Protocol Mechanics

1
Protocol Mechanics

• Historical Background
• Requirements for submitting a
• research protocol
• Basic elements of informed consent
• IRB protocol review standards
• ProtoType

2
Protection of Human Subjects

• Nuremberg Code
• Declaration of Helsinki
• Belmont Report
• Code of Federal Regulations
• - Title 45-Part 46
• International Guidelines Council of
  International Organizations of
• Medical Science (CIOMS)

3
Nuremburg Code

• Voluntary consent is essential.
• The study should benefit society.

Declaration of Helsinki(1964, 1975, 1983, 1989)

• Medical progress is based, in part,
• on human experimentation.

4
Council for International Organizations
ofMedical Sciences (CIOMS)

• In 1982, CIOMS Issued Proposed International
  Guidelines for Biomedical Research Involving
  Human Subjects.
• Guidelines served for the application,
  particularly in developing countries, of the
  principles of the Declaration of Helsinki.
• Epidemiological research issues were addressed,
  at the international level, in collaboration with
  WHO.

5
Historical Landmarks

• 1974 Congress passed Public Law 93-348,
  establishing the National Commission for the
  Biomedical and Behavioral Research.
• 1979 Belmont Report proposed by the National
  Commission.
• Respect for persons
• Beneficence
• Justice
• 1981 45CFR46 Issued federal policy for
  protection of human subjects.
• 1991 Common Rule adopted agreement by federal
  agencies to abide by 45CFR46, part A.

6
Title 45 Code of Federal Regulations Part 46
(45CFR46)

• Subpart A Federal Policy for the Protection of
  Human Subjects IRB membership, functions, and
  records.
• Subpart B Additional DHHS Protections Pertaining
  to Research, Development, and Related Activities
  Involving Fetuses, Pregnant Women, and Human In
  Vitro Fertilization.
• Subpart C Additional DHHS Protections Pertaining
  to Biomedical and Behavioral Research Involving
  Prisoners as Subjects.
• Subject D Additional DHHS Protections for
  Children Involved as Subjects in Research.

7
Institutional Review BoardAdministrative
Procedures

• IRB functions in accord with the NIH
• Multiple Project Assurance.
• Members include a biostatician, bioethical,
• and nonscientist.
• PIs are expected to present new protocols
• and to respond directly to questions.

8
What happens to your protocol when submitted?
FDA DSMC OBA
New Protocol
Pre-IRB committee
Dr Gallin
Office of Protocol Services
IRB
Continuing Review or Amendment
FDA DSMC OBA
9
http//www.cc.nih.gov/ccc/protomechanics/foreword.
html
10
Requirements for Submitting a Research Protocol
to the IRB

• Precis objectives, study population, design and
  outcome parameters
• Introduction background, references
• Objectives hypothesis to be tested
• Study design and methods

11
Requirements for Submitting aResearch Protocol
to the IRB

• Inclusion and exclusion criteria
• Monitoring subjects, criteria for withdrawal from
  study
• Analysis of the study
• Human subjects protection

12
Requirements for submitting aResearch Protocol
to the IRB

• Data and safety monitoring
• PI, independent monitor, DSMB
• Benefits and risks/discomforts
• Importance of study
• Adverse event reporting

13
Adverse Events

• Expected or unexpected
• Intensity or severity
• Related or unrelated to research

14
Informed Consent

• Introduction
• Purpose of the study
• Duration of study
• Research tests or procedures
• Research drugs or treatments

• Compensation
• Costs to participants
• Procedures for withdrawal
• Confidentiality concerns

• Risks and discomforts
• Benefits
• Alternatives to participation
• Uses of samples or information

• Genetics research risks to family
  members
• Financial or other conflict of interest
• Assent procedures

15
IRB Minutes

• Attendance
• Actions
• Votes
• Discussion
• Stipulations

16
Regulatory Elements for IRB Review

• The proposed research design is scientifically
  sound and will not expose subjects to risk
  unnecessarily.
• Risks are reasonable relative to anticipated
  benefits.
• Subject selection is equitable.
• Safeguards to protect vulnerable subjects are in
  place.
• Informed consent is obtained from research
  subjects or their legally authorized
  representatives.
• Subject safety is maintained.
• Subject privacy and confidentiality are maximized.

17
Regulatory Elements for IRB Review

• The proposed research design is scientifically
  sound and will not expose subjects to risk
  unnecessarily.
• Is the hypothesis clear?
• Is the study design appropriate to prove the
  hypothesis?
• Will the research contribution to generalizable
  knowledge be worth exposing subjects to risk?

18
Regulatory Elements for IRB Review

• The proposed research design is scientifically
  sound and will not expose subjects to risk
  unnecessarily.
• Randomization
• Masking/Blinding
• Equipoise (Benjamin Friedman) A trial can be
  ethical if there is equal uncertainty among
  groups.

19
Regulatory Elements for IRB Review

• Risks are reasonable relative to anticipated
  benefits.
• What is believed to be the level of risk?
• What is believed to be the level of
  risk/discomfort/inconvenience?
• Is there prospect of direct benefit to subjects?

20
Regulatory Elements for IRB ReviewRisks and
Benefits

• Regulatory definition of minimal risk Minimal
  risk means that the probability and magnitude of
  harm or discomfort in the research are not
  greater in and of themselves than those
  ordinarily encountered in daily life or in the
  performance of routine physical or psychological
  examinations or tests (45CFR46, 102 (h)(I)).

21
Regulatory Elements for IRB ReviewRisks and
Benefits

• Definition of benefit A research benefit is
  considered to be something of health-related,
  psychosocial, or other value to an individual
  research subject, or something that will
  contribute to the acquisition of generalizable
  knowledge. Money or other compensation is ot a
  benefit

22
Regulatory Elements for IRB Review

• Subject selection is equitable.
• Who is to be enrolled? Men? Women? Ethnic
  minorities? Children? Seriously ill persons?
  Healthy volunteers? Prisoners?
• Is the rationale for inclusion and exclusion
  criteria addressed?
• Are the subjects appropriate for the protocol?

23
Regulatory Elements for IRB Review

• Safeguards are adequate to protect vulnerable
  subjects.
• Are appropriate protections in place for
  vulnerable subjects?
• Pregnant women, fetuses, prisoners, minors
  Individuals who are socially or economically
  disadvantaged, decisionally impaired, acutely
  ill, or in chronic pain.

24
Regulatory Elements for IRB Review

• Informed consent is obtained from research
  subjects or their legally authorized
  representatives.
• Does the informed consent document include the
  eight required elements?
• Is the consent document understandable to
  subjects?
• Who will obtain inform consent and in what
  setting?
• Is there a childrens assent?
• Is it necessary for the IRB to waive or alter any
  informed consent requirement?

25
Regulatory Elements for IRB Review

• Subject safety is maximized.
• Does the research design minimize risks to
  subjects?
• Would use of a data and safety monitoring board
  or other research oversight mechanism enhance
  subject safety?

26
Regulatory Elements for IRB Review

• Subject privacy and confidentiality are
  maximized.
• Will personally-identifiable research data be
  protected to the extent possible from
  unauthorized access or applications?
• Are special privacy and confidentiality issues
  properly addressed, e.g., use of genetic
  information?
• Privacy relates to personal space.
• Confidentiality relates to the information given
  to or obtained by a health care professional.

27
Regulatory Elements for IRB ReviewAdditional
Considerations

• Ionizing radiation Is the use of ionizing
  radiation medically indicated or for research
  purposes only?
• Collaborative research Is this an international
  or domestic collaborative project? Are SPAs or
  other assurances in place?
• FDA-regulated research Is an IND or IDE involved
  in this protocol?

28
(No Transcript)
29
2004-5 Protocol Review Process
Conflict of Interest
30
(No Transcript)
31
ProtoType The Automated Protocol Writing System
An Overview Warren Grant Magnuson Clinical
Center National Institutes of Health Bethesda,
MD February. 2004
32
Tools to Facilitate Clinical Research
ProtoType Assisted protocol writing
system Scientific and Regulatory Document
Basic Clinical Care Plan
NLM ClinicalTrials.gov
Conflict-of-Interest Report of Investigators (to
ICD)
Adverse Events Reporting System CRIS-AE
CC Depts ICD
Protocol Mapping System
CD SD IRB
Cost Projections
CRIS
Protocol Monitoring
Regulatory Agencies (FDA, OBA,etc)
Results / data tagged
Data Mining
Data Warehouse
Institute Research Data Collection Systems
DSMB
Management
Advanced Rules Engine CRIS AE Reporting Template
2
Hospital Epidemiology
33
ProtoType encompasses 4 areas

• Protocol Writing
• Adverse-Event Reporting
• Protocol Tracking
• (Limited mapping capabilities)

3
34
Value Added

• Maximizes use of IT . . . employs a paperless
  system
• Standardizes the process while offering
  flexibility
• Provides a standardized template for
  investigators and reviewers
• Improves resource allocation
• Enhances patient care and safety
• Facilitates the process for all
• Increases speed of protocol writing and review
• Consolidates other protocol-management programs
  

4
35
Elements of a Protocol

• Face Sheet
• Précis
• Introduction
• Study Design
• Subject Enrollment
• Study Implementation
• Interventions
• Concomitant Care
• Data Collection
• Subject Protections
• Consent/Assent Forms
• Pharmaceutical, Biological and/or Device
  Information
• References and Appendices

5
36
Customization and Flexibility

• Format is NIH Institute-specific
• Only relevant fields appear
• e.g., Natural history study vs. Clinical Trial
  study
• Recommended language is available, but can be
  modified as the Investigator sees fit.

6
37
ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
. . . Welcome to ProtoType, and Your Protocols
7
38
Create a protocol
8
39
Select Interventions
9
40
(Presentation of interventions in the protocol)
10
41
ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
Reflecting interventions in the Study Timeline
11
42
Using standard-language cassettes (Consent Form)
12
43
ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
An electronic Comments feature
13
44
ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
Compare protocol versions, with markup
14
45
ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
Electronic approval signaturing
15
46
Value Added for the Researcher

• Online archives of all protocols
• Amendments immediately placed into protocol
• Helps mapping protocols
• Protocol moves electronically to IC, IRB, CC, etc
• Tracks states of the protocol, i.e. draft,
  pre-IRB, IRB, etc
• Updated regulatory needs automatically there,
  i.e. COI
• Wizard and/or direct links to additional forms,
  i.e. IND
• CRIS AE, i.e. adverse events
• Continuing review report - List of amendments
  and adverse events
• Cassettes of recommended language for consent
  forms and procedures
• Directly integrated with CRIS-Data mining from
  CRIS warehouse through
  unique identifiers

17
47
ProtoType/CRIS AE Development

• Summer 2003 ProtoType/CRISAE v1.0
• September 2003 ProtoType v1.0.1
• October 2003 ProtoType v1.0.2
• February 2004 ProtoType v1.5
• June 2004 ProtoType v1.5.1
• September 2004 ProtoType v2.0
• Now ProtoType v2.0b

48
ProtoType

• We encourage you to use ProtoType. The training
  link is at https//prototype.cc.nih.gov/training
  
• You need to call Phil Lightfoot at (301)
  496-0744 or you email him at plightfoot_at_mail.cc.n
  ih.gov
• An account will be set up in an hour

49
Protocol Contacts

• Phil Lightfoot
• [phone]
• plightfoot_at_mail.cc.nih.gov
• Kim Jarema
• [phone]
• kjarema_at_cc.nih.gov
• Robert Nussenblatt
• [phone]
• DrBob_at_nei.nih.gov