omp registries: are they a tool to cover the gap? · 2020-01-30 · fondazione per la ricerca...
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Fondazione per la Ricerca Farmacologica Gianni Benzi onlus
Via Abate Eustasio, 30 – 70010 Valenzano (BA) Tel.: +39 080 2052499
www.benzifoundation.org
OMP registries: are they a tool to
cover the gap?
Viviana Giannuzzi
On behalf of EuOrphanWG
THE EUROPEAN MEDICINES REGULATORY NETWORK: PRESENT AND FUTURE
X Foresight Training Course
Pavia, 28 October 2017
Economically not a rewarding market
Poor scientific knowledge of rare disorders
Difficulties in running studies in small populations
An orphan medicinal product is for the
diagnosis, prevention or treatment of a disease so
rare that the costs of developing it would not be
recovered without additional incentives
T. H.Althius
Background
Research & development in
the field of rare diseases is
characterised by many well-
known difficulties
Limits in research for new medicines
in RD field
Lower knowledge on disease pathophysiology
Preclinical models not always available
Geographic dispersion
Lack/few clinical experts – reference hospitals
Patients’ epidemiological data few
Small simple size
specific clinical studies in
this field may be difficult to
perform long and costly
Patients affected by rare
diseases have right to
treatment
1983, United States: ORPHAN DRUG ACT
1991, Singapore: ORPHAN LEGISLATION
1993, Japan: ORPHAN DRUG LEGISLATION
1998, Australia: ORPHAN DRUG PROGRAM
2000, Europe:
➢Reg. (CE) n. 141/2000,
➢Reg. (CE) n. 847/2000 27 April 2000
Regulations around the world on
orphan medicines
European orphan regulation
Provide incentives to
stimulate research
and development of
orphan medicines
Modify market
conditions (e.g. 7-year
market exclusivity)
Establish the procedures to
recognize which medicines
could apply to receive the
incentives –
Orphan Designation
How helping to overcome the existing
hurdles in orphan medicines development?
Specific rules on orphan
medicines
✓ Incentives
✓ Methodology to gain evidence
✓ Networking & collaboration
✓ Suitable access Policies
Giannuzzi V et al. Orphanet Journal of Rare Diseases. 2017 Apr 3;12(1):64
1- Incentives
No mandatory incentives
for research/clinical
research!
ERA-Net for Research Programmes on Rare Diseases
1- Incentives
• Small number of patients to be recruited in CTs
• Golden Standard RCT may be not feasible
• Alternative approaches are more and more used
Best evidence from results
Innovative designs
Identify responders and increase statistical power
Personalised Medicine
(biomarkers, -omics..)
2- R&D methodology
2- R&D methodology
International collaboration among main stakeholders
(industries, researchers, regulatory authorities, CROs, ethics committees,
patient’ associations…)
To find common approaches to develop medicines in
accordance with ethical requirements
Debates/Sharingexperience
NetworkingRegistries/Databases
3- Networking & collaboration
• to create networks of highly specialised healthcare providers
• to provide affordable, high-quality, cost-effective healthcare to patients with conditions requiring a particular concentration of resources or expertise
• to improve patient access to the best possible expertise and care available in the EU for their condition
All Members in an ERN
must have in common the
expertise specialised in
certain treatment(s)
offered or disease(s) or
health condition(s) they
focus on
3- Networking & collaboration
OMP registries: are they a
tool to cover the gap?
Registries and databases
are key tools to increase knowledge and
facilitate research in the field of rare diseases
Council Recommendation on an action in the field of rare diseases (2009/C 151/02); Commission
of the EU Communities. Communication from the Commission COM(2008) 679
Registries and databases in the field of
rare diseases
DISEASE REGISTRIES DRUG DATABASES
Registries and databases in the field of
rare diseases
Many registries focused
on rare conditions exist,
while databases on
orphan drugs are few
Drug registries
• Initially financed by the EC (eTen 510774 2003/C 118/19)
• Started in 2005
• Consorzio per le Valutazioni Biologiche e Farmacologiche (Italy)
• Softeco Sismat S.p.A. (Italy)
• Istituto Superiore di Sanità (Italy)
• Fundación para la Cooperación y Salud Internacional Carlos III (Spain)
• Universidad de Barcelona (Spain)
• Karolinska Institutet (Sweden)
• Fondazione Italiana Leonardo Giambrone per la Guarigione dalla Thalassemia (Italy)
Drug registries
Since 2008 volutarly
managed and updated by
Gianni Benzi Foundation
• Collects and catalogues information on drugs for
rare diseases in EU and US
• Sourced by official EU and FDA databases
• Links administrative and scientific data on
designated and marketed drugs for rare diseases
EuOrphan key points
Active substance
designated as OMPOMPs with a MA
Date of
designation
First and current
sponsors
MA refusals and
withdrawals
EuOrphan data
• therapeutic area,
• genetic nature,
• paediatric interest
Date of MA
MAH
Non-OMPs with
a MA Orphan-like
drugs with a MA
Orphan condition
and indication
EuOrphan data entry process
Giannuzzi V et al. Orphanet Journal of Rare Diseases. 2017 Apr 3;12(1):64
How to use EuOrphan data
• Systematic collection and storage of valid information on ODDs
• Description of therapeutic needs coverage
• Suggestions for ERNs
• Analysis of studies and evidences – stage of drug development
• A source of information in the context of EU projects on rare
diseases:
– InNerMeD-I-NETWORK (Inherited NeuroMetabolic
Diseases Information Network, 2012 12 12, Second Health
Programme)
– DEEP (DEferiprone Evaluation in Paediatrics - 261483 - FP7-
HEALTH-F4-2010)
Collecting data from
different databases:
THE CHALLENGE
Collecting EU and US data on OMPs
SOURCES: EMA Register of designated Orphan Medicinal
Products and EPARs; EC Community Register of medicinal
products; FDA Orphan Drug Designations and Approvals;
Orpha.net; EMA PIP opinions
A significant numerical disparity
between US and EU in terms of
orphan designations exists:
1264 orphan designations in EU
3082 designations in US
Giannuzzi V et al. Orphanet Journal of Rare Diseases. 2017 Apr 3;12(1):64
0
50
100
150
200
250
300
350
Nu
mb
er o
f o
rph
an
des
ign
ati
on
s
Year
EMA
FDA
..not only due to the different entering into
force of OMPs law (1983 vs 2000)…Mean of designations per year:
• 79 in EU
• 93.4 in US
Collecting EU and US data on OMPs
WHAT HAPPENS IF
DATA ARE MERGED?
Some attempts…
• To depict the status of the orphan drugs
designated that not yet received a marketing
authorisation or already marketed for
patients affected by rare diseases in the EU in
comparison with the orphan drugs marketed
in the US
• To analyse the advantages resulting for
patients, if the Orphan Drug
Designations (ODDs) and approvals
would be merged between EU and US
territories
AIMS
• Assuming that the same designation/
medicinal product is available both in
the EU and US if
– the active substance, the rare condition
and the sponsor
– the therapeutic indication and the age
covered by the indication
are the same between the two territories
• Standardising names of active
substances and conditions
Some attempts…
HOW
Some attempts…
+ number of active substances designated as “orphan”:
❖ ODDs would result 3552
❖ designations would cover 1015 rare diseases
+ number of market approvals:
❖ 362 additional therapeutic indications in the EU would be covered
❖ 72 additional therapeutic indications in the US would be covered
Some attempts…
Merging the efforts of the two agencies,
both would advantage of a greater
number of designations and approvals…
Parallel orphan designation submission
EMA and FDA
❖ started working together in 2008 to set up a Common EMA/FDA Application Form for
ODDs
❖ accept the submission of a single annual report from sponsors of orphan products
designated for both the US and the EU
❖ provide parallel scientific advice to sponsors during the drug development
62% of dossiers submitted in
parallel in 2012 !
Lack of harmonization: the existing gap
“Notwithstanding the giant steps made from the EU
and American Agencies to harmonize their strategic
plans in the field of orphan drugs, we found
difficulties in collate information between the two
Regulatory Bodies (FDA and EMA), because the
terminology and processes are not completely
harmonised.”
Lack of harmonisation: examples
✓ Differences in the name of active substance
SPONSOR DISEASE AS (EU) AS (US)
IReg Medical Rejection following solid
organ transplantation
Autologous
CD4+CD25hiFoxP3+regulatory T
cells
(November 2013)
“Autologous regulatory T cells with
an immunophenotype of
CD4+CD25hiFoxP3+”
(October 2013)
T2cure GmbH Thromboangiitis
obliterans
(Buerger’s disease)
Autologous bone-marrow-derived
mononuclear-cell fraction
(September 2010)
Bone marrow-derived mononuclear
cells
(May 2010)
Dyax
Corporation
Hereditary angioedema Recombinant human IgG1 kappa light
chain monoclonal antibody targeting
plasma kallikrein
(October 2015)
Human monoclonal antibody
directed against active plasma
kallikrein
(November 2013)
Amarantus
BioScience
Retinitis pigmentosa Recombinant human mesencephalic
astrocyte-derived neurotrophic
factor
(April 2015)
Human recombinant mesencephalic,
astrocyte derived neurotrophic
factor
(December 2014)
✓ Differences in the name of disease / indication
SPONSOR SUBSTANCE INDICATION (EU) INDICATION (US)
Diamond
BioPharm
Combretastatin A1
diphosphate
Treatment of acute myeloid leukaemia
(December 2015)
Treatment of acute myelogenous
leukaemia
(November 2012)
Wyeth
Pharmaceuticals
Bosutinib Treatment of chronic myeloid
leukaemia
(August 2010)
Treatment of chronic myelogenous
leukemia
(February 2009)
Basilea Medical Isavuconazonium
sulfate (Cresemba)
Treatment of mucormycosis
(as called zygomycosis)
(June 2014)
Treatment of zygomycosis
(as called mucormycosis)
(October 2013)
Lack of harmonisation: examples
✓ Differences in the name of active substance and disease
SPONSOR DISEASE (EU) DISEASE (US) AS (EU) AS (US)
Sanofi-
Aventis
Groupe
Plasma cell myeloma
(as called multiple
myeloma)
Multiple myeloma Humanized immunoglobulin
monoclonal antibody against
CD38 (May 2014)
Humanised monoclonal
antibody against CD38 (April 2014)
ISA
Therapeutics
Epithelial neoplasia of the
vulva, positive for human
papilloma virus
Epithelial neoplasias of the
vulva positive for human
papilloma virus type 16
Human-papilloma-virus-type-
16 E6 / E7 synthetic long
peptides
(December 2007)
HPV16 E6/E7 synthetic long
peptides vaccine
(January 2011)
Targovax Soft-tissue sarcoma Soft tissue sarcoma Genetically modified serotype
5/3 adenovirus coding for
granulocyte-macrophage
colony-stimulating factor
(June 2013)
Granulocyte-macrophage
colony stimulating factor-
coding oncolytic adenovirus,
Ad5/3-D24-GMCSF
(July 2013)
St. George's
University of
London
Mitochondrial
neurogastrointestinal
encephalomyopathy
(MNGIE) due to thymidine
phosphorylase deficiency
Mitochondrial
neurogastrointestinal
encephalomyopathydue to
thymidine phosphorylase
deficiency
Recombinant thymidine
phosphorylase encapsulated in
autologous erythrocytes
(April 2011)
Recombinant thymidine
phosphorylase encapsulated
with autologous
erythrocytes
(December 2013)
Lack of harmonisation: examples
Need for STANDARDISATION and HARMONISATION
Lack of harmonization
Several difficulties may arise in merging designations and approvals, because terms and
classifications are not standardised and sponsors may differ between the two regions as
well as may differ from the manufacturer/patent holder
This joint effort would be made possible if regulatory
procedures were harmonised, and through efforts and
cooperation between the territories
• Infos on studies supporting MA:
– Official SmPCs
– CT databases: EU register, clinicaltrials.gov
– Literature search (unique ad hoc search strategy)
Search terms.
Keywords derived from Medical Subject
Headings (MeSH) vocabulary thesaurus
were used: (MeSH <drug name> AND
MeSH <condition name>) OR (<drug
name> AND <condition name>)
synonyms or acronyms used when
relevant
Another example on the use of drug registries
Another example on the use of drug registries
Take home messages
• Registries focused on drugs result relevant in the rare diseases field
• EuOrphan provides referenced scientific and regulatory data on drugs marketed or in
development both in EU and US, providing a global measure of covered/uncovered patient
needs
• In EU patients have still access to a lower number of drugs than in US difference
reduced, considering non-ODs marketed in EU
• More efforts and cooperation seem necessary to speed up the development and
availability of medicines by merging efforts at EMA and FDA level to identify innovative
regulatory solutions for acquiring evidences from trials and other research sources
Drug registries including data we presented represent an
useful tool to focusing these efforts in the right way
To find out a solution in order to
harmonize the two different pathways…
WHAT IS COOKING?
• to implement the database with data on non-OMPs, namely the
medicines approved for rare diseases by the national Agencies
and medicines never receiving an ODD while approved by
EMA after the entry into force of Regulation (EC) 141/2000 for
rare diseases
• to make the actual database easily accessible for researchers,
companies as well as for patients to search for information and
to disseminate all the available data on OMPs approved and
designated
EuOrphan: the future
An user friendly interface
Different kinds of queries
The status of ‘designated’ and ‘approved’
The agency
The therapeutic area
The paediatric status
EuOrphan: the future
How helping to overcome the existing
hurdles in orphan medicines development?
Specific rules on orphan
medicines
✓ Incentives
✓ Methodology to gain evidence
✓ Networking & collaboration
✓ Suitable access Policies
4- Access policies
Viviana Giannuzzi
PharmD, PhD
Tel. +39. 080 2052499
Acknowledgements
Annalisa Landi
Adriana Ceci