Regulatory Approval Process Guide

Unit-II
Chapter 1. Regulatory Approval Process
Represented By,
Mr. Audumbar Mali.
(Assistant Professor)
Sahyadri College of Pharmacy
Methwade
BP804 ET: PHARMACEUTICAL
REGULATORY SCIENCE (Theory)

INTRODUCTION:
For small-molecule drugs, the path to a marketed drug involves a
long and exhaustive journey through basic research, discovery of
the medicine, pre-clinical development tests, increasingly
complicated clinical trials with humans and regulatory approval
by the Regulatory Authority. Several years (usually 10 to 15) and
hundreds of millions of dollars later, under the best of
circumstances, a new drug will be approved for marketing.
Because of its complexity, drug discovery and development are
widely recognized as one of the most financially risky endeavours
in all of science and a major challenge for the pharmaceutical
industry. Much of this cost comes from failures, which account for
75 percent of the total research and development costs. Although
these failures are disappointing and costly, they still contribute to
the body of knowledge on disease processes.

INVESTIGATIONAL NEW DRUG (IND):
It's an application filed to the FDA in order to start clinical trials in
humans if the drug was found to be safe from the reports of Preclinical
trials. The Federal Food, Drug and Cosmetics act regulated through
Title 21 of U.S. Code of federal Regulations, requires a new drug to be
approved by FDA before legally getting introduced into the market.
Investigational New Drug is defined under 21 CFR 312.3(b) as, “A new
drug or biological drug that is used in clinical investigation.”
The term also includes a biological product used in-vitro for diagnostic
purposes.
After pre-clinical investigations when the new molecule has been screened
for pharmacological activity and acute toxicity potential in animals the
sponsor requires permission from FDA for its clinical trials in humans.
The sponsor submits the application for conduct of human clinical trials
called Investigational New Drug (IND) application to FDA.
Once IND application is submitted, the sponsor must wait for 30 days
before initiating any clinical trial.

 Clinical trials in humans can begin only after IND is reviewed
by the FDA and a local institutional review board (IRB).
IRBs approve clinical trial protocol, informed consent of all
participants and appropriate steps to prevent subjects from harm.
 If the FDA accepts the IND request within 30 days of
submission, clinical testing of the new molecule on human may
begin by the investigator.
 At this point, the molecule under the legal status of FDA
becomes a new drug subject to specific requirements of drug
regulatory system.
 If at any time during clinical testing, the data furnished to FDA
indicate the Investigational Product (IP) to be toxic under the
criterion of FDA's Benefit/Risk ratio, FDA can terminate clinical
trial and its actions are not subject to any judicial review.

Types of lNDs:
A. Commercial INDs: These are applications that are submitted primarily
by the companies to obtain marketing approval for a new product.
B. Non-commercial (Research) INDs: These INDs are filed for non-
commercial research. These are: 1. Investigator’s IND: It is submitted by
a physician who both initiates and conducts an investigation and who also
administers and dispenses the Investigational Product. A physician might
submit a research IND to propose studying an unapproved drug or an
approved drug for new indications or in new patient population.
2. Emergency Use IND: This IND allows FDA to allow the use of an
experimental drug in an emergency situation that does not allow
submission of an IND in accordance with 21 CFR Sec 312.23 or Sec
312.34. It can also be used for patients who do not meet the criteria of an
existing study protocol or if an approved study protocol does not exist.
3. Treatment IND: Also called Expanded Access IND. This 1ND may be
submitted for experimental drugs showing promise in clinical testing of
serious and immediately life-threatening conditions while the final clinical
work is conducted and the FDA review takes place (21 CFR 312.34).

The IND application must contain Information In 3 broad
areas:
1. Animal Pharmacology and toxicology studies: Preclinical data to
assess if the product is reasonably safe for initial testing in humans.
2. Manufacturing Information: Information pertaining to composition,
manufacturer, stability and controls used for manufacturing drug product
to ensure that the company can adequately produce and supply
consistent batches.
3. Clinical protocol and investigator information: Detailed Protocols
for proposed clinical studies to make sure subjects are not exposed to
undue risk. Also, information on the qualifications of the investigators
(chiefly physicians) if they fulfill their clinical duties.
Finally, commitments to obtain informed consent from all research
subjects, to obtain review of the study by an IRB and to adhere to the
investigational new drug regulations.
An IND must also include The Investigator's brochure.

Criteria for IND Application: A clinical study is required for an IND if
it is intended to support
A new indication.
Change in the approved route of administration or dosage level.
Change in the approved patient population (vulnerable subjects, for e.g.
pediatrics. elderly, HIV, immunocompromised).
Significant change in the promotion of an approved drug.
Codes of Federal Regulations (CFR):
21 CFR PART 312: Investigational new drug application.
21CFR PART 314: INDA and NDA for FDA approval to market a new
drug.
21CFR PART 316: Orphan drugs.
21CFR PART 50: Protection of human subjects.
21CFR PART 54: Financial disclosure by clinical investigator.
21CFR PART 56: Institutional review boards.
21CFR PART 58: Good lab practice for Non-clinical laboratory (animal)
studies. 21CFR PART 201: Drug labeling.

Format and Content of IND:
1. Cover sheet (Form FDA1571).
2. Table of contents.
3. Introductory statement and General Investigational Plan.
4. Investigator’s Brochure.
5. Protocols.
6. Chemistry, Manufacturing and Control information.
7. Pharmacology and Toxicology Information.
8. Previous human experience with IP.
9 Additional information.
Withdrawal of an IND: At any time, a sponsor can withdraw
an effective IND. In such a case, FDA and IRS shall be so notified
with reasons for withdrawal, all clinical studies ended, all current
investigators and subjects notified, all stocks of drug returned to the
sponsor or otherwise disposed of on request of sponsor in
accordance with 312.59.

NEW DRUG APPLICATION (NDA):
If clinical studies confirm that a new drug is
relatively safe and effective, and will not pose
unreasonable risks to patients, the manufacturer
files a New Drug Application (NDA), the actual
request to manufacture and sell the drug in the
United States.
* The New Drug Application is the vehicle
through which the drug sponsors finally propose
FDA to approve a new investigational drug for
sale and marketing after Phase III A Pivot trials.

The official definition of New Drug is in Section 201(P) of
Federal Drug, Food and Cosmetics Act as; “Any new drug, the
composition of which is such that it is not recognized among
experts qualified by scientific training as safe and effective for use
under prescribed, recommended or suggested conditions". OR
“Any drug the composition of which is such that it as a result of
investigations to determine safety and efficacy for use has become
recognized, but which has not, otherwise in such investigations
been used to a material extent”.
The following letter codes describe the review priority of the drug;
S-Standard review: For drugs similar to currently available
drugs.
P-Priority review: For drugs that represent significant advances
over existing treatments.

Classification of Drugs in NDA:
Center of drug evaluation and Research (CDER) classifies new drug
applications according to the type of drug being submitted and its intended use:
i. New molecular entity.
ii. New salt of previously approved drug.
Iii. New formulation of previously approved drug.
Iv. New combination of two or more drugs.
V. Already marketed drug product Duplication (i.e. new manufacturer).
Vi. New indication (claim) for already marketed drug (includes switching
marketing status from prescription to OTC).
Vii. Already marketed drug product (no previous approved NDA).
In US following four types of applications are submitted for approval
of drug for marketing depending upon the type and nature of the drug:
1. New Drug Application (NDA).
2. Biological License Application (BLA).
3. Application u/s 505(b)(2)-Paper NDA.
4. Supplemental New Drug Application (SNDA).

Format and Content of NDA:
The application is required to be submitted in
common technical document format with the following
different sections:
1. FDA Form 356h
2. User Fee Cover Sheet (FDA Form 3397)
3. Cover letter (Comprehensive table of contents for
Modules 1 to 5)
4. Summary
5. Chemistry, Manufacturing and Control
6. Samples, Method Validation Package and Labeling
7. Non-clinical Pharmacology and Toxicology

8. Human Pharmacokinetics and Bioavailability
9. Microbiology (For anti-microbial drugs only)
10. Statistical methods and analysis of Clinical Data
11. Safety Update Report (typically submitted 120
days after NDA submission)
12. Statement regarding compliance to IRB and
Informed Consent requirements
13. Case Report Tabulations
14. Case Report Forms
15. Patent information and certification
16. Other information

General Requirements for Filling of NDA: The new NDA
regulations require the application to be submitted in two copies:
A. An Archival Copy: It is a complete copy of application submission that
serves as its permanent record.
B. A Review Copy: It is divided into 6 technical sections:
(i) Chemistry, Manufacturing and Controls (CMC).
(ii) Non-clinical Pharmacology and Toxicology.
(iii) Human Pharmacokinetics and Bioavailability.
(iv) Microbiology (if required).
(v) Clinical data.
(vi) Statistical.
On receipt of NDA, the CDER stamps with a receipt date to enable FDA to
forward action within 180 days called Review Clock under Review Time
Frames (21CFR 314.100). The FDA assigns the application for review.
The FDA has to intimate the applicant if it is incomplete within 60 days
according to Filing Time Frames (21CFR 314.101). FDA notifies the sponsor
of its completion/ incompletion and if complete sends it for secondary review
process.

FDA inspects the manufacturing facilities for the drug. It
may also inspect sample of clinical trial locations to verify
the accuracy of data submitted.
Throughout the process, FDA and sponsor communicate
through in person meetings telephone conferences, fax, etc
to seek clarification if necessary. Once all reviews are
complete; the Divisional Director evaluates the reviews and
makes FDA's decision.
The FDA may: Approve the drug for marketing.
Approve the drug with condition when problem exist with
the application that needs to be addressed before approval.
Refuse to approve the drug, when it may require additional
research or reformulation of the drug product.

ABBREVIATED NEW DRUG APPLICATION (ANDA):
It’s an application made for approval of Generic Drugs. The
sponsor is not required to reproduce the clinical studies that
were done for the original, brand name product. Instead,
generic drug manufacturers must demonstrate that their
product is the same as, and bioequivalent to, a previously
approved brand name product.
Generic drug applications are referred to Abbreviated New
Drug Application.
Pharmaceutical companies must admit ANDAs and receive
FDA’s approval before marketing new generic drugs
according to 21CFR 314.105(d).
Once ANDA is approved, an applicant can manufacture and
market generic drug to provide safe, effective and low-cost
alternative of innovator drug product to the public.

Generic drugs are termed ‘abbreviated’ as they are not required to
include preclinical and clinical data to establish safety and efficacy.
They must scientifically demonstrate bioequivalence to innovator
(brand name) drug.
A generic drug is comparable to Innovator drug I dosage form,
strength, route of administration, quality, performance and Intended
use.
One of the ways to demonstrate bioequivalence is to measure the
time taken by generic drug to reach bloodstream in 24-36 healthy
volunteers. The time and amount of active ingredients in the
bloodstream should be comparable to those of innovator drug.
Use of bioequivalence as base for approving generic drug products
was established in 1984, also known as Waxman-Hatch Act. It is
because of this act that generic drugs are cheaper without
conducting costly and duplicative clinical trials.

Code of Federal Regulations: The following
regulations apply to ANDA process:
21 CFR 314 : Applications for FDA approval to market a New
Drug or Antibiotic Drug.
21 CFR 320: Bioavailability and Bioequivalence requirements.
21 CFR 310: New Drugs.
Office of Generic Drug (OGD) strongly encourages submission
of bioequivalence,
chemistry and labeling portions of the application in electronic
format.

Format and Content of ANDA : Copies of the Abbreviated
application are required to be submitted; an archival copy, a review copy and
a field copy. An Archival copy shall contain the following:
Application form, Table of Contents, Basis for ANDA submission,
Conditions of use, Active Ingredients, Route of Administration, Dosage form
and Strength, Bioequivalence and Bioavailability, Labeling, Chemistry,
Manufacturing and Controls, Samples, Patent Certification, Financial
Certification or disclosure statement.
Other Information: Under Section 314.94 (a) (12), the patent certification
includes one of the following:
(a) Paragraph I Certification: That the patent information has not been
submitted to FDA.
(b) Paragraph II Certification: That the patent has expired.
(c) Paragraph III Certification: That the patent will expire (on date of
marketing).
(d) Paragraph IV Certification: That the patent is invalid, unenforceable,
or will not be infringed by manufacture, use or sale of generic drug.

Difference between Submission of NDA and ANDA:
NDA requires submission of:
1. Well-controlled clinical studies to demonstrate effectiveness.
2. Preclinical and clinical data to show safety.
3. Details of Manufacturing and Packaging.
4. Proposed annotated Labeling.
In contrast, ANDA requires submission of:
1. Detailed description of components.
2. Manufacturing, Controls, Packaging, data to assure
bioequivalence and bioavailability and Labeling. Labeling should
be prepared in accordance With
Study Implementation).
Exclusivity: Exclusivity is a statutory provision designed to
promote a balance between an innovator and generic drug
competitor. As long as a drug patent lasts, a reference listed drug
company

enjoy a period of market exclusivity or monopoly. Expiration of patent removes
the monopoly of the patent holder.
Terms of Exclusivity:
Orphan drugs 7 years,
New Chemical Entity 5 years,
Pediatric Exclusivity 6 months additional
Patent Challenge 180 days .
Hatch-Waxman Amendments and 180 days Exclusivity: Before
Hatch-Waxman Amendment, generic manufacturer could file ANDA only after,
innovator's patent expiry or cancellation. But under Sec 505(j)(5)(B) of Hatch
Waxman amendment it permits preparation and filing of ANDA before patent
expiration, so that the effective approval date of generic drug would be on
expiration date of the patent of innovator original drug.
The Act also establishes another procedure in which the generic company can
challenge patent of the innovator.
For generic companies, the amendment provides an inventive 180-days
exclusivity period in which no other ANDA for that drug can be approved.

This 180 day period is to encourage
generic companies to challenge validity of
Orange book listed patents or to design
around these patents to bring more quickly
a generic drug to market.
For Innovator company, filing of an ANDA
is an act of patent infringement. So, if
innovator company brings suit within 45
days, the approval of generic company's
ANDA is delayed for u to 30 months.

DRUG APPROVAL IN EUROPE
There are two regulatory steps to go through before a drug
is approved to be marketed in the European Union. These
two steps are clinical trial application and marketing
authorization application. There are 27 member states in the
European Union. The United Kingdom withdrew from the
European Union on 31 st January 2020. Clinical Trial
Applications are approved at the member state level,
whereas marketing authorization applications are approved
at both the member state and centralized levels.

1. Centralized Procedure: The centralized
procedure is one which allows applicants to obtain a marketing
authorization that is valid throughout the EU.
Results in a single authorization valid in EU, Norway, Iceland and
Liechtenstein.
Application evaluated by an assigned Rapporteur.
Timeline: EMA opinion issued within 210 days and submitted to
European Commission for final approval.
Centralized process is compulsory for:
Those medicines which are derived from any biotechnology processes;
such as genetic engineering.
Those medicines which are intended for the treatment of Cancer,
HIV/AIDS, diabetes neurodegenerative disorders or autoimmune
diseases and other immune dysfunctions.

2. Mutual Recognition procedure: It allows
applicants to Reference Member in the Concerned member
states (CMS) other than the reference member state (RMS)
where the drug is previously approved.

3. Decentralized Procedure: Using this procedure,
companies may apply for authorization simultaneously in
more than one EU country for products that have not yet
been authorized in any EU country and essentially do not
fall within the centralized procedure's essential drugs list.
Based on the assessment report which is prepared by
the RMS and any comments made by the CMS, marketing
authorization should be granted in accordance with the
decision taken by the RMS and CMS in this decentralized
procedure.
Generally used for those products that has not yet received
any authorization in an EU country.
Time: 210 days.

4. Nationalized Procedure:
The Nationalized procedure is one which allows applicants
to obtain a marketing authorization in one-member state
only.
In order to obtain a national marketing authorization, an
application must be submitted to the competent authority
of the Member State.
New active substances which are not mandatory under
Centralized procedure can obtain marketing authorization
under this procedure.
Timeline for this procedure is 210 Days.

Further the applicant is required to submit
evidence that the drug for manufacturing approval
has already been approved by DCGI.
In his name while applying to manufacture a new
drug to state licensing authority. Thus the
applicant is required to obtain necessary approval
from DCGI as well as SLA for manufacturing a
new drug for sale purposes in India.
The approval issued is manufacture for sale
rather than marketing approval as per the
practice world over.

Reporting Categories:
A. A major change is “a change that has a substantial
potential to have an adverse effect on the identity, strength, quality,
purity, or potency of a drug product as these factors may relate to the
safety or effectiveness of the drug product.”A major change differs
from the others in that it requires the submission of a Prior Approval
Supplement, which must be approved by FDA prior to distribution of
the drug product made using the change.
B. A moderate change 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 changes, which include:

1. Change requiring the submission of a Supplement Changes Being
Effected in 30 Days. Changes that fall into this category require the
submission of a supplement that must be made to FDA at least 30
days before the changed drug product is distributed.
2. Change requiring the submission of a Supplement Changes Being
Effected Changes subject to this type of supplement contain changes
for which distribution can occur when FDA receives the supplement.
C. A minor change is “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.” There is no submission or
supplement required for minor changes, the applicant must simply
describe any minor changes that have been made in its next Annual
Report that is submitted to the FDA.

Components and Composition:
Changes in components and composition that may require a
changes-being-effected Supplement or an annual report are not
addressed in this guidance document. The Agency states that these
recommendations are far too complex, but may be covered in one or
more guidance documents regarding post approval changes (e.g.,
SUPAC documents).
Any changes in the quantitative or qualitative formulation
including; inactive ingredients, are considered to be major changes and
thus, require the submission of a prior approval supplement. In
addition, FDA states that “The deletion or reduction of an ingredient
intended to affect only the color of the drug product may be reported
in an annual report.”
Manufacturing Sites: If a drug maker changes to a manufacturing
site other than those specified in the approved application, CDER must
be notified. These sites can include those used by an applicant to:

1. Manufacture or process drug products, in-process materials, drug
substances, or
drug substance intermediates.
2. Package drug products.
3. Label drug products.
4. Test components, drug product containers, closures, packaging
materials, in-process materials, or drug products.
The supplement or annual report should identify whether the
proposed manufacturing site is an alternative to or replacement for the
site(s) listed in the approved application.
“Manufacturing sites used to:
(1) Manufacture or process drug products, in-process materials, drug
substances, or drug substance intermediates or
(2) Perform primary packaging operations, the potential for adverse
effect depend upon factors such as the type of drug substance or drug
product and operation being performed.”

As such, the reporting categories that are recommended may be different for
different types of products and operations.
In addition, FDA states that construction activities that are occurring at a
manufacturing site or moving production operations within or between
buildings, but Within the same manufacturing site do not have to be reported
to the Agency. It is commended, however that any move that involves other
changes as well (such as; process or equipment changes) be evaluated as a
multiple related change to determine the appropriate reporting category.
Manufacturing Process:
According to the guidance document, “The potential for adverse effects on the
identity. strength, quality, purity or potency of a drug product as these factors
may relate to the safety or effectiveness of the drug product depends on the
type of manufacturing process and the changes being instituted for the drug
substance or drug product.” Furthermore, the Agency states that in some
circumstances there may be substantial potential for adverse effect regardless
of direct testing of the substance for conformance with the approved
specification. In these situations, a change must be submitted to the FDA in a
prior approval submission.

Specifications:
In its guidance, FDA defines specifications as: "The quality
standards provided in an approved application to confirm the quality
of drug substances, drug products, intermediates, raw materials,
reagents, components, in-process materials, container closure systems,
and other materials used in the production of a drug substance or drug
product." As such, the Agency states that all changes in specifications
from those in the approved application must be submitted in a prior
approval supplement unless otherwise exempted by regulation or
guidance.
A regulatory analytical procedure is a “Procedure in the approved
application that is designated for use in evaluating a defined
characteristic of the drug substance or drug product.” According to the
guidance document, an application may include alternatives to the
approved regulatory analytical procedures for testing the drug
substance and product.

Container Closure System: The potential that a
change in a product's container closure system will have an
adverse effect on the identity, strength, quality, purity, or
potency of the drug’s safety or effectiveness is generally
dependent on the following:
Drug’s route of administration, Performance of the
container closure system, Likelihood of interaction between
the packaging component and the dosage form.
Typically, a change to or in the packaging component
will only result in a new or revised specification for the
packaging component, which does not have to be
considered a multiple related change. In this case, only the
reporting category for the packaging change needs to be
considered.

Labeling: A change in a drug's labeling includes changes in one
of the following:
Package inserts, Package labeling and Container label.
All promotional labeling and advertising must be promptly revised to
be consistent with any labeling Change(s) implemented. In addition, all
labeling changes for ANDA drug products must be consistent with
section 505(j) of the Act.
Multiple Related Changes: Multiple related changes
involve various combinations of individual changes. If an applicant has
multiple related changes that fall into different recommended reporting
categories, “CDER recommends that the submission be in accordance
with the reporting category for the individual changes.”

References:
1. A textbook of Pharmaceutical Regulatory
Science,
By, Dr. R. Narayana Charyulu,
Dr. Jobin Jose. Nirali Prakashan,
Page No. 2.1- 2.20.
2. A textbook of Pharmaceutical Regulatory
Science,
By, Dr. Ashok Hajare. Nirali Prakashan,
Page No. 2.1-1.32.
3. www.google.com.

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