The Challenges of Developing Biologics / Biogenerics : Bioengineering, the future of healthcare.

1. The Challenges of Developing Biologics / Biogenerics:Bioengineering, the future of healthcare. • Protecting Human Subjects & Ethical Conduct of Clinical Trials:

2. Presentation Overview • A Historical Overview • What events make this topic important • What’s Good –What’s Concerning • Driven by good intentions , but is balance shifting • What should we do? • Understand , Participate, & Do the right thing

3. We can not judge what is right to do now without knowing what has gone before. Thomas Berger • Thomas Berger • Who sees things develop from their origin ,sees them better. • Aristotle

4. Why is this of concern to you? International Business Development, Investment & Innovation (BFM) Foreign Affairs and International Trade Canada Bradley.millson@international.gc.ca

5. The biotech spring arrives in Barcelona • March 8, 2010 — 9:51am ET | By John Carroll • Free newsletter via e-mail • BARCELONA -- The theme here at BIO-Europe Spring 2010 is a new season for growing collaborations between Big Pharma and Little Biotech. And the key for developers is being able to fuel drug discovery programs in an environment where there's less cash on hand to fertilize the crops. • Straight in-licensing is out, say the Big Pharma companies. Collaborating with biotech companies in the hope of exchanging cash for an injection of entrepreneurial enthusiasm and innovation--all while managing major internal reorganizations--is in.

6. Goals • Reduce development time • Cut development costs • Meet product life cycle timelines • Quick approvals • Market access • Survival

7. RETURN ON EXECUTION “Execution is the name of the game .” “If we told you that defining your strategy only accounts for 15% of your financial performance as it relates to your competition, the next question would be “What is the real difference maker?”. The answer is execution. It’s been validated over and over again - those who execute better win. “ “In today’s world, it’s very hard to have any sustained competitive advantage from superior strategies alone. It’s easy to copy a competitor’s strategy, but much more challenging to keep pace with a competitor’s high performing execution. Improved business performance is not just about leadership and management discipline; it is heavily dependent on execution.” Eric Berggren and Lars Dalgaard

8. Institutional Review Boards Under Stress: Will They Explode or Change? • 40-80 new proposals per meeting( up to 6 hours) • Massive amount of paperwork • OPRR pressures above and beyond Regulations • Lack of reward or recognition for Board Members • IRB Cost to Institution JAMA Nov.27,1996-Vol.276 No20.

9. Recommendations back then.. • Review protocols only after funding in place • Expand expedited reviews • Decrease excessive and non productive activities • Establish primary reviewer system • Record (tape) minutes, computerize • Double the effort. More boards ,more meetings • Pay members • Outsource

10. Why do we need ethics review boards? • Major resource requirement • Almost everything eventually approved • Process is seen as too slow • Is not everyone involved protecting human subjects • Who is the REB protecting • How can this be measured The Michael Smith Foundation for Health Research (2008) B.C. Ethics Harmonization Initiative Introductory Workshop: Report on Proceedings. Vancouver: MSFHR. Greg Koski, PhD, MD, CPI Harvard University,

11. What do we expect from the REB ? • “We propose that the following objectives should be met by any adequate ethics review system: • Respect the dignity and rights of research participants • Protect the safety of all research participants, as much as it is possible to do so • Build and maintain trust between the researchers, research institutions , research participants, and society as a whole • Promote potentially beneficial research • Promote safe and effective research • Analyse, balance and distribute harms and benefits • Pursue all of the above in a way that is administratively and financially efficient and fair REVISIONING THE OVERSIGHT OF RESEARCH INVOLVING HUMANS IN CANADA by Jocelyn Downie and Fiona McDonald Health Law Institute Journal

12. REB challenges-Today. • Volume of research has increased and greatly expanded outside academic centres • Paperwork has not gone away and cost of going paperless is formidable • Regulations and Guidelines have increased • Cost recovery in most institutions is impossible ( High volume board -$770,000/year) • Full cost of accreditation is big

13. Academic Boards • Administrative challenges remain • Volume will increase • Industry supported research may go down • Compliance costs will increase • Balance Internal vs External Research • Unlikely that academic boards will extend their services outside their walls

14. Regional /Provincial Boards • Administrative cost/resource issues • Second tier issues remain • Creates disincentive for Canada • Are ethical standards really determined by lines on a map? • Alberta experience • Quebec experience • OCREB • Who will pay

15. Central Boards: Private ,Federal and Specialized • Are they really different? • Are they efficient? • Are they the solution? • The Boards they operate are no different • Their operations ( administratively) need to be very different

16. What does Canada need ? • REB’s that all meet the highest standards • Academic centres will need their own REB, may look at outsourcing some research review or outsourcing administrative aspects • Smaller institutions will look at outsourcing • Special approaches (OCREB) can work IF they provide Value • Quebec has streamlined some approvals • Private REB’s continue to play important role Choice

17. Sponsor wish list? • Low overheads • 90% research completed in academic centres • No ethics fees • No long ethics delays • Clear concise patient consent • Quick resolution of contracts • Collaborative spirit from all stake holders • Studies start and finish on time Was I just remembering 1985? Or ………………..

18. More Recent events • EU Regulations • Privacy laws • TCPS • FDA Inspections • OHRP • Canadian Inspectorate • Accreditation

19. Case 1. • January 24, 2002 • CLINICAL TRIALS: • The Office of Human Research Protections (OHRP), temporarily shut down most of the 2,400 federally funded human clinical trials at Johns Hopkins, pending a university plan targeting problems identified by OHRP. • Those problems included charges that the Johns Hopkins Institutional Review Board (IRB) — was not considering each proposal thoroughly enough. • OHRP eased the suspension in July after reviewing the Hopkins corrective plan, although the office ordered that the majority of clinical trials be reviewed again before continuing.

20. What happened. • Inspection prompted by death of research subject in federally funded study • IRB part of the inspection • Led to inspections of other institutions receiving federal funds for research

21. Case 2

22. Coast FAQ. • Have you been audited by the FDA? December 15-17, 2003 - Coast IRB was selected for a routine surveillance inspection. We received commendation from the FDA Investigators regarding the thorough and effective oversight provided by our IRB operations. A follow-up audit was conducted in 2005 at which time no further action was required by the FDA investigator.

23. What happened? • Sting Operation by GOA target 3 private IRB’s • Also set up phoney IRB • Fake protocol , fake device, poor CIB • Set up fake company phone number etc. • Used name of actual physician but changed middle initial, provided false CV • 1/3 IRB approved study with minor modifications • Coast subsequently reported concerns ( but too late)

25. Case 3-Ketec • 1,800 site study -24000 patients. • Monitor reported concerns at top site to CRO • Monitor also called IRB • Sponsor /CRO/Monitor conference call • Sponsor investigated GCP deviations at site • Data from study submitted to FDA • FDA inspection revealed fraud at this site. • Subcommittee Hearings Feb 2009

26. Outcome… • Academic Boards implemented changes • Coast is gone ( about 25 people lost their jobs) • Investigator in Ketec study sent to prison and debarred from further research

28. Warning Letters • 1. The IRB approved research without determining that the following criteria were met: that risks to subjects were minimized [21 CFR 56.111(a)(1)] and risks to subjects were reasonable in relation to anticipated benefits, • 2. Specifically, the IRB has no written procedures for conducting reviews of device studies to determine whether they involve a significant risk device • 3. The IRB failed to ensure that informed consent would be sought from each prospective subject or the subject's legally authorized representative in accordance with and to the extent required • 4. The IRB failed to ensure that no member participated in the initial or continuing review of a project in which the member had a conflicting interest, • 5. The IRB failed to conduct continuing reviews for the following IRB approved studies

29. Continued… • 7. The IRB failed to prepare and maintain the minutes of IRB meetings in sufficient detail to show attendance at the meetings; actions taken by the IRB;the vote on these actions including the number of members voting for, against, and abstaining • 6. The IRB failed to maintain copies of all research proposals reviewed, scientific evaluations, if any, that accompany the proposals, approved sample consent documents, progress reports submitted by investigators • 8. Each IRB is required to have at least five members, with varying backgrounds to promote complete and adequate review of research activities

30. Other REB Warning Letters 2009 • We note that the IRB reviewed and approved only three general hospital consent forms for procedures related to Project 1125. None of these consent forms complied with the requirements of 21 CFR Part 50.25. • b. Our inspection revealed the informed consent form approved by the IRB for Project 1121 did not include an explanation of whom the subject should contact for questions about their rights as a research subject, or whom to contact in the event of a research-related injury as required by 21 CFR 50.25(a)(7). (b) (6) • Our inspection revealed five instances in which an IRB member, who was serving as the clinical investigator for a particular research study, voted on the initial or continuing review of that study. • The IRB written procedures require that information, including copies of schemas of all proposals on the agenda, be sent to IRB members prior to the meeting. The meeting minutes indicate members were mailed outlines and consent forms for new proposals prior to the meeting, but our inspection revealed that IRB members were not provided copies of protocol schemas for new proposals for the IRB meetings of February 7, 2007 and November 1, 2007.

31. Further findings • Specifically, the IRB does not have written procedures for reporting IRB findings and actions to the institution as required by 21 CFR 56.108(a)(1), and does not have written procedures for determining which projects require verification from sources other than the investigator that no material changes have occurred since previous IRB review as required by 21 CFR 56.108(a)(2). • The IRB meeting minutes for November 1, 2007, indicate that the membership of the IRB consisted of ten voting members and three ex-officio (non-voting) members. Accordingly, a minimum of six voting members were required to be present at the meeting to review proposed research. Our inspection revealed that the IRB reviewed and approved research at the November 1, 2007, IRB meeting with only five voting members present. • Our inspection revealed the minutes for the November 1, 2007, IRB meeting do not list Project 1051 as being reviewed for continuing review. However, the IRB files for Project 1051 contain an IRB re-approval letter and a progress report signed by the IRB Chair as approved at the November 1, 2007 IRB meeting.

32. CR-2008 • 1. You failed to protect the rights, safety, and welfare of the subjects under your care, and you failed to conduct the investigations according to the investigational plan, the signed investigator statement, and applicable regulations, including Part 50. [21 CFR § 312.60]. • A. You enrolled 21 indigent persons from a multi-service center for the homeless into either study [(b)(4)] or [(b)(4)] Only after enrolling eight of these subjects, you received approval from the Institutional Review Board (IRB) to enroll vulnerable subjects, as described below. Regardless of the IRB's decision to approve the enrollment of vulnerable populations,persons utilizing the multiservice center for the homeless were unsuitable for consideration for these studies for many reasons, including, but not limited to the following: • i. These individuals were unsuitable because they were economically and/or educationally disadvantaged. Some subjects could not understand or follow the protocol requirements.

34. News related to Accreditation and EU Clinical Trial Directive By Marianne Vanderwel, Director, Human Research Protection Program IRB Services

35. What is Accreditation all about? • PEERH – program for ensuring the ethical research involving humans • Process • Gap analysis • Application • Site Visit • Granting Accreditation • Annual reports • Re-accreditation

36. AAHRPP • Association for the Accreditation of Human Research Protection Programs • Offers accreditation to research organizations that provide comprehensive protections to research participants • Process is voluntary, peer-driven, and educational

37. AAHRPP Accreditation Standards • Accreditation Standards • First set of standards released in 2002 • Input sought from accredited organizations- 2008, • Public consultation on draft revisions- 2009 • Revised Accreditation Standards- March 2010 • Evaluation Instrument for use with the revised Accreditation Standards published

38. Revised Accreditation Standards • The revisions: • Clarify language • Combine, create or delete elements • Organize the sequence • Apply to research in any country • Apply to biomedical or social science research • Emphasize continuous quality improvement • Strengthen identification and management of financial conflict of interest • Elevate importance of resources for the HRPP

39. Additional Resources • Also available at www.aahrpp.org • Evaluation Instrument • Application forms and guidance • Tip Sheets • Fee schedule

40. EU Clinical Trial Directive • Since 2004, clinical trials performed in the EU are regulated by the Clinical Trials Directive (2001/20/EC) • Volume 10 on clinical trials (EudraLex) includes: • ICH E6: GCPs • Detailed guidance on the application format and documentation to be submitted in an application for an Ethics Committee opinion on the clinical trial on medicinal products for human use • Ethical considerations for clinical trials on medicinal products conducted with the pediatric populations

41. Public Consultation on Key Issues • Multiple and divergent assessment of clinical trials • Inconsistent implementation of the Clinical Trials Directive • Regulatory Framework not always adapted to the practical requirements • Adaptation to peculiarities in trial participants and trial design • Ensuring compliance with GCP in other countries

42. Some of the proposed options • One-stop shop for regulatory authority and Ethics Committee review • Clarify the scope of the assessments by regulatory authorities and Ethics Committees • Clarify the reporting of SUSARs • Excluding “academic” sponsors from the rules of the Clinical Trial Directive

43. Some extracts -UK Response • The MHRA • Does not support a “one-stop shop” for regulatory authorities and Ethics Committees • Proposes that the Directive set out the respective responsibilities of regulators and Ethics Committees • Supports clarification of the rules on SUSAR reporting and supports removal of the requirement for sponsor to provide SUSARs and annual safety reports to Ethics Committees • Strongly opposes the complete exclusion of academic or non-commercial trials from the scope of the Directive