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FDA OVERVIEW: Protecting Consumers -

Promoting Public Health

Frieda Houghton PhD

Worldwide Regulatory Strategy

Pfizer

June 2013

* SOME HISTORY, BACKGROUND & GENERAL INFORMATION ON THE US FOOD AND DRUG ADMINISTRATION

* INVESTIGATION NEW DRUG APPLICATIONS (IND’S)

* NEW DRUG APPLICATIONS (NDA’S)

TODAY

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FDA History Pure Food and Drugs Act of 1906 (concentrated on food):

– Agency was a “police force” with authority to seize adulterated or misbranded products shipped across state lines (“interstate commerce”).» Main Agency function: detect foods and drugs in violation;

samples tested in field labs » Violators prosecuted; difficult: “false and fraudulent” - proof

of intent to default consumers. Basis rested on product labeling.

» Act less effective as preventative measure; other shortcomings» Few amendments did little to correct significant shortcomings

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FDA History Federal Food, Drug and Cosmetic Act of 1938:

– Stimulus: Elixir of Sulfanilamide tragedy (diethylene glycol as a solvent)» Safety testing of drugs by manufacturer not required

– Expanded police powers and powers to regulate drugs and the industry.» FDA power expanded to regulate devices and cosmetics» Factory inspections authorized» “New Drug” defined as one “not generally recognized as safe for its

intended use” (“efficacy” added later)» Investigations in humans required to comply with Investigational

New Drug provisions» New Drug Application (NDA) must be submitted to FDA; only

safety assessment required initially (not efficacy)– Amended significantly over the years, often in response to medical

tragedy, scandal/fraud– Basis of current US drug law

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FDA Mission To promote and protect the public health by helping safe and

effective products reach the market in a timely way,

To monitor products for continued safety after they are in use,

To advance public health by helping to speed innovations that make medicines more effective, safer and more affordable,

To help the public get the accurate science-based information to improve their health

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FDA as US Government Agency FDA operates within the US Department of Health and Human

Services (HHS) - cabinet level department, reports to President– FDA is part of the Public Health Service division of HHS

FDA: Regulates drugs, foods, cosmetics, biologics, medical devices (products = ~25% of US consumer spending)– FDA employees

» ~1,000 “field” personnel (167 local offices) who inspect ~124,000 FDA-regulated firms; 17,000-22,000 inspections/year in recent years

Includes ~6,000 US pharmaceutical facilities» ~2000 scientists involved in review of new products and

product analysis

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What FDA Regulates Biologics Cosmetics Drugs Foods Medical Devices Radiation-Emitting Electronic Products Veterinary Products

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What FDA Does Not Regulate General Advertising – Federal Trade Commission (FTC); *FDA

regulates prescription drug and medical device advertising Alcohol – Bureau of Alcohol, Tobacco and Firearms (Treasury

Department) Consumer Products – Consumer Product Safety Commission (CPSC) Drugs of Abuse – Drug Enforcement Administration (DEA) Health Insurance – Centers for Medicare and Medicaid Meat and Poultry – Food Safety and Inspection Service (US

Department of Agriculture); *FDA regulates game meats, such as venison, ostrich and snake

Pesticides – US Department of Agriculture; Environmental Protection Agency (EPA)

Restaurants and Grocery Stores – Local/county health departments Water – Environmental Protection Agency (EPA); *FDA regulates

labeling and safety of bottled water

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Drug Development and US Approval Process: Overview

To market a drug in the US, the law requires that the drug must be SAFE and EFFECTIVE (Benefits outweigh Risks)

The basic process:– The drug developer (firm, sponsor) must prove to the

drug regulator (Food and Drug Administration - FDA) that the drug is safe and effective

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Drug Development and US Approval Process: Overview

Sponsor activities:– Conduct laboratory, animal and human studies to

demonstrate drug safety and efficacy– Develop testing, manufacturing and controls to assure that

the drug meets all legal requirements and “has the identity and strength…quality and purity characteristics that it purports or is represented to possess” (GMPs)

– Submit all the data and information in an appropriate format for FDA review (e.g., the IND, the NDA)

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Drug Development and US Approval Process: Overview

FDA activities:– Decide what constitutes substantial evidence of

safety and efficacy of the drug– Interpret Federal (US) Food and Drug Law– Write and enforce Federal Food and Drug

Regulations– NB: Regulations have the force and effect of law!

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The FDA Amendments Act (FDAAA) – Sept 27, 2007 Reauthorized

– Assessment of User Fees (PDUFA V)– The Pediatric Research Equity Act (PREA) – The Best Pharmaceuticals for Children Act (BPCA)

Other major topics covered include– A new fee program for obtaining FDA advisory review of direct-to-

consumer (DTC) television advertisements– New FDA authorities for requiring label changes and post-marketing

studies, and for REMS (risk evaluation and mitigation strategies)– New/expanded requirements for registration of clinical trials and

disclosure of results– Formation of the Reagan-Udall Institute in support of FDA's Critical

Path initiative– New conflict of interest rules for FDA Advisory Committee members– New rules on citizen petitions

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Prescription Drug User Fee Act (PDUFA)

Passed in 1992 (reauthorized 1997, 2002, 2007, 2012) Authorized FDA to collect fees from companies that

manufacture certain products– Fee Rates for FY 2013

» NDA ~ US$ 1.9m

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FDA Authority and Primary Sources of Information

Federal Food, Drug, and Cosmetic Act (1938) Code of Federal Regulations, Title 21 (21 CFR)

– IND : 21 CFR 312– NDA: 21 CFR 314– GMP: 21 CFR 210, 211– GLP : 21 CFR 58– GCP :

» 21 CFR 50 - Protection of Human Subjects» 21 CFR 56 - Institutional Review Boards (IRBs)» 21 CFR 312 - IND regulations

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FDA Authority and Primary Sources of Information

FDA Guidelines: No longer issued by FDA FDA Guidances: Not legal requirements;

however… Compliance Policy Guides – Important for

compliance related activities (e.g., inspections) FDA written and voice communication to sponsor,

“Advice” from Agency personnel, FDA presentations to industry/public

NOTE: While the above are all subject to change, the processes in many ways are becoming more standardized.

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FDA-Sponsor Interactions:Meetings - General Meetings with FDA covered by “Guidance for Industry

- Formal Meetings Between FDA and Sponsors or Applicants”– Final issued 5/09

Specifies:– Types of meetings (including timing of FDA scheduling of meeting):

» A - Immediately necessary for a stalled development program to proceed (30 days); e.g., dispute resolution, special protocol assessment

» B - Pre-IND, EOP 1/EOP 2/Pre-Phase 3, Pre-NDA meetings (60 days)» C - Other (75 days)

– Procedures for requesting a meeting– Contents and timing of submission of Information Package– Procedures for conduct of meeting– Documentation (e.g., minutes)

INVESTIGATIONAL NEW DRUG

IND’s

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IND - Investigational New Drug Application

"Notice of Claimed Investigational Exemption for a New Drug"

Request to FDA by a sponsor to be allowed to study an investigational new drug (unapproved new drug) in humans

“Exemption” from provisions of FD&C Act that govern shipment of unapproved drugs via interstate commerce

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IND Covers the Following for Use in Clinical Investigations:

New Drugs New Antibiotic Drugs New Biological Drug New Biological Products used in vitro for

diagnostic purposes New indication, different dosage or

different route of administration for an approved product

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IND – Not Needed For:

Approved/marketed product using an approved dosage and for an approved indication

Studies not supporting “significant”changes in labeling or advertising

Studies not putting patients at increased risk Certain bioavailability/bioequivalence studies

(See 21 CFR 320.31 Bioavailability and Bioequivalence Requirements)

A drug solely intended for in vitro or animal testing In vitro biological product for diagnostic procedure that

confirms diagnosis made by another medically established diagnostic product or procedure

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IND Types

Types of INDs:– IND submitted by commercial sponsor (by a

pharmaceutical company)– Treatment IND/Treatment Use IND– Sponsor-Investigator IND– Emergency Use (“Compassionate Use”) IND

» For a single patient only

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IND: Content

Provides data and information regarding:– The drug product– Its composition– Active ingredient, its source, synthesis– Method of manufacture and controls– How it is intended to be used in patients– Results of preclinical studies that show it is

“reasonably” safe to begin/continue testing in humans– Detailed outline of the planned human studies

(protocols)

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IND: FDA Focus Primary focus of FDA: Safety and rights of human subjects

– Assure that human subjects are not subjected to unreasonable risks– Assess the adequacy of the preclinical program to support the proposed

studies– Verify approval of the studies by the Institutional Review Board (IRB)– Review the credentials and commitments of the clinical investigators

Assess the likelihood that the clinical plan will produce information useful to the ultimate approval of the product

Assess the adequacy of the proposed clinical protocol to produce clinically meaningful results

Assess the "fair balance" of the investigator's brochure (labeling) and its ability to inform the clinical investigators of background scientific data

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FDA Review of the IND FDA receipt - Initial administrative review for completeness

– Technical reviews:» Medical Officer - Generally the team leader» Chemist - Quality of clinical supplies, GMPs» Pharmacologist/Toxicologist- Adequacy of preclinical program» Statistician - Adequacy of statistical plan, power, patient numbers, etc.

for statistical significance/proof» Project Manager - Liaison between FDA and sponsor

– 30-day “review clock”– No formal IND approval: “No news is good news”

» Minor issues, usually limited to requests for clarification - Communicated by phone

» Major issues/concerns - Generally written response required

Clinical Hold - Serious concerns!

IND maintenance Protocol amendments

– New protocol– Changes to existing protocol(s)

IND information amendments IND safety reports

– Serious and unexpected adverse experiences » Written report of adverse reactions both serious and unexpected. NMT 15

calendar days after initial receipt of information by sponsor» Telephone/fax for unexpected fatal or life-threatening reactions. NMT 7

working days after receipt of information

IND annual reports– focus for reporting status of the studies and should update the general

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IND Amendments and Reporting:Annual Reports

Individual study information Summary information for past year:

– Most frequent and serious ADRs– Summary of safety reports– Subjects who died, plus cause of death– Drop-outs associated with ADRs– Information learned regarding drug actions– Preclinical studies completed or ongoing– Significant manufacturing or microbiological changes

General investigational plan for coming year Revisions of investigator brochure, plus copy Significant Phase 1 protocol revisions not previously reported Significant foreign marketing developments (e.g., approvals, withdrawals) Outstanding business (if desired)

NEW DRUG APPLICATIONSNDA’s

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Overview of NDA Process

Sponsor believes IND studies (supported by nonclinical studies) demonstrate that drug is safe and effective

Sponsor believes that CMC (Chemistry, Manufacturing and Controls = Quality) data and information demonstrate that the finished product can be manufactured consistently to conform to appropriate controls and specifications

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Seeking Approval: Regulatory Strategy

Depending on the drug, disease, business decision, a Sponsor may seek the following types of approval– Traditional– Accelerated Approval– Orphan Drug

» Can also have accelerated approval of an orphan drug

Also must consider the filing/review type – Fast Track– Priority– Standard

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Overview of NDA Process

Sponsor submits New Drug Application (NDA), which contains detailed information regarding (among other things):– Composition of drug– Method of manufacture and control– Intended use and conditions of use of the drug (labeling: package

insert, labels, other written, printed or graphic material accompanying the product)

– Preclinical studies– Clinical studies– Statistical analysis of data

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Overview of NDA Process

New Drug:– One which is not recognized in the US as being safe

and/or effective for its intended use– Drug not yet approved in the US, even if approved in

other parts of the world NDA is reviewed by FDA team consisting of

medical officer (physician), pharmacologist, chemist, statistician and other personnel

Major NDAs and scientifically complex NDAs may be referred to an advisory committee

“Deficiencies” identified by FDA during the review are addressed by sponsor

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NDA Screening/Filing Timeframe for Reviewing Applications

– 10-month standard and 6-month priority review– Within 6 or 10 months of receipt of NDA, FDA

must review it and issue an "action letter" (statutory requirement; “never” met prior to PDUFA*)» Review clock may be extended:

By mutual agreement, or As a result of a "major" amendment to the NDA

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NDA Screening/Filing

FDA may refuse to file (RTF) the application based on quality, administrative, scientific and/or technical deficiencies

Filing of an Application– If acceptable, NDA is considered "filed"– Applicant is notified in writing

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NDA Filing Review for Filing of an Application (new PDUFA V timelines)

– 74 Day letter. To include information on the planned review timeline, the internal mid cycle review meeting, plans date and preliminary AC.

– Mid cycle FDA communication with the sponsor. Identifies any significant review issues, major safety concerns, preliminary risk management plans and AC plans. Sponsor can request a F2F mid-cycle meeting, (month 5).

– Discipline Review (DR) letter (~month 6).– Late cycle FDA sponsor communication meeting. Includes discipline

review members and DR leads from identified issues/areas of major issues, AC topics, REMS, additional data requests and clock extension implications. (~ late month 6).

– Advisory Committee meeting (if needed) @ month 7.– Action date month 10.

Do the benefits outweigh the risks??

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NDA Amendments (during review)

Amendment - Change in a pending (unapproved) application

Can be initiated by sponsor or FDA "Major" Amendment - Significant new data

– Constitutes agreement by applicant to extend the "review clock"

– FDA decides the extension time - up to 180 days– FDA must notify the applicant of the extension

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Communication with FDA During NDA Review General:

– May be telephone, letters, meetings, whichever is most appropriate– Must be documented by FDA, according to regulations and policy– Should be documented by applicant

Notification of Easily Correctable Deficiencies– Information Request (IR) Letter:

» Sent during an NDA review; request for information or clarification needed to allow completion of the discipline review

– Discipline Review (DR) Letter:» Sent at conclusion of discipline review; used to convey possible

deficiencies– IRs or DRs do not stop the “review clock,” but sponsors usually

respond quickly; FDA may specify a submission time to avoid delays in review

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FDA Action Letters:“Approval” and “Complete Response”

"Approval" Letter– Drug is safe and effective as prescribed– Approval becomes effective on the date of the letter– Allows marketing to begin, subject to specified conditions

“Complete Response" Letter– Describes the information or materials required or the conditions to be met

for approval– Within 10 days after the date of the letter, applicant must notify FDA with

one (1) of the following:– Amend the application– Intent to amend the application– Withdraw the application, without prejudice to resubmitting (failure to

respond = withdrawal)– Request a hearing– Request an extension of the review period

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Back-ups

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Drug Regulation: Key Terms FDA - Food and Drug Administration IND - Investigational New Drug Application NDA - New Drug Application GMP, CGMP, cGMP - Current Good Manufacturing

Practices GLP, CGLP, cGLP - Current Good Laboratory

Practices GCP, CGCP, cGCP - Current Good Clinical Practices

See also CDER Acronym List: 12 pages!http://www.fda.gov/cder/handbook/acronym.htm

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The Discovery, Development, & Approval Process

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IND

Focus of initial IND submission: The general investigational plan and the protocols for specific studies– Subsequent amendments, new or revised protocols: Should build

logically and scientifically on previous submissions and should be supported by additional information

Annual reports to the IND: – Should serve as the focus for reporting status of the studies and should

update the general investigational plan for the coming year

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FDA-Sponsor Interactions: IND Pre-IND Meeting

– FDA's introduction to the drug (and sponsor?)– Sponsor provides in pre-meeting submission:

» Product rationale» Product formulation, manufacture and controls» Preclinical program» Proposed clinical program, protocol(s)» Additional information as needed

– At meeting, FDA provides:» Comments/guidance regarding the above» Items necessary for IND to be acceptable

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IND Amendments and Reporting Protocol Amendments

– New Protocol» Study can begin, provided:

New Protocol has been submitted to FDA for review New protocol has been approval by IRB

– Changes in Protocol» Phase 1 - Significantly affects safety» Phase 2 and 3 - Significantly affects safety, scope of investigation or

scientific quality of the study: increase in dosage or duration of exposure significant increase in number of subjects significant protocol design change, e.g., add or delete a control group addition or deletion of procedure for monitoring safety

» Revised protocol can be implemented, provided: Revised protocol has been submitted to FDA for review Revised protocol has been approved by IRB

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IND Amendments and Reporting

Protocol Amendments (cont’d)– Protocol change to eliminate immediate hazard to

subjects» Change protocol immediately» Notify FDA and IRB

– New investigator» Notify FDA within 30 days of addition» Can begin shipping drug as soon as added

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IND Amendments and Reporting

Information Amendments– New toxicology, chemistry or other technical

information– Report of discontinuance of an investigation– “Other”– Submit amendments no more frequently than every 30

days (can combine Protocol and Information amendments in one submission)

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IND Amendments and Reporting

IND Safety Reports– Serious and unexpected adverse experience associated

with the use of the drug» Serious: Death, a life-threatening ADE, inpatient

hospitalization or prolongation of existing hospitalization, a persistent of significant disability/incapacity, or a congenital anomaly/birth defect

» Unexpected: Specificity or severity not consistent with the current investigator's brochure; ADE not previously observed

» Associated: Reasonable possibility that the experience may have been caused by the drug

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IND Amendments and Reporting IND Safety Reports

– Written Report» For adverse reactions both serious and unexpected» Any finding from tests in lab animals that suggests a significant risk

in humans» NMT 15 calendar days after initial receipt of information by sponsor

– Telephone and Facsimile Transmissions Report» For unexpected fatal or life-threatening reactions» NMT 7 working days after receipt of information» Life-threatening: Immediate risk of death from the ADE as it

occurred– Disclaimer: Submission does not necessarily reflect a conclusion

by the sponsor of admission of causal relationship

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IND Types

Treatment IND (21 CFR 312.34 and 312.35)– For serious or immediately life-threatening disease– When alternate drug/therapy not satisfactory/available– Drug is already under investigation in a controlled trial,

or all clinical trials have been completed, and– Sponsor is actively pursuing marketing approval– Drug may be allowed for use in patients not in the

clinical trials– Drug may be allowed for use as early as during Phase 2– “Treatment protocol” required– All other IND requirements apply

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IND Types

Sponsor-Investigator IND*– All legal requirements for both a sponsor and an

investigator regarding conduct of an IND apply to sponsor-investigator, including the regulations for:» 21 CFR 312 (INDs)» 21 CFR 50 (Protection of Human Subjects/Informed Consent)» 21 CFR 56 (Institutional Review Boards)

– Not intended to replace traditional company-sponsored IND to initiate clinical trials or commercialize usage

*Defined in 21 CFR 312.3(b)

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IND Types

Emergency Use IND* (21 CFR 312.36)**– Emergency need arises that does not allow time to

submit a formal IND– FDA may authorize shipment of drug for specified use

in advance of a submitted IND– Initial contact usually initiated by telephone– One-time use (i.e., one patient) only– Sponsor required to submit IND ASAP following

authorization to ship drug– Usually initiated by Sponsor-Investigator with

“permission” from drug sponsor (drug company)*AKA ”Compassionate Use”

**See also the following link: http://www.fda.gov/cder/cancer/SingleIND.htm

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FDA-Sponsor Interactions: IND End-of-Phase 1 Meeting

– Usually reserved for "expedited" review procedures (e.g., Treatment IND)

– Agree on design of Phase 2 studies End-of-Phase 2 Meeting

– Determine the safety of proceeding to Phase 3– Evaluate the Phase 3 plan and protocols– Identify additional information needed to support the NDA– Pre-meeting submission:

» Summaries of Phase 1 and 2 studies» Phase 3 protocols» Plans for additional nonclinical studies, if any» Tentative labeling, if available; confirm target indication

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FDA-Sponsor Interactions: IND Pre-NDA Meeting

– Uncover any major unresolved problems– Identify/confirm "adequate and well-controlled"

studies– Provide general information that will be submitted in

NDA– Discuss statistical analysis– Agree on presentation and format of data– Pre-meeting submission:

» Summaries of clinical studies» Proposed NDA submission content (also format, if applicable)» Specific issues to be discussed

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Filing the NDA When to File

– Filed at completion of all 3 phases (with exception of accelerated approval)

What is included– Contains all of the scientific information (studies in animals and humans) – Addresses safety and efficacy of drug

What to Consider for a Timely Review– Submit complete, high quality applications– Prompt, efficient responses to reviewer inquiries– Electronic applications– Enhanced Navigation

» Hyperlinking and Bookmarks

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NDA Content and Format

The NDA is a comprehensive, highly structured presentation of data and information which:– Demonstrates (proves) safety and efficacy of the new drug– Supports the labeling (PI), indications and intended promotion of

the new drug--all promotions must be traceable to the PI, which is supported by NDA data!

FDA expectations: Appropriate content, format:– Excellent data are the basis of an excellent NDA!– Complete, accurate, well indexed, easily accessible data and

information allow for easy FDA review

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Traditional Approval

Completion of Phase 3 clinical studies Full data package

– Application with sufficient data to demonstrate» Safety and Efficacy» Clinical Benefit

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Accelerated Approval Intended to make promising products for life threatening diseases

available on the basis of preliminary evidence prior to formal demonstration of patient benefit

» Under Subpart H (21CFR314.510) Approval based on a surrogate endpoint or on an effect on a clinical

endpoint other than survival or irreversible morbidity– A measurement that is considered likely to predict patient benefit

Considered provisional approval with a written commitment to complete clinical studies that formally demonstrate patient benefit – If studies don’t confirm the initial results, the FDA can withdraw approval– Postmarketing studies would usually be studies already underway

Approval designation does not necessarily lead to a Priority Review Examples include:

– Most HIV drugs– Certain cancer drugs

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Filing Option Fast Track

– A formal mechanism to interact with the FDA using approaches that are available to all applicants for marketing claims.

– Benefits of include » Scheduled meetings to seek FDA input into development plans» The option of submitting a New Drug Application in sections rather

than all components simultaneously» The option of requesting evaluation of studies using surrogate

endpoints (Accelerated Approval)– Intended for the combination of a product and a claim that addresses an

unmet medical need, but is independent of Priority Review and Accelerated Approval

– Upon agreement with FDA, an applicant may use any or all of the components of Fast Track without the formal designation

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Orphan Drug A rare condition that affects fewer than 200,000 people nationwide (e.g.,

cystic fibrosis, Lou Gehrig’s, Tourette’s syndrome)» There are about 6,000 rare diseases that affect about 25 million

Americans» New rare diseases are discovered every year

Congress passed the Orphan Drug Act (ODA) in 1983» Applies to drugs and biologics» Provide financial incentives, including tax credits for cost of clinical

research » Seven years of exclusivity if approved first» FDA Assistance with Protocol Development

Since 1983, ODA has resulted in the development of more than 250 orphan drugs

» A decade before, there were fewer than 10 such products

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NDA Content and Format