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An agency of the European Union
Orphan Medicine Designation and development in Rare DiseasesSegundo MarizScientific AdministratorOrphan Medicines Office
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Orphan Designation split into Three Separate Areas for consideration
1. Orphan Medicinal Designation: conducted by the Committee for Orphan Medicinal Products (COMP):
– Granting of Orphan Medicinal Designation
2. Use of Incentives obtained with Orphan Medicinal Designation (SAWP, PDCO, SME Office at EMA)
– Scientific Advice Working Party: Protocol Assistance, Pediatric Committee (PDCO) Paediatric Investigational Plan, Fee reductions and assistance at Small and Medium Enterprises Office.
3. Review of the Orphan Medicinal Designation at the time of Marketing Authorisation Application: conducted by the CHMP and COMP (Significant Benefit).
– Granting 10yr Market Exclusivity and if applicable +2yr extension for compliant PIP. 2
An agency of the European Union
Orphan Medicinal Designationconsiderations:Situation in Europe
Segundo MarizScientific AdministratorOrphan Medicines Office
Stakeholders & Development of Orphan Drugs in the EU
2000July 2015
Patients: few drugsIndustry: major ‘Big Pharma’ & development of blockbustersHealth care professionals/Academia: not involvedRegulators: at least 28 different procedures for MA
Patients: 105 ’active’ OD, > 1500 products designatedIndustry: major SMEs and Academia involvement – 2/3 of designationsHealth care professionals/Academia: Sponsors of designations / some are MAHRegulators: 1 procedure –centralised
Changes in 15 years of the Orphan Regulation
Legal references in the EU
• Regulation (EC) No 141/2000 of the European Parliament and of the Council on Orphan Medicinal Products of 16 December 1999
• Commission Regulation (EC) No 847/2000 of 27 April 2000
• Commission communication July 2003 (2003/C 178/02)
• Commission communication on Art 8(1) and (3) (C(2008) 4077)
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COMP: composition and responsabilities
• Composition: 1 elected chair, 1 representative per Member State, 3 patients’
Representatives appointed by the European Commission (EC), 3 Members appointed by
E.C. on proposal from the agency.
• Responsibilities:
• Give opinions to the Commission on products eligible for designation.
• Contribute to Protocol Assistance. Questions on Significant Benefit requirements exclusivity of the COMP.
• Give Opinions to the Commission on review of the Criteria for Designation at the time of Marketing Authorisation (MAA) and assessment of Significant Benefit.
• Opinion on granting of 10yr Marketing Exclusivity at the time of MAA.
• Advise and assist Commission on Orphan Product Policy and Guidelines
• Assist Commission in International interactions on Orphan Issues.
COMP CHMP
Designates at any stage of development
Resubmission is user friendly
Occasionally might encourage dreams
“Gate opener”
Interrogative
Adversarial
If in doubt, negative
Prudent and cautious
Quality, Safety and Efficacy
“Gate keeper”
COMP: Orphan Designation
COMP and CHMP roles
Time
Knowledge
Judgement of Medical Plausibility
CHMP: Marketing Authorisation
COMP: Orphan Designation
Evidence of positive Benefit-Risk
Evidence of Significant Benefit
Prot. Assist
Scientific Advice WP
Current EMA/COMP activities in the orphan landscape COMP mission and responsibilities
Give opinions on designation
Advise Commission on establishment
and development of a policy on orphan medicinal products
Assist Commission in international
liaison
Assist on guidelines
Contribute to Protocol Assistance
for Significant Benefit
Review of the Maintenance of
Orphan Drug Designation at the
time of MAA
Main characteristics orphan designation• Procedure are free of charge. • Submissions can be for a product which is for the treatment,
prevention or diagnosis of a rare disease.• A request for designation can be made at any stage of development
before the application for an MAA. The product must not have a previous MAA.
• The sponsor can be a company, Non-governmental organisation, Academic centre or a private individual who is established in the EEA (EU, Iceland, Liechtenstein)
• The COMP assesses the application and sends a recommendation to the Commission who grants the designation thereby opening the incentives.
• Designated products are entered into the Community register of OMPs. NO TIME LIMIT to an Orphan Designation.
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Application package Application form (if intention to file with the FDA there is a Joint Application
form).
Scientific sections A-E of the application (A-E Template)
Proof of establishment of the sponsor in the EU (passport for private person,
certificate of company registration).
Translations of the name of the product and the proposed orphan indication
into the official languages of the European Union, plus Icelandic and
Norwegian
Bibliography
If applicable, letter of authorisation from the sponsor for the person/company
acting on their behalf during the procedure
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October 201313
October 201314
FC
Key Considerations: EC Guideline on the format and content of
applications as OMPs (ENTR/6283/00)
Medical Condition under the orphan legislation: – Any deviation(s) from the normal structure or function of the body, as manifested by a
characteristic set of signs and symptoms (typically a recognised distinct disease or a syndrome)
– Must be chronically debilitating and /or life-threatening.– Different degrees of severity- stages not acceptable– Subset of patients where positive B/R is expected generally neither sufficient to define a
distinct condition.
Prevalence must be BELOW 5 in 10,000 (or no return on investment) Authorised pharmacological treatments in Europe/Member States should
be listed if there are any and European Guidelines highlighted. If any are available then the sponsor must show Significant Benefit
(either clinically relevant advantage or major contribution to patient care.)
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NO
YES
“Prevalence” criterion “Seriousness” criterion
Prevalence
(≤ 5 / 10,000)
Insufficient return on investment
(costs > expected revenues)
Life-threatening or chronically debilitating
Life-threatening, seriously debilitating or serious and chronic
Available “methods” for diagnosis / prevention / treatment
Significant benefit / non satisfactory
“Existing methods” criterion
OR
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Significant benefit (Exclusive for Europe)
Significant benefit: “A clinically relevant advantage or a major contribution to patient care”
Based on assumptions at the time of orphan designation
– Significant benefit over “satisfactory methods” generally understood to mean authorised medicines for the indications.
– Current European Guidelines regarding how to treat patients with the condition.
– COMP to assess whether or not assumptions are supported by available data/evidence supplied by applicant
– Sign benefit to be confirmed at the time of marketing authorisation to maintain orphan status. Data to demonstrate the SB.
– Recommendation document on data for SB and plausibility
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Examples assumption for significant benefit
Clinically relevant advantage
• Drug has a new mechanism of action: clinically relevant advantage to be justified/demonstrated
• Opens possibilities for drug combination• Alternative therapeutic option• Improved efficacy
Major contribution to patient care• Improvement quality of life (e.g. alternative to dietary restrictions)• More “convenient” administration route • Age adjusted formulation
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List of questions
DAY 60 (COMP meeting)
DAY 1
DAY 90 (COMP meeting)
Decision (European Commission) 30days
Opinion
The designation process in the EU
Application submission
Evaluation: Max 90days
In parallel with FDA and/ or
Japan?
validation
Oral discussion
Pre-submission
meeting with EMA staff
Appointment of COMP- and
EMA Coordinators
European Commission Step• Opinion is normally sent on the day following the last day of
COMP by the EMA Secretariat.
• The opinion is evaluated by DG Sanco who determines whether the recommendation complies with the regulation and can question the COMP and request a reassessment.
• If the Commission is still not satisfied it can organise a Standing Committee of Independent experts to give an independent opinion.
• Generally the Commission is satisfied with the recommendation from the COMP. Only two cases in the last 15yrs where it was not.
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Distribution of Opinions by therapeutic area from year 2000 – 2014
Total opinions 1430
ATC codes
22
Number and Outcome of Orphan Applications2000-2014
Adult/Paediatric Use1406 designations up to 2014
Adult, 527, 37%
Paediatric, 194, 14%
Both, 685, 49%
Areas of growing interest and trends in OMP development
Eye diseases: e.g.Retinitis pigmentosa, Non-infectious uveitis, Leber’s congenital amaurosis, Choroideremia, Stargardt’s disease
Skin diseases: e.g. Epidermolysis bullosa, Congenital ichthyosis, Dyskeratosis congenita, Pemphigus;
Genetic a/o Metabolic disorders – continuing and rising
Conditions in prematurely born infants (e.g. Bronchopulmonary dysplasia, Respiratory Distress Syndrome, Retinopathy of prematurity)
Tropical diseases: Malaria, Leishmaniasis
’The first orphan designation sparks the interest’ – clusters of applications for e.g. pulmonary arterial hypertension, hemophilias (A and B), amyloidosis, epidermolysis bullosa, Fragile X syndrome
New types of therapies - Gene therapies (one authorized so far)/ Stem cell therapies (mesenchymal etc.), cancer ’vaccines’
Conclusions
• The Committee for Orphan Medicinal Products (COMP) is a different committee to the Committee for Human Medicinal Products (CHMP) and is focused on various aspects of Orphan Designation and policy in Europe.
• Orphan Medicinal Designation is an assessment procedure conducted by the COMP that lasts maximum 90 days and requires a submission package which covers an application form and a scientific file covering the condition, medical plausibility, prevalence and where necessary significant benefit.
• A positive opinion is communicated to the European Commission who grants the Designation following a 30day procedure and puts the designation on a Community register.
• There is no time limit to an Orphan Designation once a sponsor obtains it nor access to the incentives.
An agency of the European Union
Incentives and regulatory considerations:Situation in Europe
Segundo MarizScientific AdministratorOrphan Medicines Office
2
Post-designation is complex field
• European legislation regarding post-designation is spread over several pieces of legislation.
– Orphan Designation Transfers/Orphan Condition Amendments
– Product development/ Annual reports.
– Small to medium enterprises.
– Licensing
– Conditional Licensing
– Orphan Similarity
– Post-licensing: 10yr Market Exclusivity +2yr Market Exclusivity with endorsed PIP.
Orphan Designation Transfer
• A sponsor may transfer their designation to another sponsor with no charge. Service is free.
• To transfer an orphan designation, the sponsor needs to submit an application to [email protected], together with the documents described in the 'Checklist for sponsors applying for the transfer of orphan medicinal product designation‘.
• The Agency can only provide an opinion on the transfer if all of the documentation required is complete and satisfactory. The Agency will issue an opinion within 30 days of submission of the documentation.
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A dedicated webpage for Transfers of Orphan Designations
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Orphan Product Development• Product development for Rare Diseases offers challenges which
are unique.
• In order to foster development, Europe offers assistance through its incentives mechanisms and fee reductions enshrined in EU regulations.
• Development support through:
– Protocol Assistance
– Paediatric Investigational Plan
– Compassionate Use Guidance
• These are centralised services which are operated by the EMA involving SAWP, PDCO, COMP and CHMP primarily.
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Additional Non-Orphan Designation Regulatory Pathways• Adaptive Licencing:
• early access for patients starting from a niche indication with a high unmet medical need,
• continued collection of data (both on efficacy & safety) in this niche indication and extension to broader patient groups.
• Involve HTAs, patient representatives and health care professionals throughout.
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Additional Non-Orphan Designation Regulatory Pathways continued.• PRIME or Scientific advice at key development
milestones/decision points
• Early Eligibility for accelerated assessment
• Early CHMP Rapporteur appointment
• Proactive, continuous and strengthened regulatory support
• Promote awareness and better use of existing development and authorisation tools• Timing orphan designation // SB discussions // MA data requirements vs OD
maintenance (…)
• Complementarity – collaboration with National innovation schemes
• Offer fee incentives for development for SMEs and academia
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Fee reductions and Waivers associated with Orphan Designation Incentives
• Legally binding the EMA must offer free regulatory and Protocol Assistance for Small to Medium Enterprises as well as for Paediatric Advice/PIPs through the PDCO. For these there is a fee waiver.
• SMEs also benefit from a 100% fee waiver for initial licensing submission and non-SME’s a 10% waiver
• Non-SME’s have 70% fee reduction for Protocol Assistance.
• Academics/NGOs must write to the Executive Director for a 100% fee waiver otherwise a 70% fee reduction applies.
• Potential for amendments to these reductions in 2016. 8
Fee reductions
• Annually EU allocated special fund to cover fee reductions (approx. 6 million Euro)
• EMA has consistently kept maximum coverage for SMEs
• Academia and SME responsible for 79% development of advanced therapies
• Policy reviewed annually, needed revision in 2013 according to current budget
Allocation funds for fee reductions (2012)
Protocol Assistance.• Article 6 of EC Regulation No 141/2000 is the basis for Protocol Assistance
before submitting for a Market Authorisation.
• The EMA operates a centralised Protocol Assistance system for these products through the SAWP.
• Sponsors can submit questions on quality, pre-clinical and clinical development.
• SAWP meets once a month and operates a 70 Day procedure. Fee reductions are applicable on status. There is no limit to the number of times a sponsor can request this service.
• CHMP endorses quality, pre-clinical and clinical development answers
• COMP endorses Significant Benefit answers.
• The EMA operates a parallel Scientific Advice Service with the FDA on request.
• Possibility to obtain input regarding Health Technology Assessment Agency advice.11
Dedicated Webpage to Protocol Assistance
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Scientific-advice and protocol-assistance
requests received
Scientific-advice and protocol-assistance requests received
2011
2012
2013
2014
Scientific-advice and follow-up requests
354 339 365 405
Protocol-assistance and follow-up requests
79 81 108 113
Of the above requests:
Requests for parallel SA and protocol assistance with HTA
7 11
Requests for parallel SA and protocol assistance with international regulators
8 2
Requests for qualification of novel methodologies
22
Post-authorisation scientific advice requests
116 122
• As of July 2015 the SAWP has reviewed 94 Protocol
Assistance requests.
Paediatric Investigational Plan• EC Regulation (EC) No 1901/2006 Article 37 states that “a
Marketing Authorisation Application for an Orphan Medicinal product which includes the
results of all studies conducted in compliance with an agreed paediatric investigation plan
will be eligible for a 2yr extension onto the 10yr Market Exclusivity.”
• Sponsors’ should come and establish the need for a Paediatric Investigational Plan (PIP) with the PDCO.
• The PDCO operates a 120Day procedure with clock-off periods for a PIP. The service is free.
• Sponsor’s should integrate this consultation into their development planning as failure to have a PIP may invalidate their application at the time of submission for MAA.
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Dedicated webpages to Pediatric Investigation Plans
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Specifics of a PIP and Orphan Designations• A PIP may be specific for an Orphan Designation or can cover
several orphan designations under an umbrella term.
• Sponsor’s are encouraged under the Paediatric Legislation to come to the Paediatric Committee (PDCO) after they have Phase I data.
• The Paediatric Regulation offers a rewards programme on completion of the agreed PIP which must pass a compliance test at the PDCO. Data does not have to be positive:
• 6-month patent extension for non-orphan products (to date 30 granted)
• 1yr market exclusivity based on a significant benefit for a paediatric population. (1
granted)
• 2yr extension to 10yr Market Exclusivity per Orphan Designation and condition: 3 granted
• PUMA giving data exclusivity for off-patent products: 2 granted16
Paediatric Rewards
• The Paediatric Regulation offers a rewards programme on completion of the agreed PIP which must pass a compliance test at the PDCO.
• If positive CHMP can assess and offer an opinion to the Commission who grants the reward. Data does not have to be positive:
• 6-month patent extension for non-orphan products (to date 30 granted)
• 1yr market exclusivity based on a significant benefit for a paediatric population. (1
granted)
• 2yr extension to 10yr Market Exclusivity per Orphan Designation and condition: 3 granted
• PUMA giving data exclusivity for off-patent products: 2 granted
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Compassionate Use Advice.
• EC Regulation (EC) No 726/2004 Article 83 states that “By way of
exemption from Article 6 of Directive 2001/83/EC Member States may make a medicinal
product for human use belonging to the categories referred to in Article 3(1) and (2) of
this Regulation available for compassionate use.”
• There is a guideline available for sponsors on the EMA website: GUIDELINE ON
COMPASSIONATE USE OF MEDICINAL PRODUCTS, PURSUANT TO ARTICLE 83
OF REGULATION (EC) No 726/2004
• Sponsor’s can approach the relevant National Competent Authorities to
request that the CHMP provide Advice for compassionate use programmes for
a given product. This coordinated by EMA.
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Regulatory Support for Small to Medium Size Enterprises
• EC Regulation No 2049/2005 specifically addresses assistance of
pharmaceutical SMEs in Europe.
• The EMA operates a Small to Medium Size Enterprises Office whose role is
defined in Article 11 of the Regulation No 2049/2005.
• Companies who qualify need to register with the SME Office in order to benefit
from these incentives more information is available on the EMA website.
• Article 7 of EC Regulation No 2049/2005 is the basis for free Scientific Advice
and Scientific Services for Small and Medium Size Enterprises (SMEs) who
have a product with an Orphan Medicinal Designation.
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Dedicated Webpage to Small to Medium-sized Enterprises
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Specific Orphan Fee Incentives
SMEs - fee waiver applicable for:- scientific advice- scientific services- marketing autorisation application - pre-authorisation GMP, GLP, GCP, PhVig inspections- 1st year post-licensing fees (variations etc.)
An agency of the European Union
Marketing Authorisation considerations:Situation in Europe
Segundo MarizScientific AdministratorOrphan Medicines Office
Key Considerations• Centralised procedure through the CHMP for MAA.
• Maximum 210 day procedure
• Accelerated Procedure
• Exceptional circumstances
• Conditional Licencing
• Orphan Similarity where applicable.
• Review of the Maintenance of the Orphan Designation
• Orphan condition, prevalence and if applicable Significant Benefit.
• COMP gives an opinion on granting the 10yr exclusivity.
• Paediatric Exclusivity
• PDCO responsible for giving an opinion on compliance of completed PIP which if positive opens granting of 2yr extension of Market Exclusivity per orphan condition. 23
Committees involved in assessment at Licencing Stage
• Committee for Human Medicinal Products: CHMP for benefit risk assessment at licensing.
• Committee for Advances Therapeutic Products: CAT for advice on Benefit Risk balance at licencing stage for ATMPs.
• Committee for Orphan Medicinal Products; COMP for review of the criteria for Maintenance of the Designation and Significant Benefit assessment based on Data for opinion on 10yr Market Exclusivity.
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COMP: Orphan Designation
COMP and CHMP roles
Time
Knowledge
Judgement of Medical Plausibility
CHMP: Marketing Authorisation
COMP: Orphan Designation
Evidence of positive Benefit-Risk
Evidence of Significant Benefit
Prot. Assist
Scientific Advice WP
COMP CHMP
Designates at any stage of development
Occasionally might encourage dreams
Resubmission is user friendly
Assessment of Significant Benefit claim at licencing stage.
“Gate opener”
Interrogative
Adversarial
If in doubt, negative
Prudent and cautious
Quality, Safety and Efficacy
“Gate keeper”
Marketing Authorisation
• EC Regulation (EC) No 726/2004 establishes the basis for the centralised procedure for products which have obtained an Orphan Medicinal Designation.
• Specific considerations for Orphan Medicinal Designation Products:
• Centralised Procedure for Products with Orphan Medicinal Designation.
• Conditional Licencing
• Orphan Similarity
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Specific requirements
My designated product MAA
Orphan on the market
Similarity and derogations
MARKET EXCLUSIVITY
Confirmation of PIP compliance
Additional 2yr MARKET
EXCLUSIVITY
Authorisation of an orphan drug
• Based on same standards as for non orphan products (quality / safety / efficacy)
• Authorisation only centralised procedure: Regulation 2004/746
• CHMP responsible for assessment
• Authorisation within a specific designated condition
• More than one designation possible per product so more than one 10yr Market Exclusivity possible (independent incentives)
• A completed (PDCO Compliance test) valid PIP or waiver at the time of MAA submission if new active substance. Eligibility for 2yr ME extension per Orphan Condition.
Conditional Approval
• EC Regulation (EC) No 507/2006 establishes the basis for the conditional marketing authorisation for products which have obtained an Orphan Medicinal Designation.
• MA on the basis of less complete data
subject to specific obligations
• Well motivated in CHMP
• B/R balance positive
• Benefits of immediate availability outweigh risk of incomplete data
• Possibility to supply additional data.
• Unmet medical need 30
Conditional Approval
• Only clinical part of the application dossier is less complete (Incomplete pre-clinical or pharmaceutical data only in the case of emergency situations)
• Specific Obligations: initiate or complete certain clinical studies
• Valid for 1 year and is renewable.
• Only for initial MAA
• Significant benefit is assessed by the COMP at the time of initial MAA.
31
Dedicated webpage for Conditional Licencing
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Other Licencing Considerations
• Although Orphan Medicines are not specifically mentioned in the relevant legislation companies can consider:
• An Accelerated Centralised Procedure (150Day procedure) providing the Applicant submits adequate argumentation the CHMP to support the basis for this procedure.
• A submission based on Exceptional Circumstances which can be considered in very rare conditions where very few patients have the condition.
33
Orphan Similarity
• Paragraph 3 of Article 8 of EC Regulation 141/2000 establishes the basis for Orphan Medicinal Similarity.
• Orphan Similarity involves any orphan designation product which is applying for an MAA where another Orphan Product already has an MAA for the same indication and has the 10yr Market Exclusivity.
• CHMP determines at any stage before EC approval whether there is Orphan Similarity.
• EC Guideline exists which is available on the EMA Orphan Designation legal basis webpage which explains how it works.
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Specific requirements MAA (I)Assessment of similarity
• Applies if a similar orphan medicine is authorised for same designated condition and has a10yr Market Exclusivity
• Need to submit report base on three criteria in module 1.7– Molecular structure– Mechanism of action– Similarity of indication (“significant overlap of populations”?)
• Assessment by CHMP competent working party • Final opinion by CHMP• Similarity can be triggered any time before EC decision
Guideline on Orphan Similarity
36
Derogations to market exclusivity if Orphan Similarity applies
Applicable if product is considered similar by CHMP.
Assessment based on sponsor’s report:
• Specific timetable 60 Day procedure (parallel to MAA assessment)
• If similar Product is blocked from obtaining a Marketing Authorisation.
Three derogations (Art 8(2))
• First MAH’s consent (agreement market sharing)
• Insufficient supply: long term and clinical consequences (presumably)
• Clinical superiority: better efficacy, better safety or exceptionally major contribution to patient care
Specific requirements MAA: Maintenance of the Designation Criteria
• Report must be sent to Orphan Medicines Office using the template provided on the relevant webpage on the EMA website.
• At time of submission MA (if Accelerated Procedure) at the latest at Day 120 of the MAA procedure. Possible to update.
• Need to address all designation criteria (Condition, Prevalence, update Authorised Products at the time of MAA and where applicable Significant Benefit claim using data generated by the Sponsor)
• Protocol Assistance letter should be attached as an appendix
• COMP will start Assessment after Day 121 to have a preliminary opinion at Day 180 or a List of Questions.
• Assessment by COMP; opinion at Day 210 of CHMP opinion of MAA.
• Commission takes 30 days to grant 10yr Market Exclusivity.
10yr Market Exclusivity
• The COMP will make a recommendation on the eligibility of a product for Maintenance of the Orphan Designation and granting of the 10yr Market Exclusivity.
• Each Orphan Medicinal Designation is eligible for one 10yr Market Exclusivity
• This is not the role of the CHMP
• Sponsors should ensure that Significant Benefit is adequately addressed at the time of submission of the report on Maintenance of the Orphan Designation at MAA submission
• Protocol Assistance answer from the COMP on Significant Benefit should be included in the submission and will be considered in the evaluation.
• The Commission grants the 10yr Market Exclusivity based on the recommendation of the COMP.
39
How to obtain additional 2yr extension• To obtain an additional 2yr Marketing exclusivity extension the
sponsor must be compliant with the agreed completed PIP.
• Each separate orphan designation linked to an orphan condition has its own additional 2yr Marketing Exclusivity Extension.
• The Paediatric Committee conducts the compliance check to ensure that the PIP has been completed adequately.
• The COMP is not involved. The CHMP will assess the data in the compliant PIP.
• A positive opinion from the Paediatric Committee and the CHMP opinion is communicated to the European Commission who the grants the 2yr extension for the indication(s) in the PIP.
40
Conclusions
• European Legislation provides the basis of the framework for Post-Orphan Medicinal Designation Incentives and Regulatory Guidance.
• Support of product development through Protocol Assistance, Paediatric Investigational Plans and Compassionate Use Guidance.
• Specific Regulatory support and fee reductions exist for SMEs.
• Centralised Marketing Authorisation with specific consideration to Conditional Authorisation, Orphan Similarity Issues, review of Orphan Designation and granting of 10yr+2yr Market Exclusivity.
41
