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
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
PharmacoeconomicExpanded
safety/efficacyAdditional indications
Strategies for minimization of adverse effects
Strategies for dose-individualization
Optimization of surrogate lab tests
Special populations
New formulations
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
1. Develop concept
2. Discuss idea and discern budget limits with liaison/visit web sites
3. Obtain LOI template
4. Submit LOI
5. Respond to LOI reviews/conceptual approval
6. Write full protocol (template?)
7. Submit to pharma for comments
Typical Process (continued)
8. Revise and submit to PRMC/SPRC
9. If approved, submit to IRB
10. Simultaneous:– Initiate budget/contract process– Submit IND for cross file with FDA
11. Address IRB and FDA comments
12. Finalize budget and contract
13. Conduct study
14. Report data to sponsor abstract/journal
Contents of a full IND1. Form FDA 1571 2. Table of Contents3. Introductory statement4. General Investigational plan5. Investigator’s brochure6. Protocol
a. Study protocolb. Investigator data or completed Form FDA 1572c. Facilities data or completed Form FDA 1572d. Institutional Review Board data or completed Form
FDA 15727. Chemistry, manufacturing, and control data8. Pharmacology and toxicology data9. 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:1.The study is not intended to support FDA approval
of a new indication or a significant change in the product labeling.
2.The study is not intended to support a significant change in the advertising for the product.
3.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.
4.The study is conducted in compliance with IRB and consent regs.
5.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)– 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
– 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.