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

IB

• Detail guideline is provided in GCP and ICH