Download Investigator-Initiated, Pharma-Sponsored Clinical Trials in Human

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
[email protected]
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
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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
doseindividualization
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
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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?
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“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:
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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 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:
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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
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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 chemotherapyinduced 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.