Protocol Development

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• Protocol Development Regulatory Compliance
• Wilma Hoffman, Director
• Linda Walters-Page, Protocol Specialist
• Ellen Aiken , Protocol Specialist
• Kathryn Okrent, Protocol Specialist
• Joseph Kopaczynski Protocol Specialist
• Georgette Koslosky Protocol Specialist
• Marcella Moore, Canadian Regulatory Compliance
  Associate
• Marie DAmico, Regulatory Compliance Associate
• Rose Ball, Administrative Assistant
• Sharon Allen, Randomization Secretary/Pathology

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REGULATORY COMPLIANCE
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HISTORICAL BACKGROUND OF INFORMED CONSENT

• The Nuremberg Code
• Code stating certain basic principles that must
  be observed in order to satisfy moral, ethical,
  and legal concepts for the protection of
  patients.
• Three pivotal principles of the Nuremberg Code
  that laid down conditions for ethical research
• Consent obtained from the research subject
• Conduct animal experiments first
• Supervise the research

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HISTORICAL BACKGROUND OF INFORMED CONSENT

• The Declaration of Helsinki
• Statement 1 It is the mission of the medical
  doctor to safeguard the health of the people
• Statement 2 The health of my patient will be
  my first consideration

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HISTORICAL BACKGROUND OF INFORMED CONSENT

• The Belmont Report
• Published on September 30, 1978
• Distinguishes between medical research and
  practice and develops the basic principles that
  should govern research with human subjects.
  Based on prior ethical violations.

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HISTORICAL BACKGROUND OF INFORMED CONSENT

• The Belmont Report
• Three quintessential requirements
• Respect for persons
• Beneficence
• Justice

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HISTORICAL BACKGROUND OF INFORMED CONSENT

• The Belmont Report
• Application of Principles
• Informed Consent
• Selection of human research subjects
• Is it fair?
• Is it unbiased?

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Why are These Regulations Important?

• To ensure the welfare and protection of the human
  research subject.
• To ensure the integrity and reliability of data
  submitted in support of a marketing application.
• To ensure that clinical research is conducted in
  a consistent and uniform manner.
• To remember that history can repeat itself.

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Assurance

• Institutional Assurances of Protection for Human
  Subjects
• Institutions contract with the Department of
  Health and Human Services
• Institution stipulates it will abide by 21CFR56
• Federal Wide Assurance (FWA)

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Assurance

• Institution submits application
• http//ohrp.osophs.dhhs.gov
• Receives notification of approval from OHRP
• Forward notification to CTSU

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Institutional Review Boards

• Institutions IRB
• Central Institutional Review Board (CIRB) It is
  Sponsored by the NCI. It was established the
  fall of 2002.
• Primary Goals of the CIRB
• To improve access to clinical trials
• To enhance the protection of research
  participants
• To collaborate more effectively with local IRBs
• To reduce the administrative burdens

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Institutional Review Boards

• Central Institutional Review Board (CIRB) A
  major benefit for participating local IRBs will
  be the reduction in review workload while still
  retaining its authority to accept or reject a
  "facilitated review" on a protocol-by-protocol
  basis.
• Phase III trials are available now. Likewise, due
  to the "facilitated review" process, patients and
  investigators will benefit from the resulting
  rapid opening and greater availability of new
  trials- and it is FREE!

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Institutional Review Boards

• FDA Requirements
• IRB approvals must occur within 365 days of the
  last approval.
• Meaning the protocol must be reviewed and
  approved (progress reports and all) by the IRB
  within 364 days of the last meeting.
• The meeting date of the IRB is the approval date.
  Back dating/forward dating is not allowed.

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Institutional Review Boards

• Standard IRB Approval Requirements
• Example
• Initial approval - August 1, 2000
• 1st renewal - July 8, 2001
• When is the 2nd renewal required?
• The IRB meeting must be on or before July 8,
  2002.
• The IRB cannot convene on September 9th and state
  that the approval spans back to July 8th and
  expires the following July.
• Nor can the IRB convene on June 6th and state the
  renewal covers the next 12 months from July 8th.

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Institutional Review Boards

• Anniversary IRB Approval Requirements
• An anniversary approval differs slightly from the
  standard approval. The guidelines below must be
  strictly followed
• A reapproval must occur with in 30 days of the
  anniversary date.
• If the reapproval date is greater than 30 days
  anniversary date it will be scored as a MAJOR
  deficiency at audit.
• If the reapproval date one day over the
  anniversary date it will be scored as a MAJOR
  deficiency at audit.
• Once the anniversary date is exceeded as above
  the anniversary date is NO LONGER VALID. The
  reapproval will then revert to the standard
  approval and must be approved with in 365 days of
  the last approval.

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Institutional Review Boards

• Anniversary IRB Approval Requirements
• Example
• Initial approval - August 1, 2000
• When is the 1st renewal required?
• The IRB meeting must occur between July 7, 2002
  and August 1, 2002.
• July 15th would be acceptable
• If any subsequent approval occurs after August
  2nd, this would be scored as a MAJOR deficiency
  and the anniversary date would no longer be
  valid.
• PLEASE NOTE THAT THE LETTERS, FROM YOUR IRB, MUST
  STATE THE INITIAL APPROVAL OF THE PROTOCOL FOR
  VERIFICATION OF THE ANNIVERSARY DATE.

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Institutional Review Boards

• Members serving on the IRB committee
• Committee must have a least 5 members, cannot
  consist of entirely men, women or one profession
• Sufficiently qualified (FWA, OHRP Training)
• 1 scientific, 1 non-scientific (clergy, community
  member)
• No member with a conflict of interest
• May invite additional guest with specialties
• Background have to be identified (CVs)

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Institutional Review Boards

• Valid IRB meeting
• In order for the IRB meeting to be valid a
  quorum must meet. Meaning that 51 of the voting
  IRB members must attend the meeting.

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Institutional Review Boards

• IRB Letters must contain the following
  information
• Must state the date of the IRB meeting
• Explain what is being reviewed
• Initial Approval
• Annual Approval
• Protocol amendment to include the amendment
  number
• Adverse Event
• Safety Report

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Institutional Review Boards

• IRB Letters must contain the following
  information
• State if the protocol is Approved.
• If the IRB required modifications, the letter
  must state that the protocol is approved,
  contingent on changes or modifications.
• After changes or modifications are completed, as
  required by the IRB, the IRB Chairperson may do
  an expedited review of the changes. This
  expedited review is at the discretion of your
  IRB.
• State the type of review
• Expedited Approval
• Full Board Approval

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Institutional Review Boards

• RTOG Requirements
• Name and address and chairperson
• Common Rule Form (310)
• Institution approval letter
• CTSU Requirements
• All United States sites must send documents to
  CTSU
• All Canadian sites still send documents to RTOG

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Institutional Review Boards

• Maintain copies of all reports submitted to the
  IRB and reports of all actions by the IRB
• Prior approval
• Protocol
• Modifications to the protocol/amendments, addenda
• Subject consent
• Patient/subject recruitment materials
• Investigator Brochures
• All correspondence

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Institutional Review Boards

• 3 Types of Review (21 CFR 56 and 45 CFR 46)
• Full Review
• Expedited
• Exempt

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Institutional Review Boards

• Full Review
• When is a full board approval required?
• First time approval
• Active studies with patients on treatment
• Medical devices
• When there is a risk involved. (Increase or
  additional risk)
• Change in treatment.
• Amendment with more than minimum risk

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Institutional Review Boards

• Expedited Review
• Minimal risk
• Minor changes in previously approved research
• Generally, if study is closed to group accrual,
  or no patients are on treatment, an annual review
  can be approved by expedited review.
• Reason for expedited review must be noted on
  approval
• The IRB always has the right to require Full
  Board approval.

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Institutional Review Boards

• Exempt Review
• Some examples are collection of blood samples
  from healthy/non-pregnant adults, sputum, nail
  clippings, non-invasive procedures.

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HIPAA

• The privacy provisions of the federal law, the
  Health Insurance Portability and Accountability
  Act of 1996 (HIPAA), apply to health information
  created or maintained by health care providers
  who engage in certain electronic transactions,
  health plans, and health care clearinghouses.
• The Office for Civil Rights (OCR) is the
  Departmental component responsible for
  implementing and enforcing the privacy
  regulation.

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HIPAA

• Who must comply with these new HIPAA privacy
  standards?
• Health care providers who conduct certain
  financial and administrative transactions
  electronically.

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HIPAA

• What does the HIPAA Privacy Rule do?
• The HIPAA Privacy Rule for the first time
  creates national standards to protect
  individuals medical records and other personal
  health information.

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HIPAA

• HIPPA websites
• http//www.hhs.gov/ocr/hipaa/
• http//privacyruleandresearch.nih.gov/
• Please see RTOGs website for the Groups
  position on HIPAA guidance in research.

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Informed Consent

• Purpose
• Informed consent is one of the primary ethical
  principles governing human subject research.
• Informed consent assures that prospective
  research subjects will understand the nature of
  the research and can knowledgeably and
  voluntarily decide whether or not to participate

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Informed Consent

• General Requirements
• NCI template used New June 1, 2004
• Must contain all required elements
• May add to consent but information should never
  be deleted from the consent
• If changes (deletions) are made to the consent,
  the IRB must document why these changes were made
  to the consent. This information, along with the
  changes to the consent must be forwarded to RTOG
  HQ. This information must also be available in
  your IRB folders for future audits.

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Informed Consent

• Non-English Speaking Patients
• To meet 21 CFR 50.20 requirements the IRB must
  have a fully translated informed consent document
  prepared in the participants native language and
  assure that the translation is accurate.
• A translator may be used to facilitate the
  conversation between the research subject and the
  person conducting the consent interview.

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Informed Consent

• Illiterate English-Speaking Patients
• A person who speaks and understands English, but
  does not read and write, can be enrolled in a
  study by "making their mark" on the consent
  document, when consistent with applicable state
  law.
• A person who can understand and comprehend spoken
  English, but is physically unable to talk or
  write, can be entered into a study if they are
  competent and able to indicate approval or
  disapproval by other means.

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Informed Consent

• The Consent Process
• The subject/representative must enter the date of
  signature on the consent document, to verify that
  consent was obtained before the subject began
  participation in the study.
• If consent is obtained the same day the study
  begins, the subject's medical records must have
  document that consent was obtained prior to
  randomization.
• A copy of the consent document must be provided
  to the subject and the original signed consent
  document should be retained in the study records.
  

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Special Requirements

• Some studies may have specific additional
  requirements that are needed before patient
  registration
• Examples Ethics Certification, Pharmacy
  Registration, Advanced Technology Radiation
  Therapy Credentialing
• The protocol will outline exactly what is needed

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Investigational New Drugs

• Sponsor Responsibility 21CRF312
• Investigator New Drug (IND) application
• Select Investigators
• Accountability and Usage
• Toxicity Reporting
• NCI, ACR, RTOG, Corporate Sponsor
• Accountable to the FDA

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Investigational New Drugs

• PI Responsibility
• Form 1572 Statement of Investigator, outlines
  responsibilities
• Maintain careful records
• Storage of drugs
• Return or disposal of unused drugs in accordance
  with FDA procedures and protocol instructions

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NCI - IND

• Must have current NCI CTEP Investigator Number to
  receive drug covered by an IND
• Numbers are issued by the Pharmaceutical
  Management Branch of the NCI
• Current FDA Form 1572, Supplemental Investigator
  Data Form (IDF), Financial Disclosure Form, and
  CV on file with PMB

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Drug Accountability

• Record of
• Receipt
• Use of NCI supplied agents
• Disposition
• If terminated, suspended, discontinued, or
  completed, PI will return unused supplies to the
  Sponsor or dispose the drug as arranged with the
  sponsor

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Drug Accountability Record
Drug Accountability
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Drug Accountability

•  The following information must be recorded on
  the DARF
• Date the agent left the Control pharmacy or
  satellite pharmacy
• Where the medication came from or is going to.
  I.e. from the NCI or to Patient (initials,
  patient or case number)
• Dose to the Patient, if applicable. If agent is
  received from the NCI no information would be
  expected.
• Amount dispensed to the patient.
• Amount remaining in stock.
• Manufacturer and lot number.
• The recorders initials.  

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Drug Accountability

• The institution must use the NCI supplied agent.
  
• If a commercial agent is used, the institution
  must reimburse the patient and/or the insurance
  company.
• The consent states this is supplied FREE of
  charge to the patient.

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Drug Accountability

• NEVER ever use white-out on the DARF forms or
  any study documents. This will constitute a
  major deficiency at the time of audit.

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How To Order Drug
Clinical Drug Request
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Drug Returns
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Records Retention

• Custody and Access
• Retained for Specified Time
• Individual state and HIPAA regulations may apply

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Resources

• RTOG Web site www.rtog.org
• OHRP Web site http//ohrp.dhhs.gov
• NCI Web site http//ctep.info.nih.gov
• Investigators handbook
• Forms
• FDA Web site
• www.fda.gov
• FDA regarding informed consent
• www.fda.gov/oc/ohrt/irbs/informedconsent.htmlp
• Cancer Trials Support Unit http//www.ctsu.org
• Central Institutional Review Board (CIRB)
• http//www.ncicirb.org