Chapter 3 - RAPS Regulatory Exchange

Chapter 3
Overview of Drug, Biologic and Device Regulatory Pathways
- Code of Federal Regulations (CFR) divided into
50 parts that represent broad subject areas. For
drug and devices:
-Title 21 (Food and Drugs)
-Chapter 1 (Food and Drug Administration)
are the most relevant
- Table 3.1 shows a summary of the 1499 parts
in Title 21
- You can access the CFR through the FDA for
drugs and devices at:
CFRSearch.cfm or
Generic Drugs for Human Use and the Abbreviated New
Drug Application (ANDA)
Drug Price Competition and Patent Term Restoration Act (Hatch-Waxman Act)
 Passed in1984
 Expedited availability of less-costly generic drugs by permitting FDA to approve abbreviated
applications (ANDA) after patent of innovator drug expired
 “Abbreviated” not required to include animal safety and clinical data to establish safety and
 Oral dosage forms had to demonstrate product is bioequivalent to innovator drug
ANDA comprised of three primary components
Chemistry, manufacturing and controls (CMC) information
Bioequivalence data
Administrative information (including labeling and patent certification information)
Covers how and where OGD (Office of Generic Drugs) will release bioequivalence
recommendations for specific products in the future.
All approved products listed at:
ANDA must contain statement by applicant that one of the following patent certifications
applies for the Reference Listed Drug (RLD):
 The patent information has not been filed (Paragraph I)
 The patent has expired (Paragraph II)
 The patent will expire on a specific date (Paragraph III) sponsor submitting the ANDA does not intend to
market its product before that date
 The patent is invalid or will not be infringed by the proposed drug product (Paragraph IV)
 Applicant needs to notify NDA holder and patent owner
 NDA holder brings action for patent infringement within 45 days of notification
 FDA will not approve the ANDA for 30 months
 Shorter or longer if a court orders, or until date of court decision (30 month stay)
30 month stay also known as 180-Day Exclusivity (detailed in Guidance to Industry: 180-Day
Exclusivity When Multiple ANDAs are Submitted on the Same Day (July 2003))
21 CFR 314.80 post marketing reporting of adverse drug experiences
21 CFR 314.81 field alert reports and annual reports
OGD Website is a good resource
Suitability Petitions
21 CFR 314.92 and Section 505(j) of FD&C Act
 Contains regulations regarding ANDAs
21 CFR 314.92 cross references 21 CFR 314.93
 Provides information on what characteristics a generic drug not identical to the RLD (Referenced Listed Drug)
can possess and still be submitted as an ANDA
 Subjected to acceptance by FDA of a suitability petition
Suitability Petition
Sponsor submitted
Seeks permission to file an ANDA
Contains comparisons and contrast between generic drug and the RLD
FDA required to respond within 90 days
Not accepted then NDA under section 505(b)(2) of the FD&C Act may be an option or a citizen petition
Branded Generics
 Brand: Approved in same manner as all generics
 ANDA applicant also applies for and receives a brand
 Guidance for Industry: Contents of a Complete Submission for the Evaluation of Proprietary Names (Feb
Authorized generics
 Drug product for which there is a licensing agreement between innovator company and generic
drug manufacturer
 List (updated quarterly) of authorized generics, including the original NDA applicant name is
available at:
 Benefits: avoid ANDA review/approval process, can be added to original NDA as supplement or
described in NDA annual report, allow company to continue making a profit from generic product
 Patient Protection and Affordable Care Act
 Signed March 2010
 Contains subtitle called Biologics Price Competition and Innovation Act of 2009 (BPCI Act)
 Amends section 351 of Public Health Service Act
 Creates an abbreviated approval pathway for biological products shown to be highly similar
or interchangeable with an FDA-licensed reference biological product
 Currently soliciting input regarding the implementation and considering how to deal with
biosimilars that are regulated under Section 505 of the FD&C
New Chemical Entities and the New Drug Application for a
Marketing Application for Human Use (Section 505(b)(1))
Overview of the Approach to Drug Development and Approval
 Drug is defined as a product used in diagnosing, curing, mitigating, treating or preventing a disease or
affecting a structure of the body (21 CFR 310.3)
 Under the same regulation, a drug is considered a new drug if:
 New drug use of any substance (e.g., active ingredient, excipient, carrier, coating etc.) which composes the drug
 New drug use of a combination of approved drugs
 Proportion of the ingredients in combination is changed
 New intended use for the drug
 Dosage, method or duration of administration or application is changed
 The following are subject to FDA approval:
 A drug containing a novel chemical compound as its active ingredient (new chemical entity (NCE))
 A drug containing an existing active ingredient that has never been approved for use as a medicine in the US (also an
 A drug previously approved by FDA but now proposed for a new use or indication
 A drug previously approved by FDA but in a dosage form, route of administration or other key condition of use different
from what was originally approved
Virus Serum and Toxin Act (also known as Biologics Control Act)
 Passed in 1902
 Result of St. Louis tetanus contamination
 Infected serum and smaller occurrences of contaminated smallpox vaccine and diphtheria antitoxin
 Act authorized Hygienic Laboratory of the Public Health and Marine Hospital Service (became PHS)
 Issues regulations governing all aspects of commercial production of vaccines, serums, toxins, antitoxin and similar
products with objective of ensuring their safety, purity and potency
Hygienic Laboratory (1934), (renamed NIH in 1930 by Ransdell Act)
 Issued a regulation stating that licenses to manufacture new biologics would not be granted without evidence
that products were effective
Public Health Service Act of 1944 (PHS Act)
 Reorganization of PHS
 Authority given to NIH to license, research and develop new biological products
Division of Biological Standards (part of NIH and in turn part of PHS)
 Transferred to FDA eventually became (CBER)
 Biologics are classified as drugs under FD&C Act even though PHS Act established the regulation of biologics
 New biologic products require approval based on safety and efficacy before marketing
 (Biologics License Application (BLA) as opposed to an NDA)
Biologics Continued
Biologics are defined as substances derived from or made with the aid of living organisms
Review and approval of must products conducted by CBER
Allow CBER to focus on vaccines, blood products and other more complex products such as gene
therapy FDA shifted the review and approval of biological therapeutics (primarily oncology
products, peptides or well characterized proteins) from CBER to CDER in 2003
Drug development: characterizing the safety profile (risk) and the efficacy profile (benefit) as it
relates to the body's exposure to the drug (pharmacokinetic profile)
Evaluations are performed in the following order based off of risk, cost and time.
In vitro
Live animals (juvenile if applicable)
Adult humans (often in healthy subjects before patients)
Children (if applicable)
Table 3-2. Key Questions to be Addressed in a Drug Development Program
FDA Sponsor Meetings
Prescription Drug User Fee Act in 1997
 Reauthorized in 1992
 A formal process for meetings was established
Guidance Formal Meetings Between the FDA and Sponsors or Applicants
Guidance for Industry: Special Protocol Assessment (May 2002)
 FDA will evaluate certain protocols and related issues within 45 days of receipt to determine whether they
meet scientific and regulatory requirements identified by the sponsor
 Three types of protocols are eligible for SPA under PDUFA:
 Animal carcinogenicity protocols
 Final product stability protocols
 Clinical protocols for Phase 3 trials, data from which will form the basis for an efficacy claim if the trials were discussed at
an end of phase 2/pre phase 3 meeting with the review division
Orphan Drug Designation
• Orphan
Drug Act
Signed into law in 1983
Codified in 21 CFR 316
1984 amendment redefined “rare disease or condition”
1985 amendment extended marketing exclusivity to patentable as well as
unpatentable drugs and allowed federal grants for the clinical evaluation of orphandesignated drugs.
 1988 amendment required industry sponsors to apply for orphan designation prior to
submission of a marketing application
Other Initiatives
 Food and Drug Administration Modernization Act of
 Included a provision that exempted designated orphan drug products from paying
new drug application fees
 Allowed sponsors to seek waivers of annual post approval establishment and
product fees on a case by case, year by year basis
 Food and Drug Administration Safety and Innovation
Signed in July 2012
Expanded the accelerated approval pathway
Defined a new “break through therapy” designation
Increased FDAs communication with rare disease medical experts
 Sponsor incentives
 Seven years of exclusive marketing rights for designated indication once the drug
receives FDA marketing approval
 Tax credit for up to 50% of qualified clinical research expense incurred in
developing a designated orphan
 Eligibility to apply for orphan drug grants
Fast Track Designation
 Guidance for Industry: Fast Track Drug Development Programs – Designation, Development, and
Application Review
 Describes fast track drug development program
Breakthrough Therapy Designation
 FDA posted “Fact Sheet: Breakthrough Therapies”
ICH and FDA Guidelines and Their Relationship to the Development Process
 ICH and the CTD Format
 Formed in 1990
 Brings together EU, Japan and US
 4 major categories:
 Quality
 Safety
 Efficacy
 Multidisciplinary
 CTD divided into 5 modules
 MedDRA designed to support the classification, retrieval, presentation and communication of medical information
throughout the regulatory cycle for drugs and medical devices
Module 1
 Region specific (US, EU, Japan)
 US submissions will contain various FDA forms, draft labeling, risk evaluation and mitigation strategies
(REMS), key FDA correspondence, patent information and investigators brochure (IB)
Module 2
 Intended for all regions
 CTD summaries of three technical areas
 Module 3 Quality (see Guidance for Industry M4Q: The CTD—Quality (August 2001)) and corresponding summary in
Module 2.3
 Module 4 Nonclincal/Safety (see Guidance for Industry MS4: The CTD—Safety (August 2001)) corresponding summaries
in Module 2.4 Nonclincal Overview and 2.6 Nonclinical Written and Tabulated Summaries
 Module 5 Clinical (see Guidance for Industry M4E: The CTD—Efficacy (August 2001) and corresponding summaries in
Module 2.5 Clinical Overview and 2.7 Clinical Summary
 Submitting electronically good starting point can be found in Guidance for Industry M2 eCTD: Electronic
Common Technical Document Specification (April 2003)
Over 800 guidelines issued since 1977 by CDER and CBER
The Initial IND and IND Amendment Process
Drug sponsor must submit nonclinical, CMC and previous human experience data before initiating
clinical trial
IND Application requests permission to initiate clinical trials
IND Regulations detailed in 21 CFR 312
IND Application is request for exemption from federal law, not a request for approval
After receipt FDA will send sponsor a letter with assigned IND number
 Letter indicates proposed clinical trial can’t begin until 30 calendar days after receipt of IND
 FDA required to inform sponsor within 30 calendar days, if judged not to be reasonably safe
 Sponsor not contacted within 30 days, approval to initiate clinical trials is implicit
 Advisable for sponsor to contact FDA project manager assigned to IND to develop a relationship to confirm results
Pre-IND meeting held with FDA, assigned P-IND number becomes IND number (“P” is removed) initial
submission is given a serial number (SN) 0000
Form FDA 1571 must accompany any submission (except a Pre-IND meeting request)
Form completed and signed by Sponsor
Form FDA 1571 contains sponsor and drug product information and an indication of what the submission contains
IND submission must contain clinical study protocol and at least 1 completed Form FDA 1572
 This form contains study site details and IRB name and address, signed by investigator acknowledging legal responsibilities
indicated on form and in 21 CFR 312.60
 No 30 day review period for amendments
21 CFR 312.23
 Content and format of initial IND
 Follows items listed in Section 12 of Form 1571 and includes IB, clinical protocol, CMC information,
nonclinical pharmacology and toxicology information and previous human experience information
Active INDs can be withdrawn per 21 CFR 312.38 or considered inactive (21 CFR 312.45)
 Sponsors required to submit expedited safety reports for serious, unexpected adverse reactions to IND per 21
CFR 312.32
 Serious Adverse Event (SAE)
 Any untoward medical occurrence that results in death, is life-threatening, requires subject hospitalization or prolongation
of existing hospitalization, results in persistent or significant disability/incapacity or is a congenital anomaly/birth defect
Guidance for Industry: E2F Development Safety Update Report (August 2011)
 Describes a new approach for annual safety reporting
Food and Drug Administration Amendments Act of 2007 (FDAAA)
 Includes all controlled clinical trials in patients
 Requires clinical trials to be registered with Clinical Trials Data Bank (maintained by NIH National Library
of Medicine)
 Accessed at
For electronic applications, specific instructions are available on FDA’s website for requesting a preassigned eCTD application number via secure email
Package Information can be found at:
Electronic Submission Information can be found at:
REMS (Risk Evaluation and Mitigation Strategies)
 FDA’s mandate to mitigate potential risks of drugs throughout their development and marketing life-cycled to
the issuance of three guidances in 2005
 Guidance for Industry: Premarketing Risk Assessment,
 Guidance for Industry: Development and Use of Risk Minimization Action Plans
 Guidance for Industry: Good Pharmacovigilance Practices and Pharmacoepidemiologic Assessment
Proprietary Name
 If not previously submitted, a request for review of the sponsor’s proposed proprietary name(s) should be made
to the review division under the
 IND (Draft Guidance for Industry: Contents of a Complete Submission for the Evaluation of Proprietary Names (February
User Fees
 Under PDUFA of 1992 user fees were levied on each “human drug application
 approval of a new drug submitted under section 505(b)(1) after 1 September 1992
 approval of a new drug submitted pursuant to section 505(b)(2) after 30 September 1992 for certain molecular entities or
indications for use
 licensure of certain biological products under section 351 of the PHS Act submitted after 1 September 1992
 Additional information found in Guidance for Industry: Submitting Separate Marketing Applications and
Clinical Data for Purposes of Assessing user Fees (December 2004)
 Also more information can be found at:
Periapproval Activites
 Guidance for Industry: Standards for Securing the Drug Supply Chain—Standardized Numerical
Identification for Prescription Drug Packages (March 2010)
 Federal Advisory Committee Act
 Passed in 1972
 Prescribed the formal use of Advisory Committees throughout the federal government
Establishing Listing
 Under 21 CFR 207 FDA requires establishments (e.g., manufacturers, repackers and relabelers) upon first
engaging in the manufacture, preparation, propagation, compounding or processing of human drugs,
veterinary drugs and biological products, with certain expectations, to register their establishments and
submit listing information for all drugs and biological products in commercial distribution
Form FDA 2656 used for registration of drug establishment
Form FDA 2657 used for drug product listing purposes
More information can be found in Draft Guidance for Industry: Forms for Registration of Producers
of Drugs and Listing of Drugs in Commercial Distribution (April 2001) and at
Patent Restoration
 Drug Price Competition and Patent Term Restoration Act (the Hatch-Waxman Act)
 Information found at :
 Can also request 6 months exclusivity, more details can be found at:
NDA Amendments
 Submitted to change or add information to an unapproved NDA or NDA supplement
 Exception of 120 day safety update, sponsors need to try and avoid initiating NDA amendments because they
will potentially reset the review clock
The 505(b)(2) NDA
“paper” NDA approach was created after passage of 1962 Drug Amendments to the FD&C Act
Hatch-Waxman Act, Eliminated paper NDA policy
505(b)(2) NDA is a submission type that shares characteristics of both traditional NDAs and
Application is submitted under Section 505(b)(1)
Approved under Section 505(c)
May refer to FDAs finding of safety and effectiveness for previously approved product
Additional details found in Draft Guidance for Industry: Applications Covered by Section 505(b)(2) (October
 Regulations codified in 21 CFR 314.54
Bridging and Expansion issues and Approaches
 Most common uses of 505(b)(2) are:
 change in drug product dosage form (including route of administration), formulation, strength and/or dosing regimen,
including changes that were not accepted by OGD in a Suitability Petition
 change in active ingredient (different salt, acid or base)
 new combination product in which the active ingredients have been previously approved individually
 change from a prescription indication to an over the-counter (OTC) indication
 indication that has not been previously approved for the active moiety
 NCE that is a prodrug or active metabolite of a drug approved in the US
Dietary Supplements and Natural Health Products
Dietary Supplement Health and Education Act (DSHEA)
Passed in 1994
Amended the FD&C Act
Created a new regulatory framework for the safety and labeling of dietary supplements
Set forth new labeling requirements and required manufacturers of dietary supplements to notify FDA of new
dietary ingredients prior to marketing
Authorized FDA to prescribe GMPs for the industry
The Final Rule on cGMPs in Manufacturing, Packaging, Labeling or Holding Operations for Dietary
Supplements established dietary supplement CGMPs for all domestic and foreign companies that
manufacture, package, label or hold these supplements, including those involved with testing, quality control,
packaging and labeling and distribution in the US
Don’t require premarket approval
Dietary Supplement and Nonprescription Drug Consumer Protection Act passed in 2006
 Mandates same type of adverse event reporting for dietary supplements as for prescription drugs
 claims of benefits related to nutrient deficiencies (if the prevalence of the disease in the US is disclosed)
 claims describing the role of the dietary supplement’s effects on structure or function in humans (e.g., “calcium builds
strong bones”)
 claims describing the mechanism of effects on structure or function (e.g., “fiber maintains bowel regularity”)
 claims of general well being
 More details found in Guidance for Industry: Structural/Function Claims Small Entity Compliance Guide
(January 2002) and Chapter 30 Dietary Supplements and Homeopathic Products
Over-the-Counter (OTC) Drugs
OTC product is a drug product marketed for use by the consumer without the intervention of a
healthcare professional.
 more than 80 therapeutic categories of OTC drugs
 more than 100,000 OTC drug products are marketed in the US
 encompassing approximately 800 active ingredients.
Durham-Humphrey Amendment to the FD&C Act
 Distinction between drugs that do or do not require prescription
 FDA applied the principle of retrospective review to OTC drugs starting in 1972
 21 CFR 328-358
Drug Facts label regulation in 1999
 Information must appear in the indicated order
product’s active ingredients, including the amount in each dosage unit
purpose of the product
product uses (indications)
specific warnings, including when the product should not be used under any circumstances and when it is appropriate to
consult with a doctor or pharmacist; this section also describes possible side effects and substances or activities to avoid
 dosage instructions—when, how and how often to take the product
 inactive ingredients, to help consumers avoid ingredients that could cause an allergic reaction
Guidance can be found at and
Chapter 15 Over-the-Counter Drugs for more information
Medical Devices
A “device” is defined by FDA as an instrument, apparatus, implement, machine, contrivance,
implant, in vitro reagent or other similar or related article, including a component part, or
accessory which is:
 recognized in the official National Formulary or the United States Pharmacopoeia or any supplement to them
 intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment or
prevention of disease in man or other animals
 intended to affect the structure or any function of the body of man or other animals, and which does not
achieve any of its primary intended purposes through chemical action within or on the body of man or other
animals and which is not dependent upon being metabolized for the achievement of any of its primary
intended purposes
Medical Device Amendments
 Passed in 1976 included the following major provisions
 redefined medical devices to make them more distinct from drugs and expanded the definition to include diagnostics for
conditions other than disease
 established safety and efficacy requirements for devices
 established premarket review by FDA
 established the medical device classification system
 created two routes to market (premarket notification and premarket approval) and established Investigational Device
Exemptions (IDEs)
Safe Medical Device Act
 Passed in 1990, included the following major provisions
 extended adverse device incident reporting to user facilities, including hospitals, ambulatory surgical facilities and nursing
homes (This was a landmark event because FDA had never extended its jurisdiction so broadly. When a user facility
receives information regarding a death caused by a device, it must report it to FDA and the manufacturer. If a user facility
receives information about a serious injury or illness caused by a device, it must report it to the manufacturer. A user
facility must also submit to FDA an annual summary of its reports to the agency.)
 required device tracking requirements for high-risk devices
 defined substantial equivalence required that submitters of 510(k)s receive clearance by FDA prior to marketing
 gave FDA the authority to regulate combination products
 defined the humanitarian device exemption
 gave FDA recall authority
Device Classification
 depends on intended use as well as indications for use. In addition, classification is based upon the risk the
device poses to the patient and/or the user. Class I includes devices with the lowest risk and Class III includes
those with the greatest risk
 General controls for all classes include:
 establishment registration of companies required to register under 21 CFR 807.20, such as manufacturers, distributors,
repackagers and relabelers; foreign establishments, however, are not required to register with FDA
 medical device listing with FDA
 manufacturing devices in accordance with GMP in 21 CFR 820
 labeling devices in accordance with labeling regulations in 21 CFR 801 or 809
 submission of a premarket notification (510(k)) (unless exempt) before marketing a device
Device Advice found at:
CDRH learn site at:
Chapter 18, 19, 20 and 21 of the book also cover devices
Premarket Notification 510(k) and Exemptions
 sponsor wishing to market a Class I, II or III device intended for human use in the US, for which a PMA is not
required, must submit a 510(k) exemption to FDA unless the device is exempt from those requirements and
does not exceed the limitations of exemptions in the CFR device classifications as detailed below.
 FD&C Act Section 513(d)(2)(A) authorizes FDA to exempt certain generic types of Class I devices from the
premarket notification (510(k)) requirement
 A predicate device can be:
 1. a pre-amendment device (a currently marketed device that was on the market prior to 1976)
 2. a device reclassified from Class III to Class II or I
 3. a device found to be substantially equivalent to a device in the one of the above two categories
 A device is substantially equivalent if, in comparison to a predicate, it:
 has the same intended use and the same technological characteristics as the predicate or
 has the same intended use as the predicate and different technological characteristics and the information submitted to
 does not raise new questions of safety and effectiveness
 demonstrates that the device is at least as safe and effective as the legally marketed device
If FDA determines that a device is not substantially equivalent, the applicant may:
resubmit another 510(k) with new data
request a Class I or II designation through the de novo process
file a reclassification petition
submit a PMA
FDASIA included the Medical Device User Fee Amendments of 2012 (MDUFA III)
 Introduced, in exchange for user application fees, new performance goals for FDA decision making with
respect to a variety of medical device submission types
The New 510(k) Paradigm—Alternate Approaches to Demonstrating Substantial Equivalence in
Premarket Notifications: Final Guidance (March 1998)
Investigational Device Exemption (IDE) and Premarket Approval (PMA) Process
 IDE (21 CFR 812) allows investigational device to be used in a clinical study to collect safety and effectiveness
data required to support a PMA application or Premarket Notification (510(k)) submission to FDA
 Clinical evaluation of devices that have not been cleared for marketing requires:
 an IDE approved by an IRB; if the study involves a significant risk device, the IDE must also be approved by FDA
 informed consent from all patients
 labeling for investigational use only
 study monitoring
 records and reports
Class III devices require a PMA application (21 CFR 814) due to level or risk associated
with these devices
Must receive approval prior to marketing device
Approval based on determination by FDA that the PMA contains sufficient valid
scientific evidence to assure that the device is safe and effective
PMA application is similar in content and organization to a traditional NDA
application (non CTD format)
FDA has 180 days to review, usually takes longer due to involvement of Advisory
Establishment Registration and Medical Device Listing
 Regulations for establishment provided in 21 CFR 807
 All must be submitted electronically using FDAs Unified Registration and Listing System
(FURLS)/Device Registration and Listing Module (DRLM), unless waiver has been granted
 (2013) fee for this is $4960
Quality Systems for Manufacturing
 CGMP requirements are set forth in the QSR require domestic or foreign manufacturers to have
a quality system for the design, manufacture, packaging, labeling, storage, installation and
servicing of finished medical devices intended for commercial distribution in the US
Regulations require:
various specifications and controls to be established for devices
devices to be designed under a quality system to meet their specifications
devices to be manufactured under a quality system
finished devices to meet their specifications
devices to be correctly installed, checked and serviced
quality data to be analyzed to identify and correct quality problems
complaints to be processed
Quality Systems Requirements contained in 21 CFR 820
Combination Drug-Device and Drug-Device Products
 Defined in 21 CFR 3.2(e)
 Regulated on case by case basis
 SMDA enacted by Congress in 1990
 Required the agency to designate a center (CDER, CBER or CDRH) with primary jurisdiction based on products primary mode of
 MDUFMA of 2002, congress established Office of Combination Products (OCP)
 Company may obtain a formal agency determination of a combination products primary mode of action and
assignment of the lead center by submitting a Request for Designation (RFD)
 Guidance for Industry: How to Write a Request for Designation (April 2011) and Draft Guidance for Industry and
FDA Staff: Classifications of Products as Drugs and Devices and Additional product Classification Issues (June 2011)
 FDA issued Guidance for Industry: Nonclinical Safety Evaluation of Drug or Biologic Combinations (March 2006)

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