Investigator-Initiated, Pharma-Sponsored Clinical Trials in Human Subjects February 2008 William Petros, Pharm.D., FCCP WVU Schools of Pharmacy & Medicine Mary Babb Randolph Cancer Center wpetros@hsc.wvu.edu

Clinical Trials Prospective studies comparing the effect and value of an intervention in humans (or sometimes animals) Can involve drugs, devices, procedures, etc. Informed consent required

Sponsors of New Drug Trials Philanthropic organizations Federal government Cooperative Groups Single institutions Pharmaceutical companies

What is a pharma-sponsored IIS? A research study where the idea is initiated outside pharma but they are interested in providing support for development and conduct of the project.

Types of IIS Post-marketing studies

Post-Approval Studies Drug-drug interactions Drug-food interactions Drug-herbal interactions Pharmacoeconomic Expanded safety/efficacy Additional indications Strategies for minimization of adverse effects Strategies for dose-individualization Optimization of surrogate lab tests Special populations New formulations

Anticancer Drug Development 2000s Small Biotech Academia Large Pharma Dr. R. Fleming, GSK 2008

Why do pharma companies support IIS?

Anticancer Drug Development Academia Strengths Strong basic science, translational, and clinical researchers New targets New biomarkers Assay development Translational research Weaknesses Funding Deficient in many drug development activities Dr. R. Fleming, GSK 2008

Anticancer Drug Development Small Biotech Strengths Risk taking behavior Novel targets Novel technologies Translational studies Fast milestones Weaknesses At mercy of VCs/Wall Street Have fewer shots on goal Exit strategies may not be favorable Dr. R. Fleming, GSK 2008

Anticancer Drug Development Large Pharma Strengths Lead optimization Preclinical studies Phase II-III studies Sales and marketing Have many shots on goal Weaknesses Innovation Poor risk tolerance Dr. R. Fleming, GSK 2008

Why do pharma companies support IIS? “Low cost/profile” pilot studies Provide literature on expanded indications Goodwill toward “thought leaders” Support science Increase drug utilization Natural investigator incentive to accrual

Why do investigators conduct IIS? Provides more autonomy compared to pharma initiated studies Access to new drugs/approaches for patients Funds for development of their ideas Seed monies/time/infrastructure for development of other studies

Typical Process Develop concept Discuss idea and discern budget limits with liaison/visit web sites Obtain LOI template Submit LOI Respond to LOI reviews/conceptual approval Write full protocol (template?) Submit to pharma for comments

Typical Process (continued) Revise and submit to PRMC/SPRC If approved, submit to IRB Simultaneous: Initiate budget/contract process Submit IND for cross file with FDA Address IRB and FDA comments Finalize budget and contract Conduct study Report data to sponsor abstract/journal

Contents of a full IND 1. Form FDA 1571 2. Table of Contents 3. Introductory statement 4. General Investigational plan 5. Investigator’s brochure 6. Protocol a. Study protocol b. Investigator data or completed Form FDA 1572 c. Facilities data or completed Form FDA 1572 d. Institutional Review Board data or completed Form FDA 1572 7. Chemistry, manufacturing, and control data 8. Pharmacology and toxicology data 9. Previous human experience

Cross Filing on Pharma IND Contents: FDA 1571 Table of contents FDA 1572 Collaborating pharma company cross file letter Introductory statement General investigative plan Investigators’ brochure Clinical Protocol Chemistry, manufacturing & control data IRB letter Other information: investigator CVs, package inserts, etc.

What studies are exempt from needing an IND? Studies must meet the following five criteria: The study is not intended to support FDA approval of a new indication or a significant change in the product labeling. The study is not intended to support a significant change in the advertising for the product. The investigation does not involve a route of administration or dosage level or use in a patient population or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product. The study is conducted in compliance with IRB and consent regs. The study is conducted in compliance with § 312.7 (promotion and charging for investigational drugs).

FDA Guidance on IND Exemptions for Marketed Oncology Products (1/2004) Single-arm, phase 2 trials using marketed drugs to treat a cancer different from that indicated in the approved labeling and using doses and schedules similar to those in the marketed drug labeling Phase 1 oncology trials of marketed drugs if such therapy is appropriate for the patient population at starting doses that appear safe based on approved labeling or detailed literature reports, use incremental changes in dose or schedule, and carefully evaluate toxicity prior to dose escalation. The study of new combinations of drugs, routes or schedules would not ordinarily constitute a significant risk if these combinations have been described in the professional medical literature. Studies of high-dose therapy in cancer patients if the studies use adequately evaluated regimens that appear to have an acceptable therapeutic ratio for the population being studied.

Example: Anti-Cancer Drug Typical Preclinical Information Teratogenicity Activity in cell culture Activity in xenograft models &/or transgenics Toxicology studies in rodent & non-rodent Pharmaceutical properties Pharmacokinetic studies in multiple species In vitro human metabolic enzyme studies Schedule dependency, appropriate schedule, etc.

FDA IND Reviews Medical (physicians) Chemistry (chemists) Human subject risks, study design for safety & efficacy Chemistry (chemists) Identity, manufacturing control, analysis (stability/reproducibility) Pharmacology/Toxicology Effects/MOA, ADME, toxicities Statistical

Examples of IIS Pilot study of GM-CSF Mouthwash for prevention of chemotherapy-induced mucositis Phase I/II study of Doxil + Abraxane for metastatic breast cancer Phase I/II study of bevacuzimab, erlotinib, everolimus for colorectal cancer Pilot study for prevention of chemotherapy-induced hand-foot syndrome

Types of INDs Commercial IND Investigator IND Emergency Use IND Submitted by a physician who both initiates and conducts an investigation, often to propose studying an unapproved drug, or an approved product for a new indication or in a new patient population. Emergency Use IND Use of an experimental drug in an emergency situation that does not allow time for submission of an IND also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist. Treatment IND Used for experimental drugs showing promise in clinical testing for serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.