Dr. Gabriele...

Ist die Zulassung das einzige Ziel? Eine Übersicht über aktuelle

Entwicklungen in Pharma DiagnostikEntwicklungen in Pharma, Diagnostik und Medizintechnik

Dr. Gabriele Dallmann

VBU-Mitgliederversammlungg g

4. Dezember 2012

Dr Gabriele Schäffner-Dallmann Focus: BiopharmaceuticalsDr. Gabriele Schäffner-Dallmann. Focus: Biopharmaceuticals

Spezialist für Entwicklung und Zulassung von Biopharmazeutika inkl. ATMPs und Biosimilars

Ex-Regulator PEI: Verantwortlichkeit für Zulassung und

Chargenprüfung aller Antikörper-haltigen A i itt lArzneimittel

EMA: Mitglied in Zulassungs-Gremien und E perten Gr ppenExperten-Gruppen

Entwicklung Regularien und Verfahren B t Beratung Training (EUCRAF)

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Medicinal Products Medical DevicesDrugs

(Chemical entities)

Biopharmaceuticals(Chemical entities)

AIMD MD IVD

VaccinesCells

Tissuesrec.

ProteinsBlood

Products

Combination Product ? 3

In jedem Fall:In jedem Fall:Einordnung des Produktes gemäß Definition derEinordnung des Produktes gemäß Definition der

Richtlinien bzw Verordnungen Arzneimittel? Medizinprodukt?Medizinprodukt?

Verfahren Zulassung oder Zertifizierung oder Überwachung?

BehördeBehörde Nationale Zulassungsbehörde oder EMA? Notified Body?

Üb h b hö d ? Überwachungsbehörde?4

No “Combination Product” Regulatory Status in Europe medicinal product or medical device definitions

Regulatory status defined by primary mode of action (PMOA):(PMOA):

- Metabolic, pharmacological, immunological Medicinal Product MPD

- Other and in particular mechanical/physical p p yMedical Device MDD/AIMDD/IVD

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The current Pharma dilemma Assuming a TOP20 Company with 8 new targets, all for

autoimmune diseases such as RA, psoriasis, Crohn‘s disease E h t t i t l l i th l diff ti t Each target unique, central role in pathology, differentiates

patients from healthy subjects, promising based on postulated MoA (Mode of Action)MoA (Mode of Action)

Clinical trial designs take the currently approved products as basisbasis

The dilemma: Physicians do not support them: „we do not see these patients anymorePhysicians do not support them: „we do not see these patients anymore

in our practice“ Clinical trials in other regions suffer from high placebo effects and low

f l i t i it tsuccessful screening rates in recruitment Pricing: HTA agencies are national and require additional benefit

Consequence: the definition “the market” has changed! Consequence: the definition the market has changed! 6

Biological/biotech products BiologicalsNaturally sourced products

Recombinant proteinsrDNA technologyNaturally sourced products

Hormones

rDNA technologyMonoclonal antibodies

Blood products (IVIG, albumin, clotting factors)

ErythropoeitinGrowth hormoneFilgrastimRecombinant hormones

ATMPsGene Therapy Recombinant hormones

Recombinant enzymesGene TherapySomatic Cell Therapy

Recombinant vaccinesFusion proteins

Tissue Engineered Products

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EU / EEAEU / EEA

Austria (AU) Belgium (BE) Bulgaria (BG) Cyprus (CY) Czech Republic (CZ)

Denmark (DK) Estonia (EE) Finland (FI) France (FR) Germany (DE)                 Greece (EL)National agencies

Hungary (HU) Ireland (IE) Italy (IT) Latvia (LV) Lithuania (LT)

Luxembourg (LU)           Malta (MT) Netherlands (NL) Poland (PL)                Portugal (PT) Romania (RO)

Slovakia (SK) Slovenia (SI) Spain (ES) Sweden (SE) United Kingdom (UK)

+EEA (Iceland, Norway, Liechtenstein)

EMA8

EMA

PhPharma

SCIENTIFIC ADVICE Regulatory procedures

CLINICAL TRIAL AUTHORISATION

MARKETING AUTHORISATION

Regulatory procedures

Agencies involvedMARKETING AUTHORISATION

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AGENCIES INVOLVED

• 31 national agencies and EMAg

SCIENTIFIC ADVICE

N ti ll d t ll (EMA)• Nationally and centrally (EMA)

CLINICAL TRIAL AUTHORISATION

• Nationally but register of clinical trials at EMA

MARKETING AUTHORISATIONMARKETING AUTHORISATION

• Centralised and rarely national (DCP and MRP) procedure

• Experts of national agencies perform the scientific assessment

• EMA as the central administration for the centralised procedure

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p

Clinical Trials in EU

Ph IPhase I Phase I/IIa Phase IIb Phase III

• AutoimmunePhase I• 1 Phase I

Unit• HV

• 1 Univers. hospital

• Pat. withAuto-immune

• 3 Univers. Hospitals, Tumour patients

• Dosis-Finding• PoC

• Autoimmune disease

prov

al

disease

App

UKDE 12 countries in EU,UK

SE NL, PL, Ukraine

12 countries in EU,Except UK,SwitzerlandUSA

EMAUkraine

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CTA: relevant guidanceCTA: relevant guidancehttp://ec.europa.eu/health/documents/eudralex/vol-10/

EU Commission

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MARKETING AUTHORISATION IN EU

1. Centralised Procedure (CP)2. Decentralised Procedure (DCP)3 Mutual Recognition Procedure (MRP)3. Mutual Recognition Procedure (MRP)

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Is there a choice for biopharmaceuticals?BiologicalsNaturally sourced products

Recombinant proteinsrDNA technologyNaturally sourced products

Hormones

rDNA technologyMonoclonal antibodies

Blood products (IVIG, albumin, clotting factors)

ErythropoeitinGrowth hormoneFilgrastimRecombinant hormones

ATMPsGene Therapy Recombinant hormones

Recombinant enzymesGene TherapySomatic Cell Therapy

Recombinant vaccinesFusion proteins

Tissue Engineered Products

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Is there a choice for biopharmaceuticals?Is there a choice for biopharmaceuticals?

• Not really• Mainly centralised procedure!• Mainly centralised procedure!• MRP for existing marketing authorisations – all

those for which the centralised procedure is not applicablenot applicable

• DCP only for those which are not eligible for th CPthe CP

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Agency of the European Union based in Canary Wharf,The EMA

g y p y ,London

Responsible for the administrative and proceduralaspects of EU regulations and directives related to theaspects of EU regulations and directives related to theevaluation and safety monitoring of medicines in the EU

Executive Director and secretariat of ca 550 full-timestaff

Reports to the Pharmaceuticals Unit of the DG Healthand Consumers in the EU Commission (DG SANCO)and Consumers in the EU Commission (DG SANCO)

Independent Management Board responsible forbudgetary and planning matters, monitoring of theAgency’s performance and appointment of theExecutive Director

With the exception of the pediatric activities no scientific

Link to EMA website:

With the exception of the pediatric activities, no scientificassessment and responsibility

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Link to EMA website:http://www.ema.europa.eu/ema/index.jsp?curl=/pages/home/Home_Page.jsp

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EMA responsibility: the mandatory scope of the centralised procedure

(Regulation 726/2004)

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Centralised Procedure mandatory for

– Biotech products – ATMPsATMPs– New active substances for treatment of:

• AIDSAIDS• Cancer• Neurodegenerative disorders

Di b t• Diabetes• Auto-immune diseases/immune dysfunction• Viral diseases

– Orphan drugs

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Centralised Procedure optional forCentralised Procedure optional for

– New active substances (outside mandatoryNew active substances (outside mandatory scope indications)P d t ff i i ifi t th ti– Products offering significant therapeutic, scientific or technical innovation

– Products in the interest of patients at Community levelCommunity level

– Generics of products authorised through the Centralised procedure

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Centralised Procedure – Key Points

• 1 Marketing Authorisation valid throughout the EU / EEA• 1 Trademark• 1 Legal status• Application submitted to one agency only: EMApp g y y• Review process includes all Member States• It is not possible to withdraw the application from selectedIt is not possible to withdraw the application from selected

Member States during the procedure• Results in a pan-European Decision (positive or negative)Results in a pan European Decision (positive or negative)• Expensive (254,100 Euro basic fee = 1 strength associated with

1 pharmaceutical form)1 pharmaceutical form)• Complex logistics and time-lines (submission to approval

14-15 months plus preparation period of 9 months)21

14 15 months plus preparation period of 9 months)

N di i l d t li ti t thNew medicinal product applications at theEMA via the CP

92

Biologicals SM

79

49

2315

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2009 2010 201120% failed 30% / 10% failed26% / 23% failed20% failed 30% / 10% failed26% / 23% failed

2011: 90 reviewsBiologicals: 10 (11%), 7 positive (70%)SM: 48 (53%) 41 positive (85%)

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SM: 48 (53%), 41 positive (85%) Generics: 31 (34%), 30 positive (97%)SM + Generics: 79 (88%), 71 positive (90%)

Success RateSuccess Rate

Biopharmaceuticals: Success rate 66-80%Biopharmaceuticals: Success rate 66-80%

Small Molecules: Success rate 80-88%

Main reason for failure for all: clinical dataMain reason for failure for all: clinical data insufficient adherence to regulatory principles in

the clinical development insufficient or irrelevant clinical effect or insufficient or irrelevant clinical effect or

unfavourable safety

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Authorized and rejected biosimilarsj1 Omnitrope (somatropin) Sandoz Authorised

2 Valtropin (somatropin) Biopartners Authorised

3 Alpheon (IFN alfa-2a) Biopartners Negative

4 Biferonex (IFN beta-1a) Biopartners Negative

5 Binocrit (Epo alfa) Sandoz( )Authorised6 Epoetin alfa Hexal (epo alfa) Hexal

7 Abseamed (epo alfa) Medice

8 Silapo (epo zeta) Stada8 Silapo (epo zeta) StadaAuthorised9 Retacrit (epo zeta) Hospira

10 Epostim (epoetin alfa) ood cell production Reliance GeneMedix Plc Withdrawn

11 I li M l Sh t (h i li ) M l Lif S i‘ Withd (2 )11 Insulin Marvel Short (human insulin) Marvel Lifes Sci‘ Withdrawn (2x)

12 Insulin Marvel Intermediate (human insulin) Marvel Life Sci‘ Withdrawn (2x)

13 Insulin Marvel Long (human insulin) Marvel Life Sci‘ Withdrawn (2x)

14 Filgrastim Ratiopharm (filgrastim) Ratiopharm

Authorised15 Ratiograstim (filgrastim) Ratiopharm

16 Biograstim (filgrastim) CT Arzneimittel GmbH

17 Tevagrastim (filgrastim) Teva

18 Filgrastim Hexal (filgrastim) HexalAuthorised19 Zarzio (filgrastim) Sandoz19 Zarzio (filgrastim) Sandoz

20 Nivestim (filgrastim) Hospira Authorised24

Some players in the field of biosimilar tib diantibodies

Amgen-Watson-PRAAmgen Watson PRA Boehringer Ingelheim

Celltrion Hospira first infliximab under review in EU Celltrion-Hospira first infliximab under review in EU Coherus -Daiichi Sankyo

Merck Hanwha Parexel Merck-Hanwha-Parexel Merck Serono – Dr. Reddys

M l Bi Mylan-Biocon Pfizer

S Bi Q i il Samsung-Biogen-Quintiles Sandoz TEVA

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SCIENTIFIC ADVICE IN EUSCIENTIFIC ADVICE IN EU

Regulatory input by agencies regarding Development plan

• e.g. choice of study population, endpoints, statistical plan Submission strategy Risk management

Two routes in Europe National Scientific Advice CHMP Scientific Advice at EMA

Considerations on the scope of the scientific advice: Preparation of the FTIM study,

f / ?

National agencyof the country of

i.e. mainly pre-clinical programme and manufacture/control? Discussion of critical issues related

to the manufacture characterisation

ythe first CTA

Both, national agency of theto the manufacture, characterisation

and testing scheme? Discussion of the whole

agency of thecountry of the firstCTA or EMA

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clinical development plan? EMA

Medizinprodukte National geregelt - heterogene Behördenlandschaft Richtlinien:

Richtlinie 90/385/EWG über aktive implantierbare Medizinprodukte (AIMD)

Richtlinie 93/42/EWG über Medizinprodukte (MDD) Richtlinie 98/79/EG über In-vitro-Diagnostika (IVDD)

Eigenverantwortlichkeit der Hersteller Anmeldung bei der Behördeg Einordnung des Produktes gemäß Definition, dann in der Regel

Selbstzertifizierung für CE mark („self-declaration of conformity”) Haupt-Komponenten: Qualitäts-Sicherungs-System, technische

Dokumentation und Nachverfolgungs-System nach Herstellung

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IVD-Einordnung Jedes Medizinprodukt, das als Reagenz, Reagenzprodukt,

Kalibriermaterial, Kontrollmaterial, Kit, Instrument, Apparat, G ät d S t i l d i V bi d it i dGerät oder System - einzeln oder in Verbindung miteinander -nach der vom Hersteller festgelegten Zweckbestimmung zur In-vitro-Untersuchung von aus dem menschlichen Körpervitro-Untersuchung von aus dem menschlichen Körper stammenden Proben, einschließlich Blut- und Gewebespenden, verwendet wird und ausschließlich oder hauptsächlich dazu pdient, Informationen zu liefern über physiologische oder pathologische Zustände oderp y g p g über angeborene Anomalien oder zur Prüfung auf Unbedenklichkeit und Verträglichkeit bei den g g

potentiellen Empfängern oder zur Überwachung therapeutischer Maßnahmen.g p

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Vielen Dank!