This document provides guidelines for developing a clinical trial protocol including general information, background, aims and objectives, inclusion/exclusion criteria, study design, methodology, statistics, ethics, quality control, and protocol amendments. Key elements that must be addressed in the protocol are enumerated such as the research question, treatment characteristics, data collection and analysis, and legal responsibilities. Protocol deviations and violations that occur during the study are also discussed along with examples and regulatory requirements for reporting them. Adherence to good clinical practice and obtaining necessary approvals are emphasized.

1. Clinical Trial Protocol, Amendments,
Protocol deviations & violations
Dr. Amol Patil
Assistant Professor
Department of Pharmacology
PGIMER, Chandigarh

2. Protocol
• A system of rules that explain the correct conduct and
procedures to be followed in formal situations....
Merriam Webster

3. Why?
• To enumerate the research plan
• To ensure the quality
• Document for communication
• Source for a review document
• Legal document
• Part of IND application
A clinical trial protocol is a plan that meets scientific and ethical
requirements as well as good clinical practice

4. Points to be considered
• Research question
• Target patient population
• Design characteristics
• Treatment characteristics
• Data collection and analysis
• Ethical obligations
• Legal responsibilities
• Research management

5. Construction of a protocol
• General Information
• Background Information
• Aims and objectives
• Inclusion – Exclusion Criteria
• Trial design and Methodology
• Statistics
• Ethical consideration

6. General Information
• Protocol title, protocol identifying number, and date
Example – Cresendo Study

7. General Information

8. General Information
• Name and address of the sponsor and monitor

9. General Information

10. General Information
• Name and title of the investigator
• Clinical laboratory details

11. Background Information
• Name and description of the investigational product
• Non clinical study findings
• Summary of potential risks
• Route, Dosage and regimen
• Description of the population to be studied

12. Aims and objectives
• What to be answered
• How is that “What” to be answered (END
POINT)
Aim
Objectives

13. Aims and objectives
• Primary
– Answers hypothesis
– Statistical considerations
– Decides the results
• Secondary
– Additional information
– Does not decide the result

14. Aims and objectives
• To demonstrate the efficacy of rimonabant versus placebo
in improving cardiovascular parameters in patients with
abdominal obesity at increased risk for such events

15. Secondary
• Hospitalization
• All cause mortality
• Safety

16. End point
• Results, condition or events associated with individual study
patients that are used to assess study treatments

17. Characteristics of Endpoint
• Easy to diagnose
– Easy to identify - no evaluator judgment needed
• Free of measurement error
– Reliable with repeated measure
• Internal validity
– Directly linked to property of interest
• External validity
– Ability to generalize to a wider population
• Clinically relevant

18. Surrogate Endpoint
• Surrogate endpoint – used instead of direct endpoint – ex BP
or Cholesterol LDL
• Reduction as 1˚ endpoint as opposed to a reduction in
morbidity or mortality

19. Primary and Secondary Endpoints
• Primary – single (may be composite) endpoint parameter for
rejection of the null hypothesis
– Regulatory implication
• Secondary- other endpoints pre-specified, may be powered for
hypothesis testing

20. Primary Endpoint
• Primary: First occurrence of one of the following Clinical
Events Committee-adjudicated events
– Any MI,
– Any stroke, or
– Cardiovascular death

21. Secondary Endpoints
• Hospitalization for cardiovascular cause
• All Cause Mortality
• All adverse events
• Heart rate and blood pressure
• Hematology and biochemistry assessments

22. Inclusion – Exclusion Criteria(IE)
• Should be exhaustive and not vague
• Should include potential participants
• Should exclude the population harmed by study and who
cannot demonstrate efficacy (wrong study population)

23. Inclusion
• Consent
• Men and women aged 55 or greater
• Presence of abdominal obesity, with a waist circumference
greater than 102 cm (40 inches) for males and greater than 88
cm (35 inches) for females

24. Inclusion
• Presence of at least one coronary heart disease risk equivalent
OR two major cardiovascular risk factors

25. Inclusion – CHD Risk Equivalent
• Recent (within the past 3 years) myocardial infarction
• H/o angina, multivessel disease or PCI
• Cerebral ishcemic event
• PAD

26. Inclusion – Risk factors
• Metabolic syndrome
• Asymptomatic cerebrovascular disease
• Renal artery disease
• Elevated hs-CRP
• Elevated age

27. Exclusion
• Obesity due to known endocrine disorder
• Bariatric surgery
• Low Calorie Diet
• Presence of other conditions
• Breast feeding women

28. Study Design
• Type/design of trial to be conducted
Multicenter, multinational, randomized, parallel-group, double-
blind, controlled trial of rimonabant versus placebo

29. Methodology
• Screening
• Randomization
• Blinding
• Treatment administration
• Baseline and follow-up
• Assessment of efficacy and safety
• Duration
• Medication
• Stopping criteria

30. Methodology – Treatment
Administration
• Group 1 (rimonabant 20 mg): once daily administration in
the morning of one tablet containing 20 mg of active
rimonabant
• Group 2 (rimonabant placebo) once daily administration in
the morning of one rimonabant placebo tablet
• Tablet must be administered orally in the morning before
breakfast.

31. Methodology - Blinding
• The two types of tablets developed (20 mg rimonabant and
placebo rimonabant) are indistinguishable, and are packaged in
identical wallet cards

32. Methodology - Randomization
• The Interactive Voice Response System (IVRS) center will
allocate treatment based on a pre-specified randomization list,
generated by the IVRS provider, using study center as
stratification parameter

33. Methodology – Flowchart

34. Methodology – Evaluation of endpoint

35. Methodology – Evaluation of endpoint

36. Methodology
• Definition of source data
• Permitted concomitant treatment
• Treatment compliance
• How to deal with adverse events
• How to report adverse events
• Withdrawal criteria
• Follow up after withdrawal

37. Statistics
• Determination of sample size
• Statistical plans
• Clinical Trial Protocol deviations
• Population analyzed
• Handling of missing data
• Subgroup analysis
• Interim analysis

38. Premature closure
• Results of the Clinical Trial do not appear to be scientifically
convincing
• Aim of the Clinical Trial has become outdated
• Doubtful risk/benefit ratio

39. Ethics and Regulations
• This Clinical Trial will be conducted in accordance with the
principles laid down by the18th World Medical Assembly
(Helsinki, 1964)
• This Clinical Trial will be conducted in compliance with all
international laws and regulations

40. Ethics and Regulations
• Consent procedure
• IRB approval
– Amendments
– Progress report

41. Quality and Control
• Responsibility of investigators
– Ensure compliance with all procedures
– Provide reliable data
• Responsibilities of the Sponsor
– Monitor - high level of ethical, scientific, technical and
regulatory quality

42. Quality control
• Monitor visit
– Informed consent
– Patient recruitment and follow-up
– Serious Adverse Event documentation and reporting
– Outcome events documentation and reporting
– Investigational Product allocation
– Patient compliance
– Investigational product accountability
– Quality of data

43. Quality Control
• Audit by sponsor
• Inspection by regulatory authorities

44. Others to be included
• Data handling
• Publication policy
• Finance and Insurance
• Compensation
• Confidentiality statement
• Supplements
– CRF
– ICF
– IB
– Patients information sheet

45. Protocol Amendments

46. New protocols
• New protocols can be submitted to an existing IND.
• The new study can begin once it has been submitted for review
and the study has local IRB approval.
• You can submit to the FDA and IRB in the order of your
choosing.
• The FDA submission requires a brief description of the most
clinically significant differences between the new protocol and
previously submitted protocol(s).

47. • While there is no window of DCGI review, it is strongly
recommended that you communicate with the DCGI and make
sure they are OK with your new protocol before going
forward.
• Please note that it is customary to send the FDA a copies of
IRB approval letters and approved ICF documents to show
that IRB requirements have been met.

48. Changes in a protocol
• Changes to an existing protocol should be submitted to your IND
along with a description of the changes.
• The amended study can begin once it has been submitted to the FDA
for review and the amended study has local IRB approval.
• You can submit to the FDA and IRB in the order of your choosing.
• Examples of protocol changes that must be reported include the
following=
 • Any increase in drug dosage or duration of exposure to drug
 • Any significant increase in the planned number of subjects enrolled
 • New test procedures or dropped test procedures.

49. While there is no window of DCGI review, it is strongly
recommended that you communicate with the DCGI and make
sure they are OK with your protocol amendment before going
forward.
Please note that it is customary to send the FDA a copies of IRB
approval letters and approved ICF documents to show that
IRB requirements have been met.
Note: A change designed to eliminate immediate hazards to
subjects may be implemented immediately as long as FDA is
subsequently notified

50. New investigator
• This type of amendment is relevant for multi-center studies.
• When a new site opens to enrollment, the FDA must be notified of
the new investigator (i.e. the PI at the individual site) within 30 days
of enrolling the first subject.
• This requires submission of the sites’ 1572 and the CV of the PI
from that site.
• The FDA will not ‘approve’ your new protocols, protocol changes or
new investigators.
• Notice of new investigators can be batched and submitted at 30-day
intervals. Further, when several submissions are anticipated during a
short period of time, the sponsor is encouraged to batch as a single
submission when possible

51. Information Amendments
• This is essential information that does not fall within the scope
of Protocol Amendments, IND Safety Reports or Annual
Reports. Examples include new technical information or the
cancellation of a study.
• This information should be submitted as needed but not more
than 30 days.

52. Protocol Deviations and Protocol
Violations
• A protocol deviation occurs when the activities during a study
diverge from the IRBapproved protocol; a variance from
protocol
• A protocol violation occurs when there is divergence from the
IRB-approved protocol (a deviation) that also: – reduces the
quality or completeness of the data – impacts a subject’s
safety, rights or welfare – affects the scientific integrity

53. Examples of Protocol Deviations
• Vital signs obtained prior to informed consent
• Weighing participant with shoes on
• Urine dipstick is completed, but not sent for formal U/A
• Targeted physical exam documented instead of complete PE
• Conjugated bilirubin, part of the protocol, is left off the lab
request form, but total bilirubin was drawn and is normal

54. Examples of Protocol Violations
• Inadequate informed consent
• Enrollment of subjects not meeting the inclusion /exclusion criteria
• Initiation of study procedure prior to completion of informed consent •
Unreported SAE’s
• Improper breaking of the blinding of the study
• Use of prohibited medication
• Incorrect or missing tests
• Mishandled samples
• Multiple visits missed or outside permissible windows
• Inadequate record-keeping
• Intentional deviation from the protocol, GCP or regulations by study
personnel in a non-emergency setting
• Repeated noncompliance by the subject
• Repeated deviations of the same nature
• Falsification

55. ICH GCP Regulations
• ICH GCP 4.5 Compliance with protocol
• 4.5.1 Investigator should conduct the trial in compliance with
the protocol agreed to and approved by an IRB
• 4.5.2 Investigator should not implement any changes or
deviations from the protocol unless agreed to by the IRB,
sponsor, etc. except when necessary to eliminate immediate
hazards to trial subjects, or when the changes are
administrative or logistical

56. • ICH GCP 5.20.2 If the monitoring and/or auditing identifies
serious and/or persistent noncompliance on the part of an
investigator/institution, the sponsor should terminate the
investigator’s/institution’s participation in the trial. When an
investigator’s/institution’s participation is terminated because
of non-compliance, the sponsor should notify promptly the
regulatory authority(ies).
• ICHGCP section 5.20.2, the sponsor must view protocol non-
compliance as a ‘violation’ of agreed responsibilities.

57. FDA / DCGI
• Does not distinguish between a violation and a deviation; all
protocol variances are violations
• Any deviation not reported and later discovered by an audit is
considered noncompliance with the FDA

58. Who Discovers Deviations/Violations?
• Study team
• Hospital staff:
– Nursing
– Bionutrition Staff
– Pharmacy Staff
– Regulatory Staff
• Auditors, monitors
• Participants

59. References
• Design and analysis of clinical trials
– SHEIN-CHUNG CHOW
• E6-ICH
• FDA
• CDSCO – Guidance for industry