UNIT-II A - - - - - --- ---

REGULATORY AP PROVAL
PR OC ES S
CONTENTS
✓ Approval processes and timelines involved in Investigational New Drug (IND)
✓ New Drug Application (NOA)
✓ Abbreviated New Drug Application (ANDA).
✓ Changes to an approv ed NOA / ANDA .
~
~

A. INVESTIGATIONAL NEW DRUG APPLICATION (INDA)

• INDA is a request for authorization from the govern ment authority like Food
and Drug
administration (FDA) to administer an investigational drug or biological
product to
human i.e. to start clinical trials.
• During preclinical studies, the sponsor prima ry goal is to determine
that drug is
reasonable safe for initial use in human s. When produ ct is identified as viable
candidate
for further development, the sponsor then focuses on collecting the data and informa
tion
required to establish that produ ct will not expose human s to unreasonable
risk when
used in early stage of clinical trials.
• FDA's role in development of new drug begins when drug sponsor want to
test activities
of drug in human and apply to FDA in terms of INDA .
• The INDA also allows the company to transport or impor t of unapproved drug
legally.
• Additionally; INDA gives an idea to FDA regarding possible risk to partici
pating subject
in clinical trial and based on which FDA may keep trial on hold which is
known as
'clinical hold' if they observe reasonable risk to subject.
• Clinical hold is an order given to sponsor either to delay clinical study
or suspend
ongoing investigation.
• INDA is mandatory under following conditions
i. New chemical entity subjecting to clinical study.
ii. For a drug not approv ed for indication under investigation
iii. For new dosage form of existing drug.
iv. For new combination of drugs.
• However; following cases are exempted from INDA
i. Drug not intended for human use.
@
Regulatory Approval Process 15

ii. Study of an appro ved drug for appro ved indication

iii. For non-clinical studi es.
• There are 2 categories of IND:
I. Research
II. Commercial
• INDA is broad ly divid ed into 3 types:
initiates and conducts an
1. An investigator IND: is subm itted by a physician who both
is administered.
investigation and unde r whos e direction the investigational drug
d drug or Commercial
Physician may subm it a Research IND for study ing an unap prove
IND appro ved produ ct but for i:iew indication ·
tal drug in an emergency
2. Emergency Use IND: allows FDA to authorised experimen
accordance with
situation that does not allow time for submission of an IND in
guidelines.
ing promising effect on life-
3. Treatment IND: is subm itted for experimental drugs show
threatening conditions.

• INDA must contain information in three broad areas:

data which indicates safety o[
1. Animal Pharmacology and Toxicology study: preclinical
drug for huma n studi es
lation, stability, controls
2. Manufacturing Information: composition of proposed formu
for large scale produ ction
and guidelines followed durin g manufacturing and suitability
protocol for clinical trials,
3. Clinical protocol and Investigator information: detailed
staff.
qualification and any previous experience of investigator and all

BASIC COMPONENTS OF INDA

1. Detailed cover sheet.
2. An introductory statement and investigation plan.
3. Investigators brochure.
4. Detailed investigation protocol.
.
5. Pharmacological and toxicological information of comp ound
applicable)
6. Details of previous clinical experience of same compound (if
7. Any other relevant information
1. Cover sheet: it is consist of details of INDA which inclu
des basic information like name
type of submission and
of sponsor, inves tigational new drug number, name of drug,
16 ~ A Text Book of Phar mace utica l Regulatory Scien
ce

other content of application. Sponsors are required to obtain

a signed FDA Form 1572
from each clinical investigator.

2. Introductory statement and inves tigat ion plan : It gives

an idea abou t investigational
drug (description, indication, structure, pharmacological class
, dosage form , route of
administration etc.) and plan of investigation (type of clinical
study , numb er of patient
involve in study etc.). If drug has been used previously then
brief summ ary of human
experience should be a part of this section which further assur
es the safety for clinical
trials . If drug was withd rawn from investigation or after mark
eting then reasons for
withd rawn should be discuss along with name of Country.

3. Investigators Brochure (1B): It is one of the impo rtant part

of INDA which contains
summ ary form, non-clinical and clinical data, Chemistry-Manu
facturing-Control data
(CMC) that supports the clinical study.
This section must contain following minimum information:
- Physical, chemical and pharmaceutical properties of drug.
- Supply, storage and handling information of drug.
- Chemistry of drug (name and structure).
- Summarised relevant information of non-clinical
pharmacology, toxicology,
pharmacokinetic of drug.
- Guidelines regarding management of subject participating in
the trials.
Note: the type and extent of information is variable depe nding on
stage of development.
4. Protocol of clinical study: It is information regarding
the conductance of proposed
clinical study including trail design and selection of subjects. Phas
e II and ID protocol is
more detailed as compare to Phase I protocol. Basic content of
protocol is summarised
below;
- Name, address and qualification of each investigator and co-in
vestigators.
- Nam e and address of clinical site (s).
- Name and address of each institutional review board.
- Copies of case report form (for Phase II and III).
- Inclusion and exclusion criteria of subject.
- Proposed number of subjects.
- Study design.
- Dose and duration of exposure.
- Method of analysis.
Regulatory Approval Process
17

nd Toxicological inform,1tlon: This section should describe

5. Phannacolog ~cal a
mech · f . .
Pharmacological effects
. ' amsm o action and pharmacokinetic profile which might
• .
be understood durmg preclinical s tud Y· If t h1's mforrnahon is not available then applicant
must report the same but it may leads to clinical hold .

6. Details of previ ous clinical experience of same compound (if applicable): lf drug has
been exposed to human previously then related extensive information must be provided
under this section.

7. Any other relevant infonnation: information of drug abuse potential, safety and efficacy
in paediatric population, radioactive substance dose etc must be include under this
section.

• Followed to all information Informed Consent form from the research subject and
Review of study by IRB (institutional review board) is also important part of IND
submission.

• Once IND is submitted, sponsor must wait for 30 calendar days for approval by FDA

• Upon receiving INDA, FDA subject it for critical reviews from different branches like
medical, pharmacology chemistry etc to make sure people participating in the clinical
trials will not be exposed to unreasonable risks. Statisticians and others are constantly
monitoring the data as it becomes available.

• After critical review, FDA communicates their decision to applicant. The FDA or the
sponsor company can stop the trial at any time if problems arise.

Commitment of sponsor in Form 1571:

1. The sponsor should not initiate clinical study until 30 days after the FDA receives the
INDA.
2. The sponsor should not start clinical study unless notified by FDA or when on clinical
hold.
3. The sponsor shall see the IRB do initial and continue review of each study.
Deviation from above commitment is a criminal offence.
18 W A Text Book of Pharmaceutical Regulatory Science

APPROVAL PROCESS OF IND

Approval process of IND can be summarised by using flow chart as given below;

IND

Review

Medical Pharmacology
Chemistry Statistical

Sponsor submits
1 -
Safety Review new data
I

l
Acceptance
No
t
Notify to sponsor

Yes

Complete Reviews

l I
Notify to sponsor
Acceptance regarding deficiencies
I
If sponsor overcomes
deficiencies
No deficiencies

l
IND accepted
Regulatory Approval Process 19

e. NEW DRUG APPLICATION (NOA)

• NOA is submission to USFDA or concerned regulatory authority of country for approval
of new pharmaceuticals for sale and marketing.

• The data gathered during the animal studies and human clinical trials of an
investigational new drug {IND) become part of the NDA.

• The goal of the NDA is to provide enough information to permit FDA reviewers to
establish following:
i. The safety and effectiveness of drug for proposed use
ii. New drug's proposed labelling and package insert is appropriate
iii. The adequacy of the method used in manufacturing (GMP) the drug,
iv. Control used to maintain drugs quality to preserve its identity, strength, purity and
quality.

• The documentation required in an NOA is supposed to tell whole story including what
happened during the clinical tests, what are the ingredients of formulation and role, the
results of animal studies, pharmacokinetics and dynamics, manufacturing process etc.

• NOA is consist of several thousand pages

• In 1997, the FDA's Center for Drug Evaluation and Research (CDER) published
guidelines that allow sponsors to submit NOA electronically instead of on paper.

The NOA to be submitted to FDA is prepared in multiple copies:

a. Archival copy:
I. It contains all sections of the NOA, Cover letter, Form 356 h, 4 copies of the Labeling
section.
II. Three additional copies of CMC (Chemistry, manufacture and control) and methods
validation package.
ID. Should contains Case report tabulation & case report forms.

b. Review copy:
I. Intended for reviewers in the corresponding technical disciplines.
II. Includes the cover letter, form FDA-356h, NDA index, individual table of contents,
labeling section and application summary.
20 fV A Text Book of Pharmaceutical Regulatory Science

c. Field copy:
I. It required since 1993 for use by FDA inspectors during pre-approval facilities
inspections.
TI. In addition to the content of review copy it includes the CMC and method validation
package.
• NDA may have as many as 20 different sections.
• Content of every NDA may be variable based upon nature of drug and volume of
information available at the time of submission
• Form FDA-356 h serves as a checklist as well as certification that the sponsor agrees to
comply with legal requirements.
• If applicant is from US he shall mention address of business and if not then address of
authorized US agent.
NDA sections are described below;

Section 1: Overall NDA index

• It is a comprehensive table of contents that enables the reviewers to find specific
information in this massive document quickly.
• It should follow immediately after the Form FDA-356h.
• It must show the location of every section in the archival NDA by volume and by page
number.
• It should guide reviewers the data in technical sections, summary and supporting
documents.

Section 2: Labeling
• It must include label that is intended for use on the product container, cartons or
packages.
• It also includes proposed package insert.

Section 3: Application summary

• It is an abbreviated version of the entire application which gives a clear idea of the drug
and its application.
• Summary usually consist of 50 to 200 pages.
Regulatory Approval Process 21

• It essentially includes foreign marketing history (a list of any countries in which drug is
or was marketed, along with date when it was marketed, and withdrawal from market if
any along with reason)

Section 4: chemistry, manufacturing, & control (CMC)

• Information must include:
i. Description of drug substance or active ingredient : appearance, color, odor, crystalline
form, melting point, boiling point, refractive index, viscosity etc.
ii. Stability
iii. Physical & chemical chara5teristics: solubility, ionization constant, partition coefficient,
etc
iv. Names/ designation of drug substance (IUPAC)
• This section provides a structural overview on molecular weight, molecular structure,
molecular formula.

• The CMC information must also indude: the names, addresses and functions of each
site where the drug substance is manufactured and tested.

• It includes synthesis scheme, synthesis description, analytical controls, reagents, solvents

etc.

• The section of drug product packaging must include:

i. Listing of packaging components and supplier
ii. Specifications for each packaging component
iii. Description of packaging process, test methods

• Method validation of packageis a final component of the CMC technical section, which
consist of specifications and test methods for each component, name and address of
suppliers of container, closure system.

Section 5: Non-clinical pharmacology & toxicology

• It provides a description of all animal and in vitro studies with the drug including
pharmacology, toxicology& ADME studies.
• For the Pharmacology studies, following data is required:
i. Effect related to the therapeutic indication
ii. Adverse effect
iii. Drug interaction
22
W A Text Boal< of Pharmaceutical Regulat ory Scienco

Section 6: Human phatmacokHtelics and bioavail ability

• This technical section includes data from phase-I studies in healthy voluntee rs and
ADME studies.
• It should include paramet ers such as:
i. Peak plasma concentration (Cmax)
ii. Area under curve (AUC)
iii. Time to reach peak concentration (Tmax)
iv. Volume of distribut ion (Vd)
v. Plasma & renal clearance
vi. Urinary excretion
• Drug formulation information should.include a list of formulat ions used in clinical trials
and in-vivo bioavailability.
• It contains detail information regardin g analytical method of analysis.

Section 7: Microbiology
• This section is mainly useful for antimicrobial drugs those are intended to affect
microbial physiology.
• In vitro and in vivo studies are critical in establishing the new drug's effectiveness
• Microorganisms vary widely in susceptibility to antimicrobial and effectiveness must be
demonst rated against each organism by means of standard ized susceptibility test.
• Microbiologi~al studies of antimicrobial drugs perform ed in following sequences:
i. Determination of the drugs in vitro antimicrobial spectrum
ii. Study of its mechanism of action
iii. Study of its pharmacokinetics to choose appropri ate route of adminis tration
iv. Develop ment of clinical laboratory susceptibility test method & material
v. Clinical tJ:ials with microbiol~gical studies
vi. Epidemiology of resistance

Section 8: Clinical d.1ta

It includes;
i. List of investigators, list of INDs and NDAs: include all investigators who have used any
dosage form, alphabetical list of investigator's and their address, type of study, its
location in the NDA.
ii. Background or overview of clinical investigations

J
Regulatory Approva l Process 23

iii. Clinical trials

iv. Controlled clinical trials
v. Analytical data
vi. Uncontrolled clinical trials
vu. Drug abuse and over dose information

Section 9: safety data

It includes;

'i. Contraindications: includes description of situation in which the drug should not be
used.
ii. Warnings: des·criptiori of serious adverse reaction, limitation in use and steps that should
take if they occur.
iii. Precautions: information regarding any special care to be taken for safe and effective use
of drug.
iv. Adverse effect: description of undesirable effects associates with the proper use of the
drug.

Section 10: statistical data: it contain all generated statistical 'data which can be use to claim
safety of drug.

Sediori 11: case report l~bulation: It contains data from clinical pharmacology studies and
Safety data from all studies in tabulated form .

. Sedion 12: Case report form: it includes information regarding any pati~nt who died during
a clinical study or who did not complete the study because of adverse effect, report must be
.submitted.
Secti~n 13: Patient information
Section 14: Patient certification
Section 15: Establishment description
Section16: Debarment certification
Section 17: Field copy certification
Section 18: User free cover sheet (Form FDA-3397)
Section 19: Financial disclosure (Form FDA 3454, form FDA-3455)
Sedion 20: Other/pediatric use:

\
j
24 PJ A Toxt Boole of Pltarmacoutlca/ Regulatory Science

• Process involved in NOA submission and approval is a R follows:

• NOA subm1ssion und npprovnl is ns follows:

lNDA I
1
I
Suitability~f application

Yesl --. -
Review by COE~ ~ ]

Medical Biopharmaceutical
Pharmacology Microbiology
r--------~ Chemistry Statistical
Advisory Committee Meeting with
~
meeting
~ -- Sponsors

No

Acceptance • Require additional

information
Yes '
No Labelling Inspection No
Soonsor Revises _ _,
••--•~_ r_ev_i_ew
I -
+ of Sites Require
satisfactory answer

'
NDA accepted
Regulatory Appro val Proce ss 25

C. Abbreviated New Drug Appli cation (AND A)

ption as that of
• Generic drugs have similar effects in terms of its rate and extend of absor
ability as that of
approved produ ct. In other word s generic produ ct possesses same
ct is called as
innovators produ ct to cure disease. Approval process of generic produ
Abbreviated New Drug Application (AND A).
arable to a brand or
• A generic drug or generics is defined as, 'a drug produ ct that is comp
y, performance
reference listed drug produ ct in dosage form, strength, qualit
characteristics and intend ed use'.
drug is expired or is
• ANDA filing is possible only when the paten t of innovator
ics are listed in
scheduled to expire. All appro ved products, both innovator and gener
ation' i.e. Orange
FDA's 'appro ved drug produ cts with therapeutic equivalence evalu
Book.
it takes around 10-15
• When we concern with new drug discovery and development,
time it is also
years with inves tment of more than 400 crores rupees. At the same
associated with high risk of failure at any stage of research.
only one enter in
• Journey of new drug starts with 4000-5000 .compounds out of which
market after preclinical and clinical trials.
tion under heading of
• In order to recuperate the investment, innovator _takes the protec
t at the time of
patent systems. Innovator applies to concern authority for paten
for marketing of
submission of INDA. Time requires from INDA till the approval of FDA
enjoy paten t for 20
drug produ ct is aroun d 10 years. AS we know that innovator can
ator in process of
years, out of which aroun d 10 years are already utilised by innov
to recapture the
clinical trials. Ultimately; only 10 years are available to innovator
investment by mono poly marketing.
t on produ ct has
• Generic industries utilises innovator drug produ ct once the paten
costly and faster
expired and introduce produ ct equivalent to an innovators by less
process of ANDA .
ard of innovator
• Generic produ ct must meet bioavailability-bioequivalence stand
' because they are
product. Generic produ cts applications are termed as 'abbreviated
ish safety and
generally not requir ed to include preclinical and clinical data to establ
effectiveness.
uivalence range
• As per US-FDA, generic drugs are identical or within an acceptable bioeq
to brand ed product.
t\) A Text Book of Pharmaceutical Regulatory Sc/once
26

• One way scientists demonstrate bioequivalence is ~o measure the time it takes the generic
drug to reach the blood stream in 24-36 healthy volunteers. This gives 'rate of absorption'
or bioavailability of generics which is then compare to that of innovator drugs (IVIVC).
• Use of bioequivalence as basis for approving generic version of drug product was
established by 'Hatch-Waxman Act-1984'.
• The ANDA process eliminates the lengthy and costly clinical research phase and
ultimately product development takes place within 18-24 months.
• Availability of generic products increases market competition and substantially lowers
price of branded product upto 90%.

ANDA-Growth opportunity to generic phannacculkaJ companies:

• Under provision of ANDA, first to file generic company gains 180 days exclusivity if the
patent expires is due for innovator product.
• The 180 days exclusivity can help the generic company earn a huge amount.
• During this 180 days which is called as period of exclusivity only innovator and first to
file generic company is allowed to sale product.

Types of ANDA filing:

While filing an ANDA, company has to choose one of following option;

Option Specification Acceptance of ANDA

Para I The drug has not been patented If application is complete then immediately
Para II Paten has already expired If application is complete then immediately

Para III Patent is exist but company want to After expiry of patent
launch product after expiry of patent

Para IV Patent is not infringed or is invalid After proving that either patent is invalid or
not infringed
Rcgul 1tory Approval Process 27

\ N D/\ ., p prova l p rocess is s umn1.1rised in following flo w t hart ;

s
ANDA

No
Acceptance Refused

Review by CDER

I
Chemistry J ...._M_ic_r_o _ _ _
No
Require additional
Acceptance information
Yes

Bioequivalence review Labelling review

No No approval
Bioequivalence No Acceptance
Acceptance letter
deficiency letter
Yes I I Yes

Preapproval inspection

•
No
Satisfied Hold the decision

Yes

ANDA accepted
28 ~ A Text Book of Pharmaceutics/ Regulatory Science

Changes to an Approved NDA or AND A

US FDA publis hed guida nce for indus tries who wants to make post
appro val chang es in new
drug applic ations (NDAs) and abbre viated new drug applic ations
(ANDAs). The guidance
covers recom mend ed repor ting catego ries for post appro val chang
es for drugs other than
specified biotec hnolo gy and specif ied synth etic biological produ cts.
Recom mend ations are provi ded for post appro val chang es in
• Comp onent s and comp ositio n
• Manu factur ing sites
• Manu factur ing proce ss
• Specifications
• Conta iner and closure system
• Labelling
• Miscellaneous chang es
Howe ver; this guida nce does not provi de recom mend ations on the
specific inform ation that
shoul d be devel oped by an applic ant to assess the effect of the
chang e on the identity,
streng th, quality, purity or poten cy of a drug produ ct as these factor
s may relate to the safety
or effectiveness of the drug produ ct.
An applic ant shoul d consid er all releva nt CDER guida nce docum ents
for recom mend ations
on the inform ation that shoul d be submi tted to suppo rt a given chang
e. CDER has publis hed
guida nce, includ ing the SUPAC (scale-up and post appro val changes)
guida nce, that provi de
recom mend ations on report ing categories.

Reporting Categories:
FDA has categorises changes in 3 types:
1. Major chang e
2. Mode rate chang e
3. Mino r chang e

1. Major change:
• It is a chang e that has a considerable poten tial to have an adver se
effect on the identity,
streng th, quality, purity , or poten cy of a drug produ ct as these factor
s may relate to the
safety or effectiveness of the drug produ ct.
Regu[atory Approval Process 29

• A major change requires the submission of a supplement and approval by FDA prior to
distribution of the drug product made using the change. This type of supplement is
called as a Prior Approval Supplement.
• An applicant may ask FDA to speed up its review of a prior approval supplement for
public health reasons. This type of supplement is called as a Prior Approva l Supplement.
2. Moderate change

• It is a change that has a moderate potential to have an adverse effect on the identity,
strength, quality, purity, or potency of the drug product as these factors may relate to the
safety or effectiveness of the drug product. ·
There are two types of moderate change.
a. Changes Being Effected in 30 Days:
• In this type of moderate change requir~s the submission of a supplement to FDA at least
30 days before the distribution of the drug product made using the change.
• The drug product made using a moderate change cannot be distributed if FDA informs
the applicant within 30 days of receipt of the supplement that a prior approval
supplement is required.
• For each change, the supplement must contain information determined by FDA to be
appropriate and must include the information developed by the applicant in assessing
r

the effects of the change.

• If FDA informs the applicant within 30 days of receipt of the supplement that
information is missing, distribution must be delayed until the supplement has been
amended to provide the missing information.
b. Changes Being Effected:
• Under certain conditions FDA may identify some moderate changes for which
distribution can occur when FDA receives the supplement. This type of supplement is
called as Changes Being Effected .
• If, after review, FDA disapproves with changes then FDA may order manufacturer to
cease distribution of the drug products made using the disapproved change.
3. Minor change
• , ,It1is a change that has minimal potential to have an adverse effect on the identity,
strength, quality, purity, or potency of the drug product as these factors may relate to the
safety or effectiveness of the drug product.
• The applicant must describe minor changes in its next Annual Report.
30 t\J A Text Book of Pharmaceutical Regulatory Scwnr.e

MULTIPLE CHOICE QUESTIONS

1. Jnvesllg a tional New 0mg is
A. Application for conduct study on human
B. Submitt ed between preclinical study and phase I of clinical trials
C. Both A and B
D. Submitt ed after Phase 4
2. Which of the followin g is NOT needed for an invcslig alional new drug applica tion?
A. Animal pharmac ology and toxicology
B. Manufa cturing informa tion
C. Clinical protoco l
D. Phase II data
3. New Drug Applica tion is submitt ed for
A. Beginning of clinical trial
B. Approv al of drug for marketi ng
C. For Phase I
D. For preclinical study
4. An Abbrevi ated New Drug Applica tion is an applicat ion for
A. For preclinical approva l
B. For clinical trials
C. For generic drug approva l
D. All the above

lfflf,iWiii
2.d 3.b
Regulatory Approval Process 31

SHORT ANSWER QUESTIONS

1. What do you mean by INDA/IND?
2. Write down the conditions in which filling of INDA is mandatory.
3. Under what conditions the filing of INDA is exempted?
4. Give the types of INDA.
s. What is difference between the research and commercial?
6. Write down the broad areas of INDA.
7. Enlist the basic components of INDA.
8. What is NDA?
9. What is goal of NOA?
1o. Write a short note on
a) Archival copy:
b) Review copy:
c) Field copy
11 . What is need of ANDA?
12. Enlist the part for which changes in approved NOA or ANDA is possible.
B . Define major changes/moderate changes/minor changes.
14. Give the difference between 'Changes Being Effected' and 'Changes Being Effected in 30 Days'

LONG ANSWER QUESTIONS

1. Explain the components of INDA.
2. Write a note on the process of approval of INDA.
3. Explain various sections of NDA.
4. Write a note on process of approval of NOA
s. Explain in detail ANDA.
6. Describe the concept of changes to an approved NOA or ANDA.

DESCRIPTIVE QUESTIONS
1. Explain in detail INDA. Add a note on its approval process.
2. Explain in detail NDA. Add a note on its approval process.