The Importance of Developing a Global Regulatory Strategy

Towards the Goal of RegistrationCarlos Langezaal, PhD

Director, Global Regulatory AffairsEisai, Inc.

11DRUGDRUG

10 GO 10 GO INTO INTO MANMAN

100 INTO 100 INTO DEVELOPMENTDEVELOPMENT

1000 SCREENED 1000 SCREENED FOR ACTIVITYFOR ACTIVITY

10000 COMPOUNDS10000 COMPOUNDS

From Compound to Drug

10 - 12 Years

$7500-3000M

New Drug Development Process and Strategy

Pre-ClinicalResearch

SynthesisandPurification

IND /CTA

NDA /MAAClinical

ResearchPost-

Marketing

AnimalTesting

Phase 1

Phase 2

Phase 3

Accelerated Approval

Potential Regulatory Meetings

Phase 4

PMRs

REMS / PSUR

Regulatory Affairs and the Product Life Cycle

Renewal

Variations

Advertisi

ng

Approval / Cleared

Submit MAA/NDA

Regulatory Questions

MAA/NDA

Approval

CTA/INDExtensions/

Updates

CTA/IND

Pharmacovigilance

Advice on Product Development

Regulatory Input into Development Life- cycle

manage-ment

File & Launch

Phase III

PoC to commit

to Phase III

FTIH to PoC

Candidate selection to FTIH

Lead to Candidate

Targetto

Lead

Gene - Function - Target Association

Disease selection

Target family selection

Prior to First Time in HumanWhat do the animal data tell us?

Do we need to amend our target group on the basis of toxicity findings?

Prior to First Time in HumanWhat do the animal data tell us?

Do we need to amend our target group on the basis of toxicity findings?

Initial Product ProfileWhat studies will be needed?

What are the issues we need to discuss with regulatory authorities?

Initial Product ProfileWhat studies will be needed?

What are the issues we need to discuss with regulatory authorities? Prior to Large Scale Clinical Trials

Have we agreed our development plan with Regulators?

Does the trial design meet regulatory/clinical end points?

Prior to Large Scale Clinical TrialsHave we agreed our development plan

with Regulators?Does the trial design meet

regulatory/clinical end points?

Prior to SubmissionDoes the data support the proposed

labeling?What can we learn from

competitor’s experiences?

Prior to SubmissionDoes the data support the proposed

labeling?What can we learn from

competitor’s experiences?

How do we maximize life cycle management? How do we maximize

life cycle management?Following Initial Opportunity AssessmentWhat lessons can we learn from previous

development projects?

Following Initial Opportunity AssessmentWhat lessons can we learn from previous

development projects?

Three phases of regulating products

• IND / CTA phase• Licensure phase• Post licensure phase

Regulation of Clinical Research in the US

IND

StartClinical Program Clinical Hold

30 Days

Other considerations:• Pre-IND meeting

IND Format and Content

• Provide technical information for adequate evaluation to support proposed clinical investigation– Cover letter, introduction, agreements– CMC information– General Investigational Plan, IB and Protocol– Pharmacology and Toxicology data– Any previous human experience

• Provide information on proposed clinical program• CTD format vs “old” format

Regulation of Clinical Research in Europe

• Includes all clinical trials in the EU• Describes a single harmonized process across

all EU member states – Clinical Trial Directive– Individual member states can implement the

Directive slightly differently

Timelines• CTA approvals:– allowed up to 60 days with one clock stop – as a

notification– requires written approval for biotech (60 days)

• In practice timings vary considerably e.g.:– Belgium 28 days– France, Ireland, Sweden, UK 30 days– Netherlands 49 days

• Phase I Studies– Belgium 15 days, France 14 days, Germany 20 days,

Netherlands 21 days, UK 14 – 21 days

CTAs – Format of Applications (1/2)

• Eudract Number • Application Form• Clinical Protocol– Describing in detail the objectives of the trial and

how it will be conducted• Investigators Brochure (IB)– Information on the drug that is critical to the

Investigator (e.g. results of previous studies, marketing status)

CTAs – Format of Applications (2/2)

• Investigational Medicinal Product Dossier (IMPD)– Summary of Quality – information on trial material

and how it is manufactured and controlled– Summary of Safety – information on safety studies

undertaken on the trial product– Efficacy – summary of human studies to date

• Manufacturer’s Authorization for Investigational Medicinal Products (GMP)– Manufacture outside EU - must be released by EU QP

• Examples of labeling

CTA End of Trial Notifications and Reports

• End of trial notifications – national and global reports are required within 90 days of last patient visit

• End of trial reports required within 1 year of completion

The Application

• US: New Drug Application (NDA)• EU: Marketing Authorisation

Application (MAA)• Japan: JNDA

• Format– (e)CTD format in 3 ICH regions–Other regions: national (e)CTD derivatives

NDA / MAA / JNDAThe application includes• Regional documentation (CTD Module 1)• Summaries of CMC, non-clinical and clinical (Module 2)• The drug's test results (Modules 3, 4 & 5)– CMC (CTD Module 3) includes Manufacturing information

to demonstrate proper manufacture of the drug– non-clinical (CTD Module 4)– clinical (CTD Module 5)

• Proposed label. The label provides:– necessary information about the drug, including uses for

which it has been shown to be effective, possible risks, and how to use it

US Approval Routes• NDA – 505(b)(1) Traditional– 505(b)(2) New route/form. for patented drug– ANDA Generic

• BLA (NDA for biologics)

• DEVICES– PMA (NDA equivalent)– 510(k) Based on predicates (features approved) and

NSUR (No Significant Use Risk)

US Timelines and speeding access to important new therapies

• Standard Review – 10 Months (PDUFA)• Priority Review – 6 Months (given to drugs that offer major

advances in treatment, or provide a treatment where no adequate therapy exists)

• Fast track - process designed to facilitate the development, and expedite the review of drugs to treat serious diseases and fill an unmet medical need – includes eligibility for Accelerated Approval and Rolling

Review• Accelerated Approval regulation - allowing earlier approval of

drugs to treat serious diseases, and that fill an unmet medical need based on a surrogate endpoint. Condition that post marketing clinical trials verify the anticipated clinical benefit

EU Application Procedures3 European Procedures• Centralised

– one application to the central EMA allows marketing everywhere in the EU

• Mutual Recognition– an approval in one country is ‘mutually recognised’ in a number

of other EU member states• Decentralised Procedure

– an assessment is carried out by one country – this is discussed and agreed by a number of other EU member states

Need for agreed PIP prior to EU MAA submission

National Procedures in individual countries

Centralised ProcedureKey Points

• One Dossier for the whole EU• Submitted to EMA and the CHMP members• Appointment of Rapporteur/Co-Rapporteur– CHMP members from 2 countries to perform “lead

assessment”• One evaluation period leading to a one EU-wide MA in 27 MS

(+ linking National Licences in Norway/Iceland)• Application review and maintenance all handled by the EMA• National Agencies through CHMP members have opportunity

to ask questions/comment on application

Centralised Procedure - Applicability

• Compulsory for – Biotechnology products – designated Orphan Medicinal Products – drugs for treatment of AIDS– Cancer– Neuro-degenerative disorders – Diabetes– Auto Immune diseases– Viral diseases

• Optional– New Active Substance– Significant therapeutic, scientific or technical innovation or that the

granting of authorisation is in the interest of patients– Generics / Hybrids of Centrally Authorised products– Duplicate licences of Centrally Authorised products

Submission of MAA

• Date of submission agreed between applicant and EMA in relation to published Target submission dates (www.ema.eu.int/)

• Explicit guidelines, but get confirmation in pre-submission meeting(s)– 1 Jan 10: e-CTD MAAs mandatory

• Dossier to be submitted in parallel to Rap/Co-Rap

Deciding your filing strategy

• Elegibility/compulsory Centralized Procedure• Commercial Considerations, market

accessibility• One centralized license vs individual licenses

(Filing only in certain countries)• Data protection

EU Timelines and speeding access to important new therapies

• Review: 210 days (+3 months Commission decision)

• Accelerated evaluation: 150 daysGuidance: EMEA/419127/2005

• Scientific AdviceGuidance: EMEA/4260/01

• Orphan designationRegulation (EC) No 141/2000

Post Authorization Activities

• Post Licensing commitments (US & EU)• Amendments to Marketing Authorisations

(MAs) (EU)/ Amendments to NDA / Supplements to NDA (US)• Renewals (EU)• Annual Reports (US)• PSURs (EU)• RMP / REMS

Develop Regulatory Strategy

• Think Globally

• Start early and fine tune during development