Cinical trial protocol writing
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Transcript of Cinical trial protocol writing
CLINICAL TRIAL PROTOCOL
DEVELOPMENT
AND
INVESTIGATORS BROCHURE
Dr Urmila M. Aswar,
Sinhgad Institute of Pharmacy, Narhe, Pune -41
Protocol writing
It is a complete written description and scientific
rationale for a research activity involving human
subjects.
oObjectives
oDesign
oMethodology
Writing a Protocol – First steps The PI must know the answers for
Is it reasonable? Do we have the resources?
What are the significant risks?
Do we have the patient population?
Associate Investigator/ outside investigators may be included.
Should be able to write the whole CT in few lines
Who Reads Protocols?
• The protocol language/ content should be
understood by
–Other physicians
–Nurses/CRAs
– IRB members
–Scientific reviewers
– IC for a lay person
Templates availability
• Many NIH programs encourage to use the
protocol templates available eg.– http://ctep.cancer.gov/guidelines/templates.html
• Following template guidelines can help guide
authors with proper modifications.
Parts of the Protocol
1. Introduction/Abstract
2. Objectives
3. Background/Rationale
4. Eligibility criteria
5. Study design/methods (including drug/device info)
6. Safety/adverse events
7. Regulatory guidance
8. Statistical section (including analysis and monitoring)
9. Human subjects protection/informed consent
1. Objectives
• Objectives should be stated clearly ashypotheses to be tested.
• Each objective should have a correspondingdiscussion in the statistical section.
2. Background and Rationale
• All protocols require a section detailing thescientific rationale for a protocol and thejustification in medical and scientific literaturefor the hypothesis being proposed.
• Introductory section should be organized in alogical, sequential flow.
Background and Rationale
• Double check all citations
• Common mistakes
• Name misspellings (including wrong initials),
wrong journal names, wrong years of
publication, and wrong volume numbers
3. Eligibility criteria- defn.
• Inclusion and exclusion criteria are theconditions that must be met in order toparticipate in a clinical trial.
• The most important criteria used to determineappropriateness for clinical trial participationinclude age, sex, the type and stage ofa disease, treatment history, and othermedical conditions.
Writing Eligibility Criteria for Patient
• Eligibility criteria are the largest barrier to
clinical trials.
• There is no guideline for writing these criteria
• Poorly written or poorly conceived criteria
may affect the scientific validity of CT.
• Reasons for imposing eligibility criteria
includes scientific rationales, safety concerns,
regulatory issues, and practical considerations
The points to be considered to write a good eligibility criteria
1. The number of eligibility criteria should be kept to a minimum.
2. Criteria should include only those absolutely necessary to ensure scientific validity and patient safety.
3. Eligibility criteria should be clearly defined and verifiable by an external auditor.
4. Eligibility criteria should be straightforward
and unambiguous. Which of these criteria is
better understood?
1. Pregnant and/or nursing women are not
eligible.
2. All women of childbearing age are
required to have a negative serum
pregnancy test.
3. Nursing women are not eligible for this
study. All women of childbearing potential
must have a negative serum pregnancy test
within 2 weeks of study enrollment.
Failure to write eligibility criteria
properly
• Leads to
Failure to mimic clinical practice
Increased study complexity
Increased costs
Less number of patient getting recruited
Example• Eligibility criteria given by National Institute ofNeurological Disorders and Stroke’s for recruitingparticipants for a clinical trial titled Study of Brain ActivityDuring Speech Production and Speech Perception.
• The inclusion criteria specified for the experimental groupwere (a) right-handed children and adolescents, (b) nativespeakers of American English, and (c) stuttering orphonological disorders.
• The comparison (control) group consisted of normallydeveloping right-handed children and adolescents whowere native speakers of American English.
• Exclusion criteria were (a) language use in the home otherthan American English, (b) speech reception thresholdsgreater than 25 dB, and (c) contraindications to magneticresonance scanning.
4. Study Design
• The study design section of the protocol
should contain a stepwise description of all
procedures required by the study.
• A good study design section includes sufficient
information for the participating site.
Study Design• Parts of the study design section may
include:
Initial evaluations
Screening tests
Required lab tests
Details of treatment or procedures
Device specifications
Dose scheduling and modification
Calendars
5. Safety
• Adverse effect and side effect are termscommonly associated with drugs. They are usedby nurses and doctors, to refer to undesirableeffects of a medication on a patient.
• The Safety (or Adverse Events) section shouldinclude:
• Detailed information for reporting adverse events,including reporting to the FDA and/or the sponsor
• Unblinding processes (if applicable)
• Lists of expected adverse events
6. The Statistical Section
• The study objectives and study designelements in the statistical section shouldbe described in the Objectives section
• The descriptions and definitions oftoxicities in the statistical section matchthose in the Safety/AE section.
7.Human Subjects Protection
• This section includes discussion of:
– Subject selection and exclusion
– Proposed methods of patient recruitment
– Minority representation
– Recruitment (or exclusion) of special subjects, including vulnerable subjects
– Lists of potential risks and benefits, including justification for risks
Informed Consento Disclosure of relevant information to prospective
research subjects
o Comprehension of the information provided to thesubject
o Voluntary agreement of the subject.
The protocol’s informed consent must
• Be thorough and complete
• Be written in simple, nontechnical language
• Be carefully worded to avoid complexity.
The protocol’s informed consent must
provide
• Statement that the study involves research
• Purpose of the research and the length of the study
• Description of risks and benefits
• Discussion of alternative therapies
• Confidentiality policy
• Compensation for injury
• Contact for further questions/information
• Statement of voluntary participation
Tools for Better Writing: Proofreading
Working too long on a protocol may habituate eyes
and brains to mistakes, simply because they’ve
been there all along.
Spell-checkers, etc.
– A document should be checked by automatic
software
– The document should be proofread.
• Aoccdrnig to a rscheearch atCmabrigde Uinervtisy, it deosn'tmttaer in waht oredr the ltteers in awrod are, the olny iprmoetnt tihngis taht the frist and lsat ltteer be atthe rghit pclae.
NIH Guidance on Protocol Writing
• Protomechanics:
http://www.cc.nih.gov/ccc/protomechanics/
• The Office of Human Subjects Research:
http://ohsr.od.nih.gov/info/info.html
• The NCI Investigators’ Handbook:
http://ctep.cancer.gov/handbook/index.html
INVESTIGATORS BROCHURE
IB
• It is a comprehensive document summarizinginformation about an investigational productobtained during a drug trial.
• The IB is updated with new information as itbecomes available.
• Compile data relevant to studies of theinvestigational drug in human subjectsgathered during preclinical and other clinicaltrials.
• It sd provide the information for management of CT and safety during CT
• Dose (of the study drug)
• Frequency of dosing interval
• Methods of administration
• Safety monitoring procedures
IB contains Summary of Data and Guidance for the Investigator
• Provide the investigator with a clearunderstanding of the possible risks andadverse reactions, details of tests,observations, and precautions that may beneeded for a clinical trial
• The information should be based on theavailable physical, chemical, pharmaceutical,pharmacological, toxicological, and clinicalinformation on the investigational product.
• Should also provide treatment of possibleoverdose and adverse drug reactions.
• The IB should be reviewed annually