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

vg@benzifoundation.org

Acknowledgements

Annalisa Landi

Adriana Ceci