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Objectives: . Overview Basics of Clinical ResearchReview of Regulatory RequirementsReview Site Selection CriteriaReview HIPAA Implications on Conduct of Clinical ResearchSummary of Industry Expectations. Audience Survey. Who Do You Work For? Industry/SponsorClinical Research OrganizationSiteOther?.
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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