Transparency in Clinical Trials and its Impact on the Intelligence Community SLA, Boston March 20, 2007 Mark R Little, PhD Vice President, Business Intelligence Covance, Inc

Whats Ahead Objective: to explore the impact of clinical trial transparency initiatives on pharma competitive intelligence units Has it been useful for CI activities? If so, useful for what? How do new sources rate – Amongst themselves? – Vs more traditional sources? – Vs primary sources?

Whats Ahead Introduction A History Clinical Trials What is clinical trial intelligence What makes clinical trial intelligence predictive What impact might clinical trial intelligence have Case study Impact on First in class exclusivity The Push toward Clinical Trial transparency Survey of Pharma CI units Conclusions

A Brief History of the Clinical Trial The Present-Day Controlled Clinical Trial is a relatively new Tool for Drug Development 1747: James Lind – On Board the Salisbury 1962: Kefauver/ Harris Amendment 1980: First Issue of Controlled Clinical Trials

Pharma Companies Reveal Clinical Trial Studies in various formats Clinical Trials predict the dose, patient population, efficacy endpoints and safety of future drug indications Raz I, Hanefeld M, Xu L, Caria C, Williams-Herman D, Khatami H, for the Sitagliptin Study 023 Group. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy in patients with type 2 diabetes mellitus. Diabetologia 2006 Nov;49(11): PMID: Aschner P, Kipnes M, Lunceford J, Sanchez M, Mickel C, Williams-Herman D. Effect of the dipeptidyl peptidase-4 inhibitor sitagliptin as monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care 2006; 29: PMID: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Dose-Range Finding Study of Once-Daily Dosing of MK-0431 in Patients With Type 2 Diabetes Mellitus Who Have Inadequate Glycemic Control Charbonnel B, Karasik A, Liu J, Wu M, Meininger G. Efficacy and safety of the dipeptidyl peptidase-4 inhibitor sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes inadequately controlled on metformin alone. Diabetes Care 2006;29: PMID: PUBLISHED CLINICAL STUDIES DRUG LABEL

Clinical Trial Intelligence – Defined Clinical Trial Intelligence: Actionable information and/or insights about the Design: patient population, study arms, # sites, endpoints Status: enrollment, efficacy trends, side effect (AE) trends Results of a clinical trial: statistical significance, AEs, clinical profile Clinical Trial Intelligence is a subset of Competitive Technical Intelligence (CTI) Like all intelligence, clinical trial intelligence needs to be actionable

Clinical Trial Intelligence – in Context Pharma CI Units have traditionally focused on competitor pipelines & near-market assets CI units have leveraged a variety of sources to gain insights into competitor pipeline activities One-stop shopping does not exist Different internal customers require different analytical outputs and perpectives Clinical Trial intelligence adds a layer of granularity to Pipeline Intelligence

Clinical Trial Intelligence – in Action Clinical trial intelligence can make an important contribution to Pharma CI Clinical trial intelligence needs to be actionable Likely impact Direct licensing activities Stir / accelerate fast-follower activities Influence design of clinical trials Build counter marketing strategies

CASE REPORT Pursuit of clinical trial intelligence extremely important – in this case – to licensing Company A desires to fill void in key therapeutic area Using typical pipeline databases and industry trade press, Company A targets a specific drug in Phase II testing at a smaller company Business Case for in-licensing established, and the compound target is of the highest priority. CI unit charged with gathering clinical trial intelligence CI unit hires third party to attend upcoming conference, where target company is presenting Clinical abstract is reassuring: compound has met efficacy / safety profile & POC However, in after-hour discussions, company reveals that due to issues in non-clinical testing, compound is to be discontinued in favor of back-up RESULTS: Licensing jets cooled Post-script: neither target compound nor backup reached the market

Source: DiMasi and Paquette, PharmacoEconomics 2004;22(Suppl 2):1-14 Market Exclusivity for First-in-Class has Declined: Mean Time to First Follow-on Approval Can adoption of Competitive Intelligence units be partly to blame for diminishing exclusivity?

Market Exclusivity Vs Average SCIP membership: An interesting observation Inverse relationship between Time of Market Exclusivity and Average SCIP Membership

However, Data without perspective is still data, and not information – Felix Gyi, Pharm D The Push Toward Clinical Trial Transparency Safety concerns in two widely prescribed drug classes have fueled the drive to Transparency: Safety issues involving the use of SSRI antidepressants in children (Jun04) Safety issues involving COX-II inhibitors (VIOXX withdrawal, Sep04)… and the Post-Vioxx Era begins GSK announces clinical trial database Merck, Lilly follow and PhRMA launches voluntary clinical trial results database in Sep04

Initiatives in clinical trial transparency have made competitor pipelines more accessible, but to what end? Effects of a Post- Vioxx Era 2006: Welcome to the AstraZeneca Clinical Trials web site: This web site provides clinical trial data, results and other information from or regarding AstraZeneca-sponsored clinical trials….In line with our Group Corporate Responsibility Policy on transparency, we are committed to open communication of information on AstraZenecas clinical trials. We will provide details of new and ongoing clinical trials sponsored by AstraZeneca. June 2003: As a disclosure of compound information is balanced by the business need to maintain competitive advantage, some compound information has not been disclosed at this time.* BEFORE AFTER *Source: Surfing the Pipeline: Comparing the coverage and content of drugs in development databases, June, 2003

Effects of a Post-Vioxx Era: All Aboard All of top 15 Biopharm Co's are posting active clinical trials online 93% on clinicaltrials.gov 60% centerwatch.com 33% on their own website Trial results are being published by most on the PhRMA site, clinicalstudyresults.org 15 companies have posted 1300 trials GSK has dedicated 40 FTEs for summaries and its registry. On average 40 FTE's / per company are dedicated to clinical trial transparency efforts; once backlog has been processed, 5-10 FTE's will be needed. *Source: "State of the Clinical Trials Industry" Report, 2006 ClinicalTrials.gov appears to be the most widely used registry for industry posting

A Word about Clinicaltrials.gov The Debut of ClinicalTrials.gov The debut of ClinicalTrials.gov ( took place on February 29, This service provides patients, family members, health care professionals, and members of the public easy access to information on clinical trials for a wide range of diseases and conditions. ClinicalTrials.gov contained over 4,000 clinical studies sponsored primarily by the National Institutes of Health. ClinicalTrials.gov grew out of 1997 legislation that required the Department of Health and Human Services, through the NIH, to broaden the public's access to information about clinical trials on a wide range of diseases by establishing a registry for both federally and privately funded trials "on drugs for serious or life-threatening diseases and conditions. Appears to be the registry of choice for clinical trial listing

R&D spend and trial listing* of a select Pharma cohort *Source: ClinicalTrials.gov

Ranking Companies by Trials per R&D $ Spent Novartis Bristol-Myers Squibb Co. Eli Lilly and Co. Wyeth GlaxoSmithKline Plc. Abbott Laboratories AstraZeneca Plc. Sanofi-Aventis Boehringer Ingelheim GmbH Pfizer Inc. Roche Amgen Inc. Merck & Co. Schering-Plough Corp. Astellas Schering AG Daiichi-Sankyo Takeda Chemical Industries Ltd.

CBIs 3 rd Annual Predictive Intelligence For Pharmaceutical and Biotech Companies January 22-23, 2007 A SURVEY OF CI PROFESSIONALS

Survey Method Survey Tool: Zoomerang Participants: CI network across Biopharma companies Invited: ~35 Completed Responses: N= 15 Objective: Assess the value of clinical trial transparency as a bolt-on tool for the competitive intelligence professional Survey to assess value of CT Transparency as a tool for the CI Professonal

How important is CT Intelligence to your work? 13/15 Respondents described CT Intelligence as Important or Extremely Important Extremely Important Important Unimportant Extremely Unimportant

Respondent breakdown according to company revenue Large, medium and small biopharma companies represented > $10Billion < $1Billion >$5B, but <$10B > $1B, but <$5B

How often is CT Intelligence incorporated into your output? As might be expected, clinical trial intelligence is frequently used in reporting

How is the CT Intelligence used? Product Positioning and Trial Design were most often selected uses

Who is the internal customer? The Internal Customer tended to Map to Medical/ Marketing Departments Other: New Product Planning, Corporate Strategy, Various

Has Clinical transparency helped you in your job? The Transparency push has helped the CI community……. Agree Disagree Stongly Agree Stongly Disagree

What improvements are needed? …..but more postings are needed to significantly improve the registries. More comprehensive Up-to-date Structure/Searchable Other

What is the level of satisfaction with external sources? In general, External Sources only partially satisfy demand Somewhat satisfied Somewhat dissatisfied Very satisfied Very dissatisfied

How effective are some common sources? *For Trialtrove, N=13; all others N=15.

Sources: Force Ranked ….. Effectiveness is most effectively linked to contracted primary research *For Trialtrove, N=13; all others N=15.

Categorization of the forced rank…. Interestingly, Effectiveness is linked to Humint activities using internal networks, contracted vendors, and conference coverage Human Intelligence Secondary Sources *For Trialtrove, N=13; all others N=15.

….Or are we simply viewing the Intelligence Pyramid in action…. *For Trialtrove, N=13; all others N=15. DATA Information Intelligence

CONCLUSIONS Key Findings following 30 months of transparency initiatives 12 of 15 respondents agree that transparency has had a significant impact on their CI activities – 12/13 who consider clinical trial intelligence important to their work, agree to the above 13/15 respondents are somewhat satisfied with all external sources 8/15 and 7/15 respondents selected competitor product positioning and influencing clinical trial design, resp, as a key action taken from clinical trial intelligence Human intelligence sources rate slightly more effective than secondary sources – indicative of analysis and action (moving up the pyramid)

CONCLUSIONS: Final Thoughts Intellectual Property Product Profile Clinical design Competitive Advantage Legal / Regulatory Public Safety & Trust Business Ethics April – 2nd Annual Premier Forum on Clinical Trial Registries and Results Databases ProtectProvide

ACKNOWLEDGEMENTS Jamie Denison-Pender, CIS Scott Taylor, BMS Debra Weintraub, MedImmune Tracy Degregorio, Citeline, Inc Jan Herring, Herring & Associates Joe Bedford, Covance N= 15