1. 11/11/04 Clinical Research and Development in the Pharmaceutical and Biotechnology Industry Robert Anderson, MHA, CCRA, CCRCP Director, Clinical Trials Administration www.cratraininginstitute.comwww.cratraininginstitute.com Houston Texas

2. 11/11/04 Objectives To understand the drug development process To understand the phases and components of the clinical research process To appreciate the history behind the regulations in the clinical development process To understand the current regulations involved with the clinical research process

3. 11/11/04 Healthcare Industry Players Pharmaceutical Industry Patient Care Physician Hospital Insurance Company

4. 11/11/04 Drug Discovery Process Compound Selection Proof of Concept Outcome 2 – 4 Years 4 – 7 Years Marketing Introduction *Key variable guiding development time Target Selection Target Validation & lead optimization Proof of Concept Clinical Trials Pre-clinical Phase Clinical Phases I, II III, IIIB* Drug Registration FDA Approval Marketing (Phase IV Clinical Trials) (5,000 – 10,000) (250) (5) (1)

5. 11/11/04 Clinical Trials: What Are They? An organized research study designed to investigate new methods of preventing, detecting, diagnosing, or treating an illness or disease (such as cancer).

6. 11/11/04 The Players in Clinical Research Sponsor Investigator Site Patient CRO SMO IRB

7. 11/11/04 Clinical Trials Process and Associated Regulatory Process Phase IIIPre-NDAMeeting Phase IV File NDA Drug Approval Pre-IND MeetingIND Application Phase I Phase II End of Phase IIMeeting

8. 11/11/04 Phases of Clinical Trials Category# of ParticipantsPurpose Phase ILess than 10Tests how to administer a new therapy, exam, or preventive option Phase II30-40Test patients responses to a new therapy, exam, or preventive option Phase III100-1000+Compares new therapy exam or preventive option to a standard one Phase IVVariesFor marketing purposes, to compare the effectiveness of two therapies already on the market or to study new uses of therapies

9. 11/11/04 Tasks Involved to Develop/Support Clinical Trials Protocol development Volunteer recruitment Clinical conduct (management) Monitoring Data management Clinical statistics Medical writing Quality assurance

10. 11/11/04 What is Involved in a Clinical Trial? File IND application Develop protocol Submit to FDA for comment or no action Select investigational sites based on # of patients needed for the study Regulatory requirements for each trial at each site 1571 or 1572 PI’s CV Financial disclosure forms Informed consent IRB approval Initiate site(s) Sites enroll patients Write study report Patients cycle through study Capture: Adverse events, vital signs, study drug adherence, QOL questionnaires captured on Case Report Forms Patients exit study Data collected and cleaned Sites closed Add study to NDA

11. 11/11/04 Clinical Trials Benefits & Risks Possible Benefits of TrialsPossible Risks of Trials Having access to potentially more effective therapies than those currently available Receiving quality medical care from leading physicians Being closely monitored for possible negative effects Sometimes receiving treatment at a reduced rate or free of charge Helping to further new research that may result in significant medical advances For patients in cancer therapy trials assigned to control groups, they still receive the top standard therapy available today Patients may not receive the therapy under investigation (may receive a placebo – inactive pill – instead) The new therapy may not be more effective than the standard, thoroughly tested therapy In Phase I trails, not knowing the safety consequences of the new therapy (risk is less in Phase III trials) New therapy may have unexpected, possibly severe side effects or may be less effective than standard of care Insurance companies may not cover all costs of clinical trials

12. 11/11/04 Clinical Trial Standard Language ProtocolThe planned course of action for the clinical trial. The protocol is established prior to the start of the trial and states the number of participants, eligibility requirements, agents that will be used, dosages, duration, how data is collected, etc. InvestigatorA researcher in a clinical trial. SponsorThe part of parties responsible for funding the clinical trial. Institutional Review Board (IRB) An independent board of scientists, physicians, and nurses who review the clinical trial protocol to ensure patient safety. Informed ConsentA patient’s decision to participate in the clinical trial after being informed of the potential benefits and risks of participation. Participants may withdraw their consent at any time and leave the trial. Double blindTerm used to describe a clinical trial in which neither the patient nor the researcher knows which agents are being administered to which patients. This helps prevent bias. Invention groupThe group of participants receiving the new preventive or treatment agent that is being evaluated in the clinical trial.

13. 11/11/04 Clinical Trial Standard Language, continued Control groupThe group of participants receiving a standard treatment or placebo (see below) that is being compared to the new agent in the clinical trial. RandomizationAssigning participants by chance to either the intervention group or the control group. Randomization is often done with a computer. PlaceboAn inactive substance that may be given to participant sin a clinical trial. Sometimes called a sugar pill. Follow-upMonitoring of participants for a specified time after the clinical trial is completed. Prospective studyA study of a group of patients that is conducted as they are undergoing a treatment or preventive measure. Retrospective study A study of a group of patients after they have already undergone a treatment or preventive measure. “Recall bias,” unintentional inaccurate reporting of certain information, can sometimes influence a retrospective study.

14. 11/11/04 Regulations often result in response to abuse of human research subjects and concerns about the validity of data and conclusions from clinical trials. The primary vehicles for human subject protection are IRBs and informed consent. The Declaration of Helsinki and the Belmont Report are critical documents for the protection of human subjects in research. The FDA, by means of PDUFA and FDAMA, has made significant gains in speeding the process of making new drugs available for patients who need them. Current problems with clinical trials and trial oversight may well lead to increased regulation. History Behind Regulations of Clinical Trials

15. 11/11/04 The FDA regulations pertaining to clinical trials are found in 21 CFR Parts 11, 50, 54, 56, 312 and 314. The ICH Guidelines for Good Clinical Practice should be followed in clinical trials. The FDA publishes many guidelines and information sheets pertaining to the appropriate conduct of clinical trials. Good clinical practices are the ethical and clinical standard for designing, conducting, analyzing, monitoring and reporting on clinical trials. Regulations for Clinical Trials

16. 11/11/04 Health Outcomes Health outcomes studies examine the clinical, economic and quality-of- life outcomes of pharmacotherapy. Health outcomes research expands upon the FDA-mandated efficacy and safety endpoints to give a fuller picture of the outcomes experienced by a patient. It is a relatively new discipline that combines a number of fields of study, including medicine, epidemiology, statistics, economics and psychometrics. Early in development, companies may be interested in documenting the epidemiology and cost burden of a particular disease state. As a compound moves through to Phase II and II, behavioral, humanistic and economic endpoints may be incorporated into registration trials. Concurrently, economic models may be created to quantify the economic benefit of the new therapy. Once a compound is launched, a variety of research services may be utilized, including registries, Phase IIIb/IV comparative studies and claims analyses.

17. 11/11/04 Other Issues in the Clinical Research Process National Institutes of Health Special populations Data Safety Monitoring Boards Orphan drugs