W98: Clinical Trials: The Industry Perspective

1. W98: Clinical Trials: The Industry Perspective Kathi Durdon, MA, CCRPDirector, Clinical Trials OfficeSUNY Upstate Medical UniversitySyracuse, NY

2. Objectives: Overview Basics of Clinical Research Review of Regulatory Requirements Review Site Selection Criteria Review HIPAA Implications on Conduct of Clinical Research Summary of Industry Expectations

3. Audience Survey Who Do You Work For? Industry/Sponsor Clinical Research Organization Site Other?

4. Basics of Clinical Research

7. Sponsored Clinical Trials - 2003

8. Where are Drugs Developed?

9. NIH reported to Congress in 2001 that it found a significant government investment in only 4 of 47 medicines with sales of $500 million or more Where are Drugs Developed?

10. Government & NIH-funded academic scientists do a terrific job in advancing basic knowledge about biology and disease. Their work improves our understanding of diseases. But pharmaceutical company scientists lead the way in translating basic science into practical medicines that help and heal patients. Translating Discovery into Practice

11. Phases of Clinical Research Discovery Pre-clinical IND Submission Phase I Phase II Phase III FDA Review/Approval Phase IV � Post-marketing Surveillance

12. Discovery of Leads & Candidates New compounds that may become the new medicine Millions of compounds are screened per year Vast majority fail at this stage

13. Average Number of Compounds Completed During Discovery

14. Pre-clinical Extensive toxicological tests and animal studies Determine whether drug is likely to be safe and effective in humans

15. Investigational New Drug (IND) Application includes: All pre-clinical data Manufacturing information Approval allows drug to be tested in humans 30-day review Progress reports filed annually

16. Phase I Assess drug safety Small number of healthy volunteers Determine what happens to the drug in the human body--how it is absorbed, metabolized, and excreted Investigates side effects that occur as dosage levels are increased Typically takes several months

17. Phase II Assess efficacy About 100-300 subjects w/targeted disease Most are randomized trials: one group of subjects receive the experimental drug, while second "control" group receive standard treatment or placebo Often studies are "blinded,� neither patients nor researchers know who is getting the experimental drug Can last 3 months - two years

18. Phase III Large-scale testing (1000-3000+) Provides more thorough understanding effectiveness, benefits, and the range of possible adverse reactions Most are randomized and blinded trials Typically last several years Once successfully completed, pharmaceutical company can request FDA approval for marketing the drug

19. Phase IV Studies often compare a drug with other drugs already in the market Studies are often designed to monitor a drug's long-term effectiveness and impact on a patient's quality of life Many studies determine the cost-effectiveness of a drug therapy relative to other traditional and new therapies

28. Industry: Leading the Way In the last two years: Over 100 new drugs became available 1000 new medicines in development Employs over 250,000 in the US Research spending has nearly doubled every 5 years since 1970 Average cost spent on prescription drugs = 59 cents

29. Regulatory Overview

30. Nuremberg Code - 1949 In the fall of 1943, the United States, Great Britain, and the Soviet Union agreed that, once victorious, they would prosecute individuals among the enemy who might have violated international law during the war. On August 8, 1945--exactly three months after V.E. Day and two days after the bombing of� Hiroshima--representatives of the American, British, French, and Soviet governments officially established the International Military Tribunal in Nuremberg, Germany.

31. Nuremberg Code - 1949 Voluntary consent of human subjects is absolutely essential Experiment should yield fruitful results for the good of society, unprocurable by other methods or means of study Designed and based on results of animal experimentation Avoid all unnecessary physical and mental suffering and injury

32. Nuremberg Code -1949 Degree of risk taken should never exceed that determined by the humanitarian importance of the program to be solved Proper preparations, facilities provided to protect experimental subject Conducted only by scientifically qualified persons Subject may end participation in experiment at any time

33. Declaration of Helsinki - 1964 A statement of ethical principles to provide guidance to physicians and other participants in medical research involving human subjects. Medical research involving human subjects includes research on identifiable human material or identifiable data.

34. Belmont Report - 1979 Basic Ethical Principles Respect for Persons Beneficence Justice Applications Informed Consent Assessment of Risk and Benefits Selection of Subjects

35. Tuskegee � 1932 - 1972 For forty years between 1932 and 1972, the U.S. Public Health Service (PHS) conducted an experiment on 399 black men in the late stages of syphilis. These men, for the most part illiterate sharecroppers from one of the poorest counties in Alabama, were never told what disease they were suffering from or of its seriousness. Informed that they were being treated for �bad blood,�1 their doctors had no intention of curing them of syphilis at all. The data for the experiment was to be collected from autopsies of the men, and they were thus deliberately left to degenerate under the ravages of tertiary syphilis

37. Regulations/Historical Overview

43. Code of Federal Regulations The Code of Federal Regulations (CFR) is the codification of the general and permanent rules published in the Federal Register by the executive departments and agencies of the Federal Government. http://www.gpoaccess.gov/cfr/

44. Title 21: Food and Drugs Section: 50: Protection of Human Subjects 54: Financial Disclosure by Investigators 56: Institutional Review Boards 312: Investigational New Drug Application

45. Site Selection Criteria

46. Sponsor/CRO/Site Relationship Communication Direct Contacts Prompt Response Understand Perspectives Don�t Assume

47. Site Selection Criteria Experience Trained Staff Space Subjects Protected Time Local IRB / Central IRB Agreement / Budget Processing Timelines

48. Investing in a Country Access to skilled workforce/scientists Quality of science in the country: Academia/Universities/Biotech clusters Industry/Government partnerships Fiscal/Economic climate

49. Site Questionnaire Verify # of pts. seen in _# of months Competing study? Review of standard therapy Recruitment practices Facilities Additional services required Equipment

50. Pre-study Visit Obtain documents necessary to proceed with prestudy visit (e.g., confidentiality agreement, curriculum vitae) Develop an agenda Send documents necessary for prestudy visit to the site (e.g., protocol, Investigator's Brochure) Confirm appointment and ensure necessary personnel are available

51. Pre-study Visit Explain Investigator's Brochure to investigator/study staff Explain protocol, study goals, methodology, regulatory obligations, and sponsor/CRO requirements to investigator/study staff Assess investigator/study staff Document and communicate pre-study visit findings internally

52. Study Initiation Conduct investigator's meeting(s) Send study supplies to site Initiate shipment of investigational product Confirm appointment and ensure necessary personnel are available Train site personnel on sponsor/CRO and regulatory requirements for study conduct

53. Study Monitoring Identify items for review Confirm appointment and ensure necessary personnel are available Assemble necessary documents and monitoring tools (e.g., subject enrollment status sheets, monitoring guidelines) Ensure adequacy of study supplies and investigational product at site Monitor and evaluate subject enrollment

54. Monitoring Visit Assess protocol adherence Ensure that critical studies are conducted in accordance with local, state, federal, and appropriate regulatory regulations (e.g., IRB/IEC approval, informed consent, laboratory certification) Ensure that informed consent process is conducted according to Good Clinical Practice (GCP)

55. Monitoring Visit Identify and communicate subject safety issues to appropriate staff (e.g., laboratory abnormalities) Reconcile investigational product accountability Review study files and regulatory documents at site for completeness and accuracy (e.g., FDA form 1572, sponsor/CRO correspondence, informed consent form)

56. Monitoring Visit Review CRFs and source documents for completeness and consistency Identify and report significant adverse events to appropriate staff Confirm subjects' investigational product compliance Identify study site deficiencies, provide continuing training, and implement corrective action when necessary Assess enrollment issues

57. Monitoring Visit Prepare the monitoring visit report Prepare the monitoring visit follow-up letter to the site Report problems to appropriate in-house authority Identify potential fraud and misconduct

58. HIPAA Implications

59. HIPAA Health Insurance Portability and Accountability Act of 1996 HIPAA covers insurance portability; fraud enforcement (accountability) and administrative simplification

60. HIPAA Portability: ensures that individuals moving from one health plan to another will have continuity of coverage/not denied coverage under preexisting condition clauses Accountability: significantly increases the federal government�s fraud enforcement authority

61. Administration Simplification!? Privacy Rule: protects individuals� right to control access to and disclosure of their protected health information (PHI). Security: established to complement privacy measures.

62. Research Under HIPAA Almost all research other than some Phase I studies involving healthy subjects. HIPAA covers all research activities that use individually identifiable (names, addresses, dates, phone/fax, etc.) health information about humans

63. Coverage Covered Entities Health Care Providers (Physicians, Hospitals) Health Care Plans (Insurers, HMOs, Medicare) Health Care Clearinghouses (transmit data) Business Associates � use protected health information (PHI) for or on behalf of covered entities

64. Research Under HIPAA Use: happens within a health care organization/covered entity Disclosure: information is given to someone who is not part of the organization�s work force User must use Notice of Privacy Practices

65. Impact on Research Sponsors are generally not a Covered Entity or Business Associate Most entities through which sponsors conduct human-subject research are covered entities Sponsors cannot contact potential subjects but the covered entity can

66. Impact on Research Extended Informed Consent Process Indirect Subject Recruitment Variations in Interpretation Leads to Confusion Delays

67. Industry Expectations

68. Barriers to Success Number of Investigators Decreasing Who Does the Training? Employee Turnover Regulatory Delays

69. Drivers of Innovation Market-based pricing Intellectual property protection Sustained public support for basic research and policy environment Predictable, expeditious regulatory climate based upon sound science and innovative leadership

70. Helpful Links CFR: http://www.gpoaccess.gov/cfr/ FDA: www.fda.gov PhRMA: http://www.phrma.org/ CenterWatch: http://www.centerwatch.com/index.html Sponsor Web Pages