1. 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

2. 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

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

4. 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.

5. Types of IIS
Post-marketing studies

6. 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

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

8. Why do pharma companies support IIS?

9. 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

10. 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

11. 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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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.

18. 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 § (promotion and charging for investigational drugs).

19. 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.

20. 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.

21. 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

23. 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

26. 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.