Drug Approval System of the United States of America

Drug Approval System of

the United States of America

December 2015

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Abbreviation

FDA: Food and Drug Administration

CDER: Center for Drug Evaluation and Research

FD&C Act: Federal Food, Drug and Cosmetic Act

IND: Investigational New Drug

NDA: New Drug Application

ANDA: Abbreviated New Drug Application

PDUFA: Prescription Drug User Fee Act

GDUFA: Generic Drug User Fee Amendments

Notice

1. Due to the purpose of this document, most of the information was quoted

directly from the website or related guidelines of each country‘s drug

regulatory agencies and, reviewed by the agencies.

2. This document is limited only to pharmaceutical products, no applicable to

biological and herbal products.

3. When referring to the contents of this document, check the up-to-date

information including related laws and regulations, and revision of

guidelines.

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Table of Contents

I. Drug Regulatory Agency ·································································· 7

1. Food and Drug Administration (FDA) ·················································· 7

1.1 Organization ············································································ 7

1.2 Tasks ···················································································· 8

1.3 Website ················································································ 10

II. Related Laws, Regulations, and Guidances ········································· 11

1. Federal Food, Drug, and Cosmetic Act (FD&C Act) ································ 11

2. 21 CFR ····················································································· 11

2. Guidance documents ····································································· 11

III. Classification of Pharmaceutical Products ········································ 12

1. New drug ··················································································· 12

1.1 Orphan drug ··········································································· 12

2. Generic drug ··············································································· 12

3. Over-the-Counter drug ··································································· 13

IV. Drug Approval System ································································· 14

1. Investigational New Drug (IND) application ········································· 14

1.1 Types of application ································································· 14

1.2 Procedure ·············································································· 14

1.3 Review period ········································································ 15

1.4 Meeting ················································································ 15

1.5 Use of foreign clinical data ························································· 15

1.6 Required dossiers ···································································· 16

1.7 Related guidelines ···································································· 17

2. New Drug Application (NDA)··························································· 18

2.1 NDA procedure ······································································· 18

2.2 NDA505(b)(2) ········································································ 20

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2.3 Review period ········································································ 22



3. Orphan drug designation ································································· 25

3.1 Procedure and review period ······················································· 25


3.3 Data submission or fee exemptions of orphan drug ····························· 27

4. Generic drug application ································································· 28

4.1 Abbreviated New Drug Application (ANDA, 505(j)) procedure ··············28

4.2 Review period ········································································ 30


4.4 Patents and exclusivity ······························································ 32


5. Accelerated approval of new drugs for serious or life-threatening illness ········ 33

5.1 Purpose ················································································ 33

5.2 Types of approaches ································································· 34

V. Others ······················································································· 38

1. Good Manufacturing Practice (GMP) ·················································· 38

1.1 Overview ·············································································· 38

1.2 GMP inspection for application process ·········································· 38

2. Drug Master File (DMF) ································································· 39

2.1 Overview ·············································································· 39

3. Drug labeling ·············································································· 40

3.1 Prescription drugs ···································································· 40

3.2 Over-the-Counter (OTC) drugs ···················································· 42

3.3 Drug labeling-related guidelines ··················································· 43

4. Certificate of a Pharmaceutical Product (CPP) ······································· 44

5. Establishment registration drug listing ················································· 44

5.1 Registration of drug producers and drug listing ································· 44

5.2 Information required in registration and drug listing ···························· 45

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5.3 Registration of foreign establishments ············································ 45

6. Fees ························································································· 45

6.1 Prescription Drug User Fee Act (PDUFA) ······································· 45

6.2 Generic Drug User Fee Amendments (GDUFA) ·································48

VII. References ··············································································· 50

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List of Figures

Figure 1. Organization of Ministry Food and Drug Administration (FDA)

Figure 2. Flow Chart for New Drug Approval Application

Figure 3. Flow Chart for Generic Drug Approval Application

Figure 4. Highlights and Contents Format Sample

Figure 5. Sample of the OTC Drug Product Labeling

List of Appendices

Appendix 1. IND Application Form: FDA Form 1571

Appendix 2. Application Form: FDA Form 356h

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I. Drug Regulatory Agency

1. Food and Drug Administration (FDA)1

FDA is responsible for protecting the public health by assuring the safety, efficacy and

security of human and veterinary drugs, biological products, medical devices, the Nation‘s

food supply, cosmetics, and products that emit radiation.

FDA is also responsible for advancing the public health by helping to speed innovations

that make medicines more effective, safer, and more affordable and by helping the public get

the accurate, science-based information they need to use medicines and foods to maintain and

improve their health. FDA also has responsibility for regulating the manufacturing, marketing

and distribution of tobacco products to protect the public health and to reduce tobacco use by

minors.

Finally, FDA plays a significant role in the Nation‘s counterterrorism capability. FDA

fulfills this responsibility by ensuring the security of the food supply and by fostering

development of medical products to respond to deliberate and naturally emerging public

health threats.

1.1. Organization

The FDA's organization consists of the Office of the Commissioner and four directorates

overseeing the core functions of the agency: Medical Products and Tobacco, Foods and

Veterinary Medicine, Global Regulatory Operations and Policy, and Operations (See Figure 1).

Figure 1. Organization of Ministry Food and Drug Administration (FDA)

2

1 About FDA> What We Do (http://www.fda.gov/aboutfda/whatwedo/default.htm)

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1.2. Tasks3

1) Head offices

- Office of the Commissioner (OC): Leadership of the agency's scientific activities,

communication, legislative liaison, policy and planning, women's and minority

health initiatives, agency operations, and toxicological research.

- Office of Foods and Veterinary Medicine: Leads a functionally unified FDA Foods

Program that addresses food and feed safety, nutrition, and other critical areas to

achieve public health goals.

- Office of Global Regulatory Operations and Policy: Provides leadership for FDA's

domestic and international product quality and safety efforts.

- Office of Medical Products and Tobacco: Provides advice and counsel to the

Commissioner on all medical product and tobacco-related programs and issues.

- Office of Operations: Provides agency-wide services including information

technology, financial management, procurement, library services, freedom of

information, FDA history, and facilities

2) Centers under Office of Medical Products and Tobacco

- Center for Drug Evaluation and Research (CDER): CDER performs an essential

public health task by making sure that safe and effective drugs are available to

improve the health of people in the United States. CDER regulates over-the-counter

and prescriptions drugs, including biological therapeutics and generic drugs.

- Center for Biologics Evaluation and Research (CBER): CBER regulates biological

products for human use under applicable federal laws, including the Public Health

Service Act and the Federal Food, Drug and Cosmetic Act (FD&C Act). CBER

protects and advances the public health by ensuring that biological products are safe

and effective and available to those who need them. CBER also provides the public

with information to promote the safe and appropriate use of biological products.

- Center for Devices and Radiological Health (CDRH): CDRH facilitates medical

device innovation by advancing regulatory science, providing industry with

predictable, consistent, transparent, and efficient regulatory pathways, and assuring

consumer confidence in devices marketed in the U.S.

- Center for Tobacco Product (CTP): CTP oversees the implementation of the Family

Smoking Prevention and Tobacco Control Act. Some of the Agency‘s

responsibilities under the law include setting performance standards, reviewing

premarket applications for new and modified risk tobacco products, requiring new

warning labels, and establishing and enforcing advertising and promotion

restrictions.

3) Offices under CDER

CDER consists of the following offices responsible for drug regulation:

- Office of the Center Director

2 About FDA> FDA Organization> Organization Charts > FDA Organization Overview (www.fda.gov/

AboutFDA/CentersOffices/OrganizationCharts/ucm393155.htm) 3 About FDA> FDA Organization (www.fda.gov/AboutFDA/CentersOffices/default.htm)

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- Office of Communications (OCOMM): OCOMM provides human drug information

with the following functions: 1) provide strategic communication advice to center

and agency leadership, 2) maintain a broad understanding of the information needs

of all CDER stakeholders, 3) develop and coordinate overarching public

communication initiatives and educational activities, 4) employ comprehensive

communication approaches to ensure consistent branding, messaging, and strategic

direction of CDER‘s communication products, 5) collaborate with internal and

external partners and stakeholders, and 6) provide expertise on multimedia

communication tools to inform and educate.

- Office of Compliance (OC): OC promotes and protects public health through

strategies and actions that minimize consumer exposure to unsafe, ineffective, and

poor quality drugs.

- Office of Generic Drugs (OGD): OGD is responsible for providing regulatory

oversight to expedite the availability of safe, effective, and high-quality generic

drugs to patients. OGD also provide guidance to regulated industry on a wide variety

of clinical, scientific, and regulatory matters relating to generic drugs.

- Office of Management (OM): OM delivers highly effective, responsive and timely

management resources and services for the FDA‘s Center for Drug Evaluation and

Research

- Office of Medical Policy (OMP): OMP develops medical policy by 1) providing

Center oversight and leadership in the development of medical policy, procedures,

and policy initiatives pertaining to drug development, drug approval, bioresearch

monitoring, human subject protection, post market surveillance processes, and the

science and efficiency of clinical trials, 2) providing scientific and regulatory

leadership in ensuring accurate and effective communication of medical information

to healthcare professionals and patients in compliance with applicable regulations, 3)

fostering an interdisciplinary approach to medical policy development,

implementation, and coordination through collaboration with other disciplines,

program areas, FDA Centers, and stakeholders in a manner that enhances integration

of evolving science and policy into drug development, regulatory review, and post

market surveillance processes, and 4) providing guidance and policy development

regarding prescription drug promotion and reviewing prescription drug advertising

and promotional labeling to ensure that the information contained in these materials

is not false or misleading.

- Office of New Drugs (OND): OND is responsible for providing regulatory oversight

for investigational studies during drug development and making decisions regarding

marketing approval for new (innovator or non-generic) drugs, including decisions

related to changes to already marketed products. It also provides guidance to

regulated industry on a wide variety of clinical, scientific, and regulatory matters.

- Office of Pharmaceutical Quality (OPQ): OPQ is a new office within CDER that

creates a single unit dedicated to product quality. OPQ creates a uniform drug

quality program across all sites of manufacture, whether domestic or foreign, and

across all drug product areas - new drugs, generic drugs, and over-the-counter drugs.

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- Office of Regulatory Policy (ORP): ORP develops policies and procedures related to

the regulation of human drugs under FD&C Act and disclosure information under

the Freedom of Information Act.

- Office of Strategic Programs (OSP): OSP advises and assists the Director, CDER

and other key agency officials on the performance of CDER planning, analysis, and

business informatics activities.

- Office of Surveillance and Epidemiology (OSE): OSE conducts postmarketing

surveillance and risk assessment programs to identify adverse event that did not

appear during the drug development process. Its activities includes updating drug

labeling, providing more information to the community, implementing or revising a

risk management program, and reevaluating approval or marketing decisions.

- Office of Translational Sciences (OTS): OTS promotes efficient and informative

study designs and data analysis methods to quantitatively evaluate the efficacy,

safety, and dosing of drugs through collaboration among the Office of Biostatistics,

Office of Clinical Pharmacology, and other offices in CDER and Centers in FDA.

1.3. Website

www.fda.gov

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II. Related Laws, Regulations, and Guidances

1. Federal Food, Drug and Cosmetic Act4

The Federal Food, Drug and Cosmetic Act (FD&C Act) is basis of drug approval in the

United States. It was passed in 1938, covering the public health system including authorizing

the FDA to mandate evidence of safety for new drugs, issue standards for food, and conduct

factory inspections.

The FD&C Act consists of 10 chapters.

(1) Chapters I and II: Short Title and Definitions

(2) Chapter III: Prohibited Acts and Penalties

(3) Chapter IV: Food

(4) Chapter V: Drugs and Devices

(5) Chapter VI: Cosmetics

(6) Chapter VII: General Authority

(7) Chapter VIII: Imports and Exports

(8) Chapter IX: Tobacco Products

(9) Chapter X: Miscellaneous

2. 21 CFR5

The Code of Federal Regulations (CFR) is a codification of the general and permanent

rules published in the Federal Register by the Executive departments and agencies of the

Federal Government. ―Title 21 – Food and Drug‖ of the CFR is reserved for rules of the Food

and Drug Administration. Each title (or volume) of the CFR is revised once each calendar

year.

3. Guidance documents

Guidance documents represent FDA's current thinking on a topic. They do not create or

confer any rights for or on any person and do not operate to bind FDA or the public. You can

use an alternative approach if the approach satisfies the requirements of the applicable

statutes and regulations. Useful guidances are available in the FDA website at:

(http://www.fda.gov/RegulatoryInformation/Guidances/default.htm).

4 Regulatory Information > Legislation (http://www.fda.gov/RegulatoryInformation/Legislation/default.htm)

5 Medical Devices > Device Advice: Comprehensive Regulatory Assistance > Medical Device Databases

(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Databases/ucm135680.htm)

http://www.fda.gov/RegulatoryInformation/Guidances/default.htm

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III. Classification of Pharmaceutical Products

According to the FD&C Act (21 U.S. Code Chapter 9) Sec 321, the term ―drug‖ means

―(A) articles recognized in the official United States Pharmacopoeia, official Homoeopathic

Pharmacopoeia of the United States, or official National Formulary, or any supplement to any

of them; and (B) articles intended for use in the diagnosis, cure, mitigation, treatment, or

prevention of disease in man or other animals; and (C) articles (other than food) intended to

affect the structure or any function of the body of man or other animals; and (D) articles

intended for use as a component of any article specified in clause (A), (B), or (C).‖

1. New drug

According to the FD&C Act (21 U.S. Code Chapter 9) Sec 321, the term ―new drug‖

means:

1) ―Any drug (except a new animal drug or an animal feed bearing or containing a new

animal drug) the composition of which is such that such drug is not generally

recognized, among experts qualified by scientific training and experience to evaluate

the safety and effectiveness of drugs, as safe and effective for use under the condition

prescribed, recommended, or suggested in the labeling thereof;‖ or

2) ―Any drug (except a new animal drug or an animal feed bearing or containing a new

animal drug) the composition of which is such that such drug, as a result of

investigations to determine its safety and effectiveness for use under such conditions,

has become so recognized, but which has not, otherwise than in such investigations,

been used to a material extent or for a material time under such conditions.‖

1.1 Orphan drug67

Orphan drug means ―a drug intended for use in a rare disease or condition‖ as defined in

section 526 of the FD&C Act.

According to the Orphan Drug Act, ―rare disease or condition‖ means ―any disease or

condition which (A) affects less than 200,000 persons in the United States, or (B) affects

more than 200,000 in the United States and for which there is no reasonable expectation that

the cost of developing and making available in the United States a drug for such disease or

condition will recovered from sales in the United States of such drug.‖

2. Generic drug

―Generic drug‖ is bioequivalent to a brand name drug in dosage form, safety, strength,

route of administration, quality, performance characteristics and intended use. Although

generic drugs are chemically identical to their branded counterparts, they are typically sold at

substantial discounts from the branded price.8

6 FD&C Act (21CFR 360bb), Designation of drugs for rare diseases or conditions

7 FD&C Act (21CFR 316 subpart C, 316.20-316.30) Designation of an orphan drugs

8 Resources for You > Information for Consumers (Drugs) > Questions & Answers (http://www.fda.gov/Drugs/

ResourcesForYou/Consumers/QuestionsAnswers/ucm100100.htm)

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3. Over-the-Counter drug9

Over-the-counter (OTC) drugs are defined as drugs that are safe and effective for use by

the general public without a prescription. OTC drug products are those drugs that are

available to consumers without a prescription. More than 100,000 OTC drug products are

marketed, encompassing about 800 significant active ingredients. There are more than 80

classes (therapeutic categories) of OTC drugs, ranging from acne drug products to weight

control drug products. As with prescription drugs, the Center of Drug Evaluation and

Research (CDER) oversees OTC drugs to ensure that they are properly labeled and that their

benefits outweigh their risks.

9 Drugs > Development & Approval Process (Drugs) > How Drugs are Developed and Approved > Types of

Applications > Drug Applications for Over-the-Counter Drugs

(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/ucm052786.htm)

http://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/ucm052786.htm

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IV. Drug Approval System

1. Investigational New Drug application

1.1 Types of application10

There are two Investigational New Drug (IND) categories - commercial and research (non-

commercial), and three types of IND:

- Investigator IND: This application is submitted by a physician who both initiates and

conducts an investigation, and under whose immediate direction the investigational

drug is administered or dispensed. A physician might submit a research IND to propose

studying an unapproved drug, or an approved product for a new indication or in a new

patient population.

- Emergency Use IND: This application allows the FDA to authorize use of an

experimental drug in an emergency situation that does not allow time for submission of

an IND in accordance with 21CFR, Sec. 312.23 or Sec. 312.34. It is also used for

patients who do not meet the criteria of an existing study protocol, or if an approved

study protocol does not exist.

- Treatment IND11

: This application is submitted for experimental drugs showing

promise in clinical testing for serious or immediately life-threatening conditions while

the final clinical work is conducted and the FDA review takes place. In the case of a

serious disease, a drug ordinarily may be made available for treatment use under this

section during Phase 3 investigations or after all clinical trials have been completed.

Meanwhile, in the case of an immediately life-threatening disease, a drug may be made

available for treatment use under this section earlier than Phase 3, but ordinarily not

earlier than Phase 2.

1.2 Procedure12

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 (FDA Study Data Standards Resources).

Each application should be accompanied by:

1) Form 1571 (IND application cover),

2) Form 1572 (Investigator‘s statement), and

3) Form 3674 (Certification requirement & mandatory registration and reporting of results

for applicable clinical trials through ClinicalTrials.gov)

10

FDA Website >Drugs > Development & Approval Process (Drugs) > How Drugs are Developed and

Approved > Types of Applications > Investigational New Drug (IND) Application

(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/howDrugsareDevelopedandApproved/ApprovalAppli

cations/InvestigationalNewDrugINDApplication/default.htm) 11

FD&C Act (21CFR 312.34) Treatment use of an investigational new drug 12

IND Application Procedures: Overview

( http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApp

lications/InvestigationalNewDrugINDApplication/ucm351746.htm)

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The current address for sending IND applications may be found at the FDA website under

Investigator-Initiated Investigational New Drug (IND) Applications.13

When IND

application is received, FDA will notify the sponsor of the date it receives the application

through an IND acknowledgment letter.

The IND application may go into effect 30 days after FDA receives the application, unless

FDA notifies the sponsor that the investigations described in the application are subject to a

Clinical Hold; or on earlier notification by FDA that the clinical investigations in the IND

may begin.

1.3 Review period14

Once the IND is submitted, the sponsor must wait 30 calendar days before initiating any

clinical trials. During this time, FDA has an opportunity to review the IND for safety to

assure that research subjects will not be subjected to unreasonable risk. The sponsor shall not

begin a clinical investigation subject to 312.2(a) until the investigation is subject to an IND

which is in effect.

1.4 Meeting15

During clinical trial, a sponsor could request meetings with FDA. For more information,

refer to 21CFR 312.47 and Formal meetings between the FDA and Sponsors or Applicants16

.

1.5 Use of foreign clinical data1718

FDA will accept as support for an IND or application for marketing approval (an

application under section 505 of the FD&C Act or section 351 of the Public Health Service

Act) a well-designed and well-conducted foreign clinical study not conducted under an IND,

if the following conditions are met:

(1) The study was conducted in accordance with Good Clinical Practice (GCP).

(2) FDA is able to validate the data from the study through an onsite inspection if the

agency deems it necessary.

A sponsor or applicant who submits data from a foreign clinical study not conducted under

an IND as support for an IND or application for marketing approval must submit to FDA, a

description of the actions the sponsor or applicant took to ensure that the research conformed

to GCP. The description is not required to duplicate information already submitted in the IND

or application for marketing approval. Instead, the description must provide either the

following information or a cross-reference to another section of the submission where the

information is located:

13 Drugs > Development & Approval Process (Drugs) > How Drugs are Developed and Approved > Types of

Applications > Investigational New Drug (IND) Application

(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalAppl

ications/InvestigationalNewDrugINDApplication/ucm343349.htm) 14

FD&C Act (21CFR 312.20) Requirement for an IND 15

FD&C Act (21CFR 312.47) Meetings 16

http://www.fda.gov/downloads/drugsguidancecomplianceregulatoryinformation/guidances/ucm153222.pdf 17

FD&C Act (21CFR312.120 ) Foreign clinical studies not conducted under an IND 18

FD&C Act (21CFR314.106) Foreign data

http://www.fda.gov/downloads/drugsguidancecomplianceregulatoryinformation/guidances/ucm153222.pdf

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(1) The investigator's qualifications;

(2) A description of the research facilities;

(3) A detailed summary of the protocol and results of the study and, should FDA request,

case records maintained by the investigator or additional background data such as

hospital or other institutional records;

(4) A description of the drug substance and drug product used in the study, including a

description of the components, formulation, specifications, and, if available,

bioavailability of the specific drug product used in the clinical study;

(5) If the study is intended to support the effectiveness of a drug product, information

showing that the study is adequate and well controlled under §314.126;

(6) The name and address of the Independent Ethics Committee (IEC) that reviewed the

study and a statement that the IEC meets the definition in §312.3. The sponsor or

applicant must maintain records supporting such statement, including records of the

names and qualifications of IEC members, and make these records available for

agency review upon request;

(7) A summary of the IEC's decision to approve or modify and approve the study, or to

provide a favorable opinion;

(8) A description of how informed consent was obtained;

(9) A description of what incentives, if any, were provided to subjects to participate in the

study;

(10) A description of how the sponsor(s) monitored the study and ensured that the study

was carried out consistently with the study protocol; and

(11) A description of how investigators were trained to comply with GCP and to conduct

the study in accordance with the study protocol, and a statement on whether written

commitments by investigators to comply with GCP and the protocol were obtained.

1.6 Required Dossiers19

Form FDA 1571: IND Application form (Appendix 1)

Form FDA 1572: Statement of Investigator20

.

Copies of Form FDA 1572 with its attachments may be sent by the Sponsor-

Investigator to FDA to satisfy Form FDA 1571, box 12, item 6 b-d. Information can

be supplied in the form of attachments (such as curriculum vitae) rather than entering

that information directly onto the form, but this should be so noted under the relevant

section numbers.

Form FDA 3674: Certification of Compliance

The Food and Drug Administration Amendments Act of 2007 (FDAAA) (Public Law

110-85) was enacted on September 27, 2007. Title VIII of FDAAA added new

Section 402(j) to the Public Health Service Act (42 USC § 282(j)) and expanded the

current database known as ClinicalTrials.gov to include mandatory registration and

reporting of results for applicable clinical trials of human drugs (including biological

products) and devices.

19

FDA website > Drugs > Development & Approval Process (Drugs) > Forms & Submission Requirements

(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/default.htm) 20

Form FDA 1572 is not a requirement per 21 CFR 312.23, but the information it contains must be submitted.

- 17 -

Form FDA 3454: Certification - Financial Interests and Arrangements of Clinical

Investigators

Form FDA 3455: Disclosure - Financial Interest and Arrangements of Clinical Investigators

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. For further information, refer to Guidance for Clinical Investigators, Industry, and

FDA Staff: Financial Disclosure by Clinical Investigators.21

1.7 Related guidelines22

Safety Reporting Requirements for INDs and BE/BA Studies (9/28/2010)

Enforcement of Safety Reporting Requirements for INDs and BA/BE Studies (6/6/2011)

CGMP for Phase 1 Investigational Drugs (7/2008)

Exploratory IND Studies (1/12/2006)

Content and Format of Investigational New Drug Applications (INDs) for Phase 1

Studies of Drugs, Including Well Characterized, Therapeutic, Biotechnology-Derived

Products. (Issued 11/1995)

Bioavailability and Bioequivalence Studies for Orally Administered Drug Products -

General Considerations (Issued 10/2000)

Guideline for Drug Master Files

Immunotoxicology Evaluation of Investigational New Drugs (Issued 10/2002).

Guidance for Industry Formal Meetings Between the FDA and Sponsors or Applicants:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui

dances/UCM079744.pdf

Investigational New Drug Applications (INDs) - Determining Whether Human

Research Studies Can Be Conducted Without an IND:

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Gui

dances/UCM229175.pdf

21

http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-afda-gen/documents/document/ucm341008.pdf 22

FDA website > Drugs > Development & Approval Process (Drugs) > How Drugs are Developed and

Approved > Types of Applications > Investigational New Drug (http://www.fda.gov/Drugs/Development

ApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/InvestigationalNewDrugINDAp

plication/default.htm#FDA Guidances for Investigational New Drugs)

http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-afda-gen/documents/document/ucm341008.pdf

http://www.fda.gov/ucm/groups/fdagov-public/@fdagov-afda-gen/documents/document/ucm341008.pdf

http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079744.pdf




- 18 -

2. New Drug Application approval

2.1 NDA procedure

2.1.1 Flow chart for NDA

Figure 2. Flow Chart for New Drug Application

- 19 -

2.1.2 Procedure

New Drug Application (NDA) - This is the formal step a drug sponsor takes to ask that the

FDA consider approving a new drug for marketing in the United States. An NDA includes all

animal and human data and analyses of the data, as well as information about how the drug

behaves in the body and how it is manufactured.23

NDA processes follow steps as below:

(1) Pre-NDA Meeting24

(2) NDA submission and Review

When an NDA comes in, the FDA has 60 days to decide whether to file it so that it can be

reviewed. The FDA can refuse to file an application that is incomplete.

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. No

drug is absolutely safe; all drugs have side effects. ―Safe‖ in this sense means that the

benefits of the drug appear to outweigh the known risks.

The review team analyzes study results and looks for possible issues 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.

(3) Reviews for drug labeling25

,26

Also the drug labeling is reviewed by the FDA whether the label contains the following

information:

Adequate information for such use, including indications, effects, dosages, routes,

methods, and frequency and duration of administration and any relevant warnings,

hazards, contraindications, side effects, and precautions, under which practitioners

licensed by law to administer the drug can use the drug safely and for the purposes

for which it is intended, including all conditions for which it is advertised or

represented; and

The same information concerning the ingredients of the drug as appears on the label

and labeling on or within the package from which the drug is to be dispensed.

23

FDA website > Drugs > Resources for You > Information for Consumers (Drugs) > The FDA's Drug review

process: Ensuring Drugs are safe and effective)

http://www.fda.gov/drugs/resourcesforyou/consumers/ucm143534.htm 24

FD&C Act (21CFR312.47(2)) pre-NDA and pre-BLAS meetings 25

FD&C Act (21CFR201.56) General requirements on content and format of labeling for human prescription

drugs and biological products 26

FD&C Act (21CFR201.100) Prescription drugs for human use

- 20 -

(4) FDA inspection

Inspection on the facility, etc. will be conducted by FDA. For further information, refer to

Good Manufacturing Practice (GMP) under Section V. Others of this document.

(5) Drug Approval

2.2 NDA505(b)(2)2728

2.2.1 Definition

A 505(b)(2) application is one for which one or more of the investigations relied upon by

the applicant for approval ―were not conducted by or for the applicant and for which the

applicant has not obtained a right of reference or use from the person by or for whom the

investigations were conducted.‖

2.2.2 Subjects to 505(b)(2) application

The following types of drugs or drug application is subjected to 505(b)(2) application:

New chemical entity (NCE)/new molecular entity (NME):

A 505(b)(2) application may be submitted for an NCE when some part of the data

necessary for approval is derived from studies not conducted by or for the applicant and

to which the applicant has not obtained a right of reference. For an NCE, this data is

likely to be derived from published studies, rather than FDA's previous finding of

safety and effectiveness of a drug. If the applicant had a right of reference to all of the

information necessary for approval, even if the applicant had not conducted the studies,

the application would be a considered a 505(b)(1) application.

Changes to previously approved drugs:

For changes to a previously approved drug product, an application may rely on the

Agency's finding of safety and effectiveness of the previously approved product,

coupled with the information needed to support the change from the approved product.

The additional information could be new studies conducted by the applicant or

published data.

This use of section 505(b)(2) was intended to encourage innovation without creating

duplicate work and reflects the same principle as the 505(j) application*. 505(b)(2)

applications should not be submitted for duplicates of approved products that are

eligible for approval under 505(j)

In the preamble to the implementing regulations for the Hatch-Waxman amendments to

the Act, the Agency noted that an application submitted pursuant to section 505(b)(2)

of the Act is appropriate even when it could also be submitted in accordance with a

suitability petition as defined at section 505(j)(2)(C) of the Act.

*Section 505(j) of the Act (21 U.S.C. 355) is described in Abbreviated New Drug Applications (ANDA)

for approval of a new drug. See the Chapter 3. Generic drug approval application below.

27

FD&C Act (21CFR314.54) Procedure for submission of an application requiring investigations for approval

of a new indication for, or other change from, a listed drug. 28

Guidance for Industry(Draft Guidance), Applications Covered by Section 505(b)(2)

(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm079345.pdf)

- 21 -

2.2.3 Examples of 505(b)(2) applications

Dosage form: An application for a change of dosage form, such as a change from a

solid oral dosage form to a transdermal patch that relies to some extent upon the

Agency's finding of safety and/or effectiveness for an approved drug.

Strength: An application for a change to a lower or higher strength.

Route of administration: An application for a change in the route of administration,

such as a change from an intravenous to intrathecal route

Formulation: An application for a proposed drug product that contains a different

quality or quantity of an excipient(s) than the listed drug where the studies required for

approval are beyond those considered limited confirmatory studies appropriate to a

505(j) application.

Dosing regimen: An application for a new dosing regimen, such as a change from

twice daily to once daily.

Active ingredient: An application for a change in an active ingredient such as a

different salt, ester, complex, chelate, clathrate, racemate, or enantiomer of an active

ingredient in a listed drug containing the same active moiety.

New molecular entity: In some cases a new molecular entity may have been studied

by parties other than the applicant and published information may be pertinent to the

new application. This is particularly likely if the NME is the prodrug of an approved

drug or the active metabolite of an approved drug. In some cases, data on a drug with

similar pharmacologic effects could be considered critical to approval.

Combination product: An application for a new combination product in which the

active ingredients have been previously approved individually.

Indication: An application for a not previously approved indication for a listed drug.

Rx/OTC switch: An application to change a prescription (Rx) indication to an over-

the-counter (OTC) indication.

OTC monograph: An application for a drug product that differs from a product

described in an OTC monograph (21 CFR 330.11), such as a non-monograph indication

or a new dosage form.

Naturally derived or recombinant active ingredient: An application for a drug

product containing an active ingredient(s) derived from animal or botanical sources or

recombinant technology where clinical investigations are necessary to show that the

active ingredient is the same as an active ingredient in a listed drug.

Bioinequivalence: Applications for proposed drug products where the rate and/or

extent of absorption exceed, or are otherwise different from, the 505(j) standards for

bioequivalence compared to a listed drug may be submitted pursuant to section

505(b)(2) of the Act. However, a 505(b)(2) application should not be used as a route of

approval for poorly bioavailable generic drug products unable to meet the 505(j)

standards for bioequivalence. If the proposed product is a duplicate of an already

approved product, it should not be submitted as a 505(b)(2) application.

2.2.4 Procedure

Refer to 2.1 Procedure (NDA) under IV. Drug Approval System of this document.

- 22 -

2.3 Review period

In accordance with the Prescription Drug User Fee Act (PDUFA), the FDA's Center for

Drug Evaluation and Research (CDER) expects to review and act on at least 90 percent of

NDAs for standard drugs no later than 10 months after the applications are received. The

review goal is six months for priority drugs.

The initial review cycle may be adjusted by mutual agreement between FDA and an

applicant as the result of a major amendment.

2.4 Required dossiers

2.4.1 Required Format

NDA can be processed through either paper or electronic submission using electronic

CTD (e-CTD) format. Using e-CTD format is to enhance the receipt, processing, and review

of electronic submissions to the FDA; to facilitate efficient submission handling; and to

harmonize the organization and formatting of electronic submission for multiple submission

type. For detailed information on CTD format, please refer to the Guidance for Industry:

Submitting Marketing Applications According to the ICH-CTD Format - General

Considerations29

.

2.4.2 Documentation

*Application form: FDA Form 356h30

(Appendix 2)

With the application form, the related documentation required in an NDA is supposed to

tell the drug's whole story, including what happened during the clinical tests, what the

ingredients of the drug are, the results of the animal studies, how the drug behaves in the

body, and how it is manufactured, processed and packaged. Also the application must contain

data from specific technical viewpoints for review, including chemistry, pharmacology,

medical, biopharmaceutics, and statistics.

For preparing the related documentation, guidance documents representing the FDA's

current thinking are available at FDA website. These documents are prepared for FDA review

staff and applicants/sponsors to provide guidelines to the processing, content, and

evaluation/approval of applications and also to the design, production, manufacturing, and

testing of regulated products. They also establish policies intended to achieve consistency in

the Agency's regulatory approach and establish inspection and enforcement procedures.

29

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073308.pdf 30

Application to market a new or abbreviated new drug or biologic for human use

(http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM082348.pdf)

http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm073308.pdf



- 23 -

2.4.3 Required documents for 505(b)(2)31

505(b)(2) application should include the following:

Identification of those portions of the application that rely on information the applicant

does not own or to which the applicant does not have a right of reference (for example,

for reproductive toxicity studies).

If the 505(b)(2) seeks to rely on the Agency's previous finding of safety or efficacy for

a listed drug or drugs, identification of any and all listed drugs by established name,

proprietary name (if any), dosage form, strength, route of administration, name of the

listed drug's sponsor, and the application number. Even if the 505(b)(2) application is

based solely upon literature and does not rely expressly on an Agency finding of safety

and effectiveness for a listed drug, the applicant must identify the listed drug(s) on

which the studies were conducted, if there are any. If the 505(b)(2) application is for an

NCE and the 505(b)(2) applicant is not relying on literature derived from studies of an

approved drug, there may not be a listed drug. If there is a listed drug that is the

pharmaceutical equivalent to the drug proposed in the 505(b)(2) application, that drug

should be identified as the listed drug.

Information with respect to any patents that claim the drug or the use of the drug for

which approval is sought (21 CFR 314.50(h)). This patent information will be

published in the Orange Book when the application is approved.

Information required under 314.50(j) if the applicant believes it is entitled to marketing

exclusivity

A patent certification or statement as required under section 505(b)(2) of the Act with

respect to any relevant patents that claim the listed drug and that claim any other drugs

on which the investigations relied on by the applicant for approval of the application

were conducted, or that claim a use for the listed or other drug .

If there is a listed drug that is the pharmaceutical equivalent of the drug proposed in the

505(b)(2) application, the 505(b)(2) applicant should provide patent certifications for

the patents listed for the pharmaceutically equivalent drug. Patent certifications should

specify the exact patent number(s) and the exact name of the listed drug or other drug

even if all relevant patents have expired.

If an application is for approval of a new indication, and not for the indications

approved for the listed drug, a certification so stating.

A statement as to whether the listed drug(s) identified above have received a period of

marketing exclusivity. If a listed drug is protected by exclusivity, filing or approval of

the 505(b)(2) application may be delayed.

A bioavailability/bioequivalence (BA/BE) study comparing the proposed product to the

listed drug (if any).

Studies necessary to support the change or modification from the listed drug or drugs

(if any). Complete studies of safety and effectiveness may not be necessary if

appropriate bridging studies are found to provide an adequate basis for reliance upon

the FDA‘ finding of safety and effectiveness of the listed drug(s).

31

Guidance for Industry(Draft Guidance), Applications Covered by Section

505(b)(2)( http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm0793

45.pdf)

- 24 -

Before submitting the application, the applicant should submit a plan to the appropriate

new drug evaluation division identifying the types of bridging studies that should be

conducted. The applicant should also identify those components of its application for

which it expects to rely on the FDA‘ finding of safety and effectiveness of a previously

approved drug product. The division will critique the plan and provide guidance.

2.5 Related guidelines32


General Considerations (Issued 10/2000).

Changes to an Approved NDA or ANDA (Issued 11/1999)

Container Closure Systems for Packaging Human Drugs and Biologics. (Issued 5/1999)

Format and Content of the Microbiology Section of an Application.

Format and Content of the Clinical and Statistical Sections of an Application. (Issued

7/1988)

Format and Content of the Summary for New Drug and Antibiotic Applications.

(Issued 2/1987)

Formatting, Assembling and Submitting New Drug and Antibiotic Applications.

(Issued 2/1987)

Submitting Supporting Documentation in Drug Applications for the Manufacture of

Drug Substances.

Submitting Samples and Analytical Data for Methods Validation.

Submitting Supporting Documentation in Drug Applications for the Manufacture of

Drug Products.

NDAs: Impurities in Drug Substances (Issued 2/2000)

Format and Content of the Human Pharmacokinetics and Bioavailability Section of an

Application. (Issued 2/1987)

Format and Content of the Nonclinical Pharmacology/Toxicology Section of an

Application.

Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products.

Drug Master Files.

Required Specifications for FDA's IND, NDA, and ANDA Drug Master File Binders

Qualifying for Pediatric Exclusivity.

Refusal to File. (Issued 7/12/1993)

3. Orphan drug designation

3.1 Procedure and review period33

Designated orphan drugs and medical devices will be subject to fast track drug

development program, priority review, and accelerated approval. For more details, refer to ―5.

32

FDA website > Drugs > Development & Approval Process (Drugs) > How Drugs are Developed and

Approved > Types of Applications> New Drug Application (NDA) > Guidance Documents for NDAs

(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalAppl

ications/NewDrugApplicationNDA/default.htm) 33

FDA&C Act (21CFR314.500) Accelerated approval of new drugs for serious or life-threatening illness

- 25 -

Accelerated approval of new drugs for serious or life-threatening illness‖ under Section IV.

Drug Approval System‖ of this document.

3.2 Required dossiers34

For orphan drug designation, a sponsor shall submit two copies of a completed, dated, and

signed request for designation that contains the following:

A statement that the sponsor requests orphan-drug designation for a rare disease or

condition, which shall be identified with specificity.

The name and address of the sponsor; the name of the sponsor's primary contact person

and/or resident agent including title, address, telephone number, and email address; the

generic and trade name, if any, of the drug, or, if neither is available, the chemical name

or a meaningful descriptive name of the drug; and the name and address of the source

of the drug if it is not manufactured by the sponsor.

A description of the rare disease or condition for which the drug is being or will be

investigated, the proposed use of the drug, and the reasons why such therapy is needed.

A description of the drug, to include the identity of the active moiety if it is a drug

composed of small molecules, or of the principal molecular structural features if it is

composed of macromolecules; its physical and chemical properties, if these

characteristics can be determined; and a discussion of the scientific rationale to

establish a medically plausible basis for the use of the drug for the rare disease or

condition, including all relevant data from in vitro laboratory studies, preclinical

efficacy studies conducted in an animal model for the human disease or condition, and

clinical experience with the drug in the rare disease or condition that are available to the

sponsor, whether positive, negative, or inconclusive.

Where the sponsor of a drug that is otherwise the same drug as an already approved

drug seeks orphan-drug designation for the subsequent drug for the same rare disease or

condition, an explanation of why the proposed variation may be clinically superior to

the first drug.

Where a sponsor requests orphan-drug designation for a drug for only a subset of

persons with a particular disease or condition that otherwise affects 200,000 or more

people (―orphan subset‖), a demonstration that, due to one or more properties of the

drug, the remaining persons with such disease or condition would not be appropriate

candidates for use of the drug.

A summary of the regulatory status and marketing history of the drug in the United

States and in foreign countries, e.g., IND and marketing application status and

dispositions, what uses are under investigation and in what countries; for what

indication is the drug approved in foreign countries; what adverse regulatory actions

have been taken against the drug in any country.

Documentation, with appended authoritative references, to demonstrate that:

- The disease or condition for which the drug is intended affects fewer than 200,000

people in the United States or, if the drug is a vaccine, diagnostic drug, or preventive

34

FD&C Act (21CFR316.20) Content and format of a request for orphan-drug designation

- 26 -

drug, the persons to whom the drug will be administered in the United States are

fewer than 200,000 per year or

- For a drug intended for diseases or conditions affecting 200,000 or more people, or

for a vaccine, diagnostic drug, or preventive drug to be administered to 200,000 or

more persons per year in the United States, there is no reasonable expectation that

costs of research and development of the drug for the indication can be recovered by

sales of the drug in the United States.

3.3 Data submission or fee exemptions of orphan drug35363738

A human drug application for a prescription drug product that has been designated as a

drug for a rare disease shall not be subject to (1) a fee for or a human drug application for

which clinical data (other than bioavailability or bioequivalence studies) with respect to

safety or effectiveness are required for approval or (2) for a human drug application for

which clinical data with respect to safety or effectiveness are not required or (3) a supplement

for which clinical data (other than bioavailability or bioequivalence studies) with respect to

safety or effectiveness are required, unless the human drug application includes an indication

for other than a rare disease or condition. A supplement proposing to include a new indication

for a rare disease or condition in a human drug application shall not be subject to the fee, if

the drug has been designated as a drug for a rare disease or condition with regard to the

indication proposed in such supplement.

A drug designated and approved for a rare disease or condition shall be exempt from

product and establishment fees, if the drug meets all of the following conditions:

(A) The drug meets the public health requirements contained in the Public Health Service

Act as such requirements are applied to requests for waivers for product and

establishment fees.

(B) The drug is owned or licensed and is marketed by a company that had less than

$50,000,000 in gross worldwide revenue during the previous year.

The Secretary may make grants to and enter into contracts with public and private entities

and individuals to assist in (1) defraying the costs of qualified testing expenses incurred in

connection with the development of drugs for rare diseases and conditions, (2) defraying the

costs of developing medical devices for rare diseases or conditions, and (3) defraying the

costs of developing medical foods for rare diseases or conditions.

35 FD&C Act (21CFR379h(a)(1)(F)) Exception for designated orphan drug or indication 36

FD&C Act (21CFR379h(k)) Orphan drugs 37

FD&C Act (21CFR360ee). Grants and contracts for development of drugs for rare diseases and conditions 38

FD&C Act(21CFR360cc). Protection for drugs for rare diseases or conditions

- 27 -

4. Generic drug application

4.1. Abbreviated New Drug Application procedure

Figure 3. Flow Chart for Generic Drug Approval Application

4.1.1 Procedure

(1) Application (under section 505(j))

(2) Filing review

Filing review is conducted to determine whether the application is sufficiently

complete to permit a substantive review. Acceptance/Refuse to Receive (RTR) letter

is issued based on completeness of the Abbreviated New Drug Application (ANDA).

The regulatory filing checklist is updated on a quarterly basis (calendar year) and on

an as needed basis.

- 28 -

(3) Review process

Bioequivalence review39

The evaluation of bioequivalence (BE) in the generic drug context is used to support a

determination that a generic product may be substituted for its reference listed drug,

and involves consideration of different types of data permitted in an ANDA.

Bioequivalence study evaluates the following areas:

- Clinical area (treatment)

- Analysis (biological fluid analysis)

- Statistics (bioequivalence)

Several in vivo and in vitro methods can be used to measure BA and establish BE.

These include, in general order of preference, pharmacokinetic (PK) studies, in vitro

tests predictive of human in vivo BA (in vitro-in vivo correlation), pharmacodynamic

(PD) studies, studies with clinical benefit endpoints, and other in vitro studies.

Complete study data also contains the following:

- comparative BA and BE study reports (e.g., fasting studies, fed studies)

- in vitro-in vivo correlation study reports (e.g., comparative dissolution data)

- report of bioanalytical and analytical methods provided in individual study reports.

Appropriate in vitro dissolution method (dosage forms only) is selected for stability

and controls testing. Biowaivers may be granted, where appropriate, and

bioequivalence protocols are reviewed.

Chemistry/Microbiology Review

1) Chemistry

Drug substance and drug product are reviewed for:

Components and composition

Manufacturing and controls

Batch formulation and records

Description of facilities

Product specifications

Packaging

Stability

2) Microbiology

Sterile drug products (parenteral, ophthalmic, and inhalation) are reviewed for:

Product Development (container/closure integrity validation and preservative

effectiveness)

Overall sterile manufacturing process design and process controls

Terminal sterilization/aseptic fill process validation

Drug product specifications

Release and stability

Studies to support labeling

39

Guidance for Industry Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs - General

Considerations (http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm389370.pdf)

- 29 -

3) Labeling Review

Review whether generic drug name on the labeling is ―same‖ as brand name labeling

(with exceptions)

Labeling text that reflects differences in excipients and specific pharmacokinetic

data

Supply information (e.g. packaging container)

Pharmacy practice issues - to prevent medication errors

Labeling protected by patent or exclusivity may be excluded.

(4) Inspection - cGMP/Compliance

All facilities used for manufacturing, testing, packaging/storing drug substance and

drug product are subject for inspections and must be in compliance at the time of

approval. Inspection program is also designed to check data integrity. If data integrity

is in question, all reviews will be suspended. Type of inspection includes: pre-

approval, post-approval, and for cause.

(5) ANDA Approval

According to the review result, ANDA is acceptable and all facilities are reviewed and

inspected to determine whether they meet the requirements. There are two types of

ANDA approval:

Full Approval: all valid patents and exclusivities for the reference listed drug (RLD)

are expired or any legal issues that may block approval of the ANDA are settled.

Tentative Approval – there exist unexpired patents and exclusivities for the RLD.

4.2 Review period

The initial review cycle may be adjusted by mutual agreement between the FDA and an

applicant as the result of a major amendment.

4.3 Required dossiers4041

4.3.1 Documentation

*Application form: FDA Form 356h

Under the Generic Drug User Fee Act (GDUFA), the FDA agreed to meet certain

obligations as laid out in the GDUFA Commitment Letter. One of these obligations is the

FDA‘s commitment to performance metrics for the review of new ANDAs that are submitted

electronically following the electronic CTD (eCTD) format. The ANDA CTD format

excludes module 4 nonclinical data, but includes module 5 Bioequivalence data as a part of

clinical results.

40

Guidance for Industry ANDA Submissions — Content and Format of Abbreviated New Drug Applications

(June 2014) (http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm400630.pdf) 41

Guidance for Industry: Providing Regulatory Submissions in Electronic Format — ANDAs

(http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/Electroni

cSubmissions/UCM163188.pdf)

- 30 -

4.3.2 CTD format for ANDA Submission

The CTD is comprised of the following modules:

• Module 1: Administrative information;

• Module 2: CTD Summaries;

• Module 3: Quality;

• Module 4: Nonclinical study reports; and

• Module 5: Clinical study reports.

(1) Module 1 - Administrative information

Forms and cover letter:

Completed, signed Application Form FDA 356h

Copy of the GDUFA user fee cover sheet (FDA form 3794)

Cover letter

Completed, signed Certificate of Compliance (FDA form 3674)

Administrative Information

U.S. agent letter of appointment, if applicable

Field copy certification

Debarment certification

Patent information and certification:

Applicants are required to list each patent issued by the U.S. Patent and Trademark

Office that claims the drug substance, drug product, or that claims a use of the

RLD that is cited by the ANDA. The FDA recommends that when providing patent

information, applicants include the expiration date for each patent, whether the

RLD is protected by any pediatric exclusivity, and when that pediatric exclusivity

will expire.

References: Contains the statement of right of reference for each and every DMF

referenced in the application. Applicants should submit the letter of authorization

(LOA) provided to the applicant by the DMF holder which gives authorization to rely

on the information in the DMF.

Other correspondence:

Basis for submission: (1) the name of the RLD; (2) the NDA or ANDA number of

the RLD; and (3) the holder of the application for the RLD

Information demonstrating that the generic product is the same as the RLD

Labeling

(2) Module 2 - CTD Summaries

Quality overall summary

Clinical summary - FDA has developed model summary tables to assist applicants in

summarizing these data

(3) Module 3 - Quality

All of the CMC information necessary to support the application

The description and composition of the drug substance and drug product

- 31 -

(4) Module 4 (Nonclinical Study Reports)

ANDAs generally do not contain data that are required for Module 4.

(5) Module 5 (Clinical Study Reports)

All of the clinical study report data needed to support the application and demonstrate that

the generic is bioequivalent to the RLD

4.3.2 Stability test42

Abbreviated new drug applications (ANDAs) submitted under section 505(j) of the

Federal Food, Drug and Cosmetic Act, and the drug master files (DMFs) that support

ANDAs, follow the stability recommendations provided in the International Conference on

Harmonisation (ICH) stability guidances.

When following the ICH stability recommendations, the applicant should:

Submit data from three pilot scale batches or two pilot scale batches and one small

scale batch.

At the time of submission, provide 6 months of data that include accelerated and

long-term conditions

Use multiple lots of drug substance as appropriate.

Manufacture and package the drug product using principles that are representative of

the commercial process.

Provide a fully packaged primary batch.

Use drug product from all three primary batches when using bracketing and

matrixing designs under ICH Q1D.

Provide statistical analysis of the data as appropriate, in accordance with ICH Q1E,

Appendix A.

4.3.3 Bioequivalence study43

FDA‘s final rule on ―Requirements for Submission of Bioequivalence Data‖ (the BE data

rule) requires an ANDA applicant to submit data from all BE studies the applicant conducts

on a drug product formulation submitted for approval, including studies that do not

demonstrate that the generic product meets the current bioequivalence criteria. All BE studies

conducted on the same drug product formulation must be submitted to the Agency as either a

complete study report or a summary report of the BE data

Several in vivo and in vitro studies, including pharmacokinetic (PK) studies and

pharmacodynamic (PD) studies can be used to compare the absorption rate and absorption

extent between generic drugs and reference product.

FDA regulations, as amended by and clarified in the BE data rule, require that a complete

report be submitted for the BE studies upon which the applicant relies for approval and either

a complete or summary report be submitted for each additional study conducted on the same

42

Guidance for Industry ANDAs: Stability Testing of Drug Substances and Products (June 2013)

(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm320590.pdf) 43

Guidance for Industry Bioavailability and Bioequivalence Studies Submitted in NDAs or INDs— General

Considerations (http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm389370.pdf)

- 32 -

drug product formulation. This requirement includes both in vivo and in vitro testing

conducted to demonstrate bioequivalence.

4.4. Patent and exclusivity4445

4.4.1 Patent and exclusivity in 505(b)(2) application46

A 505(b)(2) application may itself be granted 3 years of Hatch-Waxman exclusivity if one

or more of the clinical investigations, other than BA/BE studies, was essential to approval of

the application and was conducted or sponsored by the applicant. The 505(b)(2) application

may also be granted 5 years of exclusivity if it is for a new chemical entity. The application

must contain information on patents claiming the drug or its method of use.

Delay of an approval or filing of 505(b)(2) application: Approval or filing of a 505(b)(2)

application, like a 505(j) application, may be delayed because of patent and exclusivity rights

that apply to the listed drug.

4.4.2 Patent-approval linkage

Except for therapeutic biologics, all approved drug products, both innovator and generic,

are listed in FDA's Orange Book (Approved Drug Products with Therapeutic Equivalence

Evaluations).

For each patent, the applicant shall provide a certification with respect to each patent

issued by the United States Patent and Trademark Office that, in the opinion of the applicant

and to the best of its knowledge, claims the reference listed drug or that claims a use of such

listed drug for which the applicant is seeking approval and for which information is required

to be filed.

If the applicant certifies that the relevant patent is invalid, unenforceable, or will not be

infringed and the patent owner or its representative or the exclusive patent licensee brings suit

for patent infringement within 45 days of receipt by the patent owner of the notice of

certification from the applicant under § 314.52 or § 314.95, approval may be made effective

30 months after the date of the receipt of the notice of certification by the patent owner or by

the exclusive licensee (or their representatives) unless the court has extended or reduced the

period because of a failure of either the plaintiff or defendant to cooperate reasonably in

expediting the action.

180-day Exclusivity: In certain circumstances, an ANDA applicant whose ANDA contains

a paragraph IV certification (statement that such patent is invalid or will not be infringed by

the manufacture, use, or sale of the drug product for which the ANDA is submitted) is

protected from competition from subsequent generic versions of the same drug product for

180 days after either the first marketing of the first applicant's drug or a decision of a court

holding the patent that is the subject of the paragraph IV certification to be invalid or not

infringed.

44

Guidance for Industry(Draft Guidance), Applications Covered by Section

505(b)(2)(http://www.fda.gov/cder/guidance/2853dft.pdf) 45

FD&C Act (21CFR314.107) Effective date of approval of a 505(b)(2) application or abbreviated new drug

application under section 505(j) of the act

46 Guidance for Industry(Draft Guidance), Applications Covered by Section 505(b)(2)

(http://www.fda.gov/cder/guidance/2853dft.pdf)

- 33 -

4.5. Related guidelines

Guidance for Industry: ANDA Submissions - Content and Format of Abbreviated

New Drug Applications (June 2014)

Procedural Draft: Applications Covered by Section 505(b)(2) (Issued 10/1999)


General Considerations (Issued 10/2000).

Drug Master Files

Required Specifications for FDA's IND, NDA, and ANDA Drug Master File Binders

Guidance for Industry: Changes to an Approved NDA or ANDA

Refusal to Receive (Issued 7/12/1993)

Inactive Ingredient Database

5. Accelerated approval of new drugs for serious or life-threatening illness47

5.1. Purpose

The purpose of accelerated approval is to speed the availability of drugs that treat serious

diseases, especially when the drugs are the first available treatment or if the drug has

advantages over existing treatments.

The Food and Drug Administration has developed four distinct and successful following

approaches to make such drugs available as rapidly as possible:

(1) Fast Track

(2) Breakthrough Therapy

(3) Accelerated Approval

(4) Priority Review

5.2. Types of approaches

5.2.1 Fast track4849

Fast track is a process designed to facilitate the development, and expedite the review of

drugs to treat serious conditions and fill an unmet medical need. The purpose is to get

important new drugs to the patient earlier. The fast track addresses a broad range of serious

conditions.

Determining whether a condition is serious is a matter of judgment, but generally is based

on whether the drug will have an impact on such factors as survival, day-to-day functioning,

or the likelihood that the condition, if left untreated, will progress from a less severe

condition to a more serious one. AIDS, Alzheimer‘s, heart failure and cancer are obvious

examples of serious conditions. However, diseases such as epilepsy, depression and diabetes

are also considered to be serious conditions.

47

FD&C Act (21CFR314.500) Accelerated approval of new drugs for serious or life-threatening illness 48

FDA website > For Patients > Learn About Drug and Device Approvals > Fast Track, Breakthrough Therapy,

Accelerated Approval, and Priority Review> Fast Track (http://www.fda.gov/ForPatients/Approvals/Fast/ucm405399.htm) 49

FDA&C Act (21CFR356). Fast track products

- 34 -

Filling an unmet medical need is defined as providing a therapy where none exists or

providing a therapy may be potentially better than available therapy.

Any drug being developed to treat or prevent a condition with no current therapy

obviously is directed at an unmet need. If there are available therapies, a fast track drug must

show some advantage over available therapy:

Showing superior effectiveness, effect on serious outcomes or improved effect on

serious outcomes

Avoiding serious side effects of an available therapy

Improving the diagnosis of a serious condition where early diagnosis results in an

improved outcome

Decreasing a clinical significant toxicity of an available therapy that is common and

causes discontinuation of treatment

Ability to address emerging or anticipated public health need

Fast Track designation must be requested by the drug company. The request can be

initiated at any time during the drug development process. FDA will review the request and

make a decision within 60 days based on whether the drug fills an unmet medical need in a

serious condition.

Once a drug receives Fast Track designation, early and frequent communication between

the FDA and a drug company is encouraged throughout the entire drug development and

review process. The frequency of communication assures that questions and issues are

resolved quickly, often leading to earlier drug approval and access by patients.

5.2.2 Breakthrough therapy50

Breakthrough Therapy designation is a process designed to expedite the development and

review of drugs that are intended to treat a serious condition and preliminary clinical

evidence indicates that the drug may demonstrate substantial improvement over available

therapy on a clinically significant endpoint(s).

To determine whether the improvement over available therapy is substantial is a matter of

judgment and depends on both the magnitude of the treatment effect, which could include

duration of the effect, and the importance of the observed clinical outcome. In general, the

preliminary clinical evidence should show a clear advantage over available therapy.

For purposes of Breakthrough Therapy designation, clinically significant endpoint

generally refers to an endpoint that measures an effect on irreversible morbidity or mortality

(IMM) or on symptoms that represent serious consequences of the disease. A clinically

significant endpoint can also refer to findings that suggest an effect on IMM or serious

symptoms, including:

An effect on an established surrogate endpoint

An effect on a surrogate endpoint or intermediate clinical endpoint considered

reasonably likely to predict a clinical benefit (i.e., the accelerated approval standard)

50


Accelerated Approval, and Priority Review > Breakthrough Therapy

(http://www.fda.gov/ForPatients/Approvals/ Fast/ucm405397.htm)

- 35 -

An effect on a pharmacodynamic biomarker(s) that does not meet criteria for an

acceptable surrogate endpoint, but strongly suggests the potential for a clinically

meaningful effect on the underlying disease

A significantly improved safety profile compared to available therapy (e.g., less dose-

limiting toxicity for an oncology agent), with evidence of similar efficacy

Ideally, Breakthrough Therapy designation request should be received by the FDA no later

than the end-of-phase-2 meetings if any of the features of the designation is to be obtained.

Because the primary intent of Breakthrough Therapy designation is to develop evidence

needed to support approval as efficiently as possible, the FDA does not anticipate that

Breakthrough Therapy designation requests will be made after the submission of an original

biologics license application (BLA) or NDA or a supplement. The FDA will respond to

Breakthrough Therapy designation requests within sixty days of receipt of the request.

5.2.3 Accelerated approval51

When studying a new drug, it can sometimes take many years to learn whether a drug

actually provides a real effect on how a patient survives, feels, or functions. A positive

therapeutic effect that is clinically meaningful in the context of a given disease is known as

―clinical benefit‖. Mindful of the fact that it may take an extended period of time to measure

a drug‘s intended clinical benefit, in 1992 FDA instituted the Accelerated Approval

regulations. These regulations allowed drugs for serious conditions that filled an unmet

medical need to be approved based on a surrogate endpoint. Using a surrogate endpoint

enabled the FDA to approve these drugs faster.

A surrogate endpoint used for accelerated approval is a marker - a laboratory measurement,

radiographic image, physical sign or other measure that is thought to predict clinical benefit,

but is not itself a measure of clinical benefit. Likewise, an intermediate clinical endpoint is a

measure of a therapeutic effect that is considered reasonably likely to predict the clinical

benefit of a drug, such as an effect on irreversible morbidity and mortality (IMM).

The FDA bases its decision on whether to accept the proposed surrogate or intermediate

clinical endpoint on the scientific support for that endpoint. Studies that demonstrate a drug‘s

effect on a surrogate or intermediate clinical endpoint must be ―adequate and well controlled‖

as required by the FD&C Act.

Using surrogate or intermediate clinical endpoints can save valuable time in the drug

approval process. For example, instead of having to wait to learn if a drug actually extends

survival for cancer patients, the FDA may approve a drug based on evidence that the drug

shrinks tumors, because tumor shrinkage is considered reasonably likely to predict a real

clinical benefit. In this example, an approval based upon tumor shrinkage can occur far

sooner than waiting to learn whether patients actually lived longer. The drug company will

still need to conduct studies to confirm that tumor shrinkage actually predicts that patients

will live longer. These studies are known as phase 4 confirmatory trials.

Where confirmatory trials verify clinical benefit, the FDA will generally terminate the

requirement. Approval of a drug may be withdrawn or the labeled indication of the drug

51


Accelerated Approval, and Priority Review > Accelerated Approval (http://www.fda.gov/ForPatients/Approvals/Fast/ucm405447.htm)

- 36 -

changed if trials fail to verify clinical benefit or do not demonstrate sufficient clinical benefit

to justify the risks associated with the drug (e.g., show a significantly smaller magnitude or

duration of benefit than was anticipated based on the observed effect on the surrogate).

5.2.4 Priority Review52

Prior to approval, each drug marketed in the United States must go through a detailed

FDA review process. In 1992, under the Prescription Drug User Act (PDUFA), the FDA

agreed to specific goals for improving the drug review time and created a two-tiered system

of review times – Standard Review and Priority Review.

Under Priority Review designation process, the FDA‘s goal is to take action on an

application within 6 months (compared to 10 months under standard review). The Priority

Review designation will direct overall attention and resources to the evaluation of

applications for drugs that, if approved, would be significant improvements in the safety or

effectiveness of the treatment, diagnosis, or prevention of serious conditions when compared

to standard applications. Significant improvement may be demonstrated by the following

examples:

- Evidence of increased effectiveness in treatment, prevention, or diagnosis of condition;

- Elimination or substantial reduction of a treatment-limiting drug reaction;

- Documented enhancement of patient compliance that is expected to lead to an

improvement in serious outcomes; or

- Evidence of safety and effectiveness in a new subpopulation.

The FDA decides on the review designation for every application. However, an applicant

may expressly request priority review as described in the Guidance for Industry Expedited

Programs for Serious Conditions – Drugs and Biologics53

. It does not affect the length of the

clinical trial period. FDA informs the applicant of a Priority Review designation within 60

days of the receipt of the original BLA, NDA, or efficacy supplement. Designation of a drug

as ―Priority‖ does not alter the scientific/medical standard for approval or the quality of

evidence necessary.

52


Accelerated Approval, and Priority Review > Priority Review (http://www.fda.gov/ForPatients/Approvals/Fast/ucm405405.htm) 53




- 37 -

V. Others

1. Good Manufacturing Practice

1.1 Overview

The quality of drug products is monitored under the Current Good Manufacturing Practice

(cGMP) regulations. In the approval process for new drug and generic drug applications,

GMP review on facilities, equipment, and skills to manufacture the drug product is conducted.

Related regulations and guidance documents are available at the FDA website

(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm090016.htm)54

.

Not only the Office of Pharmaceutical Quality, but also CDER Office of Compliance;

ORA district offices; and FDA analyzing laboratories are all involved in the preapproval

GMP inspection.

1.2 GMP inspection for application process55

1.2.1 Objectives

1) Readiness for Commercial Manufacturing: Determine whether the establishment(s)

has a quality system that is designed to achieve sufficient control over the facility and

commercial manufacturing operations.

2) Conformance to Application: Verify that the formulation, manufacturing or

processing methods, and analytical (or examination) methods are consistent with

descriptions contained in the CMC section of the application for the biobatch (and

other pivotal clinical batches, when applicable), the proposed commercial scale batch,

and the API(s).

3) Data Integrity Audit: Audit the raw data, hardcopy or electronic, to authenticate the

data submitted in the CMC section of the application. Verify that all relevant data

(e.g., stability, biobatch data) were submitted in the CMC section such that CDER

product reviewers can rely on the submitted data as complete and accurate.

1.2.2 Assignment of Inspections – Decision Criteria

There are two types of pre-approval inspections performed: Priority and Discretionary.

Especially, the criteria for Priority Pre-Approval Inspection are as follows:

Establishment is named in an application to FDA for the first time, including

establishments that have never been inspected or have been inspected only for non-

application drugs

First application filed by applicant (for coverage of finished dosage manufacturing

and testing)

First ANDA filed for an approved drug (for coverage of finished dosage

manufacturing and testing)

54

FDA Website > Drugs > Development & Approval Process (Drugs) > Manufacturing

(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/Manufacturing/ucm090016.htm) 55

CPGM 7346.832, Pre-Approval Inspections(Compliance Program Guidance Manual, Chapter 46)

(http://www.fda.gov/downloads/drugs/developmentapprovalprocess/manufacturing/questionsandanswersoncurre

ntgoodmanufacturingpracticescgmpfordrugs/ucm071871.pdf)

- 38 -

Finished product contains a New Molecular Entity (NME) (does not apply to

supplements)

Finished product content assay has a narrow range (e.g., 95-105% labeled strength for

narrow therapeutic index drugs) or drug is expected to require titrated dosing (does

not apply to supplements)

Finished product or API is manufactured by a substantially different manufacturing

process or dosage form than previously covered at the establishment

API derivation is high risk (e.g., API is derived from animal tissues) or the intended

use has significantly changed (e.g., API previously used in non-sterile product is now

intended for a sterile drug product)

Numerous application submissions or certain site/process/product changes that are

expected to pose significant challenge to the state of control of the facility or process

Profile class status of application product or API is ―unacceptable‖ or not updated via

a site inspection within the past 2 years (3 years for control laboratories and 4 years

for packaging and labeling), for original applications or significant pre-approval CMC

supplements.

1.2.3 Completion of the Establishment Inspection Report

The investigation team will prepare a narrative establishment inspection report (EIR) per

instructions in the Investigations Operations Manual (IOM) in addition to the following: a

description of the objectives and specific data and areas covered, inspection strategy, and

citations and discussion with management organized by objective.

All completed EIRs should be submitted to Division of Manufacturing and Product

Quality (DMPQ)/Manufacturing Assessment and the Pre-Approval Compliance Branch

(MAPCB) within 30 business days after the close of the inspection (even in instances when

no FDA-483 was issued) to ensure further evaluation before a decision is made on the

application. If the 30 business day time frame occurs after the district goal date, the district

must notify the DMPQ/ MAPCB as soon as possible.

2. Drug Master File

2.1 Overview56

2.1.1 Drug Master Files

A Drug Master File (DMF) is a submission to the Food and Drug Administration (FDA)

that may be used to provide confidential detailed information about facilities, processes, or

articles used in the manufacturing, processing, packaging, and storing of one or more human

drugs. The submission of a DMF is not required by law or FDA regulation. A DMF is

submitted solely at the discretion of the holder. The information contained in the DMF may

be used to support an Investigational New Drug Application (IND), a New Drug Application

(NDA), an Abbreviated New Drug Application (ANDA), another DMF, an Export

Application, or amendments and supplements to any of these. Technical contents of a DMF

56

Guideline for Drug Master

Files( http://www.fda.gov/Drugs/DevelopmentApprovalProcess/FormsSubmissionRequirements/DrugMasterFil

esDMFs/ucm073164.htm)

- 39 -

are reviewed only in connection with the review of an IND, NDA, ANDA, or an Export

Application.

2.1.2 Types of DMF

The types of DMFs are as follows:

(A) Type I: Manufacturing Site, Facilities, Operating Procedures, and Personnel (no

longer applicable)

(B) Type II: Drug Substance, Drug Substance Intermediate, and Material Used in Their

Preparation, or Drug Product

(C) Type III: Packaging Material

(D) Type IV: Excipient, Colorant, Flavor, Essence, or Material Used in Their Preparation

(E) Type V: FDA Accepted Reference Information

2.1.3 Status of DMF

―A‖ = Active. This means that the DMF was found acceptable for filing,

administratively, and has not been closed.

―I‖ = Inactive. This means a DMF that has been closed, either by the holder or by the

FDA.

―P‖ = DMF Pending Administrative Filing review.

―N‖ = Not an assigned number. This can occur for a number of reasons, e.g., the holder

withdrew the DMF during the administrative review or the DMF was transferred to

another Center.

3. Drug labeling

3.1 Prescription drugs

3.1.1 Drug labeling and package inserts575859

Drug labeling includes three sections: Highlights of Prescribing Information (Highlights),

a Table of Contents (Contents), and the Full Prescribing Information (FPI). (For more details,

refer to the footnote [53] and guidelines specified in the Session 3.3 below)

Highlights of prescribing information: Highlights should be a concise, informative

summary of crucial prescribing information, not a verbatim repetition of selected

material from the FPI, or a repetition of the Contents.

Contents: list the sections and subsections of the FPI

Full prescribing information (FPI): The FPI in the Physical Labeling Rule (PLR)60

format contains substantially the same information as labeling in the old format,

typically with reordering and reorganization of the information.

57

FD&C Act(21CFR 201.56) 58

FD&C Act(21CFR 201.57) 59

Guidance for Industry: Labeling for Human Prescription Drug and Biological Products - Implementing the

PLR Content and Format Requirements

(http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm075082.pdf) 60

Drugs > Guidance, Compliance & Regulatory Information > Laws, Acts, and Rules > PLR Requirements for

Prescribing Information

(http://www.fda.gov/drugs/guidancecomplianceregulatoryinformation/lawsactsandrules/ucm084159.htm)

- 40 -

On January 24, 2006, the U.S. Food and Drug Administration (FDA) issued final

regulations governing the content and format of prescribing information (PI) for human drug

and biological products. The rule is commonly referred to as the ―Physician Labeling Rule‖

(PLR) because it addresses prescription drug labeling that is used by prescribers and other

health care providers.

The goal of the PLR content and format requirements as described at 21 CFR 201.56 and

201.57 is to enhance the safe and effective use of prescription drug products by providing

health care providers with clear and concise PI that is easier to access, read, and use. The

PLR format also makes PI more accessible for use with electronic prescribing tools and other

electronic information resources.

Prescription drug labeling sections are shown in Figure 4 as below:

Figure 4. Highlights and Contents Formal Sample

- 41 -

3.2 Over-the-Counter drugs61

All Over-the-Counter (OTC) drug product labeling contain the following information

about the drug product. This information must be organized according to the following

headings and must be presented in the following order:

1. Title (―Drug Facts‖ or ―Drug Facts (continued)‖) - If the drug facts labeling appear on

more than one panel, the title ―Drug Facts (continued)‖ shall appear at the top of each

subsequent panel containing such information.

2. Active ingredient(s) - Therapeutic substance in product; amount of active ingredient per

dosage unit.

3. Purpose(s) - The general pharmacological category(ies) or the principal intended

action(s) of the drug or, where the drug consists of more than one ingredient, the

general pharmacological categories or the principal intended actions of each active

ingredient.

4. Use(s) - Symptoms or diseases the product will treat or prevent.

5. Warning(s) - When not to use the product; conditions that may require advice from a

doctor before taking the product; possible interactions or side effects; when to stop

taking the product and when to contact a doctor; if you are pregnant or breastfeeding,

seek guidance from a health care professional; keep product out of children‘s reach.

6. Directions - Specific age categories, how much to take, how to take, and how often and

how long to take; followed by the directions for use described in an applicable OTC

drug monograph or approved drug application.

7. Other information - How to store the product properly and required information about

certain ingredients (such as the amount of calcium, potassium, or sodium the product

contains)

8. Inactive ingredients

9. Questions? or Questions or comments? - The telephone number of a source to answer

questions about the product.

This information must appear on the outside container or wrapper of the retail package, or

the immediate container label if there is no outside container or wrapper. A sample of the

OTC product labeling is shown in Figure 5 as below:

61

CFR 201.66-Format and content requirements for over-the-counter(OTC) drug product labeling

- 42 -

Figure 5. Sample of the OTC Drug Product Labeling

3.3 Drug labeling-related guidelines62

(1) Implementing the PLR Content and Format Requirements

(2) Determining Established Pharmacologic Class for Use in the Highlights of

Prescribing Information

(3) Labeling for Human Prescription Drug and Biological Products Approved Under the

Accelerated Approval Regulatory Pathway (draft)

(4) Dosage and Administration Section of Labeling

(5) Warnings and Precautions, Contraindications, and Boxed Warning Sections of

Labeling

(6) Adverse Reactions Section of Labeling

62

FDA website > Drugs > Guidance, Compliance & Regulatory Information> Guidances (Drugs) > Laveling

(http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm065010.htm)

- 43 -

(7) Drug Interaction Studies - Study Design, Data Analysis, Implications for Dosing, and

Labeling Recommendations (draft)

(8) Pediatric Information Incorporated into Human Prescription Drug and Biological

Products Labeling (draft)

(9) Clinical Pharmacology Section of Labeling (draft)

(10) Clinical Studies Section of Labeling

(11) Patient Counseling Information Section of labeling (draft)

4. Certificate of a Pharmaceutical Product

Certificate of a Pharmaceutical Product (CPP) is not required in the documentation for

new drug approval application. Instead, the FDA issues various types of certificates for firms

exporting products to foreign countries as below:

Drug products that are legally marketable in the U.S.: A Red ribbon will be affixed to

all (regular) Certificates of Pharmaceutical Product.

Products not authorized for sale in the U.S. and manufactured for export only that may

be legally exported to foreign governments (Certificate of Pharmaceutical Product for

Export of an Unapproved Product under Sections 801(e) or 802 of the FDA&C Act): A

Blue ribbon will be affixed to Certificates for Export of an Unapproved Product.

Foreign Manufacturer (products manufactured outside of the U.S.): A Yellow ribbon

will be affixed to Certificates with Foreign Manufacturing sites.

5. Establishment registration and drug listing6364

5.1 Registration of drug producers and drug listing

Every person upon first engaging in the manufacture, preparation, propagation,

compounding, or processing of a drug or drugs or a device or devices in any establishment

which he owns or operates in any State shall immediately register with the Secretary:

- with respect to drugs, the name of such person, places of business of such person, all

such establishments, the unique facility identifier of each such establishment, and a

point of contact e-mail address during the period beginning on October 1 and ending on

December 31 of each year.

The owner or operator of an establishment entering into the manufacture or processing of

a drug or drugs shall register the establishment within 5 days after the beginning of the

operation and shall submit a list of every drug in commercial distribution at that time. Owners

or operators shall renew their registration information annually. Owners and operators of all

registered establishments shall update their drug listing information every June and

December.

63

FD&C Act (21CFR360) Registration of producers of drugs or devices 64

FD&C Act (21CFR207) Registration of producers of drugs and listing of drugs in commercial distribution

- 44 -

5.2 Information required in registration and drug listing

* Form FDA 2656 (Registration of Drug Establishment)

This information includes, for each establishment, the name and full address of the drug

establishment; all trade names used by the establishment; the kind of ownership or operation

(that is, individually owned, partnership or corporation); the name of the owner or operator of

the establishment.

The term name of the owner or operator includes in the case of a partnership the name of

each partner, and in the case of a corporation the name and title of each corporate officer and

director and the name of the State of incorporation.

5.3 Registration of foreign establishments

Every person who owns or operates any establishment within any foreign country engaged

in the manufacture, preparation, propagation, compounding, or processing of a drug or device

that is imported or offered for import into the United States shall, through electronic means in

accordance with the criteria of the Secretary:

- upon first engaging in any such activity, immediately submit a registration to the

Secretary that includes: with respect to drugs, the name and place of business of such

person, all such establishments, the unique facility identifier of each such establishment,

a point of contact e-mail address, the name of the United States agent of each such

establishment, the name of each importer of such drug in the United States that is

known to the establishment, and the name of each person who imports or offers for

import such drug to the United States for purposes of importation

6. Fees

6.1 Prescription Drug User Fee Act6566

6.1.1 Overview

The Prescription Drug User Fee Act (PDUFA) was enacted in 1992 and renewed in 1997

(PDUFA II), 2002 (PDUFA III), 2007 (PDUFA IV), and 2012 (PDUFA V). It authorizes the

FDA to collect fees from companies that produce certain human drug and biological products.

Since the passage of the PDUFA, user fees have played an important role in expediting the

drug approval process.

There are three types of PDUFA fees - Human drug application and supplement fee,

Prescription drug establishment fee, and Prescription drug product fee, and the PDUFA for

FY201667

are as follows:

1) Human drug application and supplement fee: $2,374,200 (Requiring clinical data);

$1,187,100 (Not requiring clinical data); $1,187,100 (Supplements requiring clinical

data)

2) Prescription drug establishment fee: $585,200

65

Prescription Drug Use Fees (http://www.fda.gov/oc/pdufa/default.htm) 66

FD&C Act (21CFR379h) Authority to assess and use drug fee 67

http://www.fda.gov/forindustry/userfees/prescriptiondruguserfee/default.htm

http://www.fda.gov/forindustry/userfees/prescriptiondruguserfee/default.htm

- 45 -

3) Prescription drug product fee: $114,450

6.1.2 Types of PDUFA68

Human drug application and supplement fee

This fee is required for person that submits a human drug application, on or after

September 1, 1992, a human drug application or a supplement shall be subject to a fee as

follows:

1) A human drug application for which clinical data (other than bioavailability or

bioequivalence studies) with respect to safety or effectiveness are required for

approval is assessed a full application fee.

2) A human drug application for which clinical data with respect to safety or

effectiveness are not required for approval is assessed one-half of a full fee.

3) A supplement to a human drug application for which clinical data (other than

bioavailability or bioequivalence studies) with respect to safety or effectiveness are

required for approval is assessed one-half of a full fee.

Prescription drug establishment fee

Establishment fees are required annually to person who:

1) is named as the applicant in a human drug application; and

2) after September 1, 1992, had pending before the Secretary a human drug application

or supplement shall be assessed an annual fee established for each prescription drug

product named in the application.

An establishment fee is assessed for each prescription drug establishment listed in the

approved human drug application as an establishment that manufactures the prescription

drug product.

1) The establishment fee is assessed for each prescription drug product that is assessed a

product fee - unless the establishment listed in the application does not manufacture

the product during the fiscal year.

2) Each establishment is assessed only one establishment fee for a fiscal year.

3) If more than one applicant lists an establishment in a human drug application, the

establishment fee for the fiscal year is divided equally among the applicants whose

prescription drug products are manufactured at the establishment.

The Prescription drug establishment fee is for a foreign or domestic business which is at

one general physical location consisting of one or more buildings, all of which are within

5 miles of each other, and at which one or more prescription drug products are

manufactured in final dosage form.

68

FDA Website > Drugs > Development & Approval Process (Drugs) > CDER Small Business and Industry

Assistance >Frequently Asked Questions on Prescription Drug User Fees (PDUFA)

(http://www.fda.gov/Drugs/DevelopmentApprovalProcess/SmallBusinessAssistance/ucm069943.htm#P33_918)

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Prescription drug product fee

This fee is required by the person who is named as the applicant in a human drug

application, and who, is the applicant of the human drug application, and had a human

drug application or supplement pending after September 1, 1992.

6.1.3 Exceptions69

According to section 736(d) of the Act, FDA will grant a waiver of or reduction in one or

more user fees assessed under section 736(a) of the Act where it finds that an applicant meets

the eligibility criteria under one of the following provisions:

1) A waiver or reduction is necessary to protect the public health.

2) The assessment of the fee would present a significant barrier to innovation because of

limited resources available to the person or other circumstances.

3) The applicant is a small business submitting its first human drug application to the

Secretary for review.

The Act also provides for waiver or reduction of user fees if the fees would exceed the

anticipated present and future costs incurred by the Secretary in conducting the process for

the review of human drug applications for the person.

For more details, please refer to Guidance for Industry: User Fee Waivers, Reductions,

and Refunds for Drug and Biological Products.70

There are other exceptions for each type of PDUFA as follows:

Human drug application and supplement fee

1) Exception for previously filed application or supplement

If a human drug application or supplement was submitted by a person that paid the fee

for such application or supplement, was accepted for filing, and was not approved or

was withdrawn (without a waiver), the submission of a human drug application or a

supplement for the same product by the same person (or the person's licensee,

assignee, or successor) shall not be subject to a fee mentioned above.

2) Exception for designated orphan drug or indication

A human drug application for a prescription drug product that has been designated as

an orphan drug shall not be subject to a fee mentioned above, unless the human drug

application includes an indication for other than a rare disease or condition. A

supplement proposing to include a new indication for a rare disease or condition in a

human drug application shall not be subject to a fee

Prescription drug establishment fee

If, during the fiscal year, an applicant initiates or causes to be initiated the manufacture of

a prescription drug product at an establishment listed in its human drug application:

1) that did not manufacture the product in the previous fiscal year; and

2) for which the full establishment fee has been assessed in the fiscal year at a time

before manufacture of the prescription drug product was begun; the applicant will not

69 FD&C Act (21CFR379h) Authority to assess and use drug fee

70 http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM079298.pdf



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be assessed a share of the establishment for the fiscal year in which the manufacture

of the product began.

Prescription drug product fee

A prescription drug product shall not be assessed a fee if such product is:

1) identified on the list compiled under section 505(j)(7)(A) with a potency described in

terms of per 100 mL;

2) the same product as another product:

which was approved under an application filed under section 505(b) or 505(j); and

which is not in the list of discontinued products compiled under section

505(j)(7)(A)

3) under an abbreviated application filed under section 507

4) under an abbreviated new drug application pursuant to regulations in effect prior to

the implementation of the Drug Price Competition and Patent Term Restoration Act

of 1984.

6.1.4. PDUFA User Fee Cover Sheet (FDA Form 3331)

Upon the drug application, the applicant is required to submit the fee by filling the

PDUFA User Fee Cover Sheet. For more information, refer to the FDA website.71

6.2 Generic Drug User Fee Amendments727374

6.2.1 Overview

The Generic Drug User Fee Amendments of 2012 (GDUFA) is designed to speed access

to safe and effective generic drugs to the public and reduce costs to industry. The law

requires industry to pay user fees to supplement the costs of reviewing generic drug

applications and inspecting facilities. Additional resources will enable the Agency to reduce a

current backlog of pending applications, cut the average time required to review generic drug

applications for safety, and increase risk-based inspections.

There are four types of GDUFA (backlog fee, drug master file (DMF) fee, ANDA and

prior approval supplement (PAS) fee, and facility fees), and GDUFA for FY2016 is as

follows:

Backlog fee for ANDA: N/A

DMF fee: $42,170

ANDA and PAS fee: ANDA ($76,030); and PAS ($38,020)

Facility fees: Domestic FDF facility ($243,905); Foreign FDF facility ($258,905);

Domestic API facility ($40,867); and Foreign API facility ($55,867)

*These fees are effective on October 1, 2015 and will remain in effect through September 30, 2016.

71

FDA Website > For Industry> User Fees > Prescription Drug User Fee Act (PDUFA) > PDUFA User Fee

Cover Sheet (http://www.fda.gov/ForIndustry/UserFees/PrescriptionDrugUserFee/ucm119184.htm) 72

Generic Drug User Fees ( http://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFees/default.htm) 73

Generic Drug User Fee Amendments of 2012

(http://www.gpo.gov/fdsys/pkg/BILLS-112s3187enr/pdf/BILLS-112s3187enr.pdf) 74

FDA Announces Fiscal Year 2016 Generic Drug Fees

(http://www.fda.gov/ForIndustry/UserFees/GenericDrugUserFee/ucm456776.htm)

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6.2.2 Types of GDUFA

One-time backlog fee for ANDA75

A person that owns an abbreviated new drug application (ANDA) that is pending on

October 1, 2012 and that has not been tentatively approved on that date is subject to a fee

for each application. The fee shall be due no later than 30 calendar days after the date of

the publication of the notice.

Drug master file (DMF) fee76

A person that owns a Type II active pharmaceutical ingredient drug master file that is

referenced on or after October 1, 2012, in a generic drug submission by an initial letter of

authorization shall be subject to a drug master file fee.

Only DMFs that cover the manufacture of an API (Type II API DMFs) for use in a generic

drug application incur fees. Specifically, each person that owns a Type II API DMF (DMF

holder) that is referenced on or after October 1, 2012, in a generic drug submission by any

initial letter of authorization shall be subject to a DMF fee.

ANDA and prior approval supplement (PAS) fee77

Each applicant that submits, on or after October 1, 2012, an abbreviated new drug

application or a prior approval supplement to an abbreviated new drug application shall be

subject to a fee for each such submission.

Fees are due on the date of submission of the application

Generic drug facility fee and active pharmaceutical ingredient facility fee

Any person that owns a facility that is identified or intended to be identified in at least one

generic drug submission that is pending or approved to produce one or more generic drug

FDFs and/or APIs is required to pay facility fees.

75

Food and Drug Administration Safety and Innovation Act sec 744B (a)(1) One-time backlog fee for ANDA 76

Food and Drug Administration Safety and Innovation Act sec 744B (a)(2) Drug master file fee 77

Food and Drug Administration Safety and Innovation Act sec 744B (a)(3) ANDA and prior approval

supplement filing fee

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VII. References

1. Website of Food and Drug Administration: www.fda.gov

2. Food, Drug and Cosmetic Act (FD&C Act):

http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticAct

FDCAct/default.htm

* Detailed references are listed in footnotes of this document.

http://www.fda.gov/

http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/default.htm

http://www.fda.gov/RegulatoryInformation/Legislation/FederalFoodDrugandCosmeticActFDCAct/default.htm

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Appendix 1. IND Application Form: FDA Form 157178

78

http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM083533.pdf

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Instruction for filling out form FDA157179

Field 1: Name of sponsor

The sponsor is the person who takes responsibility for and initiates a clinical investigation.

The sponsor may be an individual, pharmaceutical company, governmental agency, academic

institution, private organization or other organization.

Field 2: Date of submission

Enter the date the submission is being submitted to the FDA. The date entered should match

the date of the cover letter for the submission.

Field 3-4: Sponsor address and telephone number

Provide the address and telephone number of the sponsor identified in Field 1.

Field 5: Name(s) of drug

For name(s) of drug, list the generic name(s) and trade name, if available. Also, provide the

dosage form(s), and the unique ingredient identifier (UNII) term and code for active

substances (if applicable).

Field 6: IND number

Provide the IND number if it was previously assigned. If an IND number has not been

assigned, leave the field blank. For IND numbers less than six digits, the IND number should

be preceded using zeros (i.e., for IND 12345 enter 012345)

Field 7: (Proposed) Indication for use

The proposed indication should be provided. Indicate if the proposed indication is for a rare

disease (prevalence <200,000 U.S. patients). If the sponsor for the submission is the holder of

the Orphan Designation Number, select ―Yes‖ and provide the six-digit Orphan Designation

Number in the appropriate field; if not, select ―No.‖

Field 8: Phase(s) of clinical investigation to be conducted

Identification of the phase or phases of the clinical investigation to be conducted

Field 9: Cross reference

It is necessary for the sponsor to submit certain information with an IND (such as

manufacturing and controls information, pharmacology and toxicology data, or data from

prior human studies) unless that information has previously been submitted to FDA. If the

sponsor of the previously submitted information is not the same as the sponsor listed in Field

1, the sponsor of the previously submitted information must provide a letter authorizing FDA

to refer to the information.

79

Instructions for filling out form FDA 1571 – Investigational New Drug Application (IND) (http://www.fda.

gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM182850.pdf)

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Field 10: Serial number

IND submissions should be consecutively numbered.

Field 11: Submission information

Initial Investigational New Drug Application (IND): Should only be checked for an

original IND submission. For subsequent submissions, check ALL the boxes below that

apply since the submission may contain more than one type of information:

Response to Clinical Hold: A submission correcting deficiencies previously cited in a

Clinical Hold letter

Response to FDA Request for Information: A submission containing responses to

information requests

Request for Reactivation or Reinstatement: A request to resume clinical

investigation under an IND placed on inactive status

Annual Report: A brief report of the progress of the investigation submitted within 60

days of the anniversary date that the IND went into effect

General Correspondence: Any communication between the sponsor and FDA

pertinent to the investigation

Development Safety Update Report (DSUR): A report that provides information to

assure that sponsors are adequately monitoring and evaluating the evolving safety

profile of the investigational drug; may be used in place of the Annual Report

Other: Any submission that does not fit in the other categories

Protocol Amendment(s):

- New Protocol: A protocol for a study not covered by a protocol already contained

in the IND

- Change in Protocol: A submission describing changes in a protocol, including

changes to investigators

- New Investigator: A new investigator added to carry out a previously submitted

protocol

- PMR/PMC Protocol: A protocol related to a postmarketing requirement or

postmarketing commitment

Information Amendment(s): Select the review discipline(s) to which the submission

applies

Request For: Select the type(s) of request(s) contained within the submission.

IND Safety Report(s):

- Initial Written Report: 21 CFR 312.32(c)

- Follow-up to a Written Report: 21 CFR 312.32

Field 21: Provide the email address of the person identified in Field 17. For INDs submitted

to the Center for Biologics Evaluation and Research (CBER), a specific statement authorizing

communication via non-secure email should be included in the cover letter as applicable.

Field 22: Provide the date the form is signed by the sponsor or sponsor‘s authorized

representative. This date may be different from the date provided in Field 2.

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Field 23: Name of countersigner

If the person signing the application in Field 25 does not reside or have a place of business

within the United States, the submission must be countersigned by an attorney, agent, or

other authorized official who resides or maintains a place of business within the United States.

Field 24: Address of countersigner

If applicable, provide the full mailing address of the individual identified in Field 23.

Field 25: Signature of sponsor or sponsor's authorized representative

The person identified in Field 17 must sign in this field.

Field 26: Signature of countersigner

If applicable, the person identified in Field 23 must countersign in this field.

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Appendix 2. Application Form: FDA Form 356h80:

80

Application to market a new or abbreviated new drug or biologic for human use (http://www.fda.gov/

downloads/AboutFDA/ReportsManualsForms/Forms/UCM082348.pdf)

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Instruction for filling out Form FDA 356h81

Field 1: Enter the date the submission is being submitted to the FDA. The date entered should

match the date of the cover letter for the submission.

Fields 2-6: Applicant information

This section should include the name, street address, telephone and facsimile numbers of the

person or legal entity submitting the application. Enter the name, street address, and

telephone number of the person or legal entity authorized to represent a non-U.S. applicant in

Field 6.

Fields 7-15: Product description

This section should include all of the information necessary to identify the product that is the

subject of this application or submission.

- Field 7: Provide the six-digit application number. For application numbers less than six-

digits, the application number should be preceded using zeros (i.e., for NDA 12345

enter 012345).

- Field 8: Provide the four-digit supplement number with preceding zeros for supplement

numbers that are less than four-digits (i.e., for Supplement 1 enter 0001).

- Field 15: For original and efficacy supplemental applications only (including

resubmissions to these application types), provide the indication(s) proposed within the

application. Indicate if the proposed indication is for a rare disease (prevalence

<200,000 U.S. patients). Indicate if the product proposed within the application (i.e. not

the reference listed drug for an ANDA) has an FDA Orphan Drug Designation and if so;

provide the six-digit Orphan Designation number. If the submission is not an original

application or efficacy supplement, select ―No‖ in response to ―Is this indication for a

rare disease?‖ Use the Continuation Page if there are more than one proposed

indications for use by adding one indication per entry and providing rare

disease/Orphan Drug Designation information for each entry, as applicable. If

continuation pages are not needed, click on the ‗Remove Continuation Page‘ button at

top/bottom of form.

Fields 16-31: Application Information

Field 16-18: Identify the appropriate application type.

Field 19: If the application is a 351(k) BLA, provide the name of the biological reference

product that is the basis for the application and the holder of the licensed application.

Field 20: If the application is an ANDA or 505(b)(2) NDA, provide the name of the reference

listed drug (ANDA) or listed drug(s) (505(b)(2) NDA) that is/are the basis for the application,

the application number(s) for the listed drug(s), and indicate what type(s) of patent

81

Instructions for filling out form FDA 356h – Application to market a new or abbreviated new drug or

biologic for human use (http://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM321897.pdf)

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certification or statement described under 21 CFR 314.50(i) is provided within the

application.

Field 21: Select one of the submission types listed or specify the type of submission under

―Other‖ if otherwise not listed.

- Original: An application for which FDA has never issued an approval letter;

- Labeling Supplement: A supplemental application for labeling changes to an

approved product as described under 21 CFR 314.70 and 21 CFR 601.12 that does not

otherwise qualify as another type of supplement (e.g., Efficacy, CMC, REMS)

- CMC Supplement: A supplemental application for chemistry, manufacturing, and

control (CMC) changes to an approved product as described under 21 CFR 314.70, 21

CFR 314.71, 21 CFR 314.72, and 21 CFR 601.12, including CMC supplements with

corresponding labeling changes;

- Efficacy Supplement: A supplemental application for changes to an approved product,

including but not limited to, a new indication, a new dosage regimen or route of

administration, a comparative efficacy claim naming another approved product, or a

significant alteration in the patient population (e.g., a switch of marketing status from

prescription to over-the-counter), or labeling or manufacturing changes requiring

clinical data for approval;

- Annual Report: See 21 CFR 314.81(b)(2) for NDAs and 21 CFR 601.12(d) for BLAs;

- Product Correspondence: Any communication or general correspondence related to

an application (e.g., routine administrative changes, donor re-entry requests, lot

distribution reports, license reissuance requests, meeting requests) that is not an

amendment to a pending application. Provide a description of the content or intent of

the Product Correspondence in Field 25 (Reasons for the Submission);

- REMS Supplement: A supplemental application proposing a new Risk Evaluation

and Mitigation Strategy (REMS), REMS modification (including changes to a

Medication Guide that is part of a REMS), or submission of a REMS assessment;

- Post Marketing Requirements or Commitments: A submission containing

information related to post marketing requirements or commitments (e.g., nonclinical

protocol, final study report);

- Periodic Safety Report: Periodic reports (Periodic Adverse Drug Experience Reports

(PADERs)) of adverse drug or biological product experience as described under 21

CFR 314.80(c)(2), 21 CFR 314.98, and 21 CFR 600.80(c)(2), including those in

Periodic Safety Update Report (PSUR) format;

- Other (specify): State the submission type if it is not one of the previous submission

types listed above (e.g., formal dispute resolution request). If this box is checked,

provide the Reasons for the Submission in Field 25.

Field 22: Select one of the submission sub-types listed.

- Presubmission: Information submitted prior to the submission of a complete

original application (e.g., submission of partial application (rolling submission);

- Amendment: A submission to a pending original application, or pending

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supplemental application, including responses to Information Request letters,

Discipline Review letters, or other FDA communications. Amendments also include

submissions that contain additional supportive material intended to augment or

revise information previously submitted in a submission type listed under Field 21

(e.g., amendment to an annual report);

- Initial submission: A submission type under Field 21 that has never before been

submitted (excluding presubmissions);

- Resubmission: A complete response to an action letter, or submission of an original

application that has been the subject of a withdrawal before FDA action or a refusal to

file action.

Field 23: Select the appropriate type of supplemental application, if applicable.

- CBE (Changes Being Effected): A supplemental application proposing certain

changes for which distribution of the product made using the change(s) can occur

upon FDA receipt of the application as described under 21 CFR 314.70(c)(6) and

21 CFR 601.12(c)(5);

- CBE-30 (Changes Being Effected in 30 Days): A supplemental application

proposing certain changes requiring submission at least 30 days prior to distribution

of the product made using the change(s) as described under 21 CFR 314.70(c) and 21

CFR 601.12(c);

- Prior Approval (PA): A supplemental application proposing a major change for

which distribution of the product made using the change(s) cannot occur prior to

FDA approval as described under 21 CFR 314.70(b) and 21 CFR 601.12(b).

Field 24: If the submission identified in Field 21 of this form contains data only from

pediatric studies, select ‗Yes‘. If the submission does not contain data from pediatric studies,

or is an original application or efficacy supplement that contains data from both adult and

pediatric studies, select ‗No‘.

Field 25: This section should contain a brief explanation of the contents of, or rationale for,

the submission (e.g., ―manufacturing change from roller bottle to cell factory‖ or ―response to

Information Request Letter of mm/dd/yy‖ or ―pediatric exclusivity determination request‖ or

―to fulfill a Subpart H postmarketing requirement‖).

Field 26: Select the appropriate Proposed Marketing Status.

Field 27: Indicate whether the submission contains only Paper, both Paper and Electronic, or

only Electronic Media (e.g., electronic media or electronic submissions sent via the

Electronic Submissions Gateway (ESG)).

Field 28: Enter the number of volumes, including electronic media, contained in the archival

copy of this submission.

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Field 29: For original (initial) applications, efficacy supplements, CMC supplements, and

resubmissions to these submission types, this section should include complete information on

the locations of all manufacturing, packaging, and control sites for both drug substance and

drug product. Establishment information on bioequivalence testing sites, excipient testing

sites, and container/ closure manufacturing and testing establishments is not required in Field

29. For presubmissions and amendments to these submission types, complete establishment

information should be provided in this section when applicable (e.g., an amendment that

describes changes to previously submitted establishment information; an amendment that

adds or removes an establishment; a presubmission that includes CMC information including

establishment information). For each site, please include the establishment name, address,

registration (FEI) number, Master File (MF; Drug Master File (DMF) or Biologic Master File

(BMF)) number (for facilities used under a MF), and establishment DUNS number. Indicate

whether or not the establishment is new to the application. New establishments will have by

default a ‗pending‘ status. If it is not a new establishment, indicate its current status (e.g.,

active, inactive, or withdrawn) in the appropriate box. Also provide the name, address, phone

number, fax number and email address for the contact at the site. In the section

―Manufacturing Steps, and/or Type of Testing‖, provide a brief description of the specific

manufacturing steps and/or type of testing (e.g., final dosage form, stability testing)

conducted at the site (i.e., describe the type(s) of assays or testing completed). Indicate

whether the site is ready for inspection, or if not, when it will be ready.

Please note that, when applicable, the complete establishment description is requested under

Field 31, item 15.

Use the Continuation Page as needed. If continuation pages are not needed, click on the

‗Remove Continuation Page‘ button at top/bottom of form.

Field 30: This section should contain a list of all Biologics License Applications (BLAs),

Investigational New Drug Applications (INDs), New Drug Applications (NDAs), Premarket

Approval Applications (PMAs), Premarket Notifications (510(k)(s), Investigational Device

Exemptions (IDEs), and/or DMFs/BMFs that are cross-referenced in the current application.

Use the Continuation Page as needed. If continuation pages are not needed, click on the

‗Remove Continuation Page‘ button at top/bottom of form.

Field 31: This section contains items 1 through 20 which is a checklist that should be used to

indicate the types of information contained within a particular application or submission.

Check all that apply. A complete index or table of contents should immediately follow the

Form FDA 356h and, if applicable, a User Fee Cover Sheet (Forms FDA 3397, 3792, or

3794). Note that the CFR references are provided for most items in order to indicate what

type of information should or must be submitted in each section. For further information, the

applicant may consult the guidance documents that are available from the Agency.

Field 32-39: Certification

Enter the name and title, telephone number, facsimile number, email address, and street

address of the applicant‘s Responsible Official in Fields 32-37 of the form. This person is

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responsible for certifying compliance with applicable laws and regulations. The authorized

U.S. agent named in Field 6 of the form may also act as the applicant‘s Responsible Official.

The form must be signed in Field 38 by the applicant, or the applicant‘s attorney, agent, or

other authorized official. 21 CFR 601.2(a). If the person signing the form in Field 38 does not

reside or have a place of business within the United States, the form must be countersigned in

Field 39 by an attorney, agent, or other authorized official who resides or maintains a place of

business within the United States. 21 CFR 314.50(a)(5).

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Drug Approval System of

the United States of America

Publication date December 2015

Published by APEC Harmonization Center

※ If there is any inquiry or comment on this document, please

contact the APEC Harmonization Center.

• Tel. 043-719-2875~2877

• Fax. 043-719-2870

Drug Approval System of the United States of America

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