THE NEW DRUG

APPROVAL PROCESS
AND
CLINICAL TRIALS
By
Kasturi Panda
M.Pharm(Pharma-Tech)
 FOOD AND DRUG ADMINISTRATION
(FDA)
 The FDA oversees the NDA process.It mainly focuses on the
disclosure of the ingredients and formulation,assay
methods,manufacuring processesand all animal and human
testing

 Amendments were made in 1962 which focused on both

saftey and efficacy of new drug products prior to approval
and requires investigstor to file Investigational New Drug
Application(INDs) prior to testing new drugs in humans.

 Center of Drug Evaluation And Researh(CDER) under FDA is

responsible for drugs and drug efficacy of all prescription and
over the counter drug products prior to marketing.

 CDER is responsible for monitoring drug saftey after initial

market approval and has the authority to withdraw from the
market posing significant health risk.
 OVER VIEW OF THE DRUG APPROVAL
PROCESS
 The development process is divided into two
section:
1. Preclinical testing:
Lead compound selection and animal testing of
new chemicals.
2 Clinical testing:

Administration of new chemicals to human

beings
 CHEMICAL SYNTHESIS CLINICAL
HOLD

FORMULATION IND
DRUR DISCOVERY BIOLO- DEVELOPMENT APPLICATION
AND GICAL IND FILING
LEAD COMPOUND ACTIVITY
SELECTION
TESTING SAFTEY TESTING
IN ANIMALS

IND
APPROVAL

PHASE 1 TRIAL PHASE 2 TRIAL PRASE 3 TRIAL

NDA
FILING

FDA CONDITIONAL APPROVAL FDA APPROVAL

FDA DISAPPROVAL

MARKET

POST APPROVAL SAFTEY REPORTS TO FDA

 DRUG DISCOVERY AND LEAD
COMPOUND SLECTION
 A chemical with potential therapeutic benefits is known as
a lead compound,must first be identified & researchers
usevarious high throughput assay techniques to rapidly
screen large numbr of chemicals for biological activity.
 Random screening as the name implies,requires biological
testing of a large variety of diverse compounds from
existing chemical libraries.
 A more mechanism-based drug design is targated synthesis
,on researchers focus on one step in a targeted for drug
intervention.While an extensive knowledge of the disease
state is requried this more directed approach increases the
likelihood of successfully identifying the lead compound.
 Combination of these discovery techniques is used to
identify the lead compounds.
 PRECLINICAL TESTING

PRECLINICAL TESTING INCLUDE:

 Discovery testing to ensure biological activity in-
vivo
 Chemical synthesis & scale up to ensure adequate
quantities of high purity can be made.
 Formulation development and stability testing to
characterize various chemical properties,develop
the initial drug delivery system & determine the
stability of the compound.
 Animal saftey testing to ensure limited toxicities
of the lead agent.
 During discovery testing testing the specific`s of
the compounds properties such as, mechanisim
of action in animal models,compound
specificity,duration of action and SAR are
determined.
 The phisiochemical property of the active
compound are determined and the drug delivery
system to be used in human testing begins to be
developed during this phase.
 Often times the most appropriate animal model
to predict human response is not known.
 Thus toxicity studies are conducted in at least
two animal species, one rodents and another non
rodent to obtain a comprehensive view of the
potential toxicity.
 Animal should be given the new drug product by
the same route as intended for human.
 Generally once discovery testing shows
therapeutic promise the chemical synthesis, fd,
and animal safety testing occurs concurrently
 INVESTIGATION AND NEW DRUG
APPLICATIONS
 An investigation new drug application must be
filed whanges ith the FDA and approved prior to
administering new drug products to humans.
 IND includes all pre clinical animal data and the
name and locations of the investigators who will
be performing the planned clinical trials.
 The clinical trials where IND is not required are
lebel changes or a new indication.
 Major changes in advertising
 Change in route of administration, dose,
or patient population that significantly
increases the risk of the drug.
 It is not required if the trial is exempt
according to the above criteria regardless
to whether a placebo is employed as a
control group.
 CLINICAL INVESTIGATIONS
 Clinical investigations involve the administration of a
drug to humans.IND must be filed with the FDA and
approvd prior to administering new drug products to
human beings.
 This segment of the drug development process requires
substantial financial and time commitment.
 Human testing is divided into 4 phases each with specific
objectives:

1. Phase 1
2. Phase 2
3. Phase 3
4. Phase 4
 PHASE 1 CLINICAL TRIALS
 The first series of experiments performed in human
beings occur during phase 1 clinical testing.generally
20-30 healthy volunteers are choose.
 In phase 1 trial the starting dose is generally
low,often 1/10 of the highest no effect dose in
animal models.after initial treatment is completed
additional subjects may be recruited and
administersd higher doses to determine the
maximum tolerated dose without significant side
effect.
 During this phase the prelimnary ADME data of the
parent drug and all metabolites are evaluated
 PHASE 2 CLINICAL TRIALS
 Phase 2 clinical trial shifts its focus from saftey to
efficacy.A large number of people participate
(100-300) where majority of the people suffer
from targeted illness.
 Side effect from the new drug is also investigeted
 Clinical protocols for phase 2 trial must be sent to
the FDA as amendments to the IND prior to
beginning of the trial.
 PHASE 3 CLINNICAL TRIALS
 Scientists carefully review of the preclinical and
clinical data in evaluating the propossed phase 3
protocol.
 Specific area of the proposed phase 3 trials
are;inclusion/exclusion criteria,dosing
regimen,method and timing of data
collecyion,duration of treatment & follow up
assesment,binding of the drug product and plans
to access compliance with the
protocol,identification of primary outcome
variables,methods to account for dropouts.
 It is the longest and most comprehensive trials
regarding efficacy and saftey of new
compounds.significantly larger number of people
are choosen (1000-3000patients)who are afflicted
with targeted illness are tested.
 The new drug may be compared to the existing
therapeutic regimen or to placebo.
 The final marketedformulation of the drug
product should be optimised prior to the start of
these phase 3 clinical trials.
 PHASE 4 CLINICAL TRIALS
 Phase 4 trials are post-approval clinical trials
designed for 1 of the several reasons.the NDA
may mandate phase 4 testing in a specific patient
population to further assess efficacy and side
effects.
 Companies may also choose to conduct additional
clinical trials to more fully understand how their
product compares to other commercially available
therapeutic regimen
 THE NEW DRUG APPLICATION
 The NDA process is the last hurdle prior to
approval and marketing.A NDA document
contains a highly detailed informations
 The primary items of NDA includes:
1. Saftey and efficacy of the drug treatment.
2. Components of drug products.
3. Description of method and controls used in
manufacturing the active ingredients and the
delivery system and its packing.
4. Proposed labelling.
 When the NDA is first submitted it is first
reviewed for its completeness
 If the document is sufficiently complete the Nda
is accepted for review and assigned a priority
status
 The NDAs for new chemical entities are classified
as either ‘P’ priority review or ‘S’ standard review.
 A ‘P’ rating is given to new drug products with
improved therapeutic effects and
saftey,and/orside effects in comparision to the
currenty marketed drug. The NDAs assigned ‘P’
are expected to be reviewed in a more timely
manner than those assigned ‘S’.
 The decision to accept the NDA is made within 60
days of the date of submission.
 Once the NDA is approved the FDA has 180 days
from the date of submission to complete the
review and give the decision of approval or not.
 POST APPROVAL ACTIVITIES

1. SAFTEY MONITORING
 After the NDA has been granted and merketing
of the drug product is initiated,the drug saftey
is still monitored.sponsers of NDA must submit
reports of adverse events periodically
 For the new drugs these are submitted quaterly
for 3 yrs and then annually.
 Serious adverse events may require minor
labeling changes or addition of warning or
precaution statement.if serious saftey cocerns
arise FDA may withdraw approval.
 CHANGES TO AN APPROVED PRODUCT
 Any changes made to an FDA approved drug
product including component or
composition,chemical synthesis,manufacturing
process,site,analytical methods,batch size,or
labelling must be submitted to the FDA.
 Depending on the type of change & the impact of
change on the quality of drug product notification
to the FDA should be made through annual
reports or supplemental new drug
applications(SNDA).
THANK YOU