Clinical Protocol Writing 101 - PowerPoint PPT Presentation

Loading...

PPT – Clinical Protocol Writing 101 PowerPoint presentation | free to download - id: 84aa7-ZThkZ



Loading


The Adobe Flash plugin is needed to view this content

Get the plugin now

View by Category
About This Presentation
Title:

Clinical Protocol Writing 101

Description:

The International Conference on Harmonisation (ICH) defines a protocol as follows: 'A document that describes ... Internet (e.g., http://clinicaltrials.gov) ... – PowerPoint PPT presentation

Number of Views:897
Avg rating:3.0/5.0
Slides: 86
Provided by: irving4
Learn more at: http://www.massbio.org
Category:

less

Write a Comment
User Comments (0)
Transcript and Presenter's Notes

Title: Clinical Protocol Writing 101


1
  • Clinical Protocol Writing 101
  • Massachusetts Biotechnology Council
  • 6 March 2009
  • Michelle Currie
  • Vice President, Clinical Operations, Veristat,
    Inc.
  • Christopher Schoonmaker, MPH
  • Associate Director, Biostatistics, Veristat, Inc.

2
Presentation summary
  • Definition of a protocol
  • Developing a study-specific protocol, including
    statistical methodology
  • Protocol amendments
  • Protocol template format / content
  • The protocol and CDISC

3
  • WHAT IS A PROTOCOL?

4
What is a protocol
  • The International Conference on Harmonisation
    (ICH) defines a protocol as follows
  • A document that describes the objective(s),
    design, methodology, statistical considerations,
    and organization of a trial. The protocol
    usually also gives the background and rationale
    for the trial, but these could be provided in
    other protocol-referenced documents.

5
What is a protocol
  • Purposes
  • Describes how to treat and manage patients
  • Describes data to be collected and collection
    methods
  • Describes the plan for data analysis
  • Used to select study centers / vendors
  • Used by IRBs/IECs to determine whether to approve
    study
  • Reference tool for monitoring and auditing study
    conduct

6
  • DEVELOPING A STUDY-SPECIFIC PROTOCOL

7
Questions to consider
  • What is the study phase?
  • Phase 1 small sample size evaluate safety
    determine a safe dosage range identify side
    effects ADME
  • Phase 2 larger sample size evaluate efficacy
    and further evaluate safety

8
Questions to consider
  • What is the study phase?
  • Phase 3 large sample size confirm efficacy,
    compare to commonly used treatments, and collect
    data to allow the drug to be used safely
  • Phase 4 post-marketing further determine
    drug's risks, benefits, and optimal use

9
Questions to consider
  • What type of study is it?
  • Treatment study test experimental treatments,
    new combinations of drugs, or new therapeutic
    approaches
  • Prevention study ways to prevent disease in
    naïve subjects or to prevent a disease from
    returning

10
Questions to consider
  • What type of study is it?
  • Diagnostic study better tests or procedures for
    diagnosing a particular disease or condition
  • Screening study best way to detect certain
    diseases or health conditions
  • Quality of Life / Supportive care study explore
    ways to improve comfort and the quality of life
    for individuals with a chronic illness

11
Questions to consider
  • What is the study drug?
  • What is the indication?
  • What is the scientific question that needs to be
    answered (i.e., what are your objectives)?
  • What is the regulatory question that needs to be
    answered?
  • What is the budget?

12
Questions to consider
  • Efficacy evaluations
  • What tests are appropriate for the indication?
  • What tests are appropriate for the study drug?
  • Is a central / independent read of test results
    needed?
  • Is a Clinical Endpoint Committee (CEC), or
    equivalent, necessary?

13
Questions to consider
  • Safety evaluations
  • How will adverse events be collected?
  • Are there specific events to be solicited?
  • What tests are appropriate for the indication?
  • What tests are appropriate for the study drug?
  • Is a central / independent read of test results
    needed?
  • Is a DSMB or formalized interim review of safety
    data necessary?

14
Questions to consider
  • Ultimately, what do you want to say in the
    clinical study report (CSR)?
  • Collect what you need.
  • Dont necessarily collect everything everybody
    wants.

15
Considerations for patients/participants
  • Is the visit schedule reasonable / feasible?
  • Are there invasive / painful study procedures?
  • How much blood will be collected?
  • What other samples will be collected (tissue,
    bone marrow, spinal fluid)?

16
Considerations for patients/participants
  • How long will the patient have to stay at the
    study center?
  • Are there costs associated with participation?
  • Are there dietary / life-style restrictions?
  • Will the patient need access to equipment?

17
Considerations for study personnel
  • Is the visit schedule reasonable / feasible?
  • Are early morning, late evening, or weekend
    appointments required?
  • How much data are to be collected?
  • Are turn-around times required by the protocol
    feasible per the facilities standard operating
    procedures?

18
Considerations for the investigator
  • Does the investigator have access to patients
    meeting the eligibility criteria?
  • Are the eligibility criteria consistent with
    clinical status of patients?
  • Is there a reasonable possibility of benefit to
    patients?

19
Considerations for the investigator
  • Are the risks to patients too high?
  • Does the protocol provide a reasonable treatment
    option relative to standard of care?
  • Will patients be subjected to procedures /
    treatments they dont need or restricted from
    procedures / treatments they do need?

20
Considerations for the sponsor
  • All of the previous, plus
  • How many patients are required?
  • Are the eligibility criteria reasonable for
    adequate enrollment?
  • How many study centers will be required to reach
    the intended number of patients?

21
Considerations for the sponsor
  • Are data needed by a particular date to plan
    future studies or meet a regulatory requirement?
  • What is the per-patient cost?
  • The more frequent the visits, the higher the
    per-patient cost
  • The more clinical tests (MRI, CT, X-rays), the
    higher the per-patient cost

22
Resources
  • Solicit input from
  • Medical monitor
  • Safety officer
  • Regulatory representative
  • Statistician
  • Drug supply
  • Clinical data management
  • Pharmacologist
  • Commercialization team (marketing, sales)

23
Reference materials
  • Refer to
  • Previous protocols for the study drug/device or
    for a similar indication
  • Clinical development plan
  • Investigators brochure
  • Publications
  • Internet (e.g., http//clinicaltrials.gov)
  • Regulatory guidance documents (general and drug
    class- or indication-specific)

24
Reference materials
  • Do not feel compelled to rewrite what has
    already been written (provided it is
    well-written)
  • If it aint broke, dont fix it

25
  • PROTOCOL CONCEPT

26
Protocol concept
  • Development of protocol concept sheet
    recommended (but not required).
  • Protocol concept essentially is the protocol
    synopsis
  • Focuses on key details
  • Limits the need to revise text across multiple
    sections
  • Review and approve before developing full
    protocol

27
Protocol concept
  • Generally contains
  • Protocol Title
  • Protocol Number
  • Study Phase
  • Investigators and Study Centers
  • Objectives
  • Study Design
  • Number of Patients Planned

28
Protocol concept
  • Diagnosis and Main Criteria for Inclusion
  • Test Products, Doses, and Administration Mode
  • Duration of Treatment
  • Study Endpoints
  • Efficacy
  • Pharmacokinetic / pharmacodynamic
  • Safety
  • Statistical Methods
  • Evaluation Schedule

29
Protocol concept
  • First Steps
  • Determine
  • Objectives / Endpoints
  • Evaluation Schedule, including dose schedule
  • Sample Size
  • Eligibility Criteria
  • Other elements of the protocol can be built from
    these pieces

30
Diagrams and flowcharts
  • A clear evaluation schedule is critical
  • Clearly identify study periods / visits
  • Organize procedures in the order in which they
    are to be performed
  • Structure in a way to minimize footnotes

31
Diagrams and flowcharts
32
Diagrams and flowcharts
  • Carefully consider the timing of evaluations.
  • For example

33
Diagrams and flowcharts
  • Mean (?SD) Corrected Calcium (mmol/L) Over Time

34
Diagrams and flowcharts
  • Mean (?SD) Corrected Calcium (mmol/L) Over Time

35
Diagrams and flowcharts
  • The evaluation schedule is useful for
  • Scheduling patient visits
  • Determining blood collection volumes
  • Scoping study costs
  • CRF development

36
Diagrams and flowcharts
  • Use other diagrams and charts to illustrate
    complicated processes and / or reduce text
  • Consider whether useful to study center personnel

37
Diagrams and flowcharts
38
Diagrams and flowcharts
39
  • STATISTICAL METHODS

40
Sample size / power calculation
  • Why is it important?
  • Will your study be powered to detect statistical
    significance if one really exists?
  • Not always necessary for Phase I studies (e.g.,
    dose escalation trials),
  • Most important for pivotal Phase III and Phase II
    studies

41
Sample size / power calculation
42
Sample size / power calculation
  • Why is it important?
  • As sample size increases, power increases. The
    higher the power, the lower the type II error
  • We limit the type II error by powering the study
    at a high level (generally gt 80)
  • We limit the type I error by predefining a low
    alpha level (generally .05)

43
Sample size / power calculation
  • What is needed to perform or describe sample size
    calculations?
  • Indication of the primary endpoint (e.g., overall
    survival, disease response)
  • What is your hypothesis?
  • What is it that you expect your drug or device to
    do?

44
Sample size / power calculation
  • What is needed to perform or describe sample size
    calculations?
  • Proposed design(s) of study and phase?
  • Dose escalation, Simon 2 Stage, randomized
    control trial, non-inferiority, etc.?
  • Indication of the number of planned treatment
    arms

45
Sample size / power calculation
  • What is needed to perform or describe sample size
    calculations?
  • Alpha level for primary and secondary endpoints
  • Any limitations to the number of subjects you can
    enroll?
  • Some statistical methods/tests might be more
    robust with smaller sample sizes while still
    maintaining the necessary statistical power.
  • Estimate of effect size/hypothesized treatment
    effect/benchmark of treatment success
  • e.g., estimated median survival of 15 weeks in
    Arm A versus 20 weeks in Arm B

46
Description of the planned statistical methods
  • What is needed to write this section?
  • Assessment schedule (particularly in table form)
  • A list of all endpoints to be measured
  • A concept of the critical or important safety
    evaluations that are needed for the study
  • A protocol concept sheet / synopsis is ideal
  • Provides description of variables to be collected
    and when

47
Description of the planned statistical methods
  • Baseline Evaluations
  • A brief description of the baseline evaluations
    and intended variables to be summarized.
  • For example
  • Demographic and baseline disease characteristic
    data summarization will be performed in order to
    descriptively assess the comparability of dose
    groups. Data to be tabulated will include sex,
    age, and race, as well as disease-specific
    information.

48
Description of the planned statistical methods
  • Safety Assessments
  • A description of the primary and secondary safety
    endpoints
  • Summary of any relevant statistical hypothesis
    testing including alpha level and/or confidence
    interval calculations

49
Description of the planned statistical methods
  • Safety Assessments
  • Summary of planned analysis for
  • adverse events (tabulation of incidence rates)
  • study drug exposure (cumulative dose received,
    cycles received, etc.)
  • laboratory assessments, vital signs, and ECG
    Analysis (change from baseline, shift tables,
    etc.)

50
Description of the planned statistical methods
  • Efficacy Assessments
  • A description of the primary and secondary
    efficacy endpoints and intended analysis of each
  • The planned analysis for the primary endpoint
    should be very detailed/analysis plan ready,
    particularly in Phase III
  • Description of any relevant statistical
    hypothesis testing including alpha level and/or
    confidence interval calculations

51
Description of the planned statistical methods
  • Efficacy Assessments
  • Will there be multiple comparisons/testing?
  • The more statistical testing you perform, the
    more likely you are to see a significant result
    by chance alone (increase in the Type I error
    rate)

52
Description of the planned statistical methods
  • Efficacy Assessments
  • Handling multiple testing
  • Should generally only have one primary endpoint
    on which study conclusions are based
  • Adjust for multiple comparisons (e.g.,
    statistical testing involving the same endpoint
    across several groups or statistical testing
    involving several endpoints/hypotheses)
  • Consider adjustment of the alpha level
    (Bonferroni, Tukey)
  • Sequential testing of your hypothesis. If the
    first statistical test is significant, proceed to
    the next (e.g., if High Dose versus Placebo is
    significant, then test Low Dose versus Placebo)

53
Description of the planned statistical methods
  • PK/PD Assessments
  • Include a description of collection intervals for
    PK plasma or urine samples
  • Include details on the parameters to be
    calculated
  • AUC0-8, Elimination Half Life, Cmax, Tmax, Plasma
    Clearance, etc.
  • Describe and correlative analysis between any
    calculated PK parameter and other study endpoint

54
Description of the planned statistical methods
  • Exploratory Endpoints
  • It is OK to have exploratory endpoints, but these
    should be stated in the protocol
  • Often you wont know the type of analysis that
    will need to be performed on these endpoints
  • Make your best guess on the anticipated analysis,
    OR
  • Clearly state that these parameters are
    exploratory and more details will be provided in
    the analysis plan, OR
  • Indicate that these endpoints may be summarized
    in a report separate from the clinical study
    report

55
Handling of missing, unused, or spurious data
  • How will you handle subjects who are missing the
    primary endpoint?
  • If this endpoint was collected at earlier periods
    in the trial, consider last observation carried
    forward (LOCF)
  • Consider the worst case, by assigning subjects
    with missing data as treatment failures
  • How will you handle spurious data?
  • If the data point is considered an outlier,
    consider removing the result from the analysis to
    determine if it is influential.

56
Procedures for reporting deviations from the
original statistical plan
  • Major deviations could involved a protocol
    amendment and possibly additional interactions
    with the FDA
  • A general statement should be added to the
    protocol to cover minor deviations
  • All deviations from protocol specified analysis
    will be described in the statistical analysis
    plan

57
Definitions of analysis populations
  • Describe the populations to be used for the
    analysis. For example
  • The following subject populations will be
    evaluated and used for presentation and analysis
    of the data
  • Intent-to-Treat (ITT) Population All subjects
    who were randomized to treatment, whether or not
    they received treatment.
  • Efficacy-Evaluable (EE) Population All
    subjects in the ITT population without any major
    protocol violations and with at least 1 efficacy
    evaluation.

58
Definitions of analysis populations
  • Describe the populations to be used for the
    analysis. For example
  • The following subject populations will be
    evaluated and used for presentation and analysis
    of the data
  • Pharmacokinetic (PK) Population All subjects
    with sufficient data ltif possible, define how
    much data is neededgt to determine ltXXgt PK
    parameters.
  • Safety Population All subjects who were
    randomized and received at least 1 dose of study
    drug.

59
Definitions of analysis populations
  • Specify which populations will be used for
    various analysis. For example
  • The ITT population is the primary population
    for the analysis of efficacy parameters. A
    subset of efficacy parameters will be evaluated
    for the EE population. The PK population is the
    primary population for the analysis of PK
    parameters. The Safety population is the primary
    population for the analysis of safety endpoints.

60
Interim analysis
  • Is there a need for a DSMB to monitor treatment
    safety or efficacy?
  • Will there be a test for superiority or futility
    that might lead to prematurely stopping the
    trial?
  • What critical values would be used as grounds for
    stopping the trial (e.g. a conditional power
    estimate less than 20, or only a 20 probability
    of seeing a significant result by the end of the
    trial given what you observe at the interim).
  • Will there be sample size re-estimation?

61
Interim analysis
  • Alpha Adjustment (adjusting the alpha level for
    the final analysis)
  • The more statistical testing you perform on a
    given endpoint, the more you increase your type I
    error rate. We want to maintain the overall
    alpha level at which the study was powered.
  • For each interim analysis, you pay a penalty (a
    reduction in your final alpha level)
  • General rule of thumb If interim analyses
    involve formal significance testing of relative
    treatment group differences, the final alpha
    level should be adjusted

62
  • PROTOCOL AMENDMENTS

63
Protocol amendments
  • There is no such thing as an amendment-free
    protocol
  • Amendments arent necessarily a bad thing

64
Protocol amendments
  • Amendments are required for any change in a
    protocol that significantly affects
  • Patient safety
  • The scope of the investigation
  • The scientific quality of the study

65
Protocol amendments
  • Examples
  • Increase in drug dose or duration of exposure
  • Significant increase in the sample size
  • Significant change in the study design
  • Addition of a new test or procedure
  • Removal of a previously required test or procedure

66
Protocol amendments
  • Amendments commonly address changes to
  • Entrance criteria to facilitate enrollment
  • Patient management as a result of new information
    about the study drug
  • Patient management or planned statistical
    analyses as a result of interim analyses

67
Protocol amendments
  • Include a change history document with each
    protocol amendment.
  • Itemizes changes to the protocol for study center
    personnel and IRB
  • Facilitates documenting the changes to the
    planned methods in the CSR
  • Facilitates CDISC activities

68
Protocol amendments
  • Minimize number of amendments / administrative
    changes.
  • Stockpile small changes (e.g., correction of
    typographical errors) until a major change is
    necessary
  • Then, fix all at once

69
Protocol amendments
  • Minimize administrative details in protocol
    (e.g., names, addresses, telephone numbers) to
    avoid administrative changes
  • However, always include SAE reporting information

70
  • PROTOCOL TEMPLATE STRUCTURE AND CONTENT

71
Protocol template structure and content
  • Strongly recommend the use of a template
  • Ensures consistency across studies and programs
  • Sets expectations for what is needed each time

72
Protocol template structure and content
  • At this time, there is no specific ICH guidance
    for the format and content of clinical protocols
  • Accordingly, templates vary
  • Basic content described in CFR 312.23, IND
    Content and Format
  • Protocol contents described in more detail in ICH
    E6, Guideline for Good Clinical Practice (GCP),
    Section 6

73
Protocol template structure and content
  • ICH E6
  • (http//www.ich.org/LOB/media/MEDIA482.pdf)
  • Specifies topics that should generally be
    included
  • Some information may be contained in other
    protocol-referenced documents (e.g.,
    Investigators Brochure)
  • Site information may be provided in a separate
    agreement

74
ICH E6 Versus E3
  • ICH E6 (GCP) Versus ICH E3 (CSR)
  • ICH E6 not as detailed as ICH E3
  • Suggest designing protocol template to correspond
    to the methods sections of ICH E3 (i.e., Sections
    5 through 9)
  • Ensures protocol contains text required for CSR
  • Simplifies writing the CSR shell

75
  • THE PROTOCOL
  • AND CDISC

76
The protocol and CDISC
  • CDISC Clinical Data Interchange Standards
    Consortium
  • CDISC has established standards for exchange,
    storage, archival and submission of clinical data
  • The more you think about CDISC from the start,
    the better off you will be in the end
  • Use the same language within and across studies

77
The protocol and CDISC
  • CDISC Protocol Representation Group
  • Content Spreadsheet of Elements
  • http//www.cdisc.org/standards/PRElements_FullList
    2-0-0.pdf
  • Primarily based on ICH E6 however, other
    guidances cited
  • Identifies elements to be included in protocol
    body

78
The protocol and CDISC
  • CDISC Protocol Representation Group
  • Protocol Supplements list
  • http//www.cdisc.org/standards/ProtocolSupplements
    1-0-0.pdf
  • Identifies documents frequently appended to
    protocols

79
The protocol and CDISC
  • CDISC Standard Terminology
  • Consider CDISC terminology (e.g., SDTM Production
    Terminology) when creating / updating protocol
    template
  • Carry forward in CRF/eCRF, Database, Datasets

80
The protocol and CDISC
  • For example
  • Clinical laboratory parameters, including units
  • Adverse event intensity
  • Reasons for study non-completion

81
The protocol and CDISC
  • Reasons for non-completion
  • Completion
  • Death
  • Lack of efficacy
  • Lost to follow-up
  • Non-compliance with study drug
  • Physician decision
  • Pregnancy
  • Protocol violation
  • Recovery
  • Trial screen failure
  • Study termination by sponsor
  • Technical problem
  • Withdrawal by subject

82
The protocol and CDISC
  • Consider your down-stream users
  • Clinical data managers
  • Database developers
  • Biostatisticians and SAS programmers

83
Summary
  • Use a template
  • Ensure consistent with ICH E6 and ICH E3
  • Consider developing a concept protocol before
    full protocol
  • Seek information / input from
  • Study team
  • Existing documents
  • Published materials
  • Dont reinvent the wheel each time

84
Summary
  • Consider all protocol users and the budget
  • Develop clear objectives
  • Create a clear evaluation schedule
  • Develop other diagrams and flowcharts to augment
    text
  • Involve your statistician early
  • Amend for significant changes to the study
  • Make minor / administrative changes at same time

85
  • Thank you for inviting us.
About PowerShow.com