European Union regulatory updates and recent developments ...€¦ · CMC Strategy Forum Japan 2014...

European Union regulatory updates and

recent developments for Biotechnology

products

Niklas Ekman, Ph.D.

Senior Researcher Finnish Medicine Agency (FIMEA), Helsinki, Finland

[email protected]

CMC Strategy Forum Japan 2014

Hotel Okura, Tokyo Japan

December 8-9, 2014

Lääkealan turvallisuus- ja kehittämiskeskus

The views expressed are my personal views and should not

be understood or quoted as being made on behalf of or

reflecting the position of the European Medicines Agency

or one of its committees or working parties.

The views expressed do not necessarily reflect the position

of the Finnish Medicines Agency either.

Disclaimer

2 Dec 8, 2014 CMC Strategy Forum JPN 2014, [email protected]


1. New Clinical Trials Regulation

2. Transparency in EU pharmaceutical sector 2014 –

Publication of clinical reports

3. Adaptive licensing

4. Future directions in the ATMP field - The Commission

report on the ATMP regulation

5. Recent activities of the CHMP Biologicals Working

Party (BWP)

3

Content

Dec 8, 2014 CMC Strategy Forum JPN 2014, [email protected]


Clinical Trials Regulation 536/2014

• Adopted on 16 April 2014 and published in the Official

Journal on 27 May 2014

• The main goal is to create an environment that is

favourable for conducting clinical trials, with the

highest standards of patient safety

• A streamlined application procedure via a single entry point

- an EU portal and database

• A single authorisation procedure for all clinical trials

ensuring one single assessment outcome

• Strengthened transparency for clinical trials data



Member states

Sponsor Headquarters

Regional office

Regional office

Regional office EudraCT

Regional office

Public

Clinical Trials - current scenario

Courtesy of I. Reischl (AGES, AT)



Concerned MS(s)

Reporting MS

Portal

Submission Sponsor

Headquarters?

Regional office

CoSponsor

Regional office

Regional office

CoSponsor

European Commission EMA

Public

Future scenario – Regulation 536/2014




Validation

Portal

3d 3d 4d

10d

Sponsor Submits

Requests rMS

Willing rMS notification

rMS selected

Final validation

Potential input by cMS until d7 Tacit approval

Notified approval

Notified deficiency

Sponsor has 10d to respond

rMS to complete validation in 5d

No response Withdrawn in all MS




Assessment

Part I

Valid

atio

n

26d 7d Consolidation Coordinated

review rMS Assessment

Draft AR Final AR

45d

Input from Ethics Committee

Notification

5d

5d

45d

Sponsor

cMS

Optional request for information

Part II

12d

Optional request for information

Sponsor response 12d max Assessment

No response Withdrawn in all MS

+31d

+31d

+50d*

+50d*

*) Optional extension for ATMPs and biotechnological products

Court

esy o

f I.

Reis

chl (A

GE

S, A

T)


cMS Assessment


The EU Portal

• Will contain all relevant information as regards CTs

• Will have easily searchable format

• Start and end dates of the recruitment should be published (first act of the recruitment strategy or date of advertisement publication)

• No personal data should be recorded in the EU database

• By default public (with exceptions), recognising, however, the legitimate economic interests of sponsors



Entry into force

• The regulation shall enter into force on the 20th day following that of its publication in the Official Journal of the EU

• The Agency shall inform the Commission upon verification that the EU portal and the EU database have achieved full functionality and the systems meet the functional specifications

• The Commission shall publish a notice to that effect in the Official Journal of the EU, when it has verified that the conditions have been fulfilled

• The Regulation shall apply as from 6 months after the publication of the notice, but in any event no earlier than 28 May 2016



Outlook

• Timelines will be shorter for all parties involved

• Implementation will be a challenge for agencies/ethics committees

• Intense communication is a prerequisite

• Requires functional IT systems (EU Portal and nationally)

• Sponsors will interact with only one member state

• Increasing transparency of process, decisions and documents



European Commission website on Clinical trials

http://ec.europa.eu/health/human-use/clinical-trials/index_en.htm

Clinical trials regulation No 536/2014

http://eur-lex.europa.eu/legal-

content/EN/TXT/PDF/?uri=OJ:JOL_2014_158_R_0001&from=EN

Further information on the clinical trials

regulation








http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=OJ:JOL_2014_158_R_0001&from=EN













Party (BWP)



EMA Transparency measures serve public

health interest*

Pivotal principles

• Transparency is a pivotal element in building trust and

confidence in the Agency’s operation hence contributing to the

promotion and protection of public and animal health.

• In addition it fulfils the right of EMA stakeholders for impartial

and comprehensible information about the medicines

regulated by the Agency and their use for the benefit of public

and animal health.

*Partly based on slides kindly provided by M. Harvey Allchurch, EMA



Transparency in the beginning…

• European public assessment reports, EPAR (1995)

• Same information for patients and healthcare professionals in all

EU languages, all accessible on a single website (1995)

• Publication of all European experts (1996)

…and some more recent examples

• CVs and declarations of interests published for all committee

members, European experts, management board and staff

• More information on workshops and meetings at EMA, more

meetings broadcast live with recordings available

• More opportunities for feedback on e.g. draft guidelines

• EudraCT and clinical trials register websites

• EMA access to documents policy (latest from 2010)



Access to documents, requests for information

• Ensures the widest

possible access to EMA

documents following

requests while providing

adequate protection of

commercial confidential

information, personal data

and other conflicting

interests

• Average 450-500

requests for information

each month



What is currently in the public domain?

• Compared to 10-15 years ago, not much of the submission

and review cycle remains systematically confidential

• Either because applicants put the information into public

domain..

• ..or because EMA publishes • Committees agendas, meeting highlights and minutes

• EPARs at approval, pending EC decisions, rejection or withdrawal

• On-going procedures

• Monthly statistics reports on medicinal products for human use, monthly INN list, SMOPs (Summary of Opinion)

• Orphan drug designation, paediatric investigation plan decisions, etc.



Transparency during centralised Marketing

Authorisation Application

• Information on medicines under evaluation

• Committee agendas, minutes and highlights

• Positive outcomes • Summaries of Opinions

• Product information (SPC, PL)

• EPAR (European Public Assessment Report)

• Assessment history

• Authorisation details

• Negative outcomes • Withdrawal letter and Q&A

• Refusal Q&A



Medicines under evaluation EPAR



The next step in transparency – Publication

of clinical reports

• Exceptional level of

contribution from

stakeholders: with

1,138 individual

comments submitted

by 169 entities

• The principles

adopted by EMA

Management Board

on 2 Oct 2014



Objectives of the policy

• To take the decision-making one step closer to EU citizens and promote better-informed use of medicines

• To promote medicine development by allowing medicine developers and the scientific community to learn from past successes and failures

• To allow third parties to verify the original analysis and conclusions, to conduct further analyses, and to examine and challenge the regulatory authority's positions

• While increasing transparency, the principles of protecting personal data (patients’ identity), protecting commercially confidential information, and protecting the Agency's and the European Commission's deliberations and decision-making process must be secured



Date coming into effect

• For any new MAAs submitted as from 1 January 2015

• For extension of indication applications and line extension

applications submitted as from 1 July 2015

• For all other post-authorisation procedures the effective date

will be determined in 2015

Stepwise implementation of the policy

• In the first phase, clinical reports* will be available on the

EMA website once the concerned procedure has been finalised

• In the second phase, various aspects in relation to individual

patient data (IPD) will be clarified with stakeholders. This will

be completed before IPD is made available

*) Clinical reports include module 2.5 (clinical overview), module 2.7 (clinical summary), module 5

(clinical study reports (CSRs) and appendices 16.1.1 (protocol and protocol amendments), 16.1.2

(sample case report form) and 16.1.9 (documentation of statistical methods))



EMA website on Transparency

http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/ge

neral/general_content_000526.jsp&mid=WC0b01ac0580789730

EMA website on the Release of data from clinical trials

http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/ge

neral/general_content_000555.jsp&mid=WC0b01ac0580607bfa

Further information on transparency and on

the policy of releasing data from clinical

trials


http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000526.jsp&mid=WC0b01ac0580789730



http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000555.jsp&mid=WC0b01ac0580607bfa

http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/general/general_content_000555.jsp&mid=WC0b01ac0580607bfa









Party (BWP)



Adaptive Licensing: Prospectively planned, adaptive approach to bringing drugs to market. Stepwise “staggered” approval.

• To balance timely access for patients with the need to provide adequate evolving information on benefits and risks

• Initial authorisation in a restricted patient population, possibly on the basis of surrogate markers

• Iterative phases of evidence gathering and licensing adaptations



• Aims to guide applicants, through an early multi-

stakeholder dialogue to make the best use of available

regulatory tools • Scientific advice

• Centralised compassionate use

• Standard and conditional marketing authorisation

• Marketing authorisation under exceptional circumstances

• Risk management plans and other provisions of the

pharmacovigilance legislation

• Standard requirements for the quality part

• Concurrent validation could be an option

• European Commission in charge of investigating legal

aspects/legal limitations within the existing EU legal

framework



Pilot project

• Explores the possibility for timely patient access in combination with providing adequate, evolving information on a medicine's benefits and risks

• Non EMA stakeholders involved; HTA bodies, organisations issuing clinical treatment guidelines, patient organizations

• Confidential discussions enabling all participants to freely explore different pathways/solutions without any early commitments

• Aim is to promote and establish early dialogue, not to pre-assess suitability of data



Candidates

• Experimental drugs/biologicals in early clinical development (generally prior to phase III) that • Have a high unmet medical need

• Show sufficient promise of addressing it

• Exploratory discussions ≠ Scientific Advice

• EMA has received and assessed 26 applications as part of the pilot project, 7 have been selected, 3 meetings have taken place (numbers from Sept 2014)

• The adaptive licensing pilot project will be reviewed at the end of 2014 decisions on the next steps will be taken



EMA web site on Adaptive licensing

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general

/general_content_000601.jsp&mid=WC0b01ac05807d58ce

Questions and answers following the initial experience of the

Adaptive Licensing Pilot project

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/0

3/WC500163409.pdf

Questions and answers following the initial experience of the

Adaptive Licensing Pilot project

http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/0

9/WC500172810.pdf

[email protected]

Further information on the adaptive licensing

pilot project


http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000601.jsp&mid=WC0b01ac05807d58ce



http://www.ema.europa.eu/docs/en_GB/document_library/Other/2014/03/WC500163409.pdf






mailto:[email protected]






4. Future directions in the ATMP field - The

Commission report on the ATMP regulation


Party (BWP)



Genetically modified cells

medical device + ATMP combined ATMP

ATMPs covered by regulation 1394/2007

Gene Therapy

Medicinal Products

Somatic Cell Therapy

Medicinal Products

Tissue Engineering

Products



Overview of the application of the ATMP

regulation

• The Committee for Advanced Therapies (CAT), established by Regulation 1394/2007 held it first meeting in January 2009

• Since then, 13 MAAs have been submitted, 4 products have been approved for marketing

• ChondroCelect – for cartilage repair

• Glybera – for treatment of LPL deficiency

• MACI – for cartilage repair

• Provenge – for treatment of advanced prostate cancer

• 5 products under evaluation, 4 applications withdrawn

• By September 2014, the CAT had discussed 110 requests for classification, 189 ATMPs scientific advices, and 5 certification procedures

• In 2014, the Commission published a report on the application of the regulation



Main recommendations from the report

• Measures to avoid disparities in ATMP classification between the Member States

• Clarification on hospital exemption, and data obtained in the HE in context of MAA

• Need for revising the requirements for the authorization of ATMPs and for streamlining of the MA procedures?

• Extending certification procedure and clarification of the link between certification and MAA

• Incentives for academic or non-for-profit developers promoting early contact with authorities, fee reduction for scientific advice, opening certification scheme

• Fee incentives for post-marketing obligations



EMA website on Advanced-therapy medicinal products

http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general

/general_content_000294.jsp&mid=WC0b01ac05800241e0

Regulation (EC) No 1394/2007

http://eur-

lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2007:324:0121:0137

:en:PDF

Commission report on the ATMP regulation

http://ec.europa.eu/health/files/advtherapies/2014_atmp/atmp_en.pdf

Further information on Advanced-therapy

medicinal products


http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000294.jsp&mid=WC0b01ac05800241e0



http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2007:324:0121:0137:en:PDF














5. Recent activities of the CHMP Biologicals

Working Party (BWP)



Recent BWP Activities – New/ Revised Guidelines

New Chair: Sol Ruiz (ES)

New Vice-Chairs: Nanna Kruse (DK) and Ilona Reischl (AT)

• GL on the use of porcine trypsin in the manufacture of human biological medicinal products – Effective date: Sept 2014

• GL on the quantitative composition / labelling of biological medicinal products that contain modified proteins as active substance – Effective date: Sept 2014

• GL on Influenza Vaccines - Quality Module – Effective date: Nov 2014

• Revision of the GL on similar biological medicinal products containing biotechnology derived proteins as active substances: Quality issues (Rev. 1) – Effective date: Dec 2014

• Revision of the GL on Similar biological medicinal products (led by BMWP) – Effective date: 30 April 2015



Revision of the biosimilar

“overarching” guideline



• The reference medicinal product must be a medicinal product authorized in the EEA (Directive 2001/83, as amended)

• With the aim of facilitating the global development of biosimilars and to avoid unnecessary repetition of clinical trials, it may be possible to compare in certain clinical and in vivo non-clinical studies (where needed) the biosimilar with a non-EEA authorized comparator

• The non-EEA comparator must be authorised by a regulatory authority with similar scientific and regulatory standards as EMA

• The Applicant must demonstrate that the non-EEA comparator is representative of the reference product authorised in the EEA

• Analytical and functional data from side-by-side analysis of the biosimilar with the EEA authorised reference will always be required

Choice of reference product



Upcoming BWP guidelines

• Revision of the GL on the adventitious agent safety of urine-derived medicinal products - End of public consultation 31 May 2014

• Revision of the GL on immunogenicity assessment of biotechnology-derived therapeutic proteins. Concept paper - End of public consultation 30 June 2014

• Viral safety of plasma-derived medicinal products with respect to hepatitis E virus. Concept paper - End of public consultation 31 July 2014

• Guideline on process validation for the manufacture of biotechnology-derived active substances and data to be provided in the regulatory submission - End of public consultation 31 Oct 2014

• Revision of the GL on epidemiological data on blood transmissible infections. Concept paper - End of public consultation 31 Dec 2014



EMA website for the Biologics Working Party (BWP)

http://www.ema.europa.eu/ema/index.jsp?curl=pages/contacts/CHMP/p

eople_listing_000009.jsp&mid=WC0b01ac0580028d2c

EMA website on Biosimilar medicines

http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/do

cument_listing/document_listing_000318.jsp&mid=WC0b01ac0580281b

f0

Guideline on similar biological medicinal products

http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_gui

deline/2014/10/WC500176768.pdf

Further information on BWP activities and

biosimilars


http://www.ema.europa.eu/ema/index.jsp?curl=pages/contacts/CHMP/people_listing_000009.jsp&mid=WC0b01ac0580028d2c



http://www.ema.europa.eu/ema/index.jsp?curl=pages/special_topics/document_listing/document_listing_000318.jsp&mid=WC0b01ac0580281bf0




http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/10/WC500176768.pdf




Drug development and scientific advice

Marketing

authorisation

application

Pre-

clinical Clinical studies

Idea

National Scientific Advice

EMA/CHMP scientific advice

Dec 8, 2014 CMC Strategy Forum JPN 2014, [email protected] 41

”Valley of death”

Manufacturing

Labo-

ratorio


Baby Medicines Welfare Clinic (BMWC)

a pilot project of the Finnish Medicines Agency

• National/ EMA scientific advice does not reach all

developers of medicines • Small local companies

• Companies from outside the ICH group

• The very early phase of drug development

• The purpose is to provide a low threshold entry point into the regulatory discussions

• No formal advice

• Short minutes, not to be used as a reference

• A follow up meeting is possible



Drug development and Fimea

Labor

atory

Marketing

authorisation

application

Pre-

clinical

Clinical

trials

Idea

National/EMA scientific advice


Baby medicines welfare clinic

For inquiries; Dr. Juha Kolehmainen, Senior Medicinal Officer, Coordinator

for Scientific Advices and BMWC; [email protected]


Thank you for your attention!

Acknowledgments

Martin Harvey Allchurch (EMA)

Peter Richardson (EMA)

Ilona Reischl (AGES, AT)

Nanna Aaby Kruse (DKMA, DK)

Outi Mäki-Ikola (FIMEA, FI)

Paula Salmikangas (FIMEA, FI)

Pekka Kurki (FIMEA, FI)


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