Clinical trial protocol, ammendments, Protocol deviations and violations

GCP course material

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 D ecides 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 R egulatory 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 R esults of the Clinical Trial do not appear to be scientifically convincing A im 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 E nsure 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 P atient recruitment and follow-up Serious Adverse Event documentation and reporting O utcome events documentation and reporting Investigational Product allocation Patient compliance Investigational p roduct accountability Q uality 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