Drug development process and regulatory submissions
Suyog Pratap Sulake
Under the Guidance of
Dr. N.H. Aloorkar
(Head of Department of Pharmaceutics)
Satara College of Pharmacy,Satara.
“DRUG DEVELOPMENT PROCESS AND REGULATORY
• Understanding the disease : to discover underlying
• Target identification : e.g Protein, genes
• Target validation : to confirm its role.
• Finding a lead : Nature, Denovo, Highthroughput Screening
• Early safety tests : ADME/Tox properties
• Lead optimization : to optimze lead properties viz. toxicity,
• Pre- Clinical testing :To assess the safety of drug
• IND (Investigational New Drug Application)
• Clinical trials : conducted in 3 Phases, Safety and efficay.
• NDA (New Drug application)
• Post marketing Surveillance: Expanded safety, PV, Rare
i) Sponsor: individual, company, institution or an organization,
responsible for initiation, management and financing of clinical
ii) Innovator Drug: drugs with patents on their chemical
formulations or production process.
Laws, Regulations, Policies and Procedures
21CFR Part 312 Investigational New Drug Application
21CFR Part 314 INDA and NDA Applications for FDA
Approval to Market a New Drug (New
21CFR Part 50 Protection of Human Subjects
5. NEW DRUG APPLICATION
• clinical testing has been completed
• final manufacturing processes and procedures are in place
• and the company has ready other required information
The Drug and/or the formulation cannot be marketed until
the FDA has approved an NDA.
Goals of the NDA
To assess whether:
• the drug is safe and effective (benefits of the drug
outweigh the risks)
• the drug’s proposed labeling (package insert) are
• the methods used in manufacturing (& controls) the drug
are adequate to preserve the drug’s identity, strength,
quality, and purity
Classification of drugs in NDA
1) New Molecular Entity
2) New Salt of Previously Approved Drug (not a new
3) New Formulation of Previously Approved Drug (not a
new salt OR a new molecular entity)
4) New Combination of Two or More Drugs
5) Already Marketed Drug Product - Duplication (i.e., new
6) New Indication (claim) for Already Marketed Drug
7) Already Marketed Drug Product - No Previously
Laws, Regulations, Policies and Procedures:
21 CFR Part 314 Applications for FDA Approval to
Market a New Drug or an Antibiotic
NDA Content and Format:
B) THE SAFETY UPDATE REPORTS
C) CHEMISTRY, MANUFACTURING AND CONTROL
An overview of the drug substance and drug product.
• Drug substance: Description including physical and chemical
characteristics and stability
• Drug product: Composition and type of dosage form,
manufacture, specifications and analytical methods,
container/closure system, stability,
D) NON CLINICAL PHARMACOLOGY AND
Toxicological effects of drugs on reproduction and the
developing fetus,ADME animal experiments of the drugs
E) HUMAN PHARMACOKINETICS AND BIOAVAILABILTY
Applicable to anti-infective and to antiviral drugs.
G) CLINICAL DATA
• Critical part of the NDA ,
• Sponsors often "push the envelope”—by wording the
indications for the drug as widely as possible, and by
downplaying the importance of the drug’s side effects—in
their proposed labeling, and negotiations to finalize the labeling
often occur when the NDA has been reviewed and deemed
"approvable” by the Agency
J) CASE REPORT FORMS ANDTABULATIONS
The sponsor must submit case study report form for every
clinical trial patient who died or withdrew from the study
because of an adverse event.
K) PATENT INFORMATION
Patent related information that covers the drug substance,
formulation, or method of use.
Upon approval of the NDA, this information is published in
the FDA’s Orange Book serves as a guide to firms wishing to
develop generic copies of the innovator’s product.
L) DRUG SAMPLES
Submitted upon the FDA’s request to the District Laboratory
assigned to test them.
GENERAL REQUIREMENTS FOR FILING AN NDA:
Submitted in two copies :
i)An Archival copy (permanent record )
ii)A Review copy
Both are submitted in hard copy, the regulations permit an
applicant to submit the archival copy as microfiche.
ReviewTime Frames (21 CFR 314.100):
• 180-day period is called the ‘review-clock’
•The FDA will review and issue an approval, approvable, or
not approvable letter.
•The time period may be extended by mutual agreement
between the FDA and the applicant.
FilingTime Frames (21 CFR 314.101):
•Within 60 days after the receipt of an application, FDA
decides whether the application may be filed or not.
• If FDA files the application, the applicant will be notified in
If FDA refuses to file the application, the sponsor will be given
the opportunity to meet with FDA to discuss the reasons why
the application is not file able.
Computer assisted NDA:
It is designed to shorten FDA review time by submitting
data to FDA in a form ready for manipulation by a
Importance is given on the clinical sections of the NDA, as
they require the maximum time to review by FDA.
6 ABBREVIATED NEW DRUG APPLLICATION
Submitted to FDA's Center for Drug Evaluation and
Research, Office of Generic Drugs, for review and ultimate
approval of a generic drug product.
Generic Drug product : comparable to an innovator drug
• in dosage form,
• route of administration,
• performance characteristics and
• intended use.
Why Abbreviated ?
because it is not necessary to include preclinical (animal)
and clinical (human) data to establish safety and
Instead, applicant must demonstrate that their product is
E.g. time taken by the generic drug to reach the bloodstream
healthy volunteers is measured and compared with the
Laws, Regulations, Policies and Procedures
21 CFR Part 314 Applications for FDA Approval
to Market a New Drug or and
21CFR Part 320 Bioavailability and
Use of bioequivalence as
the base for approving
generic drug products
was established by the
Restoration Act of
also known as the
Concept of PARAGRAPH ITO IV
For filing ANDA, generic company must include a patent
certification as per section 505(j) (2) (A) (vii) of the Hatch
I. No patent information on the drug product that is the
subject of the ANDA has been submitted to FDA
II. That such patent has expired
III. The date on which such patent expires
IV. That such patent is invalid or will not be infringed by the
manufacture, use, or sale of the drug product which the
ANDA is submitted.
The first three paragraphs (I, II, III) results in no generic drug
being sold during the term of the innovator’s patent protection.
In case paragraph IV certification generic drugs can be sold
during the term of the innovator’s patent protection.
Substantially complete ANDA:
Only the applicant submitting the first "Substantially complete
ANDA” with a paragraph IV certification would be eligible for
According to FDA all ANDA applications containing :
Paragraph IV certifications
for a particular drug product
received by the FDA on the same day
will be eligible for exclusivity if no other ANDA with a paragraph IV
certification for the drug product had been filed on an earlier day.All
such same day applicants would be considered first applicants.
Sometime there is unnecessary delay in entry of generic
drug into the market due to:
i) delay in approval of ANDA by FDA or
ii) some kind of settlement between first generic (first
ANDA approver) and innovator.
e.g. first generic tells to innovator that it will not start its 180
days until “x” number of days in return to “Y” number of
dollars from innovator.
Thus as per rule until first generic finishes 180 day exclusivity
period no other generic manufacturer can be granted 180
exclusivity period. As a result innovator and first generic enjoys
To overcome this FDA has introduced "Triggering period”
Under this concept the commencement of the 180-day
exclusivity period for the first applicant is either the first
commercial marketing of the first applicant’s product, or a
decision of a court holding the patent invalid, not
infringed, or unenforceable, whichever is earlier.
If neither of these events occurs in the triggering period
then the first generic would lose its eligibility for exclusivity
and subsequent generic filers for ANDA would be eligible
for immediate approval.
Regulatory submissions forms a very important part of Drug
The extensive review process done by the regulatory bodies,
ensures that not only effective but also a safe Drug product
reaches the market.