Investigational Drug Flashcards
Any experiment in which a drug is
administered or dispensed to one or more
human subjects.
Clinical
Investigation
A drug, antibiotic, or biologic that is used in
a clinical investigation.
Investigational
New Drug (IND)
The label of an
investigational drug must bear the
statement:
“Caution: New Drug—Limited
by Federal (or U.S.) law to investigational
use.”
IND application is a submission to the FDA containing
chemical information, preclinical data, and a detailed description of the planned clinical
trials
An IND for which the sponsor is usually
either a corporate entity or one of the
institutes of the National Institutes of Health
(NIH).
Commercial IND
Strictly for research purposes, done to prove
a theory, improve an existing treatment
institutes/academe
Research IND
The individual responsible for initiating the
clinical trial at the study site.
Investigator
An individual who participates in a clinical
investigation (either as the recipient of the
investigational drug or as a member of the
control group).
Subject
A standard for the design, conduct,
monitoring, analyses, and reporting of
clinical trials that provides assurance that
the results are credible and accurate, and
that the rights of study subjects are
protected
Good Clinical
Practice (GCP)
A committee of reviewers that is responsible
for ensuring the protection of the rights,
safety, and well-being of human subjects
involved in a clinical investigation.
Institutional
Review Board
(IRB)/Institutiona
l Ethics
Committee (IEC)
First major attempt of drug regulation
Import Drug Act of 1848
provided for the inspection, detention and
destruction or reexport of imported drug
shipments that failed to meet standards
Import Drug Act of 1848
drugs not to be mislabeled or adulterated and
must meet recognized standards for strength
and purity.
Pure Food and Drugs Act (1906)
safety of drugs, and be proven through testing
before they can be marketed
Food, Drug and Cosmetic Act of 1938
when was Food, Drug and Cosmetic Act of 1938 created
June 25,1938
creation of OTC and Rx drugs
Durham and-Humphrey Amendment
Authorized that prescriptions can be refilled
Durham and-Humphrey Amendment
Caution: Federal law prohibits dispensing
without prescription
Durham and-Humphrey Amendment
manufacturer had to demonstrate efficacy, and
safety of drug prior to marketing (because of
phocomelia secondary to Thalidomide)
Kefauver-Harris Drug Amendment
medication used to
treat motion sickness usually taken by
pregnant women, has a side effect of
teratogenic effect on infants
Thalidomide strategy
decides which drugs, biologics, and medical
devices are safe and efficacious and therefore
can be marketed.
FDA
FDA reviews priority drugs in _________ and
standard drugs within ___________
six (6) months; ten (10) months
antibiotics, cancer drugs, rx
drugs
Priority drugs
otc drugs
Standard drugs
developed a
web-based system that offers information about
ongoing clinical trials for a wide range of diseases
and conditions.
National Institute of Health (NIH)
agencies involved in the transparency and harmonisation of drug development
- National Institute of Health (NIH)
- International Conference on Harmonization (ICH)
Search for studies for particular diseases and
identify treatment centers that offer enrollment
into these studies.
National Institute of Health (NIH)
for the regulatory requirements for drug
approval
International Conference on Harmonization (ICH)
provide methods to ensure
simultaneous submission and rapid regulatory
approval in the world’s largest markets
International Conference on Harmonization (ICH)
Minimize duplication of effort, improve
efficiency, increase quality and efficiency of
medical treatments worldwide
International Conference on Harmonization (ICH)
PROTECTION OF HUMAN SUBJECTS
- Nuremberg Code
- Declaration of Helsinki (1964)
- Belmont Report (1978)
- Code of Federal Regulations (CFR)
judge the human experimentation conducted by
the Nazis in the middle of the twentieth century
Nuremberg Code
According to Nuremberg Code “__________ consent of the human subjects is
absolutely essential”
voluntary
10 point statement/quotes which limits
permissible medical experimentation on human
subjects
consent
re-emphasized protection of human subjects
Declaration of Helsinki (1964)
Developed by WMA (world medical
Association)
Declaration of Helsinki (1964)
Respect for individuals
Declaration of Helsinki (1964)
Right to be informed on decisions
Declaration of Helsinki (1964)
Recognition on Vulnerable groups
Declaration of Helsinki (1964)
basic ethical principles underlying medical
research on human subjects
Belmont Report (1978)
Ethical principles involved in belmont report
- Respect
- Justice
- beneficence
designed to make the protection of human
subjects in all federal agencies uniform
Code of Federal Regulations (CFR)
The drug approval process in the United States is
standardized by FDA review
DRUG APPROVAL PROCESS
testing conducted either in
vitro or in animals. (harmful effects)
Preclinical testing
Before filing an IND, the sponsor must have
developed a ___________ of the drug,
determined its acute and subacute toxicity, and
have sufficient information regarding chronic
toxicity to support the drug’s use in humans
pharmacologic profile
Before filing an IND, the sponsor must have
developed a pharmacologic profile of the drug,
determined its ___________ toxicity, and
have sufficient information regarding ___________ to support the drug’s use in humans
acute and subacute; chronic
toxicity
INVESTIGATIONAL NEW DRUG
APPLICATION (IND) is done before or after pre-clinical testing?
Done after pre-clinical testing
the application by the study sponsor
(eg. pharmaceutical company, individual investigator
as sponsor-investigator) to the FDA to begin clinical
trials in humans.
IND
Tests are reviewed by
FDA
T/F: Informed consent is included in IND
T
when will IND be not required
- drug is marketed in the
USA - Study is not reported to the FDA in support of
a new indication - Study does not involve a different dose,
route, patient population that increase risk to
patients - IRB approval and informed consent are
secured - Study will not be used to promote drug’s
effectiveness for a new indication
INVESTIGATIONAL NEW DRUG (IND) APPLICATION inclusions
- Cover Sheet (Form 1571)
- Table of Contents
- Introductory statement
- General Investigational Plan
- Investigator’s brochure
- Clinical protocol
- Chemistry, manufacturing and control data
- Pharmacology and toxicology data
- Previous human experience
- Additional information
Four types of documents that may be used to amend
the IND
- Protocol amendments
- Information amendments
- IND Safety Reports
- Annual Reports
Submitted when a
sponsor wants to change a previously submitted protocol or add a new study
protocol to an existing IND
Protocol amendments
Submitted when
information becomes available that would not
be presented using a protocol amendment,
IND safety report, or annual report (e.g., new
chemistry data).
Information amendments
reports clinical and
animal adverse reactions; reporting
requirements depend on the nature, severity,
and frequency of the experience.
IND Safety Reports
describe the progress of the
investigation including information on the
individual studies, summary information of the
IND (summary of adverse experiences, IND
safety reports, preclinical studies completed in
the last year)
Annual Reports
Suspected adverse reaction: An adverse
reaction for which there is evidence to suggest
a causal relationship between the drug and
the adverse event.
IND Safety Report
An event that
results in any of the following outcomes:
death, a life-threatening adverse drug
experience, inpatient hospitalization or
prolongation of existing hospitalization, a
persistent or significant disability/incapacity, or
a congenital anomaly/birth defect.
Serious adverse event or serious
suspected adverse reaction:
in IND Safety Report, FDA must be notified within __________ calendar days
15 calendar days
An adverse
reaction that is not listed in the current labeling
for the drug product.
Unexpected adverse event or unexpected
suspected adverse reaction:
Once submitted to the FDA, the IND will be
forwarded to the appropriate review division based
on the __________ of the product.
therapeutic category
the IND and clinical trial will
be assigned to a review team that includes:
- project manager
- chemistry, manufacturing, and controls
(CMC) reviewer - nonclinical pharmacology/toxicology
reviewer - clinical reviewer,
The FDA has _______ days after receipt of an IND
to respond to the sponsor.
30
First use of the agent in humans
PHASE I
Usually treat 20-80 patients (healthy volunteers)
PHASE I
Used to determine the safety and toxicity of the
agent
PHASE I
Evaluation of the effect of the drug on a subject who
does not have any pre-existing conditions
PHASE I
PHASE I last an average of ________
six months to one year
Small number of subjects who suffer from the
disease or condition that the drug is proposed to
treat
PHASE II
Used to evaluate the efficacy of the agent.
PHASE II
Usually treat between 100-200 patients
Phase II
Phase II duration
2 years
Used to further define the efficacy and safety of the
agent
PHASE III
Comparison of the new agent is compared to
current therapy
PHASE III
Usually multicenter studies
PHASE III
Usually treat hundred to 3,000 patients
PHASE III
Lasts about three years
PHASE III
Considered “pivotal studies” basis for new drug
application product’s marketing approval
PHASE III
the study of variations of
DNA and RNA characteristics as related to drug
response including effectiveness and adverse
effects
PHASE III
phase wherein pharmacogenomics is already included
Pharmacogenomics
impact of a certain genotype or phenotype relative
to response or adverse events
PHASE III
NEW DRUG APPLICATION (NDA) is done after
Phase III trials
Within ________ days, FDA will review the application (NDA) and
send the applicant an approval letter or complete
response letter
180
Allows investigational drugs to be used for treatment
use in patients with serious or life-threatening
diseases where there is no other comparable or
satisfactory alternative therapy.
EXPANDED ACCESS TO INVESTIGATIONAL DRUGS
FOR TREATMENT USE
those associated with
morbidity that has substantial impact on day-to-day
functioning
Serious conditions
Authorization from FDA to charge for an IND in the
following conditions:
○ drug has a potential benefit
○ drug is effective/safe
○ RCT could not be conducted without
charging because the cost of the drug is
extraordinary to the sponsor.
In priority review drug will potentially a significant
advance in medical care and sets a target to
review the drug within________ instead of the
standard ten (10) months
six (6) months
Drugs can treat unmet
medical needs.
Fast Track Review
Allows for early
approval of a drug for serious or life-threatening
illness that offers a benefit over current treatments.
Accelerated Approval Program
allows for expedited
development and review of drugs which are
intended to treat serious conditions and which may
demonstrate substantial improvement over
available therapy
Breakthrough Therapy
EXPEDITED REVIEW OF DRUGS
Priority Review
Fast Track Review
Accelerated Approval Program
Breakthrough Therapy
Aka postmarketing studies after drug approval
PHASE IV
Utilized by FDA when they determine that safety
measures are needed beyond the labeling to ensure
that a drug’s benefits outweigh its risks
RISK EVALUATION AND MITIGATION STRATEGIES
(REMS)
size and population likely to use the drug,
seriousness of disease, expected benefits,
expected duration of treatment, seriousness of
events (known or potential), whether drugs is an
NME.
Factors to consider in determining the need for
REMS:
REMS must be assessed for adequacy at least by
18 months, 3 years and 7 years after approval
used for treatment of a rare
disease, affecting fewer than 200,000 people in the
USA, or one that will not regenerate enough
revenue to justify the cost of research and
development
THE ORPHAN DRUG ACT
Committee formed to review proposed clinical trials
and the progress of such studies to ensure that the
rights and welfare of human subjects are protected.
INSTITUTIONAL REVIEW BOARD/INSTITUTIONAL
ETHICS COMMITTEE (IEC)
liaison between IRB
and the sponsor
Principal Investigator (PI)
After clinical trial, records must be maintained:
○ 2 years after approval of the NDA or
○ 2 years after FDA received notification that
investigation was discontinued.
only individual who is not
aware of what the patient is receiving is the patient
him or herself.
Single-blind study
the nurse, physician, and
patient are all unaware of what the patient is
receiving.
Double-blind study
when the drug that arrives at
the pharmacy is already blinded.
Triple-blind study
