Investigational Drug

Presented by: Ivory Diane C. Amancio, RPh CPh

 Investigational Drug
Investigational New Drug Application
- filed with FDA
- approved prior to administering new drug
products to humans
Components:
*Name of the inactive component
*Name and chemical description of the active
component
 Investigational Drug
Components:
* name of the manufacturer
* method of preparation
* dosage form
* all preclinical data
* name and location of the investigators
 Investigational Drug
Components:
* data from clinical trials conducted in other
countries
Within 30 days from receipt of IND, the FDA decides
if the proposed clinical trial should proceed.
The trial may proceed if the investigator is not
contacted within 30 days.
 Investigational Drug
Reviews at the FDA may place a clinical hold
on the clinical trial at any time.

Reasons for placing an IND under clinical hold:

1.) Unreasonable or significant risk of illness or
injury to trial subjects.
2.) Insufficient information to assess patient risk
 Investigational Drug
Reasons for placing an IND under clinical hold:
3. Inadequate qualification of the clinical
investigator
4. Misleading, erroneous or incomplete
investigator’s brochure (a document that contains
all relevant information about the drug.
Investigational Drug
No experimental agents may be
administered to patients for research in
the US without an IND.

It should be noted that not all clinical

trials require an IND.
 Investigational Drug
A sponsor proposing a trial with a commercially
available, FDA-approved drug product is
exempted from IND requirements if:

1. It is not intended to be submitted to the FDA to

support labeling changes or a new indication.
2. It is not intended to support a major change in
advertising.
 Investigational Drug
A sponsor proposing a trial with a commercially
available, FDA-approved drug product is
exempted from IND requirements if:

3. does not involve a route of administration,

dose, or patient population that significantly
increases the risk of the drug.
 Clinical Investigation
The clinical investigation involves the
administration of a drug to humans.
4 phases of clinical trial:
PHASE I Clinical Trial
- is the assessment of the compound’s safety
- small # of generally healthy volunteers
(approximately 20-80 people)
 Clinical Investigation
PHASE I Clinical Trial
For the investigation of drugs to treat life-
threatening diseases, such as cancer or AIDS,
patients afflicted with the disease may be
enrolled.
The starting dose is generally low, often 1/10 of
the highest no-effect dose in the animal models.
 Clinical Investigation
PHASE I Clinical Trial

After the initial treatment is completed, additional

subjects may be recruited and administered
higher doses to determine the maximum dose
tolerated without significant side effects.
 Clinical Investigation
PHASE I Clinical Trial
- preliminary ADME data of the parent drug and
all metabolites should be evaluated.

- data regarding pharmacokinetic and

pharmacologic effects are also obtained to be
used in designing future II trials.
 Clinical Investigation
PHASE Il Clinical Trial
- - is the assessment of the compound’s efficacy
- a large # of people are enrolled
( 100-300 patients)
- participants suffer from the target illness
- side effects of the new drug are investigated
- failure during the trial is common
(as the human body is more complex than the test tube)
 Clinical Investigation
PHASE Il Clinical Trial
At the end of phase II trials:
*The sponsors meet with the FDA to review the
acceptability of the past trials
*The FDA carefully review preclinical and clinical
data in evaluating proposed III protocols
 Clinical Investigation
PHASE Il Clinical Trial
At the end of phase II trials:
*The FDA scrutinizes the proposed phase III trials
eg., dosing regimen
duration of treatment
blinding of the drug product
 Clinical Investigation
PHASE Il Clinical Trial
At the end of phase II trials:
The overall goal of the meeting between the
sponsor and the FDA:
* Agreement regarding data required for
submission of a New Drug Application ( NDA )
-it is a document of hundreds of thousands of pages containing
highly detailed information
Clinical Investigation
PHASE Il Clinical Trial
At the end of phase II trials:

Before phase III trials, the final market

formulation for the drug product should be
optimized.
 Clinical Investigation
PHASE IlI Clinical Trial

 The safety and efficacy of the new compound is monitored

 Involves a large # of patients (1000-3000) who are afflicted
with the target illness
 The longest and most comprehensive trial
 Patients are recruited, tested, and monitored by several
major hospitals and clinics throughout the country
 May be conducted internationally
 Clinical Investigation
PHASE IlI Clinical Trial

 the drug product may be compared to an existing

therapeutic regimen or a placebo

 Compounds that complete Phase III testing have

a 95% chance of being approved by the FDA.
 Clinical Investigation
PHASE IlI Clinical Trial
 Before the completion of the Phase III testing
and NDA submission, sponsors and FDA meet
again; to establish the appropriate format of the
submission so that the review proceeds smoothly
 To determine if an additional animal or human
trials are necessary
 Clinical Investigation
PHASE IlI Clinical Trial
 Once the Phase III trials have been completed,
all preclinical and clinical data are compiled and
submitted to the FDA for review.

 FDA reviews the proposed product

labeling and package insert.
 Clinical Investigation
PHASE IlI Clinical Trial
 NDA review has been reduced from a median
of 22 months in 1992 to approximately 15
months in 2000.
 The FDA may approve or disapprove the
drug product for market.
 Clinical Investigation
PHASE IlI Clinical Trial
Reasons for the disapproval by the FDA of the drug
product for the market:

 lack of demonstrated safety and efficacy

 issues with the manufacturing /processing
procedures
 false/misleading labels
 Clinical Investigation
PHASE IlI Clinical Trial
If NDA is not approved, a letter is sent to the
sponsor detailing deficiencies in the application.

If the NDA is approved, an approval letter

along with a draft of the product labeling is sent
to the sponsor.
 Clinical Investigation
PHASE IlI Clinical Trial
 Before NDA approval, the FDA inspects the sponsor’s facilities
to ensure compliance with the cGMP.

 If deficiencies are noted during the inspection, a letter is sent

to the sponsor delineating the problems.

 Once the deficiencies are resolved, the company must provide

written certification and the FDA will clear the application
within 45 days.
 Clinical Investigation
PHASE IV Clinical Trial
 post-approval clinical trial

 Since the duration of exposure is often limited

during phase III testing, phase IV trials may be
required to assess long-term safety of the drug.
 Clinical Investigation
PHASE IV Clinical Trial
 the FDA may mandate a phase IV trial in a specific
patient population to further assess efficacy and
side effects
 - Companies may also choose to conduct
additional clinical tests to more fully understand
how their product compares to another
commercially available therapeutic regimen.
 Clinical Investigation
PHASE IV Clinical Trial
Post-approval activities:
 after NDA has been granted, and marketing is
initiated, drug safety is still monitored
 sponsors must submit reports of AEs
 AEs reports are filed quarterly for the first three
years and then annually
 Clinical Investigation
PHASE IV Clinical Trial
Post-approval activities:
 For serious and unexpected AEs, ( eg., fatal, life-
threatening, permanent disabling, or requiring
prolonged hospitalization), the sponsor must
provide a written report to the FDA within 15
days of receipt of the information.
 Clinical Investigation
PHASE IV Clinical Trial
Post-approval activities:
 Serious AEs may require minor labeling changes or
the addition of warning or precaution statements.
 If serious safety concerns arise, the FDA may
withdraw approval of the NDA.
 An FDA Advisory Committee reviews the NDA
before an official NDA withdrawal.
 Clinical Investigation
PHASE IV Clinical Trial
Post-approval activities:

 The FDA MedWatch program encourages health-care

providers to directly report serious ADRs to the FDA.
( www.fda.gov/medwatch ).

 The MedWatch program also provides to practitioners

regarding the actions and recommendations of the FDA.
 Clinical Investigation
PHASE IV Clinical Trial
Post-approval activities:

 In some instances, manufacturers have withdrawn drug

products before FDA action.

 Periodic random inspections of drug production facilities

are conducted by the FDA to ensure conformance with
the cGMP.
Thank you