UNIT 2: Regulatory Approval Process | Dr Navya Sree K S

UNIT II: Regulatory Approval Process Approval processes and timelines involved in
Investigational New Drug (IND), New Drug Application (NDA), Abbreviated New Drug
Application (ANDA). Changes to an approved NDA / ANDA.
REGULATORY APPROVAL PROCESS
The research, development, and approval of a drug product are continuous but lengthy
processes that involve drug discovery, laboratory development, animal studies, clinical trials,
and regulatory registration. This lengthy process is necessary to assure the effectiveness and
safety of the drug product. The global discovery and approval of new drugs, devices, and
biologics have revolutionized the availability of health care products to every corner of the
world. The crucial areas of life-saving drugs play a major part in new product discoveries that
can be made available to the entire world population. In addition to the pharmaceutical
industry's aggressiveness in marketing these products, bureaucratic agencies regulating these
products also play a part in how fast they are approved for the global market. The opportunity
to accomplish this task has been greatly enhanced with the introduction of guidelines and
recommendations formulated by the International Committee of Harmonization (ICH). This
committee established safety, efficacy, and quality guidelines for new drug development to
speed up international registrations. These guidelines give a basis for uniformity of data and
information developed for pharmaceutical products that are used as evidence for product
approvals.
ICH guidelines have created the foundation necessary for new product approval
internationally, each country's regulations for new product approval must be considered and
incorporated within global submissions. There were no regulations until the Pure Food and
Drug Act was passed by the USA's Congress in 1906. The regulatory agencies of all
countries expect that all new drug-related data must support safety and efficacy for new
product submissions and must meet the regulatory standards required by these agencies.
Some countries require that a part of clinical research be conducted in that country before the
approval of products is granted. In synchronization with these demands, regulatory and
clinical personnel are continually dealing with the challenges of submitting data that will
meet and support the requirements for global new product approvals. Each person who plays
a role in the process of new product development is aware of their responsibilities and
activities needed to be done to meet these regulatory requirements and therefore puts for a
great deal of time, hard work and expense to accomplish these goals.
Innovator companies are actively looking for new ways to reduce the time and costs for the
development and approval of new products. These goals can be achieved by submitting
applications for new products simultaneously in more than one country. Regulatory agencies
cooperate in the rapid reviewing of submissions and accept international data to provide
benefits of new products to the world population. New product development team members
along with sponsors and other related professionals work more closely with regulatory
agencies to facilitate their needs and requests so that less time is involved in the approval
process. To increase the number of approvals thorough understandings of all the regulations
and guidelines and how to effectively implement the complex steps in new drug development
are vital.

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There are many components in the drug, device, and biologic approval process that must be
defined, documented, and understood. The knowledge gained from reading a book or taking a
course is the only basis of what is needed in getting a new product approved. In fact, a
successful product submission and approval requires an experience of doing trial and error
and constant training and retraining to become capable of expressing enough understanding.
Each regulatory aspect must be seriously applied in overall product development. All clinical
research must reflect the primary goal of human safety and investigator and sponsor integrity.
The sponsors must assure the quality of all the data within the submissions.
DRUG APPROVAL PROCESSES
For the approval of drug products, each country and/or region such as the European Union
(EU), Japan, and the United States of America (USA) has similar but slightly different
regulatory processes and requirements for the conduct of clinical trials and the submission,
review, and approval of clinical results. This section, for illustration purposes, will focus on
the regulatory process and requirements adopted in the USA. For evaluation and approval of
drugs, sponsors are required to submit to the U.S. FDA substantial evidence of effectiveness
and safety accumulated from adequate and well-controlled clinical trials. The current
regulations for conducting clinical trials and the submission, review, and approval of clinical
results for pharmaceutical compounds in the USA can be found in the Code of Federal
Regulations (CFR).
A treatment consisting of a combination of drugs, biological products, and/or medical devices
is usually referred to as combined therapy. A combined product consists of a combination of
drugs, biologics, and/or devices, such as a drug with a device, a biologic with a device, a drug
with a biologic, or a drug with a biologic in conjunction with a device According to U.S.
FDA a combined product consisting of different pharmaceutical entities requires that each of
the entities is reviewed separately by appropriate centers at the US FDA. In order to avoid
confusion of jurisdiction over a combination product and to improve the efficiency of the
approval process, the principle of the primary mode of action of a combination product was
established in the Safe Medical Devices Act (SMDA) in 1990 (21 U.S.C. 353). In 1992,
based on this principle, three inter-center agreements were signed between the Center for
Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research
(CBER) and Center for Devices and Radiological Health (CDRH) and between CBER and
CDRH to establish the ground rules for assignment of a combined product and inter-center
consultation. Although, different regulations exist for different products the courage and
principles for the conduct, submission, review, and approval of clinical trials are the same.
As mentioned before regulatory requirements for approval of new drug varies from countries
to countries. For MAA every country has its own regulatory authority. Thus, submitting
MAA to agencies of a different country is almost a difficult task for any manufacturer as it is
necessary to know the regulatory requirement for MAA of each country. It is well known that
the USA and the EU are the most potential markets for drug products in the world; thus,
many manufacturers focus on USA and EU pharmaceutical legislation. The basic regulation
process for a new drug or device is demonstrated in Fig. 2.1 The NDA is an application that
is submitted to the respective regulatory authority of the country for permission to market a
new drug in that country.

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Investigational New Drug Application (INDA)

INDA in USA:
Once the lead molecule (investigational drug) is identified for a target disease, it is optimized
for its therapeutic effectiveness, Sponsor companies, research institutions, and other
organizations that take responsibility for marketing a drug must show U.S. FDA the results of
pre-clinical testing they've done in laboratory animals and what they propose to do for human
testing. At this stage, the U.S. FDA decides whether it is reasonably safe to move forward
with testing the drug on humans. But before a drug can be studied in humans, its sponsor
must submit an IND application (INDA) to the U.S. FDA. The U.S. FDA first comes into the
picture when a drug sponsor submits an IND. When submitting original IND applications,
sponsors are expected to send their applications in triplicate (one original and two copies).
Electronic submissions should be considered whenever possible. Each application should be
accompanied by Form 1571 (INDA cover), Form 1572 (Investigator's statement), and Form
3674 (certification requirement and mandatory registration and reporting of results for
applicable clinical trials through ClinicalTrials.gov). While IND application sponsors are not
required to submit information regarding clinical investigators financial interests or
arrangements in the original IND applications. They are expected to collect this information
before a clinical investigator participates in a clinical study. Upon receipt of an IND
application, U.S. FDA notifies the sponsor of the date it receives the application through an
IND acknowledgment letter. An IND application may go into effect 30 days after U.S. FDA
receives the application unless U.S. FDA notifies the sponsor that the investigations
described in the application are subject to a Clinical Hold; or on earlier notification by U.S.
FDA that the clinical investigations in the IND may begin.
Once an IND application is in effect, a drug manufacturer may ship the IND to the
investigator(s) named in the application. An investigator may not administer an IND to
human subjects until the IND application goes into effect. In addition to knowing the
requirements for safety and other reporting, investigators submitting IND applications should
be familiar with procedures pertaining to the exemptions from IND application submission
requirements, interactions with U.S. FDA, procedures related to Clinical Hold, and
responsibilities of investigators. Unless otherwise notified, the sponsor may begin to
investigate the IND 30 days after the U.S. FDA has received the IND application. The IND
requirements are applicable throughout the period during which an IND is under study.
As mentioned in Section 312.1 and 312.3 of 21 CFR, an IND is synonymous with the notice
of claimed investigational exemption for a new drug. Therefore, an IND is an exemption to
the law that prevents the shipment of a new drug for interstate commerce. As a result, the
sponsorer's who file an IND have the flexibility of conducting clinical investigations of IND
across the USA. There are two types of INDS namely; commercial IND and noncommercial
IND. A commercial IND permits the sponsor to gather the data on clinical safety and

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effectiveness needed for an NDA. If the drug is approved by the U.S. FDA the sponsor is
allowed to market the drug for specific uses. On the other hand, a noncommercial IND allows
the sponsor to use the drug in research or early clinical investigation to obtain advanced
scientific knowledge of the drug. It is important to note that the U.S. FDA itself does not
investigate new drugs or conduct any clinical trials. Pharmaceutical manufacturers,
physicians, and other research organizations such as the NIH, etc. may sponsor INDs. If a
commercial IND proves successful, the sponsor normally submits an NDA. During this
period, the sponsor and the U.S. FDA usually negotiate over the adequacy of the clinical data
and the phrasing proposed for the label accompanying the drug which includes description,
clinical pharmacology, indications and usage, contraindications, warnings, precautions,
adverse reactions, and dosage and administration.
By the time an IND is filed, the sponsor should have enough information about the CMC of
the drug substance and drug product to assure the identity, strength, quality, and purity of the
investigational drug covered by the IND. In addition, the sponsor should provide adequate
information about pharmacological studies for absorption, distribution, metabolism, and
excretion and acute, sub-acute, and chronic toxicological studies and reproductive tests in
various animal species to support that the investigational drug is reasonably safe to be
evaluated in clinical trials of various durations in humans. The focus of the IND submission
is on the general investigational plan and protocols for specific human studies. Therefore, a
copy of the protocol which includes study objectives, details of investigators, criteria for
inclusion and exclusion, study design, dosing schedule, endpoint measurements, and clinical
procedure should be submitted along with the investigational plan and other information such
as CMC, pharmacology and toxicology, previous human experiences with the investigational
drug, and any additional and relevant information related to the investigational drug. The US.
FDA requires that all sponsors submit an original and two copies of all submissions to the
IND file, including the original submission and all amendments and reports.
During the clinical investigation of the drug under an IND, it may be necessary and ethical to
make the drug available to those patients who are not enrolled in clinical trials Since 1987,
the U.S. FDA permits an investigational drug to be used for treatment under a "Treatment
Protocol" or "Treatment IND' if the drug is intended for treating a serious or immediately
life-threatening disease, especially when there is no comparable or satisfactory alternative
drug or other therapy available to treat that stage of the disease in the intended patient
population. The US, FDA, however, may deny a request for treatment use of an
investigational drug under a treatment protocol or treatment IND if the sponsor fails to show
that the drug may be effective for its intended use in its intended patient population or the
drug may expose the patients to an unreasonable and significant additional risk of illness or
injury. Vaccines under investigation for Covid-19 treatment is the recent classical example of
Treatment IND.
At any time, a sponsor may withdraw an effective IND without any discrimination. If an IND
is withdrawn, U.S. FDA shall be notified and all clinical investigations conducted under the
IND shall be stopped. If an IND is withdrawn against a safety reason, the sponsor shall
promptly inform the U.S. FDA, all investigators, and all reviewing the Investigational
Review Board (IRB) with the reasons for the withdrawal. If there are any deficiencies in an
IND or the conduct of an investigation under an IND, the U.S. FDA may reject the IND. If an
IND is rejected, the sponsor shall end all clinical investigations conducted under the IND and

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recall or dispose of all unused supplies of the investigational drug. The U.S. FDA may
propose rejecting the IND if it finds that human subjects would be exposed to an
unreasonable and significant risk of illness or injury. Under these circumstances, the U.S.
FDA notifies the sponsor in writing and invites correction or explanation within a period of
30 days. A rejected IND is subject to restoration based on additional submissions that
eliminate deficiencies such as risks. In such a case, a regulatory hearing on the question of
whether the IND should be restored is held.
(i) Communication with the U.S. FDA: U.S. FDA encourages open communication as a
physical meeting to discuss any scientific or medical questions that may arise during the
clinical investigation. A meeting may be held at the end of clinical trial Phase-I wherein the
results of tolerance/safety studies and adequacy of the remaining development program are
reviewed. In this meeting, the sponsor may request an agency when a drug or biologic
product is being developed for a life-threatening disease and the sponsor wishes to file under
the expedited registration regulations. Similarly, at the end of the Phase-II study and prior to
a MAA another meeting is expected to be arranged. The purpose of this meeting is to review
the safety of a drug proceeding to Phase-III and helps evaluate Phase-III plan and protocols
as well as it also identifies any additional information necessary to support a MAA Also, a
pre-NDA meeting is called, to discover any major unresolved problems and identify those
studies that are needed for the establishment of drug effectiveness. This communication
enables the sponsor to explain U.S. FDA reviewers with the general information to be
submitted in the MAA. This communication more significantly provides the opportunity to
discuss appropriate methods for statistical analysis of the data and the best approach to the
presentation and formatting of the data.
(ii) Clinical trials: After the discovery of a lead drug, pre-clinical trials are conducted.
animals to ensure safety and efficacy. This is followed by the submission of an INDA to the
competent authority of a concerned country to seek permission for conducting human clinical
studies. Drug studies in humans can begin only after an IND is reviewed by the US FDA and
IRB. IRBS approve the clinical trial protocols, which describe the type of volunteer who may
participate in the clinical trial, the schedule of tests and procedures, the medications and
dosages to be studied, the length of the study, the study's objectives, and other details. IRBS
make sure that the study is acceptable, volunteers have given consent and are fully informed
of their risks, and researchers take appropriate steps to protect volunteers from any harm.
Clinical trials are performed in four Phases to assure safety and efficacy, and then the drug
dose is optimized in humans.
Once clinical trials are conducted successfully sponsor submits MAA, which is then
approved by the competent authority; if the drug satisfies the requirements of safety and
efficacy and proves that its benefits outweigh its risks. In order to obtain this permission, a
sponsor submits preclinical and clinical test data through NDA for analyzing the drug
information and for knowing the description of methodologies and manufacturing procedures
adopted.
Following are the different phases of human clinical trials:
(a) Phase 1: This phase is called ad human pharmacology trial wherein safety and tolerability
of new drug is estimated.

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(b) Phase II: This phase is called an exploratory trial in which the effectiveness and short-
term side effects of a new drug are estimated. (c) Phase III: This phase is called a
confirmatory trial in which the therapeutic benefits of a new drug are confirmed.
(d) Phase IV: This phase is called a post-marketing trial wherein studies are done after drug
approval when the drug is marketed in public for use. 2. INDA in INDIA:
INDA in India as per Rule122-DA (3) of the D&C Act and Rules 1945 means "A chemical
entity or a product having therapeutic indication but which have never been earlier tested on
human beings." Clinical trials for the new drugs as well as INDs are mandatory before their
manufacturing approvals. The clinical data and the requirement of animal toxicology.
reproduction studies, teratogenic studies, perinatal studies, mutagenicity, and carcinogenicity
may be modified or relaxed in case of new drugs marketed in other countries and there is
adequate published evidence of its safety.
(i) Clinical trials: No clinical trial for a new drug, whether for clinical investigation or any
clinical experiment by any institute can be conducted except under, and in accordance with,
the permission, in writing, of the DCGL, the licensing authority. There are two types of
provisions under the Indian drug regulation for conducting clinical trials. First, for new drug
substances discovered in India, clinical trials are required to be carried out in India right from
Phase-I and are called domestic clinical studies. Second, for those drugs which are discovered
in countries other than India, Phase-1 data generated outside India may be submitted and
direct Phase-II trials may be permitted and are termed as global clinical trials. Application to
conduct clinical trials in India is submitted by the sponsors through Form 44 along with the
requisite fee (Rs. 50000) and documents as provided under Schedule Y appended to the D&C
Act 1940. The sponsor is responsible for implementing and maintaining a quality assurance
system to ensure that clinical trial is conducted and data generated and reported in
compliance with the protocol and GCP guidelines issued by CDSCO as well as all applicable
statutory provisions of the D&C Act 1940 and Rules 1945. The other details of clinical trial
documentation to DCGI are as follows:
(a) The status report has to be submitted on clinical trials to the DCGI at prescribed timelines.
(b) A summary report has to be submitted within 3 months, if the studies are discontinued
prematurely for any reason.
(c) The summary report must specify a brief description of the study, the number of patients
exposed, drug dose, duration of exposure, details of adverse drug reactions (ADR) if any, and
reason for discontinuation of the study. (d) Any serious adverse event (SAE) occurring during
the clinical trial must be communicated promptly within 14 days by the sponsor.
The data to be submitted along with the application on Form 44 to conduct clinical trials
consists of 2 hard copies and two soft copies (CD's in PDF format). Following is the brief
summary of components of the application:
1. Application on Form 44.
2. Introduction of the drug.
3. Prescribed fee Rs. 5000 through challan.
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4. Chemical and pharmaceutical information as per Appendix I of Schedule Y.

5. Animal pharmacology as per Appendix IV of Schedule Y.
6. Animal toxicology as per Appendix III of Schedule Y.
7. Human/clinical pharmacology data as per Appendix I of Schedule Y. 8. Regulatory status
in other countries as per Appendix I of Schedule Y.
In the case of a new drug discovered in countries other than India, Phase-I data generated in
other countries are required to be submitted along with the application. DCGI may grant
permission to conduct Phase-II trials and Phase-III trials or may direct to repeat Phase-I trials.
Phase-III trials are to be conducted in India before permission to market the new drug in India
is granted. After receiving the application for the clinical trial, the CDSCO refer it to the new
drug division where it is reviewed by the New Drug Committee (NDC), The NDC after
completing the review submits its report along with the recommendations to the DCGL. If the
report of the committee is favorable, the DCGI approves the application. For international
applicants import license to import the clinical trial samples and permission from Director
General Foreign Trade (DGFT) to export blood samples for analysis is needed. 2.2.2 New
Drug Application (NDA)
NDA in USA:
NDA is the formal step a drug's sponsor takes to request that the USFDA consider approving
a new drug for marketing in the USA. The NDA includes all animal and human clinical trial
data and analyses of the data, as well as information about how the drug behaves in the body
and how it is manufactured. When an NDA is submitted, the U.S. FDA takes 60 days to
decide whether to file it so that it can be reviewed. The U.S. FDA can refuse to file an
application if it is incomplete. The reasons for refusal may be that some required studies may
be missing. In accordance with the Prescription Drug User Fee Act (PDUFA), the FDA's
CDER expects to review and act on at least 90% of NDAs for standard drugs no later than 10
months after the applications were received. The review goal is six months for priority drugs.
(1) Reviewing applications: Though U.S. FDA reviewers are involved with a drug's
development throughout the IND stage, the official review time is the length of time it takes
to review an NDA and issue an action letter, an official statement informing a drug sponsor
of the agency's decision. Once a new drug application is filed, an FDA review team (medical
doctors, chemists, statisticians, microbiologists, pharmacologists, and other experts) evaluates
whether the studies the sponsor submitted show that the drug is safe and effective for its
proposed use. The review team analyzes study results and looks for possible problems with
the application, such as weaknesses of the study design or analyses. Reviewers determine
whether they agree with the sponsor's results and conclusions, or whether they need any
additional information to make a decision. Each reviewer prepares a written evaluation
containing conclusions and recommendations about the application. These evaluations are
then considered by team leaders, division directors, and office directors, depending on the
type of application. Sometimes the U.S. FDA calls on advisory committees made up of
outside experts who help the agency decide on drug applications.

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(ii) Accelerated approval: Traditional approval requires that clinical benefit be shown before
approval can be granted. Accelerated approval is given to some new drugs for serious and
life-threatening illnesses that lack satisfactory treatments. This allows an NDA to be
approved before measures of effectiveness that would usually be required for approval are
available. Instead, less traditional measures called "surrogate endpoints" are used to evaluate
effectiveness. These are laboratory findings or signs that may not be a direct measurement of
how a patient feels, functions, or survives, but are considered likely to predict benefit. For
example, a surrogate endpoint could be the lowering of HIV blood levels for short periods of
time with anti-retroviral drugs. Most drugs to treat HIV have been approved under
accelerated approval provisions, with the company required to continue its studies after the
drug.
Regulatory Approval Process on the market to confirm that its effects on virus levels are
maintained and that it ultimately benefits the patient. Under accelerated approval rules, if
studies don't confirm the initial results, the US. FDA can withdraw the approval. Because
premarket review can't catch all potential problems with a drug, the US. FDA continues to
track approved drugs for adverse events through a post-marketing surveillance program.
(iii) Review decisions: Once NDA is submitted to the regulatory agency, it undergoes a
technical screening to ensure for sufficiency of data and drug information under each section
that justifies the filing of the NDA. Upon review, any of the following three possible actions
are taken by the agency and are communicated to the sponsor through a letter. Approved:
Upon reviewing the NDA, if the U.S. FDA decides that the benefits of a drug outweigh the
risks, the drug sponsor will receive a letter of a grant of approval. The statement in the
approval letter comprises that the drug is approved and can be marketed in the USA. But if
there are problems with an NDA, the FDA may decide that a drug is "approvable" or "not
approvable.
Approvable: In this case, a letter is issued stating that the drug can be approved but minor
deficiencies observed such as labeling changes need to be corrected and possible instructions
for commitment to do post-approval studies. A designation of "approvable" means that the
drug can probably be approved provided that some issues are resolved first. For example, the
sponsor and the U.S. FDA coming to a final agreement on what should go on the drug's label.
It could also involve more difficult issues, such as the adequacy of information on how
people respond to various dosages of the drug.
Not approvable: In this case, a letter is issued that contain a list of deficiencies and asking the
reasons to explain for the same. A designation of "not approvable" describes deficiencies
significant enough that it is not clear that approval can be obtained in the future, at least not
without substantial additional data. Common problems include unexpected safety issues that
crop up or failure to demonstrate a drug's effectiveness. A sponsor may need to conduct
additional studies, perhaps studies of more people, different types of people, or for a longer
period. Manufacturing issues are also among the reasons that approval may be delayed or
denied. Drugs must be manufactured in accordance with GMP, and the U.S. FDA inspects
manufacturing facilities before a drug can be approved. If a facility isn't ready for inspection,
approval can be delayed. Any manufacturing deficiencies found would need to be corrected
before approval. The USFDA in its action letter to the drug sponsor outlines the justification
for its decision. In case of either approvable or not approvable decisions, CDER gives the

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sponsor a chance to meet with agency officials to discuss the deficiencies. At that point, the
sponsor can choose to ask for a hearing or correct any deficiencies and submit new
information.
Supplemental NDA: A supplemental NDA (SNDA) is a document submitted to the US, FDA
on a drug substance or product which is already the subject of an approved NDA.
Supplements may be submitted for a variety of reasons such as labeling changes, a new or
expanded clinical indication, or a new dosage form. For example, for labeling changes, the
sponsor may want to add a new specification or test method or changes in the methods,
facility, or controls to provide increased assurance that the drug will have the characteristics
of identity, strength, quality, and purity that it purports to possess. For drug substance and/or
drug product, the sponsor may want to relax the limits for a specification, establish a new
regulatory analytical method, or delete a specification or regulatory analytical method. Also,
the sponsor may want to extend the expiration date of the drug product based on data
obtained under a new or revised stability testing protocol that has not been approved in the
application or to establish a new procedure for reprocessing a batch of the drug product that
fails to meet specification. In SNDA, the sponsor is required to fully describe the change in
each condition established in an approved application beyond the variation already provided
for in the application.
SUMMARY OF DRUG REVIEW BY USFDA:
The review steps taken by the U.S. FDA are described in brief as follows:
(a) Pre-clinical (animal) testing.
(b) An IND application outlines what the sponsor of a new drug proposes for human testing
in clinical trials.
(c) Phase-I studies (typically involve 20 to 80 people).
(d) Phase-II studies (typically involve a few dozen to about 300 people).
(e) Phase-III studies (typically involve several hundred to about 3,000 people).
(f) The pre-NDA period, just before a NDA is submitted. A common time for the USFDA
and drug sponsors to meet.
(g) Submission of a NDA asking the U.S. FDA to consider a drug for marketing approval.
(h) After an NDA is received, the U.S. FDA has 60 days to decide whether to file it so it can
be reviewed.
(I) If the U.S. FDA files the NDA, an FDA review team is assigned to evaluate the sponsor's
research on the drug's safety and effectiveness.
(J) The U.S. FDA reviews information that goes on a drug's professional labeling, guidance
on how to use the drug. (k) The U.S. FDA inspects the facilities where the drug will be
manufactured as part of the approval process.
(K) U.S. FDA reviewers will approve the drug or find it either "approvable" or "not
approvable.

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Advisory Committees : The U.S. FDA has established advisory committees which consist of
clinical, pharmacological, and statistical experts and one consumer advocate (not employed
by the US FDA) in designated drug classes and sub-specialties. The responsibilities of the
committees are to review data presented in NDAs and to advise the U.S. FDA as to whether
or not substantial evidence of safety and effectiveness exists based on adequate and well-
controlled clinical studies. In addition, the committee may also be asked at times to review
certain INDs, protocols, or important issues relating to marketed drugs and biologics. The
advisory committees not only supplement the U.S. FDA's expertise but also allow an
independent peer review during the regulatory process. The US. FDA usually prepares a set
of questions for the advisory committee to address at the meeting For example, the following
is a list of some typical questions.
(1) Are there two or more adequate and well-controlled trials?
(2) Have the patient populations been well enough characterized?
(3) Has the dose-response relationship been sufficiently characterized?
(4) Does the committee recommend the use of the drug for the indication sought by the
sponsor for the intended patient population?
NDA in India:
The new drug approval in India is a two-phase process. The first phase is for clinical trials
and the second phase for marketing authorization of the drug. New drug according to Rule
122-E of the D & C Rules, 1945, is defined as "A drug which has not been used in the
country to any significant extent under the conditions prescribed, recommended or suggested
in the labeling thereof and has not been recognized safe and effective by the DCGI for the
proposed claims. According to Rule 122-E new drug is defined into the following categories:
1. A drug as defined in the act including bulk drug substance which has not been used in the
country to any significant extent under the conditions prescribed. recommended, or suggested
in the labeling thereof and has not been recognized as effective and safe by the Licensing
Authority for the proposed claim: Provided that the limited use, if any has been with the
permission of the Licensing Authority.
2. A drug already approved by the Licensing Authority for certain claims, which is now
proposed to be marketed with modified or new claims, namely, indications, dosage. dosage
form (including sustained release dosage form), and route of administration.
3. A fixed-dose combination of two or more drugs individually approved earlier for certain
claims, which are now proposed to be combined for the first time in a fixed ratio, or if the
ratio of ingredients in an already marketed combination is proposed to be changed, with
certain claims, viz., indications, dosage, dosage form (including sustain released dosage
form) and route of administration.
4. All vaccines are considered as new drugs, unless notified otherwise by the DCGI.
5. A new drug continues to be considered as a new drug for a period of 4 years from the date
of its first approval or its inclusion in the Indian Pharmacopoeia, whichever is earlier.

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After successful completion of the clinical trials, the applicant seeking for approval to
manufacture a new drug is required to submit application on Form 44 along with the data as
given in Appendix 1 to the Schedule Y of the Rules, 1945, that also need to include the
results of clinical trials carried out in the country, bio-availability/bio-equivalence, regulatory
status in other countries, prescribing information, samples, and testing protocols, etc, to the
DCGI, who approves form 46 or 46A.
The applicant is also required to submit evidence that the drug for the manufacture of which
application is made has already been approved by the DCGI in his name while applying to
manufacture a new drug to the State Licensing Agency (SLA). Thus, the applicant is required
to obtain necessary approval from the DCGI as well as the SLA for manufacturing a new
drug for sale purposes in India. Since November 2010 NDA filing in India has also been
allowed through Common Technical Document (CTD). The approval issued is "Manufacture
for Sale rather than "Marketing Approval. A brief summary of the documents required along
with the application on Form 44 for different categories of NDA is as under:
(A) Permission to manufacture a new drug:
(a) Brief introduction of the new drug.
(b) Chemical and pharmacological information.
(c) Animal pharmacology.
(d) Animal toxicology.
(e) Human clinical pharmacology (Phase-1).
(f) Exploratory clinical trials (Phase-II).
(g) Confirmatory clinical trials (Phase-III).
(h) Bio-availability, dissolution, and stability study data.
(i) Regulatory status in other countries.
(j) Application for a test license.
(k) Marketing information.
(l) Proposed product monograph.
(m) Draft of labels and cartons.
(n) Subsequent approval/permission for the manufacture of already approved new
drug:
(I) Formulations:
(a) Bio-availability/ bio-equivalence protocol.
(b) Name of the investigator/ centre.
(c) Source of raw material and stability study data.
(II) Raw Material (Bulk drug substance):

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 UNIT 2: Regulatory Approval Process | Dr Navya Sree K S

(a) Manufacturing method.

(b) Quality control parameters and/or analytical specification, stability report.
(c) Animal toxicity data.

(III) Approval/ permission for fixed-dose combination:

(a) Therapeutic justification.
(b) Data on pharmacokinetics/pharmacodynamics combination.
(c) Any other data generated by the applicant on the safety and efficacy of the
combination.

(IV) Subsequent approval or approval for new indication-new dosage form:

(a) Number and date of approval already granted
(b) Therapeutic justification for the new claim, for example, modified dosage form.
(c) Data generated on safety, efficacy, and quality parameters.
Abbreviated New Drug Applications (ANDA)
ANDA in USA:
In 1970, the U.S. FDA established the Abbreviated NDA (ANDA) as a mechanism for the
review and approval of generic versions of drug products approved during 1938 and 1962.
For drugs approved after 1962, complete safety and efficacy through clinical trials were made
mandatory for generic applicants. After 1978, the manufacturers were required to cite
published reports of such trials documenting safety and efficacy. In 1984, the US. Drug Price
Competition and Patent Term Restoration (DPC & PTR) Act, popularly known as the
"Hatch- Waxman Act", standardized procedures for recognition of generic drugs. As per this
Act, the U.S. FDA may approve generic drug products if the generic drug companies can
provide evidence that the rates and extents of absorption of their drug products do not show
significant differences from those of the innovator drug products when administered at the
same molar dose of the therapeutic moiety under similar experimental conditions
(21CFR320). The DPC&PTR Act states that the U.S. FDA has authority for all generic drug
approvals through an ANDA submission for bioequivalence review.
An ANDA is usually used for generic drug products in which duplicate products are
previously approved under a full NDA. For an ANDA, reports of nonclinical laboratory
studies and clinical investigations of the drug product are not required. Rather it requires
results of studies pertaining to in vivo bioavailability of the drug. An ANDA submission
should include product information, pharmacokinetic data and analysis, statistical analysis,
analytical methodology and validation, and clinical data. The information may be omitted
when the U.S. FDA has determined that the information already available is adequate to

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establish that a particular dosage form of a drug meets the statutory standards for safety and
effectiveness. The duplicate products are usually referred to as products with the same active
ingredient(s), route of administration, dosage form, strength, or condition of use which may
be made by different manufacturers.
To ensure the validity of bioequivalence assessment, the U.S. FDA's CDER's Division of
Bioequivalence's Office of Generic Drugs (OGD) issued a "Guidance on Statistical
Procedures for Bioequivalence Studies Using a Standard Two Treatment Crossover Design"
in July 1992. The guidance sets forth regulations for valid statistical analysis for
bioequivalence assessment. In addition, any relevant clinical findings, adverse reactions, and
deviations from the protocol also need to be included in the ANDA submission. In 2001
guidance on "In Vivo Bioequivalence Studies Based on Population and Individual
Bioequivalence Approaches" was developed by the U.S. FDA. This guidance is intended to
replace the 1992 guidance for the assessment of bioequivalence for regulatory approval of
new dosage forms of an innovator drug and its generic copies after it is finalized.
Approval process: A generic product applicant is required to demonstrate therapeutic
equivalence to a specified previously approved Reference Listed Drug (RLD) without the
submission of clinical trial studies and other data required in a full NDA. An ANDA contains
data that, when submitted to U.S. FDA's CDER, OGD, provides for the review and ultimate
approval of generic drug products. The application for generic approval is required to be
submitted in CTD format to the U.S. FDA. Under Section 314.94, three copies of an ANDA
are required to be submitted as an archival copy, a review copy, and a field copy. An archival
copy shall include the following information:
(a) Application form
(b) Table of contents
(c) The basis for ANDA submission (giving reference to the reference listed drug)
(d) Conditions of use
(e) Active ingredients
(f) Route of administration
(g) Dosage form and strength
(h) Bioequivalence: Labeling
(i) Chemistry
(j) Manufacturing and Controls
(k) Samples
(l) Other information
(m) Patent certification
(n) Financial certification or disclosure statement, etc.

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Under Section 314.94(a)(12), the applications also include one of the following patent
certification information:
(a) Paragraph-1 certification: Patent information has not been submitted to the U.S. FDA
(b) Paragraph-II certification: Patent has expired.
(c) Paragraph-III certification: Patent will expire on the date of marketing.
(d) Paragraph IV certification: That the patent is invalid, unenforceable, or will not be
infringed by the manufacture, use, or sale of the drug product for which the abbreviated
application is submitted.
Review Decision: Three divisions within USFDA's CDER, OGD, review all ANDAS. On
receipt of the application, a pre-filling assessment of its completeness and its acceptability is
performed by a project manager within the regulatory support branch. If the initial review is
found in order, then the acceptability letter is sent to the applicant. The application is
reviewed at bioequivalence division, chemistry division, microbiology division, and division
of labeling and program support. The applicant is intimated to provide information or data if
any deficiency is found at any review division to address the deficiency. After all components
of the application are found to be acceptable, an approval or tentative letter is issued to the
applicant.
Exclusivity: Exclusivity is a statutory provision and is granted to an NDA applicant if
statutory requirements are met. This was designed to promote a balance between an innovator
and generic drug competitor. During the drug patent life period, a brand name company
enjoys a period of market exclusivity (monopoly), in which the company can set the price of
the drug at a level to earn maximum profits. Upon expiry of the patent, the monopoly of the
patent holder on drug sales licensing is removed. Patent lifetime varies from country to
country and no patent is renewed after it expires. Before GATT, except in the USA, the
patent life was less than 20 years in several countries, including India. After GATT patent life
in most countries including India is made 20 years.
Hatch-Waxman Act 1984 has limited the ability of innovators to have exclusive rights to
certain data that demonstrated the safety and efficacy of the approved drugs which was not
limited in duration before 1984 Act. For an NCE drug, an applicant cannot submit an ANDA
or a paper NDA application for a generic version of the drug to the FDA until 5 years after
the date of approval of the pioneer NDA, or until 4 years if a Paragraph-IV certification was
made. For non-NCE drugs, the US FDA cannot approve an ANDA or a paper NDA
application for a generic version of a non-NCE drug for 3 years after the date of approval of
an innovator's NDA. The terms of exclusivity are as follows:
(a) Orphan drugs: 7 Years
(b) New chemical entity: 5 Years
(c) Pediatric exclusivity: 6 Months additional : 180 Days
(d) Patent challenge

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180-days Exclusivity: The first successful company to submit a Paragraph-IV certification to

the U.S. FDA has the exclusive right to market the generic drug for 180 days This provision
was made to encourage generic companies to invest in the required product testing and to
cover expensive legal challenges to innovator products. The US FDA is precluded from
approving subsequent ANDA before the expiration of the first applicants 180 days
exclusivity period. The 180-days exclusivity period begins at the earlier occurrence of either
of the two instances (i) when the first successful applicant initiates commercial marketing of
its generic drug or (ii) after the decision of a court holding the patent which is the subject of
the certification to be invalid or not infringed.
Reference Listed Drugs: Under the Hatch-Waxman Act 1984 manufacturers seeking
approval to market a generic drug must submit data demonstrating that the drug product is
bioequivalent to the innovator drug product. This drug is referred to as the 'Reference Listed
Drug' (RLD) and is identified by the U.S. FDA as the drug product upon which an applicant
relies in seeking approval of its ANDA. In most countries, the RLD is generally a branded
drug product which is marketed on the basis of a full dossier that includes chemical,
biological, safety, clinical efficacy, labeling, etc. A standard RLD may avoid possible
significant variations among generic drug products and their brand name counterparts. RLD
are listed in Approved Drug Products with Therapeutic Equivalence Evaluations, popularly
known as Orange Book. Some examples of RLD of Nifedipine Tablet ER 90mg are Adalat
CC (Bayer Pharma) and Procardia XL (Pfizer).
ANDA in India:
According to Indian D&C Act, 1940, the term 'drug' under section 3(b) also includes the term
'generic drug' as well. Since no separate definition for 'generic drug' has been given in the
statute similar regulations for both, the branded, as well as generic medicines, are applicable.
The license/approval for the manufacture of drugs (both branded as well as generic) other
than the 'new drugs' is granted by the respective SLA under the D&C Rules 1945. The
applicant has to submit the application for grant of license or approval to manufacture for sale
of the drug product(s) to the concerned SLA, with the required fees, the composition of the
formulation, pharmacopoeial status (if applicable), packing labeling details and test procedure
(in case of non-pharmacopoeial drugs). The SLA, after conducting its inspection (if required)
and satisfying that the requirements of the Rules under the Act have been complied with and
that the conditions of the license and the Rules under the Act have been observed, shall issue
a license. Bio-equivalence studies are not required for approval of generic or branded drugs;
however, such studies are mandatory for approval of a new drug. There is no concept like an
abbreviated application for generic approval In India as the patent regime has just started.
Normally approval of generic or branded drugs does not require inspection of the facilities
and is granted spontaneously. There exists a system of dual approval/licensing in some
critical products like large volume parenterals, vaccines sera, blood, blood components, and
blood products, etc, where the approval/license is approved by the SLA as well as the DCGI.
The section 107-A of the Indian Patents Act 1970s the equivalent of the Bolar Provisions,
which allows a generic manufacturer, to start working on the generic drug development, even
before the expiry of the drug patent. However, the various court rulings in India have
established that there exists no linkage between a "drug approval process" and "patent
certification". The Indian drug laws does not provide any definition for the terms 'generic

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drug', 'innovator or branded drug', and Investigational New Drug Similarly, Indian drug
regulations do not provide for ANDA or SNDA as prevalent in overseas countries.

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