Protocol Mechanics

1
Protocol Mechanics

• Why do we write one?
• How to begin
• Requirements for submitting a
• research protocol and types
• - Nuts and Bolts
• Basic elements of informed consent
• COI
• IRB protocol review standards
• ProtoType

2
Historical Landmarks

• 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.

3
Protocols Why do we write them?

• CFR Title 21 Food and Drugs
• Several other Manuals, Reports
• European Directive on GCP 2001/20/EC
• ICH guidelines
• Guidance developed the Expert Working Group of
  the International Conference on Harmonization of
  Technical Requirements for Registration of
  Pharmaceuticals for Human Use (ICH)
• Recommended by EU, Japan, and the US.
• Published in the Federal Register May 9, 1997 (62
  FR 25692
• Represents the Agencys current thinking on good
  clinical practices
• Alternative approaches can be used if they meet
  the requirements outlined

4
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.

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Code of Federal Regulations (21 CFR)

• Part 50 Protection of human subjects including
  informed consent
• Part 56 Regulates the conduct of the IRB
• Part 312 Investigational New Drug (IND)
  application to the FDA
• Part 11 Regulates management of electronic
  records

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International GuidelinesThe rules for Clinical
Research

• International Conference on Harmonization (ICH)
• Unified International standard to facilitate the
  mutual acceptance of clinical data by regulatory
  authorities
• E6- Guidelines for Clinical Practice
• E2A- Clinical Safety Data Management
• Definitions and Standards for Expedited
  Reporting
• E8- General Considerations for Clinical Trials

7
If you plan to do clinical research you need a
copy of the regulations
www.clinicalresearchresources.com
8
Thinking about writing a Protocol?

• Protocol- a complete written description of,
  and scientific rationale for, a research activity
  involving human subjects. (Protomechanics NIH)
• 3 general types of protocols
• 1. Retrospective review- usually with data
• 2. Natural History study- may get tissue samples,
  DNA
• 3. Interventional Phase I/II most common, Phase
  III, Phase IV

9
Writing a Protocol First steps

• As PI, you usually are the one who has an idea
• Is it reasonable? Do we have the resources?
• Significant risks?
• Do you have the patient population?
• Include those important to the conduct of the
  protocol as an Associate Investigator
• IND request, outside investigators, COI
• Initially most ICs will ask you to write an
  abbreviated conceptual sheet outlining what you
  wish to do- to the Pre-IRB committee

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What happens to your protocol when submitted?
FDA DSMC OBA
New Protocol
Pre-IRB committee
Dr Gallin
IRB
Office of Protocol Services
Continuing Review or Amendment
FDA DSMC OBA
11

• Writing a Protocol
• Nuts and Bolts

12
http//www.cc.nih.gov/ccc/protomechanics/foreword.
html
13
An 1195 that begins every Protocol at the NIH
14
A continuing Review 1195 Filled in for every
Protocol
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The major topics to be covered in a Protocol

• Face Sheet
• Glossary
• Précis-Abstract
• Objectives, study population, design and outcome
  parameters
• Introduction Background
• Background, references
• Hypothesis Objectives
• What you are testing
• Study Design and Methods
• Benefits and risks/discomforts
• Importance of study
• Subject Enrollment
• Inclusion and exclusion criteria

• Study Analysis
• Adverse Event Reporting
• Data and Safety Monitoring Plan
• Human Subject Protection
• Monitoring subjects, criteria for withdrawal from
  study
• Pharmaceutical, Biologic Device Info
• References Appendices
• Consent/Assent Forms

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Protocols for INDs (312.23 CFR)

• Statement of objectives
• Name/address/qualifications of investigators
• Criteria for patient selection
• Description of the design of the study
• Method for determining doses
• Description of observations and measurements to
  be made
• Description of the clinical procedures and lab
  tests

17
Protocols for INDs (312.23 CFR)Required by FDA
but need not be in the protocol but usually is

• Chemistry, manufacturing, and control information
• Pharmacology and toxicology information
• Previous human experience with the
  investigational drug
• Additional information such as radioactive drugs,
  pediatric studies,

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Consent Forms

• Why all the fuss?

19
The Doctors Trial at Nuremburg
KARL BRANDT
SIEGFRIED HANDLOSER
PAUL ROSTOCK
OSKAR SCHROEDER
KARL GENZKEN
WOLFRAM SIEVERS
HELMUT POPPENDICK
JOACHIM MRUGOWSKY
KARL GEBHARDT

• The EXPERIMENTS
• High Altitude Exps
• Freezing Exps
• Malaria Exps
• Lost (Mustard) Gas Exps
• Sulfanilimide Exps
• Bone, Muscle, and Nerve Regeneration and Bone
  Transplantation Exps
• Sea Water Experiments
• Epidemic Jaundice Exps
• Sterilization Exps
• Spotted Fever Exps
• Experiments with Poison
• Incendiary Bomb Experiments
• Crimes against Humanity

SIEGFRIED RUFF
HANS WOLFGANG ROMBERG
GEORG AUGUST WELTZ
RUDOLF BRANDT
KURT BLOME
VIKTOR BRACK
GERHARD ROSE
HERMANN BECKER- FREYSENG
FRITZ FISCHER
HERTA OBERHEUSER
WILHELM BEIGLBOECK
KONRAD SCHAEFER
ADOLF POKORNY
WALDEMAR HOVEN
USHMM
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The Nuremburg Code

• Voluntary consent is essential
• The experiment should yield fruitful results for
  the good of society, unprocurable by other
  methods or means of study
• Design of study based on animal work and natural
  hx of disease and the results justify the
  experiment
• Avoid all undue physical and mental pain
• No exp to be done with death as endpoint (except
  if MD)

• Degree of risk never outweighs the results of the
  experiment
• Proper care to prevent adverse events
• Experiment should be conducted only by
  scientifically qualified persons
• Subject has the right to stop at any time
• The PI should be prepared to stop exp if patient
  is at risk of harm.

21
Not only in Germany-The Tuskegee Exps

• From 1932-1972, the Tuskegee Public Health Study
  was conducted by the U.S. Public Health Service
  to observe 400 sharecroppers with untreated
  syphilis to document the course of the disease in
  African-Americans and the racial differences in
  the clinical manifestation of the disease.
• These men were not informed of their disease
  status nor given counseling to avoid the spread
  of the disease
• In 1972, the study was disclosed to the public

22
Consent form and discussion requirements ICH
4.8.10

• Participation is voluntary subject may refuse or
  withdraw at any time
• Who will granted access to the subjects original
  files subjects legal representative has access
  also
• Records kept confidential if published identity
  is confidential
• Subject will be informed in a timely fashion of
  information important to the conduct of the trial
• Contact information re rights, complaints,
  injuries
• Reasons why subject could be terminated from the
  study
• Duration of participation in study
• Approximate number of subjects in the trial

• Trial involves research
• Purpose of trial
• Treatments and Randomization
• Trial procedures
• Subjects responsibilities
• Experimental aspects
• Risks or inconveniences to subject or fetus
• Expected benefits if any
• Alternative therapies
• Compensation or rx for trial related injury
• Prorated payment if any
• Expenses to the subject if any

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NIH Informed Consent

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

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

• 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

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Part of the Protocol submission

• Conflict of Interest of the Clinical Researchers

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A Guide to Preventing Financial and Non-financial
Conflicts of Interest In Human Subjects Research
at NIHJanuary 4, 2005 ( Revised, December 2005)

• Avoiding financial and other conflicts of
  interests is important for NIH, where the trust
  and protection of research subjects is vital to
  our mission to improve the public health.
• This specific guide applies to all investigators
  who substantively participate in the development,
  conduct, or analysis of clinical research
  protocols, both diagnostic and therapeutic, and
  are listed as investigators on the front sheet of
  protocols
• The Principal Investigator is responsible for
  assuring that each investigator listed on the
  protocol front sheet receives a copy of the
  Guide. In addition, the PI is responsible for
  providing his or her IC Deputy Ethics Counselor
  (DEC) with a list of all investigators on the
  protocol before beginning the scientific review.

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Examples of Investigator COI

• Serving as a director, officer or other
  decision-maker for a commercial sponsor of the
  human subjects research
• Holding any stock or stock options in a
  commercial sponsor of the human subjects research
  (unless held in a diversified, independently
  managed mutual fund)
• Receiving compensation for service as consultant
  or advisor to a commercial sponsor of the human
  subjects research (excluding expenses)
• Receiving honoraria from a commercial sponsor of
  the human subjects research
• Personally accepting payment from the human
  subjects research sponsor for non-research travel
  or gifts (government receipt of in-kind,
  research-related travel is not included)
• Obtaining royalties or being personally named as
  an inventor on patents (or invention reports) for
  the product(s) being evaluated in the human
  subjects research or products that could benefit
  from the human subjects research (special rules
  apply in this case when NIH holds the patent)
• Receiving payments based on the research
  outcomes
• Having other personal or outside relationships
  with commercial sponsors of the human subjects
  research
• Having financial interest in companies with
  similar products known to the investigator to be
  competing with the product under study.

27
Institutional Review Board (IRB)/Independent
Ethics Committee (IEC)

• CFR 56.102 and ICH 3.1 This is set in law in the
  US
• An IRB/IEC should safeguard the rights, safety,
  and well-being of all trial subjects. Special
  attention should be paid to trials that may
  include vulnerable subjects
• IRB functions in accord with the NIH
  (Institutions)
• Multiple Project Assurance.
• CFR 56.107. IRB should have at least 5 Members of
  varying background. The choices should promote
  respect for its advice and counsel in
  safeguarding the rights and welfare of human
  subjects. At NIH need to include a biostatician,
  bioethicist,and nonscientist.
• PIs are expected to present new protocols
• and to respond directly to questions.
• CFR 56.109 An IRB shall review and have
  authority to approve, require modifications in
  (to secure approval), or disapprove all research
  activities covered by these regulations

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Some Protocol Elements the IRB looks for

• The proposed research design is scientifically
  sound and will not expose subjects to risk
  unnecessarily.
• Risks are reasonable relative to anticipated
  benefits minimize risks to subjects?
• Subject safety is maintained
• Subject selection is equitable rationale for
  inclusion and exclusion criteria
• Safeguards to protect vulnerable subjects are in
  place.
• Informed consent is obtained from research
  subjects or their legally authorized
  representatives
• Will the research contribution to generalizable
  knowledge be worth exposing subjects to risk?
• Equipoise (Benjamin Friedman) A trial can be
  ethical if there is equal uncertainty among groups

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Some Protocol Elements the IRB looks for

• 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?

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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?

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IRB Minutes

• Attendance
• Actions
• Votes
• Discussion
• Stipulations

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2003 Protocol Review Process
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ProtoType The Automated Protocol Writing System
An Overview Warren Grant Magnuson Clinical
Center National Institutes of Health Bethesda,
MD February, 2006
37
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
38
ProtoType encompasses 4 areas

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

ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
39
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
  

ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
40
Elements of a Protocol

• Face Sheet
• Glossary
• Précis-Abstract
• Introduction Background
• Hypothesis Objectives
• Study Design
• Subject Enrollment
• Study Analysis
• Adverse Event Reporting
• Data and Safety Monitoring Plan
• Human Subject Protection
• Pharmaceutical, Biologic Device Info
• References Appendices
• Consent/Assent Forms

ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
41
Elements of a Protocol

• Face Sheet
• Glossary
• Précis-Abstract
• Introduction Background
• Hypothesis Objectives
• Study Design
• Subject Enrollment
• Study Analysis
• Adverse Event Reporting
• Data and Safety Monitoring Plan
• Human Subject Protection
• Pharmaceutical, Biologic Device Info
• References Appendices
• Consent/Assent Forms

ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
42
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.

ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
43
. . . Welcome to ProtoType, and Your Protocols
44
Create a protocol
45
Select Interventions
NIH Pharmacy Formulary pre-loaded to choose from
46
(Presentation of interventions in the protocol)
47
Reflecting interventions in the Study Timeline
48
Using standard-language cassettes (Consent Form)
Edit capabilities can be held on special
components
Language pre-loaded when consent created.
49
An electronic Comments feature
50
Compare protocol versions, with markup
New Text Bracketed
Old Text Crossed Out
51
Electronic approval signaturing
52
Integrated with ProtoType is an Adverse Event
Reporting System
53
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,
  Scientific Review, 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

ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
17
54
Program Status

• ProtoType, Ver. 2.1 CRIS AE May, 2005
• ProtoType, Ver. 2.2 July, 2005
• ProtoType, Ver. 2.4 October, 2005
• ProtoType, Ver. 3.0 Mid-Year, 2006

ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
55
New Features v2.4

• IRB Stipulations Addressed For Every Review
• New Text Editor (EditLive v5.0)
• A Resource Browser for Text Editing
• Drag and Drop Image/Reference/Cassette Entry
• Enhanced Reference Entry
• And Many More Functional Enhancements

ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
56
ProtoType

• We encourage you to use ProtoType. The training
  link is at https//prototrain.cc.nih.gov
• To set up an account call Philip Lightfoot at
  [phone] or you can email him at
  plightfoot_at_mail.cc.nih.gov
• An account will be set up in an hour

ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
57
Protocol Contacts

• Phil Lightfoot
• [phone]
• plightfoot_at_mail.nih.gov
• Brian Chamberlain
• [phone]
• bchamberlain_at_mail.nih.gov
• Kim Jarema
• [phone]
• kjarema_at_mail.nih.gov
• Robert Nussenblatt
• [phone]
• DrBob_at_nei.nih.gov

ProtoType (the Protocol Typewriter) A
web-based clinical protocol-writing application
58
Lists to Avoid

• FDA list of Clinical Investigators who gave
  assurances
• http//www.fda.gov/ora/compliance_ref/bimo/dis_res
  _assur.htm
• FDA Disqualified/Totally restricted list
• http//www.fda/gov/ora/compliance_ref/disalist.htm
  
• FDA Debarred list
• http//www.fda.gov.ora/compliance_ref/debar/defaul
  t.htm

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Thank you

• Joel Moss NHLBI
• Kim Jarema
• Brian Chamberlain
• Phil Lightfoot

• Karen Charron
• Eric Zimmerman
• Johns Hopkins Bloomberg School of Public Health