Module 11 2018

©TOPRA ( The Organisation for Professionals in Regulatory Affairs) 2018

Please note that all printed material contained in the course handouts is, unless copyright is assigned elsewhere, the copyright of The Organisation for Professionals in Regulatory Affairs. Such materials are intended for the personal use of the registered students/delegates. Agreement must be reached with the Institute before any part of this material is reproduced, abstracted, stored in a retrieval system or transmitted in any form or by any means – that is, electronic, mechanical, photocopying, recording or otherwise.

Module 11: The US Regulatory Environment 11 th – 13 th April 2018

Location: De Vere Latimer Estate, Chesham, UK

Module Leader(s) : Nancy Pire Smerkanich DRSc

Date: Wednesday 11 th April 2018

Chairperson

Time

Activity

Speaker

16.00

Registration

16.15 – 16.30

Welcome & Introduction to the Module

NANCY PIRE SMERKANICH

Nancy Pire-Smerkanich, DRSc International Center for Regulatory Science University of Southern California, Nancy Pire-Smerkanich, DRSc International Center for Regulatory Science University of Southern California, USA

16.30 – 17.30

Lecture 1: History and Basis of Drug Regulation in the USA

US legislative process

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Role and structure of the FDA

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FDA jurisdiction and statutory powers

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Relevant legislation, policy and guidance documents L cture 2: FDARA, PDUFA VI and all the UFAs

17.30 – 18.30

• Background, initiatives, progress to date, issues and challenges

FDA Website Navigation

18.30 – 19.30

New Student Tutorial

USA Dr Laura Brown Course Director

19.30

Dinner

Module 11: The US Regulatory Environment 11 th – 13 th April 2018

Date : Thursday 12 th April 2018

Time

Activity

Speaker

Lecture 3: IND Process and How to Manage it

Nancy Pire-Smerkanich, DRSc

09.00 – 10.30

International Center for Regulatory Science University of Southern California,

IND process: submission, review, approval and 30 day notification period Types of IND (sponsor, investigator, compassionate use) Components of the IND: technical sections, financial disclosure, commitments undertaken, Form FDA 1571 and 1572 Issues: clinical hold, how to manage inactive INDs, GCP compliance and enforcement Maintenance of INDs: updates and annual reports

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USA

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10.30 – 10.45

Refreshment Break

Electronic Submissions

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Nancy Pire-Smerkanich, DRSc

10.45 – 12.00

Lecture 4: Adverse Event Reporting

International Center for Regulatory Science University of Southern California,

FDA regulations and reporting procedures Pre-marketed and marketed products Domestic and international activities

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USA

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CIOMS and ICH

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12.00 – 13.00

Lunch

Workshop/Activity

Module 11: The US Regulatory Environment 11 th – 13 th April 2018

13.00 – 14.45

Lecture 5: Communicating with the FDA

Product assigned- Division and therapeutic group Division structured and organization; Role of regulatory project manager Initiating and maintaining contact (formal and informal). What is FDA’s expectation Types of meetings (A, B, C) with their respective timetables and package requirements, including “the program” for NMEs/NCEs. Advisory committee meetings: structure, format, preparation, working examples of meetings and their outcomes, insight into the public influence on approvals

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Mary Wilhelm,BS MS

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Senior Director,

Regulatory Affairs,

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Halozyme Therapeutics

And

Adjunct Professor, Regulatory Affairs,

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San Diego State UniversitY

USA

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Communicating with field officers

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FDA Communication Activity

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14.45– 15.00

Refreshment Break

Lecture 6: Breakthrough Therapy Designation

Mary Wilhelm,BS MS

15.00 – 16.00

Senior Director,

Fast Track Approvals and Orphan Drugs

Regulatory Affairs,

Eligibility and Practical issues

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Halozyme Therapeutics

Post approval obligations

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And

Orphan drug definition

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Adjunct Professor, Regulatory Affairs,

Provisions and consequences of Orphan Drug Act

San Diego State UniversitY

USA

Case Study using TPP and US PI

16.00 – 18.30

Nancy Pire-Smerkanich

19.30

Dinner

Module 11: The US Regulatory Environment 11 th – 13 th April 2018

Date: Friday 13 th April

9:00 – 10:30

Emerging Technologies

Michael Jamieson, DRSc

Lecture 7

Stem Cell Therapies

International Center for Regulatory Science University of Southern California,

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Biosimilars

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Combination Products

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USA

10.30 – 10:45

Break

10.45 – 12:15

The NDA and BLA

Nancy Pire-Smerkanich, DRSc

Definition of drugs, biologics and devices Types of NDAs: 505(b)(1) and (b)(2) Pre-NDA/BLA meetings and pre- submission issues NDA/BLA application structure and components. Also paediatric requirements and waivers, financial disclosure, debarment certification, drug listing /NDC codes, user fees FDA review process and Advisory Committee meetings Supplemental NDA (sNDA) and NDA maintenance Post approval obligations and annual reports

International Center for Regulatory Science University of Southern California,

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Lecture 8

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USA

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Electronic submissions

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12:15 – 13:15

Lunch

13:15 – 14:00

Generics and OTC Products:

Nancy Pire-Smerkanich, DRSc

Drug Competition and Patent Term Restoration Act Abbreviated New Drug Applications (ANDAs): Content, Data requirements and FDA Review

International Center for Regulatory Science University of Southern California,

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Lecture 9

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USA

GDUFA

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Module 11: The US Regulatory Environment 11 th – 13 th April 2018

Legal basis for OTC

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Registration of new OTC formulations Switching from prescription to OTC

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14.00 – 14.15

Break

14.15 – 15.30

Labelling and Advertising Controls

Nancy Pire-Smerkanich, DRSc

International Center for Regulatory Science University of Southern California,

Definitions

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Lecture 10

Controls and meaning of the legislation Role and practises of the FDA Influences on industry and academia Direct to consumer advertising

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USA

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OPDP Interactions and Submissions

15.30 – 16:00

Course Evaluation and Close

The US Regulatory Environment

History and Basis of Drug Regulation

10 April 2018

Nancy Pire-Smerkanich, DRSc, University of Southern California

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

REGULATORY HISTORY United States Food & Drug Administration

Caveat Emptor The US Regulatory Environment Before 1906

Buyer Beware

• Initially, much of the nation was composed of small towns and farming communities where you primarily “fended for yourself” and/or bartered or sold goods to your neighbor; • Evolved into an industrialized nation where people became segregated and decentralized from the consumers purchasing their goods; • Gave birth to nostrum dealers, snake oil salesmen and dishonest manufacturers.

Patent Medicines Proving the Need for Drug Regulations

Patent Medicine: Drug compounds primarily sold in the 18th & 19th Century with exaggerated and/or unsubstantiated claims that contained potentially dangerous ingredients; The mixture of ingredients was not patented, but rather the bottles/labels; There were no regulations on the ingredients; many contained opium, morphine, cocaine and/or alcohol;

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In the 19th Century, the patent trade was booming; by 1930 the industry grew to over $350M.

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Cover of Collier’s Weekly (circa 1905-1906)

Medical Mercury

Undisclosed Ingredients

No vegetables… just 18% alcohol

Morphine & Ammonia for Kids!

The Turning Point Literary Truths & Social Activism Push Congress

Pure Food & Drug Act of 1906 Adulterated and Misbranded Drugs

Created the nations first regulatory agency, the FDA

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Patent medicines could not be adulterated or impure

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Banned false and misleading labels – “Truth in Labeling”: If any statements were made on a label they had to be true Required to disclose the presence and amount of alcohol, opium, cocaine, morphine, chloroform, marijuana, acetanilide, chloral hydrate or eucaine in the product

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Enforcing the Act Loopholes, Corruption & Commerce

• Limitations of the 1906 Pure Food & Drug Act – Weaknesses in the language of the act and its definitions

• Adulterated: Filthy, decomposed or putrid; containing poisonous or other added deleterious ingredients that can render a product injurious to health • Misbranded: False or misleading label – Only prohibited shipping falsely labeled products across state lines ; advertisements, brochures, etc. were not covered, neither were ‘in-state’ sellers – No additional funds allocated by Congress for FDA operations and enforcement – Did not give the FDA power to determine when the law was violated; the government had to prove the drug was adulterated/misbranded – Meager punishments and petty fines for sellers convicted in a court of law • First conviction: Robert Harper, maker of “Cuforhedake Brane-Fude,” which killed at least 22 people, was only fined $700… Harper made $2M on the product overall

Biologics Act of 1902 Establishment License for Manufacturers

• Careless errors were made during early biologics manufacturing • In St. Louis, a horse contaminated with tetanus was used to produce antitoxin; 5 children died from contaminated product In New Jersey, a contaminated smallpox vaccine killed 9 children •

• The Act established licenses for those who wanted to manufacture vaccines and antitoxins • Licenses were renewed annually; manufacturers were subject to inspection, and revocation of licenses was possible punishment

Products were subject to certification prior to release

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The Act was an immediate success… but why this one and not the 1906 Act? Because there were few politics and less money in biologics at the time!

After the Pure Food & Drug Act Over the Next 32 Years…

Sherley Amendment

Election of FDR (Term 1933 –1945)

Tugwell Bill

Chamber of Horrors

Supreme Court: claims made for effectiveness were not in scope of the Act. In 1912, Sherley brought claims under jurisdiction of the Pure Food and Drugs Act.

Attacked FDA & manufacturers.

Created by the FDA; poster displayed patent medicine and cosmetic horrors to the public such as Lash Lure, Habitina, Crazy Water Crystals, etc.

Built the New Deal Coalition to realign politics, and ‘fix’ the depression. Set up the Brain Trust, appointing Rexford Tugwell as one of the key advisors.

Issued a bill to cover ‘truth in advertising’; ingredients on bottle; no claims to cure diseases; products must show they are safe.

FDA was attacked by drug makers.

Elixir Sulfanilamide The Straw that Broke the Camels Back

• In 1937, the Massengill Company was looking for a way to make their new bestselling antibiotic treatment more tolerable • Harold Watkins, experimented with several solvents, eventually choosing diethylene glycol for its “flavor and fragrance”

• Shipped in September 1937, and by

the end of November over 107 people were dead, most were children

Massengill was prosecuted and fined $26,000 Watkins eventually commits suicide

Food Drug & Cosmetic Act of 1938 The Start of a Regulatory Revolution

Signed into law by FDR on 15 June 1938 to tighten existing controls and include new protections against unlawful cosmetics and medical devices.

• Extended FDA control to cosmetics and therapeutic devices • Required drugs to be shown safe before marketing • Eliminated the Sherley Amendment requirement to prove intent to defraud in drug misbranding cases • Provided that safe tolerances be set for unavoidable poisonous substances • Authorized standards of identity, quality, and fill-of- container for foods • Authorized factory inspections by regulatory agencies • Expanded enforcement ability of FDA to include court injunctions as well as the previous penalties of seizures and prosecutions

The FDCA is still in effect today… with several amendments.

Public Health Service Act of 1944

The act clearly established the federal government’s quarantine authority for the first time. It gave the US Public Health Service responsibility for preventing the introduction, transmission and spread of communicable diseases from foreign countries into the United States

The PHSA is still in effect today for biologics

Kefauver-Harris Amendment of 1962 Drugs Must Be Safe and Effective

• Thalidomide created in 1953 by German drug manufacturer Grunenthal – First licensed for use in UK in 1958 under the brand name Distaval and given to pregnant women in Europe to treat sleep disorders and morning sickness • The Merrill Company hoped to market thalidomide in the US under the brand name Kevadon, but was stopped by Frances Kelsey for lack of sufficient safety data • It was later proven that thalidomide resulted in fetal death and severe birth defects including limb deformities and brain damage • The Kefauver-Harris Amendment was quickly signed into law by JFK to require that drugs were proven safe and effective before sale

Subsequent Congressional Acts Orphans, Generics & Rare Diseases

Orphan Drug Act (1983) • Established to facilitate the development and marketing of drugs for rare diseases Drug Price Competition and Patent Term Restoration Act (1984) • Commonly called the Hatch-Waxman Act • Amended the FDCA to allow for the creation of

Orrin Hatch, Utah (R)

an Abbreviated New Drug Application (ANDA) approval process, which permits generic versions of previously approved innovator drugs to be approved without submitting a full NDA for FDA review.

Rare Diseases Act (2002) • Established the Office of Rare Diseases under the National Institutes of Health

Henry Waxman, California (D)

Marketing & User Fees

• Prescription Drug Marketing Act of 1987 (1988) – The PDMA was enacted (1) to ensure that drug products purchased by consumers are safe and effective, and (2) to avoid the unacceptable risk to American consumers from counterfeit, adulterated, misbranded, sub-potent, or expired drugs. – The legislation was necessary to increase safeguards in the drug distribution system to prevent the introduction and retail sale of substandard, ineffective, or counterfeit drugs. • Prescription Drug User Fee Act (1992) – PDUFA was enacted in order to permit the FDA to collect user fees (i.e. application fees) from drug manufacturers to fund the New Drug Approval process. – Reauthorized several times under subsequent Acts/Amendments. • Last reauthorized in 2017; currently on PDUFA VI (expires in 2022).

Pediatrics Protecting the Safety and Well-Being of Children

Best Pharmaceuticals for Children Act (2002) Provides an incentive for drug companies to conduct FDA requested pediatric studies by granting an additional six months of marketing exclusivity. •

Pediatric Research Equity Act (2003)

Requires drug companies to study their products in children under certain circumstances. When pediatric studies are required, they must be conducted with the same drug and for the same use for which they were approved in adults.

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Multi-Faceted Acts Reauthorizations & Expansion of Power

• Food & Drug Administration Modernization Act (1997) – FDAMA reauthorized PDUFA, attempted to harmonize biologic and drug regulations, and increase patient access to experimental drugs and devices; – Abolished long-standing rules that manufacturers cannot promote off-label indications • Permitted circulation of peer reviewed journal articles about off-label use, if firms filed proof of research within specified period of time; – Provided special exemption to ensure continued availability of drugs from compound pharmacies; – Permitted one clinical investigation as the basis for product approval, but preserved the presumption that two well-controlled trials are needed to prove safety and effectiveness. • Food & Drug Administration Amendments Act (2007) – FDAAA increased the responsibilities of FDA and reauthorized several FDA critical programs such as the user fee amendments (i.e. PDUFA and MDUFA); – An expanded clinical trials database enacted requiring clinical trial information to be provided to the National Institutes of Health (NIH) ClinicalTrials.gov; – Provides FDA with additional requirements, authorities, and resources with regard to both pre- and post-market drug safety including the authority to require post-market studies and clinical trials, safety labeling changes, and Risk Evaluation and Mitigation Strategies (REMS).

Multi-Faceted Acts: Reauthorizations & Expansion of Power

• Food & Drug Administration Safety & Innovation Act (2012) – FDASIA expands the user fee program, promotes innovation, increases stakeholder involvement, and enhances the safety of the product supply chain . • Food & Drug Administration ReauthorizationAct (2017) – FDARA builds upon the goals outlined in previous user fee agreements and in the 21st Century Cures Act and provides funding and focus for priority areas including products for rare diseases, medical device regulation changes, combination products and patient focused product development.

Other “acts” of Congress

• The Biologics Price Competition and Innovation Act (2010) – BPCI was enacted under Title VII of the Patient Protection and Affordable Care Act , often referred to as “Obamacare”; – Established an abbreviated licensure pathway for biological products shown to be biosimilar to, or interchangeable with, an FDA-licensed reference product; – More to follow on this topic (Lecture 7) • Drug Supply Chain Security Act (2013) – The DSCSA outlines critical steps to implement an electronic system to identify and trace prescription drugs throughout their distribution cycle.

REGULATORY FRAMEWORK United States Food & Drug Administration

US Government Primer

Legislative Enacts Legislation • Senate = 2 elected

officials per state (serves 6-yr term); • House = 435 elected officials; divided per state population (serves 2-yr term)

Executive Enforces Laws

Judicial Evaluates & Interprets the Meaning of Laws

Hierarchy of Federal Laws

• The United States Constitution is the “Supreme Law of the Land”. It provides for the basis of the US government; guarantees freedom and rights to all citizens; etc.

Constitution

• An Act of Congress is a public or private law passed by majority vote. Acts may be amended (i.e. modified/changed) by subsequent Congressional acts.

Acts & Amendments

• Public laws enacted by Congress and signed into law by the President are recorded in the United States Code (USC) as statutes; arranged by subject matter and shows the present status of laws and amendments.

Statutes

• Regulations are codified in the Code of Federal Regulations (CFR). Federal Agencies adopt regulations to provide more granular detail on how to operationalize a law.

Regulations

https://www.federalregister.gov

Locating Laws & Regulations

Citations of the United States Code (USC)

Citations of the Code of Federal Regulations (CFR)

Drug & Biologic Regulations

• Code of Federal Regulations, Title 21: Food and Drugs

– 21 CFR 11, Electronic Records Electronic Signatures – 21 CFR 50, Protection of Human Subjects – 21 CFR 54, Financial Disclosure by Investigators – 21 CFR 56, Institutional Review Boards – 21 CFR 58, Good Laboratory Practices for Non-Clinical Lab Studies – 21 CFR 210 & 211, Good Manufacturing Practices (Drugs) – 21 CFR 312, Investigational New Drug Application – 21 CFR 314, Applications for FDA Approval to Market a New Drug – 21 CFR 600, Biological Products, General – 21 CFR 601, Licensing (Biologics) – 21 CFR 610, General Biological Products Standards

Regulations vs. Guidance

• Regulations

– Drafted to comply with requirements set forth by Acts & Amendments – Enforceable laws codified in the United States Code of Federal Regulations • CFR Title 21, Food & Drugs

• Guidance for Industry – Contains non-binding

recommendations representing the agency’s current thinking

on a topic; not legally enforceable but highly encouraged

Health & Human Services Protecting Americas Health

The Department of Health and Human Services (HHS) • Cabinet-level department in the Executive Branch of government; • Responsible for protecting public health and providing essential human services; • Food & Drug Administration (FDA) is part of the HHS organization.

FDA Jurisdiction

Biologics Vaccines, blood and blood products, cellular and gene therapies, tissue and tissue products and allergenics .

Foods Dietary supplements, bottled water, food additives, infant formula, certain food products.

Drugs Prescription and non-prescription drug therapies.

Medical Devices Devices of varying complexity such as tongue depressors, pacemakers, dental devices, surgical implants.

Radiation Products Products such as microwave ovens, x-Ray equipment, laser products, sunlamps, ultrasonic therapies.

Cosmetics Color additives in makeup and personal care products, skin moisturizers and cleansers, nail polish and perfumes.

Veterinary Products Livestock feed, pet foods, veterinary drugs and devices.

Tobacco Products Cigarettes and tobacco.

US FDA Organizational Chart

Office of the Commissioner Leadership of the Food & Drug Administration

Office of the Commissioner

• “Provides centralized agency-wide program direction and management services to support effective administration and FDA's consumer protection efforts within its regulatory framework and to put available resources to the most efficient use.” • Responsible for “policy making, program direction, coordination, liaison, and expert advice to agency leadership and programs in support of FDA's science-based regulatory work.”

Dr. Scott Gottlieb was sworn in as the 23rd Commissioner of Food and Drugs on May 11, 2017. Dr. Gottlieb is a physician, medical policy expert, and public health advocate who previously served as the FDA's Deputy Commissioner for Medical and Scientific Affairs and before that, as a senior advisor to the FDA Commissioner

FDA Offices & Divisions

Center for Biologics Evaluation and Research Regulates blood and blood products; cellular and gene therapies; tissue and tissue products; vaccines; xenotransplantation; biologic products and establishments.

CBER

Center for Drug Evaluation and Research Regulates over-the-counter (OTC) and prescription drugs, including biological therapeutics (in vivo monoclonal antibodies, proteins, immunomodulators, growth factors) and generic drugs.

CDER

Center for Devices and Radiological Health Regulates medical devices and radiation-emitting products.

CDRH

CDER - 6 Offices of New Drugs (organized by areas of medicine)

• Office of Drug Evaluation I (ODE I) • Cardiovascular and renal

• Neurology • Psychiatry

• Office of Drug Evaluation II (ODE II) • Anesthesia, analgesia, and addiction • Metabolism and endocrinology • Pulmonary, allergy and rheumatology • Office of Drug Evaluation II (ODE III) • Dermatology and dental • Gastroenterology and inborn errors • Bone, reproductive and urologic

CDER – 6 Offices of New Drugs: (organized by areas of medicine) • Office of Drug Evaluation IV (ODE IV) • Medical Imaging • Radioactive Drug Research Committee Program • Nonprescription clinical evaluation • Nonprescription regulation development • Office of Antimicrobial Products • Anti-infective • Antiviral • Transplant and ophthalmology • Office of Hematology and Oncology Drug Products • Hematology • Oncology 1 - Breast, Gynecologic, Genitourinary, supportive care • Oncology 2 - Other solid tumors

Other Related Offices in CDER

• Office of Compliance • Office of Drug Security, Integrity and Recalls • Office of Manufacturing and Product Quality • Office of Scientific Investigations (DSI) • Office of Unapproved Drugs and Labeling Compliance • Office of Pharmaceutical Quality • Office of Biotechnology Products • Office of New Drug Quality Assessment

• Office of Testing and Research • Office of New Drug Products • Office of Surveillance

Other Offices in CDER

• Office of Surveillance and Epidemiology • Division of Epidemiology • Division of Medication Errors, Prevention and Analysis • Division of Pharmacovigilance I and II • Division of Risk Management • Office of Translational Sciences • Office of Biostatistics • Office of Clinical Pharmacology • Office of Medical Policy • Office of Prescription Drug Promotion (OPDP) • formerly Division of Drug Marketing, Advertising & Communications (DDMAC)

Other Offices in CDER

• Office of Generic Drugs • Office of Research and Standards • Office of Bioequivalence • Office of Generic Drug Policy • Office of Regulatory Operations • Office of Orphan Product Development

Questions

Module 11: The US Regulatory Environment

Lecture 2 FDASIA and PDUFA

10 April 2018

Nancy Pire-Smerkanich, DRSc, The University of Southern California

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

Session Agenda

• Prescription Drug User Fee Act (PDUFA) Background • Financial Issues/Fee Structure • Reauthorizations and Associated “Acts” • Performance Goals and Results • Reauthorization Process Overview and PDUFA VI • Other UFAs

PDUFA Background

DRIVER: Before 1992, timeliness of FDA drug review was a big concern PDUFA • User fees added resources for more review staff to eliminate the backlog of overdue applications and improve review timeliness • FDA agreed to meet specific performance goals Result: More predictable, streamlined process • Average clinical development time has dropped 10% and average time to approval dropped nearly 60% * • Patients gain earlier access to over 1500 new drugs and biologics approved since 1992

* Source: Tufts Center for the Study of Drug Development

Financial Issues/Fee Structure

• It is a Fee not a Tax – User fees pay for services that directly benefit fee payers (ie Industry) • Fee funds are added to government appropriated funds and were/are intended to increase staffing and other resources to speed and enhance review process • Fee negotiations with industry focus on desired enhancements in terms of specific aspects of activities in “process for the review of human drugs”.

Current Fee Structure

Established at start of PDUFA in 1993 • Total target revenue is collected via 3 equal components – Full-Application-Equivalents – Establishment fees – Product Registration fees • Current Fees for FY 2018 – Applications w/ Clinical Data = $2,421,495 – Applications w/o Clinical Data & Supplements w/ CD = $1,210,748 – Program fee = $304,162

Reauthorization Process

• PDUFA REAUTHORIZATION and REPORTING REQUIREMENTS as of PDUFA V. • (d) REAUTHORIZATION.— • (1) CONSULTATION. —In developing recommendations to present to the Congress with respect to the goals, and plans for meeting the goals, for the process for the review of human drug applications for the first 5 fiscal years after fiscal year 2017 and for the reauthorization of this part for such fiscal years, the Secretary shall consult with— (A) the Committee on Energy and Commerce of the House of Representatives; (B) the Committee on Health, Education, Labor, and Pensions of the Senate; (C) scientific and academic experts ; (D) health care professionals ; (E) representatives of patient and consumer advocacy groups ; and (F) the regulated industry . • (2) PRIOR PUBLIC INPUT .— Prior to beginning negotiations with the regulated industry on the reauthorization of this part, the Secretary shall— • (A) publish a notice in the Federal Register requesting public input on the reauthorization; (B) hold a public meeting at which the public may present its views on the reauthorization, including specific suggestions for changes to the goals referred to in subsection (a); (C) provide a period of 30 days after the public meeting to obtain written comments from the public suggesting changes to this part; and (D) publish the comments on the Food and Drug Administration’s Internet Web site. • (3) PERIODIC CONSULTATION .— Not less frequently than once every month during negotiations with the regulated industry , the Secretary shall hold discussions with representatives of patient and consumer advocacy groups to continue discussions of their views on the reauthorization and their suggestions for changes to this part as expressed under paragraph (2). • (4) PUBLIC REVIEW OF RECOMMENDATIONS .— After negotiations with the regulated industry , the Secretary shall— (A) present the recommendations developed under paragraph (1) to the Congressional committees specified in such paragraph; (B) publish such recommendations in the Federal Register; (C) provide for a period of 30 days for the public to provide written comments on such recommendations; (D) hold a meeting at which the public may present its views on such recommendations; and (E) after consideration of such public views and comments, revise such recommendations as necessary. • (5) TRANSMITTAL OF RECOMMENDATIONS .— Not later than January 15, 2017, the Secretary shall transmit to the Congress the revised recommendations under paragraph (4), a summary of the views and comments received under such paragraph, and any changes made to the recommendations in response to such views and comments. • (6) MINUTES OF NEGOTIATION MEETINGS .— • (A) PUBLIC AVAILABILITY .—Before presenting the recommendations developed under paragraphs (1) through (5) to the Congress, the Secretary shall make publicly available, on the public Web site of the Food and Drug Administration, minutes of all negotiation meetings conducted under this subsection between the Food and Drug Administration and the regulated industry. • (B) CONTENT.—The minutes described under subparagraph (A) shall summarize any substantive proposal made by any party to the negotiations as well as significant controversies or differences of opinion during the negotiations and their resolution . Don’t‘

attemp to read this!

Reauthorization and Associated “Acts”

PDUFA I: 1993-1998 – Added funds for pre-market review; reduce backlog and set predictable timelines (goals) for review action PDUFA II (FDAMA): 1998-2003 – Shorten review timelines, add review goals; add process and procedure goals; some added funding

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• PDUFA III (BioTerrorism Preparedness & Response Act): 2003-2008 –

Significant added funding; increase interaction in first review cycle (GRMPs); allow limited support for post-market safety

PDUFA IV (FDAAA): 2008-2013 – Increased and stabilized base funding; enhanced pre-market review; modernize post-market safety system PDUFA V (FDASIA): 2013-2018 – Small increase to base funding; review enhancements increase communication with sponsors; strengthen regulatory science & post-market safety; electronic data standards

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PDUFA VI (FDARA): 2018-2023 –

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Ensure effective review process incorporating patient perspective, focus on rare diseases and breakthrough therapies, strengthen drug safety surveillance, explore use of real world evidence and promote staff hiring and retention

NOTE: These are fiscal not calendar years. Fiscal year for government is Oct 1- Sept 30 .

FDA/CDER Performance Goals

FDA-TRACK CDER Dashboard

https://www.fda.gov/AboutFDA/Transparenc y/track/ucm206444.htm Goals: https://www.fda.gov/downloads/forindustry /userfees/prescriptiondruguserfee/ucm5114 38.pdf

Enhancing Regulatory Science and Expediting Drug Development • Promoting Innovation Through Enhanced Communication Between FDA and Sponsors During Drug Development – Evaluate “The Program” using independent assessment (third party

review), public workshop and guidance – Changes to FDA Meeting Management

• Ensuring Sustained Success of Breakthrough Therapy Program

• Early Consultation on the Use of New Surrogate Endpoints

• Advancing Development of Drug-Device and Biologic- Device Combination Products Regulated by CBER and CDER • Enhancing Use of Real World Evidence for Use in Regulatory Decision-Making

FDA Meeting Management

• End-of-Phase 2* meetings are now in a new category, Type B

(EOP) meetings with unique parameters – Earlier notification that meeting is granted – Earlier submission of background package – FDA commits to send preliminary comments – Industry commits to respond to prelim comments – 70-day scheduling goal

• Type C meetings also changed

– Earlier submission of background package – FDA commits to send preliminary comments – Industry commits to respond to prelim comments

• Written Response Only meetings: Sponsors may request this option for any meeting category

Surrogate Endpoint Consultation

➢ Early consultation can be important when a sponsor intends to use a biomarker as a new surrogate endpoint ➢ Consultation is intended to discuss feasibility of the surrogate as a primary endpoint, any knowledge gaps, and how these gaps should be addressed ➢ Consultations will be a Type C meeting with the following modifications: – Meeting background package is due at time of request and must include preliminary human data indicating the impact of drug on biomarker – Meeting preparation will involve CDER’s Medical Policy Council – Meetings will be F2F; they will not be converted to a Written Response Only meeting

Continuation of PDUFA V Goals

• Benefit-Risk Assessment – B-R framework phased into review template and part of NME/NCE Reviews • Patient-Focused Drug Development – Continued focus on patient reported outcomes (PRO) • Enhancement and Modernization of the FDA Drug Safety System Standardizing – REMS – Sentinel • Electronic Submissions Requirements • Clinical Terminology Standards

Other UFAs

Medical Devices

Other UFAs

Generic Drugs

Other UFAs

Biosimilars

Sources

FDA Website(s) and Notices Home: www.fda.gov

Drugs: http://www.fda.gov/Drugs/default.htm

Let’s Navigate!

WORKSHOP ACTIVITY

Look up the listing on the FDA website (Drugs@FDA) for a recently approved new drug OCALIVA:

• Identify the FDA NDA application number:

• Identify the indications and usage found on the label:

• Identify available dosage form(s) and strength(s) of the drug:

Identify the route(s) of delivery:

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• Identify the original approval date and the company name:

• What are the submission classification and the review priority for this product?

• Describe the status of the required pediatric assessments for this product:

• Identify the black box warning for this product. When/why did this occur?

Module 11: The US Regulatory Environment

Lecture 3: The Investigational New Drug Application (IND)

11 April 2018

Nancy Pire-Smerkanich, DRSc, The University of Southern California

ENABLING AND PROMOTING EXCELLENCE IN THE HEALTHCARE REGULATORY PROFESSION

TOPICS

➢ IND Basics ➢ When is an IND Required/Not Required ➢ IND Submission Process/Timeline ➢ Types of INDs ➢ IND Components ➢ Submitting eCTD INDs ➢ IND Maintenance ➢ IND Issues/Actions

IND = Investigational New Drug Application

• IND is not the same as a Clinical Trial Application (CTA)! • CTA is for one study • IND is for one product or indication • IND is not the same as Investigational Medicinal Product Dossier (IMPD) • But it does contain many/most of the same components

IND = Investigational New Drug Application

• Notice of Claimed Investigational Exemption for a New Drug • Exemption, under §505(i), from the

requirement of the FD&C Act that a new drug have an approved application to be introduced into interstate commerce

• Application to FDA to seek permission to test a new drug (or biologic) in humans Regulations: 21 CFR 312

IND Requirement

• Whenever clinical studies are initiated on a new unapproved drug or biologic product being tested in the US

IND Requirement

• Whenever clinical studies are initiated on an approved drug or biologic for any of the following: • A new indication or same indication but a different population • A new route of administration • A change in formulation that increases risk • A significant change in dosing regimen

IND Requirement

• Can be waived for bioavailability/bioequivalence studies • Most bioequivalence studies conducted to support Abbreviated New Drug Applications (ANDA) for generic drugs do not need to be conducted under an IND REFERENCE: Guidance for Industry: Investigational New Drug Applications (INDs) – Determining Whether Human Research Studies Can Be Conducted Without an IND (Sep 2013)

Types of INDs

• Commercial IND • “Standard” IND and focus of this course • Non-standard INDs • Exploratory IND • Sponsor-Investigator IND • Expanded Access IND

Commercial IND

• Application submitted by sponsor/company with eventual goal of FDA marketing approval of a drug or biologic product • Safety and efficacy will be evaluated under the IND • Used by FDA to distinguish from INDs for non-commercial research (e.g. for most sponsor-investigator INDs)

Exploratory IND

• Phase 0 or Pre-Phase 1 • Permits very limited human exposure • Has no therapeutic or diagnostic intent • May be used to assess more than one candidate for further development • e.g. microdosing or pharmacodynamic screening studies • Less nonclinical and CMC data typically expected to support this type of IND • When a candidate is selected for full development, the exploratory IND is withdrawn and replaced by a standard IND

REFERENCE: Guidance for Industry: Exploratory IND Studies (Jan 2006)

Sponsor-Investigator IND

• IND sponsored by an individual investigator • Individual assumes regulatory responsibilities of both sponsor and investigator • Not intended to replace traditional sponsor INDs as a mechanism to initiate clinical trials Regulations: 21 CFR 312.3(b)

Expanded Access IND

• Three categories of expanded access use • Individual patients, including for emergency use • Intermediate size populations • Treatment IND/Treatment Protocol • Data needed to support expanded access depends on seriousness of the condition and how many patients will be treated • Expanded access cannot interfere with development Regulations: 21 CFR 312.300 (Subpart I)

IND Components Subpart B--Investigational New Drug Application (IND) § 312.20 - Requirement for an IND. § 312.21 - Phases of an investigation. § 312.22 - General principles of the IND submission. § 312.23 - IND content and format. § 312.30 - Protocol amendments. § 312.31 - Information amendments. § 312.32 - IND safety reporting. § 312.33 - Annual reports. § 312.38 - Withdrawal of an IND.

IND Components

Original INDs are usually submitted as (e)CTD and contain the following:

eCTD IND Implementation

➢ eCTD format will be mandatory for INDs starting in May 2018 ➢ ICH CTD Guideline (M2-5) and Regional (Module 1) Guidance ➢ Must use fillable forms and e-signatures ➢ No scanned images of forms ➢ Refer to Technical Conformance Guide

FDA Guidance on eSubmissions

✓ Providing Regulatory Submissions in Electronic Format —Certain Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (R4 –April 2017) ✓ Comprehensive Table of Contents Headings and Hierarchy (on FDA website) ✓ This maps from the IND and NDA regulations and traditional format to the CTD format https://www.fda.gov/downloads/drugs/ucm1631 75.pdf

The Common Technical Document (CTD)

1 Regional Administrative Information

Not CTD

2.1 TOC 2.2 Introduction 2.4 Nonclinical Overview 2.5 Clinical Overview

2.7 Clinical Summaries

2.6 Nonclinical Written & Tabulated Summaries

2.3 Quality Overall Summary

CTD

5 Clinical Study Reports

4 Nonclinical Study Reports

3 Quality Data

IND Requirements • The chemistry, manufacturing and controls information must support all drug product(s) being used in the proposed study(s), including comparator and placebo • The nonclinical section must also support the proposed dosing (frequency, duration and amount) • As additional study protocols are filed this information is filed as IND amendments

➢ Module 1 • Item 1: Form FDA 1571* • Item 2: TOC

• Item 3: Environmental Assessment (waiver) and Investigational Labels • Item 4: General Investigational Plan • Item 5: Investigator’s Brochure *Also now need Form FDA 3674

Item 1: Form FDA 1571 This form must accompany all IND submissions

Form FDA 1571 – page 2 (back)

Form FDA 1571 - Signatures

IND Study Registration Requirements IND Acknowledgement will cite additional requirements: 1.You are also responsible for complying with the applicable provisions of sections 402(i) and (j) of the Public Health Service Act (PHS Act) [42 USC §§ 282 (i) and (j)], which was amended by Title VIII of the Food and Drug Administration Amendments Act of 2007 (FDAAA) (Public Law No, 110-85, 121 Stat. 904). This means registering trial if applicable on www.clintrials.gov

Form FDA 3674

✓

Certification of Compliance with Requirements of ClinicalTrials.gov Data Bank Applies to certain IND, NDA, ANDA, BLA and medical device submissions Under Section 9, check ✓ Box A if no clinical trials referenced in submission ✓ Box B if requirements to register on ClinicalTrials.gov do not apply ✓ Box C if requirements to

✓

✓

register do apply. Include NCT (National Clinical Trial) number

Item 2: Table of Contents

• Construction of a Table of Contents is useful for sponsor as a planning tool for IND preparation • When using eCTD the XML backbone will serve as the Table of Contents

Item 4: General Investigational Plan

• Provided in initial IND and annual reports • Rationale for drug/clinical research • Indications to be studied • General approach to be followed in evaluating the drug • Kinds of clinical trials to be conducted in the next year • Anticipated risks

Item 5: Investigator’s Brochure

• Serves as a “label” and is a summary of all data known to sponsor • Supplied to investigators and IRBs • Regulatory references to be used: • 21 CFR 312.23(a)(5) • ICH E6 (GCP Guideline) includes information on format and content of Investigator’s Brochure

The Common Technical Document (CTD)

1 Regional Administrative Information

Not CTD

2.1 TOC 2.2 Introduction 2.4 Nonclinical Overview 2.5 Clinical Overview

2.7 Clinical Summaries

2.6 Nonclinical Written & Tabulated Summaries

2.3 Quality Overall Summary

CTD

5 Clinical Study Reports

4 Nonclinical Study Reports

3 Quality Data

Items 3 & 9: Module 2 Summaries

• Introductory Statement • M2.3 Quality Overall Summary (QOS) • M2.4 Nonclinical Overview • M2.5 Clinical Overview – Previous Human Experience – Benefits-Risk statement regarding investigational use

Item 6: Protocol(s) and Investigator Information

• Information resides in Module 5 • Protocol content and format is per 21 CFR 312.23(a)(6) and ICH E6 (GCP Guideline) • Investigator information

• Investigator’s Curriculum Vitae • Form FDA 1572 (signed copy) • Facilities information (Site and Lab), IRB Information

• NOTE: Submission of 1572 itself is not required; information can be provided on cover sheets but often it is more convenient to submit the 1572

Form FDA 1572

Statement of Investigator Information Sheet Guidance for Sponsors, Clinical Investigators and IRBs: Frequently Asked Questions - Statement of Investigator (Form FDA 1572) (May 2010 )

Item 7: Chemistry, Manufacturing and Controls

• Information resides in Module 3 • Chemistry, manufacturing, and control information & summary • Drug substance, drug product, placebo, active comparator • Per 21 CFR 312.23(a)(7)(a)(b) and (c)

Drug Substance (DS)

• Description of Drug Substance (Active Pharmaceutical Ingredient, API) • Physical, chemical biological properties

• Molecular formula • Structural formula • Elucidation of structure • Reference Standard • Can be brief for Phase 1 Studies

Drug Substance

• Name and address of DS manufacturer • Manufacture information on synthesis or formulation of drug substance • Specifications and analytical methods to assure the identity, strength, quality and purity of the drug substance • Stability

Drug Product (DP)

• List of components • Quantitative composition • Name and address of DP manufacturer(s) • Drug product, contract manufacturer, packager or labeler • Suppliers of components (compendial vs. non-compendial) • Contract QC laboratory

Drug Product

• Method of manufacturing and packaging • Specifications and analytical methods for inactive components • Compendial (e.g. USP-NF) standards and non-compendial • Specifications and analytical methods for the drug product • Stability

Additional CMC Items

• Placebo or Comparator Information • Additional drug product sections are needed if a placebo or comparator will be used in the trial • CMC data must be submitted to support each clinical trial for each formulation/strength

REFERENCES: FDA CMC Guidance for Industry - Investigational Products • cGMP for Phase 1 Investigational Drugs (Jul 2008) • INDs for Phase 2 and 3 Studies: Chemistry, Manufacturing and Controls Information (May 2003) • Content and Format of Investigational New Drug Applications (INDs) for Phase 1 Studies of Drugs, Including Well-characterized, Therapeutic Biotechnology-derived Products (Nov 1995)

Item 8: Pharmacology and Toxicology • Reports reside in Module 4 • Written and Tabulated Summaries in Module 2 – Tabulated summaries are applicable for IMPD – Written summaries not required but helpful • Pharmacology and Toxicology data must be submitted to support the dosing in each clinical study (duration and dose)

Duration of Repeated Dose Toxicity Studies to Support Clinical Trials – ICH M3(R2)

REFERENCE: ICH M3(R2): Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (Jan 2010) and ICH M3(R2): Questions and Answers (Feb 2013)

Duration of Clinical Trials

Minimum Duration of Repeated Dose Toxicity Studies

Rodents

Nonrodents

Up to 2 Weeks

2-4 Weeks

2 Weeks

Up to 6 Months

same as clinical trial

same as clinical trial

> 6 Months

6 Months

Chronic (9 months)

Item 9: Previous Human Experience

• Can be provided in Module 2 (2.5 and 2.7) • If available, study reports should be included • Integrated summary of previous investigational experience (US or Non-US) – Integrated summary of published clinical experience and copies of reprints – Non-US marketing experience • List of countries where marketed outside US and significant regulatory actions

Material in a Foreign Language

➢ Must submit an accurate and complete English translation of each part of IND not in English. Original material goes in this section.

Submission of the Initial IND

• Submit initial eCTD INDs through FDA’s Electronic Submission Gateway (ESG) • Submit initial paper submissions (only until 5/2018) to designated CDER or CBER document rooms for the type of product • 21 CFR 312.23(d) - for paper submissions, include original IND plus 2 copies • Red (archival/original), green and orange jackets » Forms FDA 2675, 2675a, and 2675b give jacket specifications

IND Timeline

• IND Review by FDA – FDA has 30 days to review an IND

• IND becomes “active” on the day of FDA receipt – Clinical investigations cannot begin until after the 30-day review period time unless FDA notifies sponsor earlier • Sponsor agrees to this when signing Form 1571 – FDA letter of acknowledgement will typically include the IND number and receipt date, and the 30-day date before which the clinical study in the IND cannot begin