 1995 (1). These animals show markedly reduced FVIII activity, a prolonged partial activated thromboplastin time and spontaneous bleedings similar as in human patients [Muchitsch et al, 1999]. •Breeding colony of these hemophilia A mice and will be used for preclinical efficacy, pharmacokinetic and acute toxicology studies for the study of a FVIIa. •Proposed study • Original r-FVIIa will be compared to standard of care factorVIIa regarding efficacy on bleeding/thrombus forming parameters. Deficient mice will be treated with 3 different doses and the effect on selected bleeding/thrombus forming parameters will be determined. 11-Jan-08
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Proof of concept
"The Proof of concept is the scientific demonstration of clinical Pharmacological Activity / efficacy either on human patient or on an In Vitro or In Vivo model for which its extrapolation in a clinical context was scientifically demonstrated and validated" 11-Jan-08
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Conclusion Funding decision, Technical Assessment and due diligence
are essential within the development of new treatment
Such decisions are taken on the basis of the demonstration of a proof of concept
Depending project and products it could need the completion of appropriate Phase II studies or other approach such as relevant demonstrated In Vitro or In Vivo pre-clinical studies
Anecdotal reports, case reports or open label observational studies are of little value in the decisional process
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Conclusion
Each project/product should be evaluated according to its own merit and specificities
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Dr Kerstin WESTERMARK Chairperson of the COMP MD, PhD, Associate Professor Specialist in Internal Medicine and Endocrinology, Uppsala University Hospital Since 1996: Medical Products Agency, Uppsala, Sweden. 1997-2005: Head of Department of Clinical Trials. Since 2005: Senior Expert, Medical Products Agency 2000-2006: Member of the COMP, EMEA Since 2006: Chairperson of the COMP Contact details: Dr Kerstin Westermark Medical Products Agency Husgartan 8 P.O. Box 26 751 03 Uppsala Sweden
[email protected] Tel. + 46 18 17 46 00
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"Proof of Concept as a green light for regulators" Kerstin Westermark Chair of the COMP
“Proof of concept” "If a pharmacological effect can be shown according to the rationale and the rationale seems plausible" (B. Jonsson, Jonsson, MPA)
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Basis for "Proof of Concept"
• "Basic rationale" rationale" (pharmacological (pharmacological properties, properties, •
mechanism of action etc.) "Supportive evidence": evidence": 1. in vitro 2. in vivo preclinical 3. clinical Level of evidence required for proof of concept? concept?
When applying for "Named Patient Prescription" (Swedish example) – (cf Compassionate Use)
• Quality of the product: product: GMP standard • "Proof of concept": concept": Support for efficacy from
•
clinical use/Support use/Support from Scientific papers/Abstracts. papers/Abstracts. For drugs in MAA phase in the EU – support for efficacy and no serious safety concerns "According to science and wellwell-tested experience" experience"
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At the time of Orphan Drug Designation – Proof of Concept/ Concept/Rationale/Medical Rationale/Medical Plausibility Draft Guideline on elements required to support the medical plausibility and the assumption of significant benefit for an orphan designation (EMEA/COMP/66972/2004)
Since - in many cases - little or no clinical experience is available: available: • • • • •
Relevant in vitro and in vivo data in appropriate preclinical models If available: available: established in vivo models for the global condition If in vitro evidence only – relevance to be discussed in the context of the proposed condition When available: available: comparative data or a discussion comparing the results obtained with the product to those obtained with comparators The preclinical data should be discussed even if preliminary results from first administration to humans are available
Orphan Drugs as Examples
Nexavar (sorafenib) sorafenib) in Renal cell cancer Tracleer (bosentan) bosentan) in Pulmonary arterial hypertension Elaprase (idursulfase) idursulfase) in Hunter syndrome
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Nexavar in Renal Cell Cancer (RCC) • RCC - highly vascularised tumour. tumour. RCC frequently associated with a constitutively activated RAF/MEK/ERK pathway. pathway.
• Nexavar: Nexavar: protein kinase inhibitor • Rationale/Medical Rationale/Medical plausibility: plausibility: 1. Inhibition of the activated RAF/MEK/ERK signal transduction pathway in tumor cells - inhibition of tumour progression 2. Antiangiogenesis by inhibition of receptor tyrosine kinases of endothelial cells in the tumor – additive antitumoural effects
Nexavar in RCC cont. • Preclinical data on dual mechanism of action of sorafenib human colon tumour xenografts. xenografts.
• In vivo anti/tumour efficacy against a murine renal tumour xenograft in athymic mice (dose(dose-dependent percent tumour growth inhibition)
•
Clinical: Early phase I data prove evidence of activity of sorafenib in metastatic renal cell carcinoma: 9 patients; 1 partial response with 48 weeks to progression and 5 stable disease (Data above available at ODD)
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Nexavar in RCC cont. • Phase III trial: randomised, randomised, doubledouble-blind, blind, placeboplacebo-controlled in
•
patients with advanced RCC who had received one prior systemic antianti-cancer treatment. treatment. - Primary endpoints: endpoints: Overall survival (OS) and progressionprogression-free survival (PFS). - Results: Results: Survival data nonnon-significant at the time of MA but based on PFSPFS-data, data, statistically robust and mean time to progression or death prolonged in the sorafenib group (167 vs 84 days) days) concluded that a favourable and clinically meaningful effect had been demonstrated. demonstrated. Supportive study: study: Phase II randomised, randomised, placeboplacebo-controlled discontinuation trial in patient with advanced, advanced, refractory solid tumours. . tumours
Tracleer in Pulmonary Arterial Hypertension (PAH) •
Pulmonary Arterial Hypertension - progressive disease; disease; vasoconstriction, vasoconstriction, vascular remodelling and thrombosis in situ
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Tracleer: Tracleer: antagonist of human endothelin receptors, intended to affect vasoconstricting, vasoconstricting, hypertrophic and fibrotic effects by blocking the actions of the endothelin receptors ETA and ETB
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Rationale/Medical Rationale/Medical Plausibility: Plausibility: Endothelin (ET) levels are elevated in patients with PAH and correlate with disease severity and prognosis, prognosis, suggesting a causal role
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Tracleer in PAH cont. Preclinical: Preclinical:
• In vitro functional experiments on animal and human tissues – bosentan competitive antagonist on ET receptors. Similar potency in isolated vessels of different species. species.
• In vivo - 2 animal models of PAH; PAH; Bosentan prevented development of pulmonary hypertension. Partly reversed established pulmonary hypertension.
Tracleer in PAH cont. Clinical: Clinical:
• Exploratory phase II (safety (safety,, efficacy, efficacy, PD and PK) Primary efficacy: mean pulmonary arterial pressure (MPAP), pulmonary vascular resistance (PVR). (PVR). Secondary endpoints a.o. a.o. 6 min. walk test, quality of life. Second study part randomly assigned to placebo or bosentan 1 g b.i.d. b.i.d. Prematurely terminated after 7 patients entered, entered, due to 2 deaths (withdrawal effect?) effect?) and several SAEs. SAEs.
• Phase III, randomised, doubleplacebo-controlled trial in 32 double-blind, placeboPAH patients. Change from baseline to week 12 in excercise capacity. Significant improvement in 6 min. walk test at 12 weeks weeks (primary endpoint) in bosentanbosentan-treated patients compared to placebo. (Data available at ODD)
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Elaprase in Hunter syndrome (HS) (Mucopolysaccaridosis type II) • Hunter Syndrome: Syndrome: X-linked recessive disease caused by deficiency of iduronateiduronate-2-sulfatase (I2S). GAGs accumulate in the lysosomes throughout the body Common pathophysiology: pathophysiology: cellular engorgement, engorgement, organomely, organomely, tissue destruction and organ system dysfunction. dysfunction. Progressive disease. disease.
• Elaprase: Idur-2-sulfonate produced in a human cell line with Elaprase: Idurinserted gene for I2S
• Rationale/Medical Rationale/Medical plausibility: plausibility: Enzyme replacement therapy
Elaprase in HS cont. Preclinical: Preclinical:
• In vivo K/O mouse model of HD. HD. Elaprase decreased GAGs from urine, urine, liver, kidney, kidney, hearts, hearts, lungs, lungs, spleen and skin.
• In vitro: Fibroblasts from patients with HS store undegraded GAGs. GAGs.
Elaprase clears accumulated 35SGAGs in fibroblast cultures from HS syndrome patients, dosedose-dependently. dependently. These data demonstrate that Elaprase corrects the metabolic defect in HS fibroblasts. fibroblasts. (Data available at ODD)
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Elaprase in HS Clinical: Main study: study: Pivotal 12 m. phase II/III db randomised, randomised, placebo/dummy controlled study (96 pat.) Results: Results: After 52 weeks, weeks, patients receiving Elaprase could walk 43.3 m in 6 minutes, minutes, whereas patients receiving placebo could walk 8.2 m. The medicine also produced an improvement in lung function, function, while the patients on placebo showed a slight worsening. worsening.
POC - Guideline on clinical trials in small populations (CHMP/EWP/83561/05) - What is known about the disease pathophysiology? pathophysiology? - Pharmacology of the drug - PrePre-clinical pharmacodynamic studies (ODs (ODs in particular) particular) - Deficiency diseases 'substitution' – wellwell-characterised short/ short/longterm consequences; consequences; PK/PD of drug – helpful - (DoseDose-response relationship increases credibility) credibility) - Endpoints: Endpoints: Surrogate endpoints/Clinical endpoints/Clinical endpoints - how to rate in POC discussions? discussions? To be considered when POC is discussed… discussed…
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Not Proof of concept - but Proofs of concept? "Multilevel"… Multilevel"… • Molecular • Cellular • Animal • Human "From molecular - to mice - to man"
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Ms Niclas and Prof Amesein both made oral presentations on the topic “Proof-of-Concept as a Green Light for Ethics”
Ms Olivia NICLAS Chairperson of the French Organization for Ectodermal Dysplasia (AFDE) Olivia is the mother of a 10 year old boy affected by ectodermal dysplasia. She runs the French organization for ED and another French organization for all rare disorders. She is completing a Masters on medical ethics. Her son's disease, EDA, is about, we hope, to get a treatment for newborn babies and Olivia is very involved in the process. Contact details: Mrs Olivia Niclas Chairperson Association Française des Dysplasies Ectodermiques (AFDE) 3 rue Alsace Lorraine
[email protected] 92100 Boulogne, France Tel. +33 (0)1 46 03 28 33
Prof. Jean-Claude AMESEIN President of the INSERM Ethical Committee. Prof Amesein has been President of the Ethical Committee for medical research and health (ERMES) at Inserm since 1993. His other main activity is Senior Lecturer in Medicine (immunology) at Université Paris 7/Medical Faculty Xavier Bichat/CHU Bichat-Claude Bernard (since 1998). In addition, he is a member of the “Comité Consultatif National d’Ethique” and of the “Commission française pour l’UNESCO”. Contact details: Prof. Jean-Claude Amesein Faculté de Médecine Xavier Bichat, Inserm U552 16, rue Henri Huchard 75870 Paris cedex 18 France
[email protected] Tel. +33 (0)1 44 85 61 50
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“Proof- of- Concept as a Green Light for Ethics” (Olivia Niclas, patient representative AFDE)
As a mother and as an associative leader, I have been asked to share with you my preoccupations about ethic in the field of the proof of concept. As I understand this concept, proof of concept is the exact moment where a scientifical intuition, after having been tested on animals and in vivo can get a chance to get to human.
What is scientific is not always ethical but, in clinical trials, especially in therapeutic trials, the good news is that what turn out for the benefit of the patient, with his free consent and, of course, a fulfilled information, is ethic for the families. If a non-ethical research exists, a research good in itself doesn’t really exist, only the outcome is or isn’t good.
Without information there is no real consent. We, association, must be aware that information has nothing to do with convincing patients to participate to the research. The ethical problem we meet here, with our rare and severe diseases, is that the way to access to treatment is through research. Research and therapeutic are mixed up. On the other hand, we can be happy to know for sure that the purpose is individuals benefits.
Assessment of Risks and Benefits Research that turns out to be therapeutic is ethic. We are here in the field of an evidence based ethics. The benefit/ burden balance must be our goal but this is as well submitted to personal appreciation and is not always predictable. Learning what will in fact benefit may require exposing persons to risk. The problem posed by these imperatives is to decide when it is justifiable to seek certain benefits despite the risks involved, and when the benefits should be foregone because of the risks. Risk is properly contrasted to probability of benefits. The benefice must be for the particular individual and not for the Science. The Belmont report tells us to put emphasis on beneficence individuals and that patients should be treated as autonomous agents. Learning to listen to what for patients are willing to take risk is part of treating them as autonomous people. One can think very differently from the authorities.
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For example, in my disease, we are about, I hope, to get a treatment. This treatment works better on animal during pregnancy and avoids babies to born sick. They born cured! We have FDA authorization to start human trials. But they have decided for ethical reasons to treat newborn babies and not pregnant women. For the mothers involved, I think that we feel more comfortable with such a treatment on ourselves than on the only newborn baby, because we feel responsible for them and sharing the risk is a way to deal with this responsibility.
So the problem we get now is when the promises are not fulfilled. The” zero risk” doesn’t exist, we all acknowledge so, life in itself is a risked process and that’s one of its specificity, is a life where everything is on control, predictable, still a life? If we don’t expect life to be predictable so don’t we expect research to be so.
Voluntariness An agreement to participate in research constitutes a valid consent only if voluntarily given. I must say here that a vulnerable sick person has little choice. It is always a matter of urgency. So it’s impossible to be purist and to seek for a real voluntariness it is always the choice between a no choice and another.
Trust Patients can be more defiant when they don’t have trust in the clinician and trust comes from their common history and is build up through a long period of time. The trust is also build up by how the project in itself has been matured between the patients (by this, I mean through their association when it exists) and the laboratory. In my personal experience, I can see how to have a close relationship with the promoter can lead the patients to feel more concerned, in a mature way and more trustful in the process. We association have a key role to play in explaining to our fellows about the role of all the institutions that act to protect them. It’s have been a real surprise for me to hear a laboratory explaining the promises of a potential new treatment in front first of the French patient community and few months later in front of the American patients. I want here to share with you a strong disappointment: the American people asked a single one question: do you have the FDA authorizations and that was enough for them. The French patients were a lot more anxious. It seemed that they don’t feel reassured by their institutional authorities. I think that we have all together a role here, it’s part of our job to explain and to communicate. Afssaps here in France is watching over and
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very vigilant but probably there is here a lack of communication on their actions that I personally regret.
Research for our rare diseases is most often related to children. Sick persons and vulnerable persons represent easily a danger for ethics. Sick children are both of it. But, I would like here to add that patients aren’t concerned with this issue; they feel the same toward their 6 years children or their young adult. For both of them, they feel responsible in the same way. They aren’t aware of any major problem concerning younger children. Justice The principle of justice instructs us that subjects should not be chosen simply because they are available and easy to manipulate. In addition it requires that subjects who are likely to benefit from a study should not be excluded. This happens too frequently. I often hear that investigators look for a perfect pure patient. This is unnatural. The perfect patient doesn’t exist in the real world. So please, don’t let out patients who can benefit from the research although it can seem in the interest of the research. It’s always a short-term interest. The non ethic trial would be a trial that doesn’t get the chance to get into realization. And for this, there is no way to make any scientific publication. The project stay silent, and only the patient’s disease is shouting out.
To sum up my presentation; it’s true that it can seem critical to be a subject of research. But how does it seem not to be a subject of research and to live with no hope of treatment?
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Dr Bonnie MILLS, Vice President, Clinical Operations, IDM Pharma Dr. Bonnie Mills received a Ph.D. in medical sciences from the University of New Mexico. She has worked in the immunology/oncology development area both as an academic researcher and in pharmaceutical drug development for more than thirty years. She spent ten years at the City of Hope National Medical Center in Duarte, California prior to joining Baxter Healthcare in 1988. Dr. Mills’ industry experience has focused on the development of immunologic therapy approaches in oncology including drugs, biologics and combination therapies that include devices through all phases of clinical development. In 1997, the Baxter Immunotherapy Division became Nexell Therapeutics Inc., where Dr. Mills was the Senior Director of Clinical and Regulatory Affairs and Quality Assurance until 2002 when she joined IDM Pharma. At IDM Pharma where Dr. Mills is Vice President of Clinical Operations the company is focused on the development of innovative cancer products that either destroy cancer cells by activating the immune system or prevent tumor recurrence by triggering a specific adaptive immune response. The goal is to maximize the full therapeutic potential of each of its innovative products to address the needs of patients and the physicians who treat these patients Contact details: Dr Bonnie Mills Vice President, Clinical Operations IDM Pharma 9 Parker, Suite 100 Irvine CA.926/8-1605 USA
[email protected] Tel.+ 1 (949) 470-6465
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EURORDIS Round Table of Companies
Cooperative Group Studies in Rare Pediatric Cancers: Perspectives Bonnie Mills, Ph.D. Vice President Clinical Operations
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Challenges in pediatric oncology • Small numbers of patients with high cure rates compared to adult cancers – Need for long term follow up for patient outcomes • How best to design a trial that: – Can be completed in a reasonable time – Can detect a treatment difference of clinical interest with traditionally small α and β errors. • Study cohort is not a sample from the population but is the population (given low incidence)
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Why use cooperative group studies? • Trials are standard of care in pediatric oncology as the majority of patients are treated in clinical research protocols • Since 1950s, cooperative research has raised pediatric cancer survival rates from ≤10% to 77% • Regulatory agencies, e.g. FDA, provide specific guidance for use of cooperative groups in planning and conducting studies in pediatric oncology • Cooperative groups are independently funded and provide unbiased assessment
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Cooperative group studies • Aim is treatment, not drug-specific, development: “Therapeutic research aimed at improving the survival and quality of life is of highest priority.”* • Multiple study objectives • Focus on clinically important adverse events: Unexpected, serious, grades 3 and 4 • Less centralized documentation with reliance on centers of excellence – Site-specific, rather than study-specific, monitoring • Long timelines cover changing norms *US National Cancer Institute, Cancer Therapy Evaluation Program “Goals of Cooperative Group Research”; http://ctep.cancer.gov/resources/coop2.html
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Relevance to orphan diseases • Recognition that academic consortia may be the only feasible way conduct large trials in certain rare diseases • Need to carefully consider long-term studies in rare diseases where clinical practices and regulatory guidelines may evolve over time • Importance of involving disease specialists in all phases of study planning, conduct and review
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Topics for discussion • What is the role of cooperative group data – particularly data collected independent of an industry sponsor – in drug development? • What kind of dialogue should be facilitated between regulators, industry, and cooperative groups about orphan disease study designs and the use of data to support approval?
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Dr Andreas ORFANOS, Executive Vice President, Neurochem Inc. Dr. Andreas Orfanos, Executive Vice President Neurochem, obtained his medical degree (MBBCh) in 1991 from the University of Witwatersrand in Johannesburg, South Africa, where he also obtained his MBA. He has over 25 years diverse experience in the medical, healthcare, pharmaceutical and biotechnology fields. Following various medical roles in hospitals, Dr. Orfanos began his career launching and managing hospitals in South Africa with Lifecare. In 1987, he joined Sandoz Products as Medical Director. He was transferred to Sandoz Canada (now Novartis) in 1991, where he led the R&D department and soon thereafter established the Immunolgy –Transplantation group. Within Novartis, as Vice President of the Specialty Business, he established the oncology group as well as led the neurology, immunology and oncology areas. Thereafter he was responsible for the Strategic Planning and New Product Development. In 2002 he joined Picchio Pharma, and was responsible for identifying, evaluating and determining licensing opportunities in the biotechnology field. He joined Neurochem in October 2004 and as Executive Vice President, Strategic Planning and Scientific Affairs has the overall responsibility for many areas including research and development, drug development and strategy. Contact details: Dr Andreas Orfanos Executive Vice President, Strategic Planning and Scientific Affairs NEUROCHEM Inc. 275 boul. Armand Frappier
[email protected] Laval (Quebec) Tel: (450) 680 4432 H7V 4A7 Canada
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EURORDIS 7th Workshop Proof of Concept and Level of Evidence in Orphan Drug Development Case Study: Challenges faced by an SME developing a treatment for AA amyloidosis Evolving scientific knowledge Designing, conducting and analyzing trial in complex clinical setting Regulatory Considerations
Dr Andreas Orfanos Neurochem 14 Dec 2007
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AA amyloidosis: background Rare, life-threatening complication of underlying inflammatory conditions Difficult to estimate prevalence : EU: < 20 000 patients Systemic multi-organ deposition of AA amyloid kidney main organ affected: > 90% have renal involvement; other manifestations less frequent e.g. gastrointestinal
Over 40% patients progress to end-stage renal failure within a median of 6 years of diagnosis No specific treatment currently available Limited understanding of the disease compounded by advances in underlying therapy and change in patient clinical features 2
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Designing trial in a complex clinical setting First RCT & largest trial conducted in field Difficulty as evolving disease & knowledge particularly impacting on choice of end points Design reflects current practice heterogeneity of underlying disease: RA, CD, bronchiectasis use of underlying therapy i.e. effect on top of other drugs
Recruitment potential limited: reliance on pool of patients 27 sites in 13 countries (U.S., Europe, Middle East, Africa) 18 months to recruit & 5 years to conduct
Importance of CRO selection & expertise Challenge in design, recruitment and conduct of study in rare disease 3
Evaluating effect of drug Effect size difficult to predict as no specific Rx available & difficulty in doing adequate calculations of study power Pre-specified p value on basis of single study Evolving knowledge of disease led to revised & more appropriate end point analyses
Original end point : composite including GI Value of EMEA and FDA scientific advice End point revised (renal) but prior to completion of study & unblinding Followed regulatory discussions, driven by physician expertise & access to National Amyloidosis Centre, UK database
Secondary analyses e.g. individual components of composite Retrieved data on hard end points: ESRD/Dialysis or death
Statistical expertise needs to be complemented with understanding of disease and clinical practice to appropriately evaluate drug effect 4
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CL-503004: 2 year, double-blind (DB) study
Primary composite endpoint 42% reduction in risk of
worsening (p=0.025) With retrieved data, 38% reduction (p=0.046)
Adjustments for baseline covariates have minimal effect on risk reduction Supported by open label data Overall safety profile comparable to placebo
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Treatment effect size in impaired Renal Function
Disease
Patients
Study
Treatment
Reduction in Relative Risk
Reduction in Renal Rate of Decline
Reduction in Renal Rate of Decline (%)
AA Amyloidosis
183
CL-503004
NC-503
42% (p=0.025)
4.7 mL/min/ 1.73m2/yr
30.1% of CrCl
Diabetic Nephropathy
1715
IDNT
Irbesartan (ARB)
20% (p=0.023)
1.0 mL/min/ 1.73m2/yr
15.4% of CrCl
Diabetic Nephropathy
1513
RENAAL
Losartan (ARB)
16% (p=0.02)
0.8 mL/min/ 1.73m2/yr
15.2% of GFR
Chronic Renal Insufficiency
422
n/a
Benazepril (ACEi)
43% (p=0.005)
2.0 mL/min/ 1.73m2/yr
24% of GFR
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Regulatory considerations How does one best evaluate a drug effect in disease with small patient numbers, limited and evolving knowledge? Clinical feasibility and regulatory requirements Guideline on Clinical Trials in Small Populations
Consideration for totality of the data as strength of evidence? Most relevant analyses: renal end points + retrieved data on hard end points: ESRD/Dialysis or death Open label extension data Subgroup analyses limited value as small numbers
Should guidelines applicable to single trial design be applicable to orphan drugs or should the guidelines to small studies be more liberally applied as more flexible If impose too stringent regulatory requirements one may only authorise orphan drugs with major effect while denying approval of drugs with important clinical or therapeutic benefit? 7
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