1. Clinical Trial Process: An Overview Dennis R. DeRosia, PA, MA Director, Business Development Profil Institute for Clinical Research dennis.derosia@profil-research.com Past President & COB Association of Clinical Research Professionals www.acrpnet.org

2. What Is a Clinical Trial? Effectiveness of intervention to treat a disease Effectiveness of intervention to treat a disease Safety of a new drug or device Safety of a new drug or device Defining dose administration Defining dose administration Testing drug formulation Testing drug formulation Exploring combination therapies Exploring combination therapies Evaluating effect of therapies on quality of life Evaluating effect of therapies on quality of life

3. Types of Clinical Trials Treatment Treatment –Test new approaches to treat a disease Prevention Prevention –What approaches can prevent disease Early-detection/screening Early-detection/screening –What are new ways to find hidden disease Diagnostic Diagnostic –How can new tests or procedures ID disease

4. Phases of Drug Development Phase 1 Phase 2 Phase 3 Phase 4 No. of Participants 15-30100-300 100 to thousands Several hundreds to several thousands Purpose First in humans safe dose POC 1/3 fail Determine efficacy Safety 50% fail Compare new agent with standard treatment Safety 1/3 fail Post –market Long-term safety and efficacy

6. Who are the Players? Human Subject Volunteers Human Subject Volunteers Physician Investigators & Staff Physician Investigators & Staff NIH – National Institutes for Health NIH – National Institutes for Health Manufacturing companies (Sponsor) Manufacturing companies (Sponsor) OHRP - Office for Human Research Protections OHRP - Office for Human Research Protections FDA – Food & Drug Administration (CDER, CBER, CDRH) FDA – Food & Drug Administration (CDER, CBER, CDRH) Settings: Academic, Private Practice, Professional Settings: Academic, Private Practice, Professional

7. Evolution of Regulations 1938 – Food, Drug & Cosmetic ACT 1938 – Food, Drug & Cosmetic ACT 1962 – Kefauver-Harris Amendment 1962 – Kefauver-Harris Amendment 1968 – Drug Efficacy Study Implementation 1968 – Drug Efficacy Study Implementation 1981 – IRB Review Required 1981 – IRB Review Required 1983 – Orphan Drug Act 1983 – Orphan Drug Act 1997 – ICH-E6 Good Clinical Practice (GCP) 1997 – ICH-E6 Good Clinical Practice (GCP) 1998 – Pediatric Rule 1998 – Pediatric Rule 2000 – NIH launches www.clinicaltrials.gov 2000 – NIH launches www.clinicaltrials.gov

8. Human Research is Highly Regulated Code of Federal Regulations (CFR) Code of Federal Regulations (CFR) –Title 21- Food and Drugs »Part 50 Informed Consent »Part 56 IRB »Part 312 IND »Part 314 NDA »Part 600, 6001 Biologics »Part 812, 813, 814 Medical Devices –Title 45- Public Welfare »Part 46 (subparts B, C, D) DHHS, Protection of Human subjects

9. What About International Regulation? International Conference on Harmonization International Conference on Harmonization E6 Good Clinical Practice (GCP): Consolidated Guidance E6 Good Clinical Practice (GCP): Consolidated Guidance –International ethical and scientific quality standard for designing, conducting, recording and reporting trial results. (US, EU & Japan)

10. Why is Human Research Highly Regulated? Past transgressions lead to the need for laws that protect the rights and welfare of human subjects. Past transgressions lead to the need for laws that protect the rights and welfare of human subjects. –Nuremberg Doctors Trial of 1946 (Nuremberg Code) –Thalidomide Tragedy (Kefauver-Harris Amendment) –Tuskegee Experiments (Belmont Report) –Human Radiation Experiments –Gene Transfer Experiment

11. Research Protocol: Roadmap Detailed Research Plan that Includes: Detailed Research Plan that Includes: –Objectives –Background and Rationale –Subject Selection Criteria –Treatment Plan –Study Procedures –Response Evaluation Criteria –Statistical Section

12. Protocols A Phase I, Double-blind, Placebo- controlled, Dose-escalation Study of the Safety and Pharmacokinetics of Drug A31 in Subjects with Type 2 Diabetes Mellitus A Phase I, Double-blind, Placebo- controlled, Dose-escalation Study of the Safety and Pharmacokinetics of Drug A31 in Subjects with Type 2 Diabetes Mellitus A randomized, double-blind, placebo- controlled study assessing the effect of (study drug) Controlled-Release Tablet on hypoglycemia in type 1 diabetic subjects intensively treated with insulin A randomized, double-blind, placebo- controlled study assessing the effect of (study drug) Controlled-Release Tablet on hypoglycemia in type 1 diabetic subjects intensively treated with insulin

13. Protocol Mouthful A PHASE 1, RANDOMIZED, PLACEBO- CONTROLLED, SEQUENTIAL PARALLEL GROUP, MULTIPLE DOSE ESCALATION TRIAL TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF 28 DAYS OF ADMINISTRATION OF ND- 00254 TABLETS TO SUBJECTS WITH TYPE 2 DIABETES MELLITUS A PHASE 1, RANDOMIZED, PLACEBO- CONTROLLED, SEQUENTIAL PARALLEL GROUP, MULTIPLE DOSE ESCALATION TRIAL TO EVALUATE THE SAFETY, TOLERABILITY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF 28 DAYS OF ADMINISTRATION OF ND- 00254 TABLETS TO SUBJECTS WITH TYPE 2 DIABETES MELLITUS

14. Study Flow Chart

16. Institutional Review Board (IRB) All clinical trials must be approved and monitored by an IRB. All clinical trials must be approved and monitored by an IRB. IRB is an independent committee of physicians, nurses, statisticians, community advocates and others. IRB is an independent committee of physicians, nurses, statisticians, community advocates and others. The function of the IRB is to ensure that a clinical trial is ethical and the rights welfare of study participants are protected. The function of the IRB is to ensure that a clinical trial is ethical and the rights welfare of study participants are protected.

17. Informed Consent Learning the key facts about a trial before deciding whether to participate. Learning the key facts about a trial before deciding whether to participate. –Research study purpose –Risks/Benefits –Alternative treatments –Confidentiality of records –Medical treatment available if injury occurs –Whom to contact for answers to questions –Statement that participation is voluntary

18. Patient Recruitment Challenge Poor patient recruitment is the number one reason that trials fail. Poor patient recruitment is the number one reason that trials fail. Only 3 to 5 percent of newly diagnosed adult cancer patients participate in a clinical trial. Only 3 to 5 percent of newly diagnosed adult cancer patients participate in a clinical trial. Reasons for this relatively low number are many. Reasons for this relatively low number are many.

19. Recruitment Strategies Physician trust and contact Physician trust and contact Study staff contact Study staff contact Speaking to community groups Speaking to community groups Newspaper and radio Ads Newspaper and radio Ads Internet websites Internet websites Physician referrals Physician referrals

20. Subject Data Collection Data is collected on case report forms (CRF) Data is collected on case report forms (CRF) Much of clinical data is taken from the subjects medical record (source documents) Much of clinical data is taken from the subjects medical record (source documents) Pharmaceutical and device trials, data is verified by multiple players Pharmaceutical and device trials, data is verified by multiple players

21. Serious Adverse Events Events that results in any of the following: Events that results in any of the following: –Death or life-threatening –Hospitalization or prolonged hospitalization –Persistent or significant disability/incapacity –Congenital anomaly/birth defect Events that are serious, unexpected, and related or possibly related to participation in the research must be reported to the Sponsor, FDA and IRB in a timely manner. Events that are serious, unexpected, and related or possibly related to participation in the research must be reported to the Sponsor, FDA and IRB in a timely manner.

22. Clinical Trial End Product Ideal: Unambiguous conclusion regarding the clinical outcome of the test treatment/device. Ideal: Unambiguous conclusion regarding the clinical outcome of the test treatment/device. Always strive for the ideal, but in most cases have to settle for the best comprise. Always strive for the ideal, but in most cases have to settle for the best comprise.

23. Positive-leaning articles tend to focus on gains made in fighting particular diseases. “Alzheimer’s vaccine study promising” “Treatment for cancer advances in trials” “A promising weapon in the fight against MS” * * * * * * * * * * * * * * * * * * * * * “Medical Miracles or Misguided Media” The Los Angeles Times “It sometimes seems as if there are Page 1 stories, television news reports and magazine cover stories almost daily on medical breakthroughs - new treatments for everything from the flu, obesity, AIDS and heart disease.”

24. News Update “Medical clinical research slows for lack of patients” Los Angeles Times – March 14, 2009 Enrollment problems delay more than 70% of clinical trials from one to six months In cancer care, less than 5% of patients enter clinical trials 700 cancer therapies in pipeline

25. News Update “It’s time to speed up drug approvals” The San DiegoUnion-Tribune – July 11,2008 by Sally C. Pipes FDA approved just 18 cancer drugs in past three years CyberKnife shoots beams of radiation at tumors Every day 1,500 Americans die from cancer

26. Coalition of National Cancer Cooperative Groups

27. Pay Attention to the Clinical Research Around You You may be the beneficiary some day! Thank you