Protecting Human Subjects

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The Challenges of Developing Biologics /
BiogenericsBioengineering, the future of
healthcare.

• Protecting Human Subjects Ethical Conduct of
  Clinical Trials

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Presentation Overview

• A Historical Overview
• What events make this topic important
• Whats Good Whats Concerning
• Driven by good intentions , but is balance
  shifting
• What should we do?
• Understand , Participate, Do the right thing

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• 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

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Why is this of concern to you?
International Business Development, Investment
Innovation (BFM) Foreign Affairs and
International Trade Canada Bradley.millson_at_interna
tional.gc.ca
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• The biotech spring arrives in Barcelona
• March 8, 2010 951am 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.

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Goals

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

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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. Its been validated over
  and over again - those who execute better win.
• In todays world, its very hard to have any
  sustained competitive
• advantage from superior strategies alone. Its
  easy to copy a competitors strategy, but much
  more challenging to keep pace with a competitors
  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
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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.
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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

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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,
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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
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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

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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

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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

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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

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What does Canada need ?

• REBs 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 REBs continue to play important role

Choice
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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 ..
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More Recent events

• EU Regulations
• Privacy laws
• TCPS
• FDA Inspections
• OHRP
• Canadian Inspectorate
• Accreditation

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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.

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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

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Case 2
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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.

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What happened?

• Sting Operation by GOA target 3 private IRBs
• 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)

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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

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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

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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

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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

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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.

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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.

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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.

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

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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

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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

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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

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Additional Resources

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

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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

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Public Consultation on Key Issues

1. Multiple and divergent assessment of clinical
   trials
2. Inconsistent implementation of the Clinical
   Trials Directive
3. Regulatory Framework not always adapted to the
   practical requirements
4. Adaptation to peculiarities in trial participants
   and trial design
5. Ensuring compliance with GCP in other countries

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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

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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

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