1. Linda Bowen, MS, RAC Director RI, US Region sanofi-aventis
Researching Drug Studies across European Public Assessment Reports & FDA Approval Packages
Linda Bowen, MS, RAC
Director RI, US Region
sanofi-aventis
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2. Disclaimer
The views expressed in this presentation are personal views of the author and do not necessarily represent the views of sanofi-aventis

3. Discussion Points Regulatory Authority transparency
Unpublished* information and Precedence US EU
Canada
Case Study “TORISEL”
*Unpublished” means not compiled and distributed through traditional publishers but publicly available  Published literature is usually indexed and goes through a review and approval process in order to be cited, etc.

4. Transparency
Commitment from Health Authorities for greater transparency, while maintaining sponsor confidentiality, to help build public confidence:
FDA; Summary Basis of Approval
EMEA; Summary of Opinion, European Public Assessment Reports and CMD(h) MRI-Product Index
Health Canada; Notice of Decision/Summary Basis of Decision

5. SBoA, EPAR and SBD
Important to remember that similar to strategy, a Summary Basis of Approval, European Public Assessment Report, and a Summary Basis of Decision, are a snapshot in time which reflects the legislative, regulatory and scientific environment at the time of drug review and approval.

6. SBoA as a Learning Tool Approval Letter
Timeline from submission to approval
Phase IV commitments
Pediatric commitments
Risk Management Plans

7. SBoA as a Learning Tool Administrative and Correspondence Section
Background information and regulatory history
Meeting minutes; discussion points/responses
Timeline and progression from Phase-to-Phase
Issues with trade names (DMETS)
Scheduling
Reviewer profiles
Executive Summary
Expert Opinions
Previous Action Letters

8. SBoA as a Learning Tool
What statute, regulation or guidance were cited during the review? Executive Summary of the Pravigard NDA:
"There is at present no Agency standard for the approval of such co-packaged products. One potential rationale for approval is the approval of co-packaging of any drugs for which a population can be defined that would benefit by both of the components. A more limiting algorithm for approval would limit such co-packaged products to drugs that treat the same symptoms in a defined population......

9. Others Parts of an SBoA Chemistry Review Medical Review
Pharmacology Review
Statistical Review
Microbiology Review
Clinical Pharmacology & Biopharmaceutics Review
Takeaway: Acceptable benefit/risk ratio, pivotal studies, agreed to endpoints, population, demographics, adverse reactions, data sources, review strategy….

10. Other Learning Tools - US
AdCom briefing packages and transcripts
Postmarketing Commitments Database
Patent and Exclusivity Information (Drugs)
Summaries of Medical and Clinical Pharmacology Reviews of Pediatric Studies
ClinicalTrials.gov database

11. FUTURE - FDAAA Title VIII Clinical Trial Databases
Expands current NIH Clinical Trial Registry
All Phase II and III Drug or Biologic product trials
Medical Device Trials
Expanded data elements
Clinical Trials Results Database
Provides for civil monetary penalties for noncompliance

12. FUTURE - FDAAA Title IX, Drug Safety Provisions
Action packages must be posted to the FDA website within 30 days of approval for NCE and not later than 30 days after the third FOIA request for an SBoA for any other drug.
Within 48 hours of approval (except in cases of redaction) a “summary review that documents conclusions from all reviewing disciplines about the drug, noting any critical issues and disagreements with the applicant…..”

13. EU Learning Tools European Public Assessment Report (EPAR)
Summary of Opinion
Opinions/decisions on PIP applications
Marketing Authorization Withdrawals & Suspensions
Public Assessment Report in case of Withdrawal of Application
Refusal Assessment Report in case of negative CHMP opinion
Latest Press Releases, including monthly CHMP reports
MRI-Product Index

14. Canadian Transparency Initiatives
Drug Product Database
Searchable database of approved drugs (Rx and non-Rx) and biologics
Brand Name, Drug Identification Number, Company, Active Ingredient, Route of Administration, Product Monograph (PM), Pharmaceutical Form, Package Sizes, Therapeutic Classification, Active Ingredient Group Number, and Pharmaceutical Standard.

15. Canadian Transparency Initiatives
Notice of Decision (ND)
One-page summary outlining the authorization received and general information related to the drug or medical device. Notice of Decision will be posted independently approximately two weeks after product authorization. When the SBD is published, the ND will be incorporated into the SBD as Section 2.

16. Canadian Transparency Initiatives
Summary Basis of Decision (SBD)
Document that outlines the scientific and benefit/risk based decisions that factor into Health Canada’s decision to grant market authorization for a drug or medical device. The document includes regulatory, safety, efficacy and quality considerations.
Implemented in a phased approach beginning with New Drug Submission (NDS), New Active Substances and a subset of Class IV medical device applications.

17. Case Study – Torisel Approval

18. Case Study – Torisel Approval
EU Approval
Electronic Submission
Orphan Product Designation
Centralized Procedure
Submitted 05-October-2006
Approved 20-September-2007
Active Review Time 203 days
Canadian Approval
Priority NDS
Submitted 20-November-2006
NOC issued 21-December-2007
Uploaded to DPD 24-Jan-2008
ND issued 27-Jan-2008
US Approval
Electronic Submission
Orphan Product Designation
Priority Review
Submitted 05-October-2006
FDA acceptance of additional data April 2007
Approved 30-May-2007
235 day review time to approval

19. Case Study – Torisel Approval
Notice of Compliance 21-Dec-2007
Notice of Decision Issued 27-Jan-2008/Posted 04-Feb-2008
Summary Basis of Decision pending
6-year no file date
8-years data protection
CHMP Opinion 20-Sep-2007
Commission Decision 19-Nov-2007
Initial EPAR 05-Dec-2007 (available within 15 days of commission decision)
FDA approval date 30-May-2007
SBoA posted 30-July-2007
Patent expiration 14-Apr-2014
Orphan Drug Exclusivity 7-years 30-May-2014

20. Case Study – Torisel Indications
TORISEL is indicated for the first-line treatment of patients with advanced renal cell carcinoma who have at least three of six prognostic risk factors. (PL TORISEL is used as an initial treatment for advanced cancer of the kidney)
TORISEL is indicated for the treatment of metastatic renal
cell carcinoma.
TORISEL is indicated for the treatment of advanced renal cell carcinoma

21. Case Study – Torisel Approval
The clinical dossier includes a pivotal multicentre multinational randomised Phase III study involving more than 626 patients and a supportive randomised dose-comparing Phase II study involving 111 patients. The study design of the pivotal study comparing temsirolimus with IFN-alpha and the combination of both is endorsed. IFN-alpha-2a is a well known reference therapy and was considered an appropriate comparator since, at the time the study was planned, there was no other therapy leading to a survival benefit in second line RCC.
One supporting Phase II Study and One Pivotal Phase III
The pivotal study of temsirolimus showed that the drug significantly increased median overall survival by 49% compared with interferon-alpha (10.9 months vs. 7.3 months, P=0.0078), an active comparator that has been the clinical standard of care. The 3-arm, Phase 3 clinical trial included 626 patients with advanced RCC and poor prognosis who had received no prior systematic therapy. Temsirolimus also showed a statistically significant improvement over interferon-alpha in progression-free survival (PFS), the secondary endpoint (5.5 months vs. 3.1 months, P=0.0001).
Clinical data supporting the safety and efficacy of Torisel were obtained primarily from a Phase II dose-finding study and a pivotal Phase III study. The pivotal study involved over 600 patients. An increase in overall survival of 3.6 months was seen with Torisel treatment when compared with interferon treatment. There were also significant improvements in secondary outcomes of progression-free survival, objective response rate, and time to treatment failure.

22. Case Study – Torisel Post-approval commitments
Steps taken for the assessment: During the meeting on September 2007, the CHMP, in the light of the overall data submitted and the scientific discussion within the Committee, issued a positive opinion for granting a Marketing Authorisation to TORISEL on 20 September The applicant provided the letter of undertaking on the follow-up measures to be fulfilled post-authorisation on 19 September 2007.
The following post-approval marketing commitments are described in the Approval Letter • Submit two completed study reports and data sets: one on a thorough QT prolongation study and one on an ongoing hepatic impairment study. • Investigate the use of a flag label, or a suitable alternative, in order to incorporate additional information in the container labels for both the diluent and active vials. • Submit the developed strategy for the above agreement in a prior approval supplement. • Discuss with the FDA packaging technology options available to ensure the physical connection of the two co-packaged vials.

23. Case Study – Torisel (US) 585 page SBoA
Approval Letter(s) – 4 pages
Printed Labeling – 22 pages  
Medical Review(s) – 171 pages
Chemistry Review(s) – 19 pages  
Pharmacology Review(s) – 156 pages  
Statistical Review(s) – 31 pages  
Microbiology Review(s) – 6 pages  
Clinical Pharmacology Biopharmaceutics Review  
Administrative Document(s) & Correspondence –  

24. Case Study – Torisel (EU) 84 page EPAR
In all 22 languages
Summary for the public – 2 pgs
All Authorised Presentations - 1 page
SPC – 31 pgs
In English Only
Scientific Discussion (6) – 47 pgs
Procedural steps before authorisation – 2 pgs
Steps taken after authorisation (8) - 1 page

25. Case Study – Torisel (Canada) 2 page Notice of Decision
Notice of Decision issued 27-Jan-2008
Summary Basis of Decision (SBD) not yet posted on Health Canada site; average lag to posting of SBD is 5 months
Included on the Register of Innovative Drugs; 6 year no file date and 8 years data protection

26. References - US
CDER approved NDAs (SBoA)
CDER FOI New Drug Approval Packages
CBER approved devices
CBER approved biologics
CDRH approved PMAs

27. References - US
Summaries of Medical & Clinical Pharmacology Reviews of Pediatric Studies
Pediatric Exclusivity Determinations Made under Section 505A of the Federal Food, Drug, and Cosmetic Act (the Act), as amended by FDAAA

28. References - US
Advisory Committee briefing packages, transcripts, minutes
Clinical Trial Disclosure
Patent and Exclusivity Information (Drugs)
Postmarketing Commitments Database

29. References - EU
Summaries of Opinion
EPARs for authorized medicinal products for human use
European MRI-Product Index
EudraPharm

30. References - EU
Marketing Authorization Withdrawals and Suspensions - Medicinal Products for Human Use
Public Assessment Report in case of Withdrawal of Application
Refusal Assessment Report in case of negative CHMP opinion
Latest Press Releases

31. References - EU
Summaries of Opinion Orphan Designation
Decisions of the EMEA on pediatric investigation plans, deferrals or waivers
Opinions on medicines for use outside the EU

32. References - Canada
Summary Basis of Decision (Drugs)
Drug Product Database
Notice of Compliance
NOC with Conditions
Patent Register

33. Contact Information
Phone
Special thanks to my RI colleagues
at sanofi-aventis, especially Elisabeth
Fournier-Qezari, and the members of the
DIA RA SIAC Regulatory Intelligence
Working Group, for their insight and
suggestions on this presentation