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DRUG REGULATORY ASPECTS USA Presented by: Miss. Kalyani Dhaigude M. Pharm SemII(Pharmaceutics)Guide:Mr. Amol S. BansodeAsst. Professor(Medicinal Chemistry)

Sinhgad Institute of Pharmacy, Narhe, Pune.

DATE -17/04/20151/13/20051

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Contents What is Drug Regulatory Aspects ?United States Food and Drug Administration (USFDA)Center for Drug Evaluation and Research (CDER)Code of Federal Regulations(CFR)Investigational New Drug Application (INDA)New Drug Application (NDA)Abbreviated New Drug Application (ANDA)

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What is Drug Regulatory Aspects?

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What is Drug Regulatory Aspects?

The main responsibility of Drug Regulatory Aspects (DRA) is to ensure that all products being made available to the general public confirms to acceptable standards of safety, quality and efficacy.

All the drugs are required to be registered before marketing and distribution.

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FDA or USFDA

Definition

The United States Food and Drug Administration is an agency within the U.S. Established for Public Health and Service.1/13/20055

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History

The United states Department of Agricultures division of chemistry was established by President Abraham Lincoln in year 1862 .

In 1901, the division became the bureau of chemistry, led by Dr. Wiley who was primarily responsible for enforcing the 1906 Food and Drug Act.

In 1927 the Part of Bureau became a separate agency called the Food, Drug and Insecticide Administration, which, 3 years later, became the Food and Drug Administration .

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Introduction

The FDA is led by the Commissioner of Food and Drugs, who is appointed by the President and confirmed by the Senate.

The Commissioner reports to the Secretary of Health and Human Services.

The agency is headquartered in White Oak, Maryland.

In 2008, the FDA started opening offices in foreign countries, including China, India, Costa Rica, Chile, Belgium and the United kingdom.

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What does FDA do ?

FDA is responsible for:

Protecting the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products, medical devices, nations food supply, cosmetics, dietary supplements, and products that give off radiation.

Regulating tobacco products.

Advancing the public health by helping to speed product innovations.

Helping the public get the accurate, science-based information they need to use medicines and foods to improve their health.

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Organization

The FDA comprises several offices and centers:

Office of Commissioner The FDA is headed by the Commissioner of Food and Drugs .

Center for Biologics Evaluation and Research Ensuring the safety and efficacy of biological therapeutic agents.

Center for Devices and Radiological Health (CDRH) Responsible for the premarket approval of all medical devices, as well as overseeing the manufacturing, performance and safety of these devices.

Center for Drug Evaluation and Research (CDER) New drugs, generic drugs and over-the-counter drugs.

Center for Food Safety and Applied Ensuring the safety and accurate labeling of nearly all food products in the United States .

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Organization ( continued)

Center for Tobacco Products The Family Smoking Prevention and Tobacco Control Act became law in 2009, the FDA also has had the authority to regulate tobacco products .

Center for Veterinary Medicine Regulates food, food additives, and drugs that are given to animals, including food animals and pets.

National Center for Toxicological Research Conducts research to define biological mechanisms of action underlying the toxicity of products regulated by the FDA .

Office of Regulatory Affairs Enforces the laws governing biologics, cosmetics, drugs, food, medical devices, radiation-emitting electronic devices, tobacco products, and veterinary products which may have potentially harmful side effects for the consumer .

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Mission

The Food and Drug Modernization Act states that the FDA has 4 roles :

To promote health by reviewing research and approving new products.

To ensure foods and drugs are safe and properly labeled.

To work with other nations to reduce the burden of regulation.

To cooperate with scientific experts and consumers to effectively carry out these obligations.

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Parts of US FDA

Center for Drug Evaluation and Research (CDER)

Code of Federal Regulations(CFR)

Investigational New Drug Application (INDA)

New Drug Application (NDA)

Abbreviated New Drug Application (ANDA)

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Center for Drug Evaluation and Research (CDER)

CDERs Responsibility To ensure the availability of safe and effective prescription, non-prescription, and generic drugs to the American people.

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History

Pure Food and Drugs Act 1906 Prohibits interstate commerce of misbranded and adulterated foods, drinks, and drugs.

Sherley Amendment 1911 Prohibits labeling medicines with false therapeutic claims intended to defraud the purchaser.

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History (Continued )

Roosevelt signs the Federal Food, Drug, and Cosmetic Act into law in 1938Required new drugs to be tested for safety prior to marketing, the results of which must be submitted to FDA in a new drug Application (NDA). Also required adequate labeling for safe use.

Kefauver-Harris Drug Amendments 1962Started June 1960, Signed into law Oct 1962Required drug manufacturers to prove to FDA effectiveness of products prior to marketing, to comply with Good Manufacturing Practices(GMPs), to register and be subject to inspection, etc.

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CDER Activities

Oversee research, development, manufacture, and marketing of drugs to ensure compliance with regulations.

Reviews the evidence of safety and effectiveness of new drugs.

Monitors the safety of drug products for unexpected drug risks post-market.

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CDER Activities

Pre-IND Consultation Program CDER'sPre-Investigational New Drug Application (IND) Consultation Programfosters early communications between sponsors and new drug review divisionsto provide guidance on the data necessary to warrant IND submission.

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Code of Federal Regulations(CFR)

The final regulations published in theFederal Register (daily published record of proposed rules, final rules, meeting notices, etc.) are collected in theCode of Federal Regulations (CFR).

TheCFRis divided into 50 titles that represent broad areas subject to Federal regulations.

The FDA's portion of theCFRinterprets the The Federal Food, Drug, and Cosmetic Act and related statutes.

Section 21 of theCFR contains most regulations pertaining to food and drugs. 1/13/200519

The following regulations apply to the IND application process

1/13/200520Regulation Content21CFR Part 312Investigational New Drug Application21CFR Part 314INDA and NDA Applications for FDA Approval to Market a New Drug(New Drug Approval)21CFR Part 316Orphan Drugs

21CFR Part 58Good Lab Practice for Nonclinical Laboratory [Animal] Studies21CFR Part 50Protection of Human Subjects21CFR Part 56Institutional Review Boards21CFR Part 201Drug Labeling21CFR Part 54Financial Disclosure by Clinical Investigators

WHO CAN APPLY FOR INDA , NDA ,ANDA ?

APPLICANT (SPONSOR)Is a person or entity who assumes responsibility for the marketing of a new drug.The sponsor is an individual, partnership, corporation, government agency, manufacturer or scientific institution.

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Investigational New Drug Application (INDA) After successful performance of pre-clinical studies , the investigator has to apply to FDA for permissionto administer unapproved drug product to human beings.

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Goals of Nonclinical IND Studies

Identify starting dose

Identify organ toxicities and reversibility

Guide dosing regimens and escalation schemes

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Types of IND Investigator IND It is submitted by a physician who both initiates and conducts an investigation, and under whose immediate direction the investigational drug is administered or dispensed.

Emergency use IND It 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 .

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.

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Types of IND ( continued)

Treatment IND It 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.

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Classification of INDA

Commercial

Permits sponsor to collect data on clinical safety and effectiveness needed for application for marketing in the form of NDA.

Research (non-commercial)

Permits the sponsor to use drug in research to obtain advanced scientific knowledge of new drug. No plan to market the product.

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THE IND APPLICATION CONTAIN INFORMATION IN THREE BROAD AREAS

Animal Pharmacology and Toxicology Studies

Manufacturing Information

Clinical Protocols and Investigator Information

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1.Animal Pharmacology and Toxicology Studies

Animal Pharmacology

Preclinical data to permit an assessment as to whether the product is reasonably safe for initial testing in humans.

Summary report, without individual animal records or individual study results, usually suffices.

Also included are any previous experience with the drug in humans (often foreign use).

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1. Animal Pharmacology & Toxicology Studies ( continued )

Toxicology Study Design

Pivotal for safety/start dose decision.

Toxicology studies should mimic the schedule, duration, formulation, and route as that proposed for the clinical trial.

Conform to standard toxicology protocols.

Conduct according to Good Laboratory Practices (GLP).

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2. Manufacturing Information

Information pertaining to the composition, manufacturer, stability, and controls used for manufacturing the drug substance and the drug product.

This information is assessed to ensure that the company can adequately produce and supply consistent batches of the drug.

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3.Clinical Protocols & Investigator Information

Clinical ProtocolsIt is a written mechanism that describes how a trial design (clinical / experimental) will be implemented.A documentation of all procedures to be carried out when a medical hypothesis is to be evaluated.

Investigator Information Information on The qualifications of clinical investigators professionals who oversee the administration of the experimental compound to assess whether they are qualified to fulfill their clinical trial duties.

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Format of INDACover sheet Name, address, telephone of sponsorIdentification of phasesCommitment not to begin CT until IND approvalCommitment by IRB- Form 56Commitment for conducting CT- accordance with regulationsName, title MonitorName, title person(s) for reviewingName, Address of CRO, Signature of sponsor

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Table of contentsIntroductory statement & general investigational planInvestigators brochureStudy protocolInvestigator facilities & IRB dataChemistry manufacturing & control dataPharmacology & toxicology dataPrevious human experience

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Guidance documents of INDs

Safety Reporting Requirement for INDs and BE/BA s studies (9/28/2010)

Enforcement of Safety Reporting Requirement for INDs and BA/BE studies (6/6/2011)

CGMO for Phase 1 Investigational Drug (7/2008)

Exploratory IND studies (1/12/2006)

Content and Format of IND Application study for Phase 1 Studies of Drug, Including Well characterized, Therapeutics, Biotechnology Derived Products . Provides description of required sections of an application. (Issued 11/1995)

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Guidance documents of INDs (continued)

Q & A Content and Format of INDs for Phase 1 Studies of Drug, Including Well Characterized , Therapeutic , Biotechnology Derived Products This guidance is intended to clarify when sponsors should submit final, quality-assured toxicology reports and/or update the Agency on any changes in findings since submission of non-quality-assured reports or reports based on non-quality-assured data. (Issued 10/2000)

Bioavailability & Bioequivalence Studies for Orally Administered Drug Product General considerations (Issued 10/2000, Posted 10/27/2000). This guidance should be useful for applicants planning to conduct BA and BE studies during the IND period for an NDA, BE studies intended for submission in an ANDA, and BE studies conducted in the post approval period for certain changes in both NDAs and ANDAs.1/13/200535

Guidance documents of INDs (continued)

IND Experimentations for Studies of Lawfully Marketed Drug or Biological Product for the Treatment of Cancer. (I/2004)

Guideline for Drug Master File A Drug Master File (DMF) is a submission toFDA 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.

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

11. Immunotoxicology Evaluation of Investigational New Drugs.

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Approval for Investigating New Drug Application

Once the IND is submitted, the sponsor must wait 30 days before initiating any clinical trials. During this time, FDA review the IND for safety to assure that research subjects will not be subjected to unreasonable risk.

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NEW DRUG APPLICATION (NDA)

INTRODUCTIONNDA is a critical component for drug approval process which required to submit to USFDA (Food & Drug administration) before drug commercialization.The data gathered during the animal studies & human clinical trials of an investigational new drug (IND) become part of the NDA.

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GOAL OF NDA To provide enough information to permit FDA reviewer to reachSafetyEfficacy Quality for pharmaceutical productionAppropriate labelingMethods used in manufacturing (GMP)

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RiskBenefit

NDA is Applicable New molecular entityNew salt of previously approved drugNew formulation of previously approved drugNew combinationNew indication for already marketed drug

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NDAForms

1/13/200541Form NoContentForm FDA -356 hApplication to Market a New Drug, Biologic, or An Antibiotic Drug For Human UseForm FDA 356 h Instructions Form FDA -3397User Fee Cover SheetForm FDA - 3331New Drug Application Field Report

Assembling application for submission FDA requires drug sponsors to submit multiple copies of the NDA:The Archival CopyThe Review CopyThe Field Copy

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1.Archival CopyIt contains all sections of the NDA Including the cover letter4 copies of the Labeling sectionThree additional copies of CMC(Chemistry, manufacture, & control) & methods validation packageShould contains Case report tabulation & case report forms.

2. Review copyIntended for reviewers in the corresponding technical disciplines.Includes the cover letter, form FDA-356h, the administrative sections, comprehensive NDA index, individual table of contents, the labeling section & the application summary.

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3. The Field CopyIt required since 1993 for use by FDA inspectors during pre approval facilities inspections.It includes cover letter, form FDA 356h, the administrative sections, the comprehensive NDA index , individual table of contents, the labeling section, the application summary, CMC, & methods validation package.

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1/13/200545NDA contents

1/13/200546NDA contents

Guidance documents NDAs

BA & BE Studied for Orally Administered Drug Product (Issued 10/2000, Posted 10/27/2000). This guidance should be useful for applicants planning to conduct BA and BE studies during the IND period for an NDA, BE studies intended for submission in an ANDA

Changes to an Approved NDA or ANDA (Issued 11/1999, Posted 11/19/1999)

Changes to an Approval NDA or ANDA Questions and Answers (Issued 1/2001, Posted 1/22/2001)

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Guidance documents NDAs (Continued)

Containers Closure System for Packaging Human Drugs and Biologics (Issued 5/1999, Posted 7/6/1999) Format and Content of the Chemistry, Manufacturing and Controls. Section of an Application (Withdrawn as per FR notice, 6/1/2006)

Format and Content of Microbiology Section of an Application

Format and Content of the Clinical and Statistical Sections of an Applications (Issued 7/1988, Posted 5/21/1997)

Format and Content of the Summary for New Drug and Antibiotic Applications (Issued 2/1987, Posted 3/2/1998)

Formulating Assembling and Submitting New Drug and Antibiotic Applications (Issued 2/1987, Posted 3/2/1998)

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Guidance documents NDAs (Continued)

Submitting Supporting Documentation in Drug Applications for the Manufacturing of Drug Substance

Submitting Documentation for the Stability of Human Drugs and Biologics. (Withdrawn as per FR notice, 6/1/2006)

Submitting Samples and Analytical Data for Method Validation

Submitting Supporting Documentation in Drug Application for the Manufacture of Drug Products

NDAs : Impurities in Drug Substance (Issued 2/2000, Posted 2/24/2000)

Format and Content of the Human Pharmacokinetics and Bioavailability Section of an Application (Issued 2/1987, Posted 3/2/1998)

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Guidance documents NDAs (Continued)

Format and Content of the Nonclinical Pharmacology / Toxicology Section of an Application( Posted 3/2/1998)

Providing Clinical Evidence of Effectiveness for Human Drug and Biological Products Describes the quantity of evidence, and the documentation of the quality of evidence necessary to support a claim of drug effectiveness.

Drug Master File (DMF)

Required Specifications for FDAs IND,NDA and ANDA Drug Master File Binders

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Guidance documents NDAs (Continued)

Qualifying for Pediatric Exclusivity

Certain applications may be able to obtain an additional six months of patent exclusivity.

PET Drug Applications Content and Format for NDA and ANDAs (Issued 3/7/2000, Posted 3/7/2000)

Refusal to File (Issued 7/12/1993, Posted 11/26/99) Clarifies CDER's decisions to refuse to file an incomplete application.

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NDA PROCESS

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Reason to refuse applicationApplication does not contain results of tests to show drug is safe.The methods, facilities, & controls used for manufacturing, processing & packaging of such drug are inadequate to preserve its identity, strength, quality & purity.Insufficient information regarding the safety & efficacy.If no deficiencies, the application is approved within 180 days of the submission of application.Some possible action letters that can be sent to the sponsor:Not approval letter lists the deficiencies in the application & explains why the application can not be approved.Approval letter signals that, ultimately, the drug can be approved. Lists minor deficiencies that can be corrected.

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NDA submission to FDA

Once the application is submitted, the FDA has 60 days to conduct a preliminary review which will assess whether the NDA is sufficiently complete to permit a substantive review.

If everything is found to be acceptable, the FDA will decide if the NDA will get a standard or accelerated review and communicate the acceptance of the application and their review choice in another communication known as the 74-day letter.

A standard review implies an FDA decision within about 10 months .

Application to market a New OR Abbreviated New Drug OR Biologic for human use

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Abbreviated new drug application (ANDA) Generic drug applications are called "abbreviated" Once approved, an applicant may manufacture and market the generic drug product to provide a safe, effective, low cost .1/13/200555

Reference Product

Identified by the Regulatory Authorities as Designated Reference Product

Usually the Global Innovators Product

Protected by a patent

Marketed under manufacturers brand name

Clinical efficacy & safety profile is well documented in extensive trials

All generics must be Bioequivalent to it

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Generic Drug

Drug product which is identical or bioequivalent to Brand/ Reference drug in: Active ingredient (s) Route of administration Dosage form Strength Indications Safety

May have different: Inactive ingredients Color Shape

Almost half of drugs in market have Generics

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Bioequivalence

Pharmaceutical equivalent / alternative of the test product,when administered at the same molar dose,has the rate and extent of absorption not statistically significantly different from that of the reference product

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Drug Price Competition and Patent term restoration act of 1984(Waxman-Hatch Act)

This Act expedites the availability of less costly generic drugs by permitting FDA to approve applications to market generic versions of brand-name drugs without conducting costly and duplicative clinical trials.

At the same time, the brand-name companies can apply for up to five additional years longer patent protection for the new medicines they developed to make up for time lost while their products were going through FDA's approval process. 1/13/200559

Orange Book

All FDA approved drugs listed (NDAs, ANDAs & OTCs)

Expiration of patent dates

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NDA Vs ANDA Review Process NDA Requirements ANDA Requirements

1. Chemistry1. Chemistry2. Manufacturing2. Manufacturing3. Controls3. Controls4. Labeling4. Labeling5. Testing 5. Testing6. Animal Studies7. Clinical Studies6. Bioequivalence8. Bioavailability

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Guidance documents for ANDAGenerics (Draft Distributed for comment purpose only)Procedural Draft Applications Covered by Section 505(b)(2) (Issued 10/1999, Posted 12/7/1999)BA & BE Studied for Orally Administered Drug Product General Considerations (Issued 10/2000, Posted 10/27/2000).Drug Master File (DMF) Required Specifications for FDAs IND,NDA and ANDA Drug Master File BindersGuidance for Industry : Changes to an NDA & ANDA Refusal to Receive Inactive Ingredient Database

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ANDA process1/13/200563

ANDA Forms and Electronic Submissions

ANDA Filing Checklist FDA Form 356h Application to Market a New Drug for Human Use/Antibiotic Drug for Human Use The CDER Office of Generic Drugs has developed a guidance document entitled Providing Regulatory Submissions in Electronic Format ANDAs (Issued 6/2002, Posted 6/27/2002)

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Key Reference http://www.fda.gov/AboutFDA/CentersOffices/OfficeoofMedicalProductsandTobaco/CDER/(Date -23/03/2015)

http://www.fda.gov/drugs/developmentapprovalprocess/howdrugsaredevelopedandapproved/approvalapplications/investigationalnewdrugindapplication/default.html (Date -23/03/2015) http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/NewDrugApplicationNDA/default.html (Date -23/03/2015)

Alice Kuruvilla, A. D. Paul Alice Kuruvilla(2013),Clinical Trials A Beginners Guide, First edition, Paras Medical Publishers ,p.p. 242-243,247

B.S.Kuchekar,A.M.Khadatsre,S. C.Itkar(2012)Forensic Pharmacy,Ninth edition,Nirali Prakashan,p.p.17.8-17.9

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Thank You