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1. COMPLIANCE AND CLINICAL TRIALS Prof. Dr. Michael Panijel Dr. Paull G. Radu Varna, Oct. 2005


3. “Compliance means the degree of how a person reacts to a certain kind of medicine, a diet, or a change of lifestyle in correspondence with medical advice” R. Brian HAYNES

4. ADHERENCE VS. COMPLIANCE Adherence is preferred term Adherence: Active, choice, interactive Compliance: Passive, non-selective

5. Definition of Compliance Data on dose taking - taking the prescribed number of pills each day Timing of doses - taking pills within a prescribed period

6. Drugs don't work in patients who don't take them C. Everett Koop, MD The Real Drug Problem: Forgetting to Take Them

7. Compliance and non-compliance are like identical twins

8. Some level of non-adherence in a clinical trial can be considered a good thing because there's always some level of noncompliance in real-world clinical practice John Yates, M.D

9. History Following the snake’s advice can be looked at as compliance. But the consequences of taking the snake’s advice which led to a changed situation of life for Adam and Eve can be seen as non-compliance.

10. “The physician should always be aware of the fact that patients might be lying when saying that they took the prescribed medicine.”

11. Economic aspects Poor adherence accounts for substantial worsening of disease, death and increased health care costs In the US - 33-69% of medication-related hospital admission are due to poor medication adherence ? costs of ? 100Bil$/year.

12. DATA on Negative Economic Effects 23% of nursing home admissions due to noncompliance 10% of hospital admissions due to noncompliance About 50% of the 2 billion prescriptions filled each year are not taken correctly 1/3 of patients take all their medicine, 1/3 take some, 1/3 don't take any at all

13. CLINICAL TRIALS FUNDAMENTAL POINT: PARTICIPANT ADHERENCE Many potential adherence problems can be prevented or minimized before participant enrollment. Once a participant is enrolled, taking measures to enhance and monitor participant adherence is essential.

14. Presence of psychological problems, particularly depression Presence of cognitive impairment Treatment of asymptomatic disease Inadequate follow-up or discharge planning Side effects of medication Patient’s lack of belief in benefit of treatment Patient’s lack of insight into the illness Poor provider–patient relationship Presence of barriers to care or medications Missed appointments Complexity of treatment Cost of medication, co-payment, or both

15. Goal orientated aspects Charles H. Goldsmith “The influence of compliance – distributed among therapeutic studies” Counting the number of pills that are being brought back (drug accountability). the number of pills that are being brought back has to be correct the number of pills that are missing have actually been taken by the patient

16. No of pills taken by patient PC = ----------------------------------------- X 100 No of prescribed pills C (Goldsmith) or PC (patient compliance).

17. Positive tests PC = ---------------------- X 100 All tests BLOOD/URINE LEVEL TESTS

18. Systematic observations with longtime patients and/or a complicated form of the medicine usage influence the compliance/non-compliance balance towards non-compliance.

19. Compliance control (by Charles H. Goldsmith) – distribution sample Patient’s compliance: Gordis et al. studies in the epidemiology and preventability of rheumatic fever was the first try to graphically present compliance. In this study with 136 patients on the lucrative field of prophylaxis of rheumatic fevers the following data was found. 36 % small compliance (= 25 %) 32 % medium compliance (25 % = C = 74 %) 32 % high compliance (75 % = C = 100 %)

20. The graphic display of these results has the following U-shape:

21. Roth et al. – measuring the intake of a prescribed medication (Clin. Pharm Ther 11:228-237 1970) The amount of medication prescribed over the amount of medication actually used was taken as data sample • Prescribed: 0.57 bottles/day • Actually used: 0.30 bottles/day

23. In an Irish study concerning chemotherapy in tuberculoses patients (Ireland – out of patients chemotherapy for tuberculoses: Amer. Rev. Rest. Dis. 82, 378-383, 196), concerning 264 patients; or In a psychotherapeutic study (Mason et al. adherence to maintenance therapy and re-hospitalization Dis new system. :103-104 1963

24. The graphical display of the data was linear because compliance stayed the same over the whole time of the study

25. There are a lot of possibilities for measuring and displaying compliance. That compliance may worsen and get better anytime a. If the u-shaped compliance curve would shift to the right then this would mean that the patient is overdosing on the prescribed medication. b. By shifting the arch-shaped compliance curve to the left then results would become better.

27. The distribution sample can be an important factor in finding the optimal doze. Compliance equals quality in clinical studies.

28. Important aspects of compliance for finding the right-doze studies

30. Nonadherence in Clinical Trials One-third of volunteers who were assigned regular use of an inhaled bronchodilator in a clinical trial dumped the contents shortly before clinic follow-up visits in an effort to conceal their failure to take the medicine properly

31. “If 30 percent of patients are not using their medications at all or hardly using them, you could misinterpret data on the efficacy of a drug or overestimate the dose required to provide a desired effect," Donald P. Tashkin, M.D.

32. You can prescribe all the pills in the world, but it still comes down to patient behavior Noncompliance among subjects in clinical trials is believed to be much lower because of volunteers' willingness to participate in research Recent studies using objective measures, such as pill counting or weighing canisters, have found that non-adherence is more widespread in clinical trials than previously thought

33. MONITORING THE LEVEL OF MEDICATION ADHERENCE Pill counts Pharmacy tracking of medication pick-ups - Clinic visits - MEMS bottle cap devices - Self-reports - Morisky 4-question tool Clinician assessment

34. Morisky Simplified Self-Report Measure of Adherence SCORING: 0 = HIGH ADHERENCE; 1-2 = MEDIUM ADHERENCE; 3-4 = LOW ADHERENCE Do you ever forget to take your medicine? Are you careless at times about taking your medicine? When you feel better do you sometimes stop taking your medicine? Sometimes if you feel worse when you take the medicine, do you stop taking it?

35. Medication Event Monitoring System

36. 1 opening since the beginning of the day 4 hours passed since the last opening

37. 1 opening since the beginning of the day 12 hours passed since the last opening

38. 1 opening since the beginning of the day 16 hours passed since the last opening

39. Medication Adherence Monitoring System - Telemed

40. Database

41. Graf

43. Strategies for Improving Adherence Identify poor adherence Emphasize the value of the regimen and the effect of adherence Provide simple, clear instructions and simplify the regimen as much as possible Encourage the use of a medication-taking system Listen to the patient, and customize the regimen in accordance with the patient’s wishes Obtain the help from family members, friends, and community services when needed Reinforce desirable behavior and results when appropriate

45. Patient compliance : Prerequisite: the patient is cooperative and well informed honesty respects the method of application respects the appointments times correct uses journals and/or questioners appropriate answers the questions of the investigator.

46. Investigator Compliance: Prerequisite: the investigator is recruiting, after thorough explanations, of patients thorough studying of the protocol respecting the appointments complete and correct filling in of the CRFs thorough checks and analysis of laboratory data, ECG, etc. announcing the AE and SAE on time fair co-working with monitor

47. Monitor Compliance Prerequisite: the monitor is conscientious and serious worker thorough study of the patient’s protocol in comparison with data monitoring visits thorough checks the CRF's thorough checks the entrants from A to Z but also chronologically and dynamic manner check of the investigator’s file fair co-working with the investigator

48. ‘Principles of Good Clinical Practice’

49. Investigator

50. Failure to select qualified investigators “ .. PI ‘s curriculum vitae fails to demonstrate that he/she is qualified by experience and training as an appropriate expert to investigate this drug…” Inadequate training of staff - Study personnel turnover with no documented training by the Sponsor/Monitor - Inexperienced investigator/coordinator - Lack of GCP knowledge Failure to fulfill general responsibilities of investigator “ … investigator did not personally conduct or supervise the study… 2 unlicensed staff members conducted the physical exam…” “… the investigator signed and dated the source document & Informed Consent on days in which he was absent from the institution…” “…PI failed to adequately protect the rights of subjects [by not reviewing pertinent safety information]…”

51. Failure to obtain Informed Consent “…Informed consent were not always dated at the time signatures were obtained by the subject, witness or PI…” “…for 10 subjects, PI failed to obtain informed consent prior to performing protocol procedures and diagnostic tests to qualify subjects…” Failure to obtain IRB/IEC approval

52. Failure to fulfill the general responsibilities of investigators by adequately protecting the safety and welfare of subjects… Enrolled several subjects who were not eligible for the study Failed to conduct the appropriate test to ensure that only eligible subjects were entered into the study Failed to perform the study procedures required by the protocol to monitor the effects of the study drug in subjects Failed to abide by the safety provisions required in the protocol

53. Failure to conduct study in accordance with approved protocol “…several subjects were not administered the drug over the period specified in the protocol…” Enrolling subjects who did not meet eligibility requirements failure to report protocol violations to Sponsor and EC

54. Failure to notify Sponsor and IRB/EC “…PI failed to report AE to Sponsor…” “…PI failed to report serious unexpected AE (death) and failed to provide records to National Authority …” failure to report SAE to IRB/EC in a timely manner Timeframe of reporting SAE not reported within 24 hours of identification Follow-up data not reported in a timely manner Failure of investigator to review safety information “…PI did not review and evaluate safety and effectiveness of drug . No source documents were available during the inspection to document that the subject death was reviewed and evaluated...” “…Failure to include deaths in annual report…”

55. Failure to maintain adequate & accurate Source Documents “..failure to maintain adequate and accurate records, including subject raw data records on loose notes…” “…no SD of follow-up visits performed for all subjects…” “…failure to prepare and maintain adequate case histories to record ALL observations…” “..The study coordinator would pre-record the start/stop times of the study drug infusion…” “…no source document for screening data nor study physical exam conducted by the study coordinator…”

56. Failure to maintain adequate drug disposition records “..PI did not prepare and maintain adequate records of drug dispensing, including dates, quantity and use by subjects…” Failure to adequately store unused and returned study drug Failure to maintain records of storage conditions Failure to control the investigational drug

57. Monitor

58. Organization, condition, completeness, and legibility Assure subjects did exist, were alive, and available for stated participation Method of data capture (e.g., forms) Inclusion/exclusion criteria met Occurrence of adverse events

59. Occurrence of protocol deviations Screening, study, and follow-up as stated in protocol Records of exposure to the test article Compare data capture forms/CRF’s with the source documents Identity of all persons involved in obtaining raw data, collection, or analysis


66. Less Can Be More Focus on the Fundamentals Elements of Data Quality Attributable Legible Contemporaneous Original Accurate

67. Less Can Be More Elements of Data Integrity Credible Consistent Corroborated

68. Remember Where Less Is Never More Education Training Clinical Investigator Supervision

69. The Next Challenge Maintaining our compliance success, but also achieving performance success through risk-based management of our limited resources Establishing how and where Less CAN be More and implementing accordingly Keeping on the Critical Path….

70. Thank You M&M Clinical Research Enterprise Ltd.

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