Solutions to the meet global requirements for public

Solutions to the meet global requirements for public data disclosure An Overview of Trial Transparency Requirements

Note about this presentation This presentation is intended as an introduction to clinical trial registration and results disclosure requirements. Level: BEGINNER • This presentation is intended to provide an overview of the evolution and current state of clinical trial registration and results disclosure and regulatory requirements are paraphrased using lay language for clearer communication. However, the presentation should NOT be considered a complete or authoritative source of information. • April 15, ARMA Presentation

Agenda • • • A Brief History of Clinical Trial Transparency . Clinical Trial Transparency Requirements . The Challenges with Trial Transparency . The Cost of Compliance – Survey Results . Solution Overview . April 15, ARMA Presentation

A Brief History of Clinical Trial Transparency Agenda April 15, ARMA Presentation

What is a Clinical Trial A clinical trial evaluates new therapies to test whether they are safe and effective • Clinical Trials are generally divided into four phases: • • • Phase II: Initial efficacy investigation and further safety assessment • Phase III: Extensive exploration of efficacy and safety in a larger population • • Phase I: Initial safety investigation and evaluating dosage ranges Phase IV: Post market evaluation of the drug in the “real world” And two main types : • Interventional: The investigators give the research subjects a particular medicine or other intervention. • Observational: The investigators observe the subjects and measure their outcomes. The researchers do not actively manage the experiment. April 15, ARMA Presentation

Have You Ever Participated in a Clinical Trial? April 15, ARMA Presentation

A Problem with Transparency • Trials repeated unnecessarily, adding to patient risk • • TGN 1412. In 2006, the drug caused catastrophic systemic organ failure in the trial subjects. A similar study had been conducted in 1994 (March 2006) Potential safety concerns or lack of efficacy not adequately reported Paxil – Apparent suppression of unfavorable research (2004) • Vioxx – Meta analysis published with safety concerns (November, 2004, The Lancet) and NEJM editorial (December, 2005) • Trasylol – Negative results from a retrospective study initially withheld (September 2006) • Avanida – Meta analysis published with safety concerns (June, 2007, NEJM) • April 15, ARMA Presentation

A Problem with Perception • In 2006, only 7% percent of Americans believe that statements made by Pharmaceutical Companies are "generally honest and trustworthy” - Harris Poll Survey in July 2006 • There was a perception that Life Sciences companies engage in selective publication: By not publishing Trials that don’t support the desired efficacy statements • By not including Trials that indicate undesired adverse events in peer -review articles • By not conducting meta-analysis across trials looking for adverse events with enough rigor • • There was a perception that the FDA was too cozy with Life Sciences companies April 15, ARMA Presentation

Timeline – Mandatory Disclosure Maine Law Enacted Int. Legislation Israel 1988 Hope Act AIDS Study Enrollment 1980 Int. Legislation South Africa Clinicaltrials. gov implemented 1990 2001 2002 2003 2004 FDA-AA 2007 Title VIII Int. Legislation Italy FDAMA 113 (Mar 2002) Registry Available FDAMA 113 1997 (No Registry Available) Maine Regulation Registration Required Argentina, Brazil, Czech Republic (gov't posts, like Eudra. CT) India, France, etc. Multiple States introduce Legislation 2005 2006 2007 EMEA Eudra. CT for Pediatric Trials 2008 2009 Mandatory disclosure includes trial registration and, under some laws, results posting April 15, ARMA Presentation

Voluntary and Mandatory Disclosure • Voluntary Disclosure • • • Africa (Pan-African registry) Australia China Cuba Germany Japan Netherlands (may be mandatory soon) Sri Lanka UK April 15, Disclosure Required – – – – – Argentina Brazil Czech Republic France India Israel Italy South Africa Taiwan US FDAMA 113 (1997) and FDAAA (2007) ARMA Presentation

Clinical Trial Transparency Requirements Agenda April 15, ARMA Presentation

Trial Registration in the US • Trials that DO require registration Most Phase II , III and IV drug clinical trials • Sponsors may voluntarily register trials that do not require registration by law • • Trials that DO NOT require registration according to FDAAA Phase I Trials • Observational Studies • April 15, ARMA Presentation

Trial Registration in the US • State of Maine Registration of Trials • • The State of Maine has recently passed an amendment to their disclosure law that additionally requires registration of observational studies, as well as making most optional fields mandatory. Registration for device trials Device trials have a slightly different definition for ‘applicable clinical trial’. • Under FDAAA there is a special provision that allows “delayed public disclosure” of registration information for trials for a novel device. • April 15, ARMA Presentation

Results Disclosure Status in the US • FDAAA • Disclosure of results required for a sub-set of registered clinical trials. Results must be disclosed for all interventional trials of FDA approved marketed products. • Note: - It is possible that results disclosure will be required for unapproved drugs by September 27, 2010 under FDAAA • Results Disclosure – Maine • The State of Maine has recently passed an amendment to their own trial disclosure law that requires disclosure of results for observational trials and discontinued trials. April 15, ARMA Presentation

Deadlines: Results • FDAAA requires results not later than 12 months after: The earlier of either the estimated or actual date of the last visit of the last patient specifically for purposes of data collection for the primary outcome of the trial • Within 30 days of receiving a marketing authorization for a new drug • • Note: - Sponsor can apply for an extension in certain circumstances when a trial is still ongoing with blinded data. April 15, ARMA Presentation

Elements that may be added in 2010 • The expansion of FDAAA, mostly for trial results disclosure, is under consideration by US lawmakers and must be finalized by September 27, 2010. Under consideration are: • • • Adding a summary of the trial and results in non-technical language. Adding a technical summary of the trial and results Disclosing the full protocol or at least that information on the protocol for the trial that may be necessary to help evaluate the results of the trial. Requiring results for unapproved products Other categories as the HHS Secretary determines appropriate. April 15, ARMA Presentation

EU Clinical Trial Results Disclosure • Legal requirement • • Disclose Results on Eudra. CT (EU Clinical Trials Database) Applies to pediatric trials (for now) All Pediatric trials conducted in the EU or if part of a PIP • For pediatric trials, results are to be disclosed within 6 months of study completion for both unapproved and marketed products. • For adult trials, results are to be disclosed 1 year after study completion. • • Results to be made public sometime in early 2011 • Note: Eudra. CT to make protocol registration data public in Q 3, 2010 April 15, ARMA Presentation

The Challenges with Trial Transparency Agenda April 15, ARMA Presentation

Clinical Trial Registry Landscape • Areas that influence disclosure • Legal requirements and the registries ORGANIZATIONAL SOP that support their regulations such as FDAAA, Maine, Eudra. CT, clinicaltrials. gov. • Policy Influences such as International Committee of Medical Journal Editors (ICMJE), WHO, WMA • Organizational SOPs and guidelines • Institutional Review Boards (IRB) and Ethics Committees (EC) ICMJE REGULATORY IRB & EC • These four areas establish • Required data (depth and breadth of data) • Timing for submission and disclosure Requests and interests from patient advocacy groups and the media add further disclosure pressures • The requirements from these four may not align with one another. April 15, ARMA Presentation

Multiple Registries / Different Timelines Update Study at Eudra. CT Register trial before study approval with Eudra. CT, South Africa, etc. Study Approved Register Study at Clinical. Trials. gov to comply with FDAAA, Maine and ICMJE First Patient Enrolled Register Study in local country Update Study at Clinical. Trials. gov Open New Site In US Update Study at Clinical. Trials. gov Open New Site In EU Submit Results at Eudra. CT of pediatric trials (expected by early 2011) Submit Results to Clinical. Trials. gov Study Complete Primary Completion Date • Study and results data must be provided to multiple registries • Accurate and consistent data should be reported across registries. • Registries may have different disclosure timeframes April 15, ARMA Presentation

Complex Compliance Environment • • • Globally, there are many interest groups closely monitoring clinical trials Regulations and data requirements are frequently changing and are not aligned internationally Deadlines demand rapid integration of new requirements Rules for disclosure are complex and often subject to interpretation Organizations may not have full control over what is disclosed Registration and results disclosure information remains publicly available on clinicaltrials. gov indefinitely (including the complete record of data changes) April 15, ARMA Presentation

Consequences for Non-Compliance • US FDAAA - $10, 000 for first event - $10, 000 per day for every day late (if not corrected within 30 days) - Public notice of failure in registry/results data bank - Withholding remaining or future grant funding (where applicable) • State of Maine - Barred in Maine from advertising prescription drugs on television, radio or in print - Up to $10, 000 per day • April 15, ARMA Presentation

Consequences for Non-Compliance • International No application possible without prior registration where trial registration is mandated • Local IRB/ethics boards may deny approval, even in areas where registration is voluntary • • ICMJE • Unable to publish articles in peer-review journals that follow the strict interpretation of the ICMJE rules. April 15, ARMA Presentation

Other Non-Compliance Risks • • Violation of FDA labeling and advertising regulations Violation of the False Claims Act Violation of SEC rule prohibiting “forward-looking statements” Significant restitution payments to private insurance companies Damage to reputation, good will and brand equity Company placed under consent decree In the US, Sponsors must submit Form 3674 certifying compliance, with criminal and civil penalties for submitting a false certificate April 15, ARMA Presentation

The Cost of Compliance Survey Results Agenda April 15, ARMA Presentation

Departments Responsible for Posting Department Primarily Responsible for Registration Clinical Operations Regulatory Affairs Clinical Sciences / Clinical R&D Medical Writing Medical Affairs Clinical Communications and Standards Department Primarily Responsible for Results Regulatory Affairs Clinical Operations Biostatistics Medical and Scientific Affairs Publication Clinical R&D Medical Writing Clinical Communications and Standards April 15, ARMA Presentation

Trial Disclosure - Stakeholders April 15, ARMA Presentation

Trial Transparency – Time Allocation April 15, ARMA Presentation

Results Disclosure – Time Allocation April 15, ARMA Presentation

Cost for a Typical Company # of Processes per Month Cost per Year Process # of Processes per Year $75, 836. 14 General Administrative Tasks # of new trials registration 43 $27, 441. 82 # of site/location updates # of clinical trials registration updates (excl. site/location updates) # of new trial results disclosures 23 273 $9, 433. 51 15 180 $12, 390. 31 31 $136, 875. 35 # of trial results disclosure updates 9 111 $117, 114. 81 # of ICH E 3 study synopsis prepared 34 $35, 780. 29 Total Cost $414, 872. 24 Number of International Registries Additional Registries April 15, # of additional Regs. # of Months in 2010 with new registries 5 6 Total costs in 2010 with Additional Registries ARMA Presentation Cost per Year $216, 983. 10 $631, 855. 34

Solution Overview Agenda April 15, ARMA Presentation

Common Data Sources Clinical Trial Management System (CTMS)/Clinical Trial Database or Trial Spreadsheet • Protocol/Clinical Study Report • Informed Consent Forms • Clinical Data Management System (CDMS) such as SAS • Pharmacovigilance System • April 15, ARMA Presentation

Common Requirements for a Solution • Centralized data capture and transformation for protocol registration and results posting (automated to minimize manual data entry, ensuring ensure data integrity) • Automated upload of protocol registration and results to registries • A flexible platform that supports extension to international registries • Mapping of common data elements across registry records to maximize efficiency and guarantee consistency • Robust workflow for registration and results, including disclosure assessment, review and approval workflows • Full audit trail & version control April 15, ARMA Presentation

Support for Data Standards April 15, ARMA Presentation

Clinical Trial Design The BRIDG Model Protocol Authoring and Documentation Clinical Trial Registration Structured Statistical Analysis Protocol activities and Safety monitoring (AE) Eligibility Determination April 15, ARMA Presentation From Douglas B. Fridsma, MD, Ph. D

Structured Content Management Non-Clinical Phase I-III Phase IV Submission Planning IND Protocols Analysis Data Sets toxicology pharmacokinetics Registries and Journals Study Planning & Management Study Concepts Protocol Authoring & Collaboration • Objective • Stat Plan • CRF • Schedule Amendments NDA Site Management Clinical Data Management Safety CM&C IRB Approvals Data collection Randomization CRF Edit checks Site queries AE/SAE Case Management Product manufacture Route USPI/SPL 1572 Forms Data Sets Interim Final Expedited Reporting Control of Excipients Procedures validation Promotional & Ads CV’s DMC Collaboration Aggregate Reporting PSUR ASR Control of Product procedures batch analysis Investigator Brochure Budget Funding & Tacking Enrollment / Consent Protocol Disclosures & CSR Publication Monitoring April 15, Annual ARMA Presentation Labeling & Commercial

Key Questions Companies Face • • • How will they deal with non-US registries? …and differing US states? How will they keep up with rapidly evolving requirements How do they ensure disclosure consistency globally? Where does the data exist inside their organization? What validation requirements do they have? What are the Best Disclosure Practices? Can they support an audit of their registry and results disclosure process? Will they consider Saa. S solutions Is business process outsourcing an option for them? April 15, ARMA Presentation

Thomas Wicks Intrasphere Technologies (212)937 -8225 thomas. wicks@intrasphere. com