Presented by: Sylvia Saade, Rph, PharmD
Hypothetical Case
What is FDA looking for
◦ IND process
◦ Clinical protocol and clinical review process
◦ Hold reasons for INDs
◦ Common clinical reasons for Clinical Hold by
citations
Good Clinical Practice
Discussion of the hypothetical case
An investigator discovers a gene
therapeutic agent 00800008. In vitro testing
shows that this agent has “superactivity” in
lysing a wide variety of tumor cells. In
particular, the agent kills pancreatic cancer
cells more efficiently. Intratumoral injection
of this agent to a human pancreatic tumor
implanted in one mouse causes an
incredible tumor regression.
The investigator decides to move this agent to
1st in human testing.
Patient population: anybody with pancreatic cancer
Intratumoral injection (the only description of the
treatment procedure without specifying the dose and
schedule, procedure for injection, site of injection etc.)
Document in medical record in 2 months (the only
description in the monitoring and patient follow-up
without specifying items and schedule for followup etc).
Plans to write to FDA after treating 3 patients to check
whether an IND is needed
Is the patient population appropriately
identified?
Is the treatment plan adequately described?
Are the plans for monitoring and reporting
adverse events adequately described?
Is the required regulatory procedure
appropriately followed?
IND process
Clinical protocol and review process
Hold reasons for IND submission
Common clinical reasons for Clinical Hold
by citations
Investigational New Drug Application
Preclinical testing/investigation
◦ In vitro tests/animal testing
“reasonably safe” determination (21 C.F.R. § 312.23)
◦ Pharmacological data
◦ Toxicity testing
“Good Laboratory Practice” (GLP) (21 C.F.R. Part 58)
◦ Governs preclinical testing conduct
Organization, personnel, facilities, study conduct, and
records retention
Cover sheet Form 1571 (21 C.F.R. § 312.23(a)(1))
Table of contents (21 C.F.R. § 312.23(a)(2))
Introductory statement and general investigational
plan (21 C.F.R. § 312.23(a)(3))
◦ Brief 2-3 page summary
◦ Helps FDA anticipate sponsor needs
Investigator’s brochure (21 C.F.R. § 312.23(a)(5))
◦ Compilation of the clinical and non-clinical data on the
investigational product(s) that are relevant to the study
of the product(s) in human subjects
◦ Facilitates investigator understanding of rationale of key
features of the protocol (dose frequency/interval,
methods of administration)
Protocols (21 C.F.R. § 312.23(a)(6))
Chemistry, Manufacturing, and Control (CMC)
information (21 CFR § 312.23(a)(7))
◦ Information on drug substance, drug product
(preparation, manufacturer, components, etc.)
Sponsor’s pharmacological and toxicological
studies (21 C.F.R. § 312.23(a)(8))
◦ Description of pharmacological effects
◦ Integrated summary of toxicological effects in
animals and in vitro studies
Study reports should be available to FDA within 120
days of the start of the human study
Previous human experience summaries (21
C.F.R. § 312.23(a)(9))
◦ previous human experience should be presented in
an integrated summary
Team Approach
Communication
Multidisciplinary
Consensus building
Decision Making
Evidence-based
Safety-dependent
Phase-dependent
Initial administration of drug to humans
Assessment of human toxicology
Determine Maximum Tolerated Dose (MTD)
or Optimal Biological Dose (OBD)
Begin if Phase 1 studies do not reveal
unacceptable toxicity.
Primarily focus on collection of preliminary data
on
◦ whether the drug has effect in a defined patient population
◦ the relationship between dose and effectiveness.
Continue to evaluate safety and short-term side
effects.
For controlled trials, patients receiving the drug
are compared with similar patients receiving a
different treatment -- usually a placebo or a
different drug.
Begin if preliminary evidence of
effectiveness is shown during phase 2.
Gather more information about safety and
effectiveness in a defined population.
May form the primary basis of an efficacy
claim
Pre-IND meetings with the sponsor (although
not a requirement)
IND submission
Non-Clinical Review Clinical Review
CMC Pharm/Tox
The product manufacturing and
characterization?
The level of safety assurance needed for
beginning clinical trials
Clinical study design
Clinical Protocol
Protection of human subjects
Written plan for how the drug is to be
studied and the procedures to be followed
by each investigator
1. A statement of the objectives and purpose of the
study.
2. The criteria for patient selection and for exclusion of
patients and an estimate of the number of patients to
be studied.
3. A description of the design of the study, including the
kind of control group to be used, if any, and a
description of methods to be used to minimize bias
on the part of subjects, investigators, and analysts.
4. The method for determining the dose(s) to be
administered, the planned maximum dosage, and the
duration of individual patient exposure to the drug.
5. A description of the observations and
measurements to be made to fulfill the
objectives of the study.
6. A description of clinical procedures, laboratory
tests, or other measures to be taken to monitor
the effects of the drug in human subjects and
to minimize risk.
7. The name and address and a statement of the
qualifications of investigators (Form 1572); the
name and address of the research facilities to
be used; and the name and address of each
reviewing Institutional Review Board
Details of the clinical protocol depend on the phase of the
study
Patient population
Dose, schedule and administration
Dose escalation
Dose Limiting Toxicity (DLT) definition and
Optimal Maximum Dose determination
Stopping rules
Safety monitoring and evaluation
Safety Reporting
Case Report Form
Informed consent
Investigator’s brochure if applicable (21
C.F.R. § 312.23(a)(5))
Clinical Protocol
Protection of human subjects
Informed consent (21 C.F.R. Part 50)
◦ Ensures voluntary participation
◦ Required disclosures:
Risks, benefits, and alternative treatments
◦ No contracting out of liability
◦ “No more than minimal risk”
“Institutional Review Boards” (IRBs) (21 C.F.R. Part 56)
◦ Composed of at least 5 members from the health care
community and public
◦ Approve and monitor protocol
◦ Authority to approve, require modifications, or disapprove
research
IRBs should review proposed clinical trial within a
reasonable time
IRBs should provide dates for the following
◦ Approval/favorable opinion;
◦ Modifications required prior to its approval/favorable
opinion;
◦ Disapproval/negative opinion; and
◦ Termination/suspension of any prior approval/favorable
opinion
Sponsor obligations (21 C.F.R. § 312.50)
◦ Management of IND
◦ Safety reports
◦ Transportation/shipment of drug
◦ Collection of unused drug
◦ Records: maintenance and retention
Investigator obligations (21 C.F.R. § 312.60)
◦ Assure IRB review and informed consent
◦ Adherence to protocol
◦ Adverse event reporting
◦ Trial supervision
◦ Records: maintenance and retention
FDA inaction in 30 days triggers the study under
the IND to “proceed”
or
FDA issuance of “clinical hold”
A clinical hold is an order issued by FDA to the
sponsor of an IND to delay or to suspend a clinical
investigation
Partial or complete clinical hold
◦ Partial
A delay or suspension of only part of the clinical work
requested under the IND
◦ Complete
A delay or suspension of all clinical work requested under
an IND
Can occur during phase I, II, or III
Human subject exposure to an
unreasonable and significant risk of illness
or injury;
1. Incomplete information to assess the risk
to subjects;
2. Deficient plan or protocol (additional for
Phase 2 or 3);
3. Misleading, erroneous, or materially
incomplete investigator brochure; or
4. Unqualified clinical investigators.
Analysis of IND Review Decisions between
October 1, 2002 and December 31, 2004
Citations for Pharmacology, Toxicology and or CMC
Most common clinical deficiencies were related to
unreasonable and significant risk with need for
change to the eligibility criteria, safety monitoring
plan and stopping rules
The second most common citations were related to
insufficient information to assess the risk to
subjects
Patient population:
◦ Eligibility and/or exclusion criteria inappropriate
◦ Number of subjects not specified or unreasonable
Starting dose:
◦ Insufficient data to support the intended starting
dose
◦ Product preparation or formulation inadequately
described
Dose regimen:
◦ Administration of product risky or inadequately
described
◦ Proposed dose increases too aggressive
◦ Dose modification plan unreasonable
◦ Repeat treatment plan unreasonable or not
supported
◦ Reporting
Safety monitoring:
◦ Anticipated toxicities inadequately monitored
◦ Lack of appropriate Toxicity Scale
◦ Individual Patient Treatment Discontinuation Criteria absent
or unreasonable
◦ Study Stopping Rules absent or unreasonable
◦ Withdrawn subjects not adequately followed
◦ Long term follow up for patients absent or inadequately
described
◦ Adverse event
Good Clinical Practice (GCP)
Good clinical practice (GCP) is an international
ethical and scientific quality standard for
designing, conducting, recording, and reporting
trials that involve the participation of human
subjects.
Good clinical practice (GCP) is an international
quality standard that is provided by ICH: The
International Conference on Harmonisation of
Technical Requirements for Registration of
Pharmaceuticals for Human Use
1. Clinical trials should be conducted in accordance with
the ethical principles that have their origin in the
Declaration of Helsinki, and that are consistent with
GCP and the applicable regulatory requirement(s).
2. Before a trial is initiated, foreseeable risks and
inconveniences should be weighed against the
anticipated benefit for the individual trial subject and
society. A trial should be initiated and continued only if
the anticipated benefits justify the risks.
3. The rights, safety, and well-being of the trial subjects
are the most important considerations and should
prevail over interests of science and society.
4. The available nonclinical and clinical information on an
investigational product should be adequate to support
the proposed clinical trial.
5. Clinical trials should be scientifically sound, and
described in a clear, detailed protocol.
6. A trial should be conducted in compliance with the
protocol that has received prior institutional review
board (IRB)/independent ethics committee (IEC)
approval/favorable opinion
7. The medical care given to, and medical decisions
made on behalf of, subjects should always be the
responsibility of a qualified physician or, when
appropriate, of a qualified dentist.
8. Each individual involved in conducting a trial
should be qualified by education, training, and
experience to perform his or her respective task(s).
9. Freely given informed consent should be obtained
from every subject prior to clinical trial
participation.
10. All clinical trial information should be recorded,
handled, and stored in a way that allows its
accurate reporting Interpretation, and verification.
11. The confidentiality of records that could identify
subjects should be protected, respecting the
privacy and confidentiality rules in accordance with
the applicable regulatory requirement(s).
12. Investigational products should be manufactured,
handled, and stored in accordance with applicable
good manufacturing practice (GMP). They should
be used in accordance with the approved protocol.
13. Systems with procedures that assure the quality of
every aspect of the trial should be implemented.
Electronic Records; Electronic Signatures (21 CFR Part 11)
Human Subject Protection (Informed Consent) (21 CFR Part 50)
Additional Safeguards for Children in Clinical Investigations of FDA-
Regulated Products (Interim Rule) (21 CFR Part 50, subpart D)
Financial Disclosure by Clinical Investigators (21 CFR Part 54)
Institutional Review Boards (21 CFR Part 56)
Investigational New Drug Application (21 CFR Part 312)
Forms 1571 (Investigational New Drug Application) and 1572
(Statement of Investigator)
Applications for FDA Approval to Market a New Drug (21 CFR Part
314)
Applications for FDA Approval of a Biologic License (21 CFR Part
601)
Investigational Device Exemptions (21 CFR Part 812)
Premarket Approval of Medical Devices (21 CFR Part 814)
[Link]
What were the problems?
◦ Rationale
◦ Objective
◦ Patient eligibility
◦ Trial design
◦ Treatment: dose, schedule, route etc.
◦ Safety monitoring and follow up
◦ Informed consent
◦ IRB approval
◦ IND submission
Solutions
◦ Follow regulations
◦ Follow GCP
◦ Interactions with FDA
Early interactions with FDA are critical
Know your guidance documents
Consider early in translational research the questions that
will be asked at the clinical trial phase
Phone, face to face; formal or informal: dialogue is
encouraged