Book Excerpt: Prescription Drug Product Submissions

RAPSRAPS' Latest | 28 June 2013

The following chapter is an excerpt taken from Fundamentals of US Regulatory Affairs, Eighth Edition.

Chapter 11: Prescription Drug Product Submissions


  • Understand the classification of prescription drug products
  • Provide an overview of the goals and types of applications, as well as FDA's New Drug Application/Biologics License Application review process, content and format (including the Common Technical Document)
  • Become familiar with presubmission and postapproval activities
  • Understand the mechanisms to expedite drug development and approval


  • Federal Food, Drug, and Cosmetic Act of 1938
  • Public Health Service Act of 1944
  • Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act)
  • Prescription Drug Marketing Act of 1987
  • Prescription Drug User Fee Act of 1992
  • Federal Advisory Committee Act of 1972
  • Food and Drug Administration Modernization Act (FDAMA) of 1997
  • Food and Drug Administration Amendments Act (FDAAA) of 2007
  • Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012
  • 21 CFR 314 Applications for FDA approval to market a new drug
  • 21 CFR 601 Licensing (biological products)
  • Guidance for Industry: Providing Clinical Evidence for Effectiveness for Human Drugs and Biological Products (May 1998)
  • Guidance for Industry on the Disclosure of Materials Provided to Advisory Committees in Connection with Open Advisory Committee Meetings Convened by the Center for Drug Evaluation and Research Beginning on January 1, 2000 (November 1999)
  • Guidance for Industry: Reports on the Status of Postmarketing Study Commitments-Implementation of Section 130 of the Food and Drug Administration Modernization Act of 1997 (February 2006)
  • Guidance for Industry: Postmarketing Studies and Clinical Trials - Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act (April 2011)
  • Guidance for Review Staff and Industry: Good Review Management Principles and Practices for PDUFA Products (April 2005)
  • Guidance for Industry: Fixed Dose Combinations, Co-Packaged Drug Products, and Single-Entity Versions of Previously Approved Antiretrovirals for the Treatment of HIV (October 2006)
  • Guidance for Industry: Fast Track Drug Development Programs-Designation, Development, and Application Review (January 2006)
  • Draft Guidance for Industry: Accelerated Approval Products-Submission of Promotional Materials (March 1999)
  • Guidance for Industry: Formal Meetings with Sponsors and Applicants for PDUFA Products (May 2009)
  • Draft Guidance for Industry: Applications Covered by Section 505(b)(2) (October 1999)
  • Manual of Policies and Procedures 6020.3: Review Classification Policy: Priority (P) and Standard (S)
  • Final Rule for Responding to Drug Applications
  • Guidance for Industry: Providing Regulatory Submissions in Electronic Format-Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications (October 2005)
  • Comprehensive Table of Contents Headings and Hierarchy
  • Guidance for Industry: Providing Regulatory Submissions in Electronic Format-Content of Labeling (April 2005)
  • Guidance for Industry: Contents for a Complete Submission for the Evaluation of Proprietary Names (February 2010)
  • Electronic Common Technical Document Specification (ICH)
  • Guidance for Industry: M4: Organization of the CTD (August 2001)
  • Draft Guidance for Industry: How to Comply with the Pediatric Research Equity Act (September 2005)
  • Patient-Reported Outcome Measures: Use in Medical Product Development to Support Labeling Claims (February 2006)
  • Draft Guidance for Industry: Qualification Process for Drug Development Tools (October 2010)
  • Draft Guidance for Industry Format and Content of Proposed Risk Evaluation and Mitigation Strategies (REMS), REMS Assessments, and Proposed REMS Modifications (September 2009)
  • Draft Guidance for Industry and Review Staff: Target Product Profile-A Strategic Development Process Tool (March 2007)


Drugs are regulated under the Federal Food, Drug, and Cosmetic Act of 1938 (FD&C Act) and its subsequent amendments. The FD&C Act also applies to biological products subject to regulation under Section 351 of the Public Health Service Act (PHS Act).1 Under the FD&C Act, Congress gave the US Food and Drug Administration (FDA) authority and responsibility to oversee public health by regulating and enforcing (among other things):

  • human and veterinary drugs and vaccines, blood and other biologics and medical devices intended for human use to ensure they are safe and effective, are manufactured in accordance with specified quality standards and their labeling enables safe use
  • food, dietary supplements and cosmetics so they are safe and labeled adequately

Additionally, FDA has other responsibilities, such as protecting the public from electronic product radiation, regulating tobacco products and disseminating science-based information to the public on the products that it regulates.

This chapter provides a broad understanding of FDA's regulations and the regulatory process for obtaining marketing approval for prescription drug products.

A drug is broadly defined as:

  • any product (or any component of such product) that is intended for use in the diagnosis, cure, mitigation, treatment or prevention of disease in man
  • a product (other than food), or a component of a product, that affects the structure or function of the human body
  • a product that is recognized in the United States Pharmacopoeia (USP), Homoeopathic Pharmacopoeia of the United States (HPUS) or the National Formulary (NF) and their supplements

A "new" drug is generally any drug that contains an ingredient, or combination of ingredients, for which the safety and effectiveness under the labeled conditions for use are not previously known. However, a new drug also may be a drug that has a known safety and effectiveness profile under the labeled conditions for use, but has not been in use to a material extent or for a material time under those conditions. Generally, such drugs can be obtained only through a prescription from a healthcare provider. Thus, a prescription drug is any drug that has been approved or licensed for distribution by FDA and requires a healthcare practitioner's authorization before it can be obtained. Prescription drugs are differentiated from over-the-counter (OTC) drugs that may be obtained without a prescription. Prescription drugs are also called Rx-only drugs or "legend" drugs because they bear a legend prohibiting sale without a prescription. Prescription drugs are accompanied by a detailed package insert or prescribing information (PI), which contains specific drug information. The content of the PI is regulated by FDA as it informs both the prescriber and the patient about the drug's intended effects, its mechanism of action (MOA), its side effects, how to take the drug and what to do in case of overdose, and warnings and precautions about using the drug.

Physicians may legally prescribe approved drugs for uses other than those approved by FDA; this is known as off-label use. However, drug companies may not promote or advertise drugs for off-label uses.

The FD&C Act prohibits the introduction into interstate commerce of a prescription drug unless the drug's manufacturer has submitted a New Drug Application (NDA) to FDA and obtained agency approval. Likewise, the PHS Act prohibits the introduction into interstate commerce of any biologic product unless a biologic license is in effect and each package is plainly and properly marked with specific requirements (e.g., proper name).

The NDA or Biologics License Application (BLA) must contain "substantial evidence" from adequate and well-controlled investigations, including clinical investigations, conducted by qualified experts. These investigations should demonstrate that the drug is safe and effective under conditions for use described in the labeling and that it can be manufactured consistently, in a manner that will preserve its identity, strength, quality and purity.

Manufacturers often strategize how many pivotal (generally Phase 3) clinical trials are needed to provide substantial evidence for a drug's effectiveness. The most widely applied interpretation is that two separate, adequate and well-controlled trials (one investigation confirming the results obtained from a prior/concurrent investigation) are needed to establish effectiveness. However, under certain circumstances, FDA may find data from one well-controlled clinical investigation to be adequate to provide the evidence of effectiveness required to support approval of a new drug, or a new use of the drug.

Aside from effectiveness, the application must provide evidence that the prescription drug is reasonably safe when used under the conditions described in the labeling. Although a new drug's safety is assiduously studied through clinical trials (which often enroll several thousand patients), the reality is that the variables in a clinical trial are specified and controlled, and the results relate only to the populations studied within the trial. Therefore, adverse drug reactions (ADRs) reported to occur less frequently in the trial population become more apparent and sometimes more frequent or severe only after a drug enters the market and is used by millions of people who likely have different demographic profiles than the clinical trial populations. Nevertheless, evidence from clinical trials is critical in identifying ADRs associated with the drug and establishing its benefit:risk profile. The benefit:risk profile evaluates all known data for the drug and attempts to provide answers to such key questions as: does the drug do more good than harm and, if so, how much more good? If the drug has a potential for harm, how probable and how serious is the harm? So, while clinical trials do not tell the whole story of the drug's effects in all populations and all situations, they provide a good indication of the drug's safety that can be extrapolated from the populations studied to larger populations.

To enhance FDA's oversight of drug safety issues, Congress gave the agency new authorities under the Food and Drug Administration Amendments Act of 2007 (FDAAA). If FDA becomes aware of new safety information about a serious risk associated with a drug's use, the agency can require a manufacturer to implement safety labeling changes, conduct postmarketing studies or clinical trials, or establish Risk Evaluation and Mitigation Strategies (REMS). FDAAA also mandated that FDA establish an active, integrated, electronic surveillance system for monitoring the safety of drugs and other medical products continuously and in real-time. FDA is working toward this mandate and in May 2008 launched the FDA Sentinel Initiative to strengthen the agency's ability to track how drugs and other healthcare products perform once they go on the market. While the Sentinel System will be developed and implemented in stages, ultimately it will help monitor healthcare products throughout their entire lifecycle. It will allow FDA to effectively communicate the risks associated with the product to the public, thus better achieving its mission of protecting and promoting public health.

[media:1698:embed:left]The Food and Drug Administration Safety and Innovation Act (FDASIA), signed into law in July 2012, includes the reauthorization of the Prescription Drug User Fee Act (PDUFA V). While FDASIA includes numerous changes that will benefit patients, industry and FDA, a main component affecting the prescription drug review process is the establishment of a new review model referred to as "the Program." This new review model applies to all New Molecular Entity NDAs (NME NDAs) and original BLAs,2 including applications resubmitted after a refuse-to-file (RTF) action, received from 1 October 2012 through 30 September 2017. Applicants who submit applications in the Program will experience greater transparency, with two meetings to be held during the review process (i.e., the mid-cycle communication and the late-cycle meetings). Additionally, Program applications with a priority review designation have an action goal of eight months, and standard applications have an action goal of 12 months.

Regulatory Responsibility

This chapter covers the review and oversight of small molecule drugs and certain therapeutic biologics regulated by the Center for Drug Evaluation and Research (CDER) that are the subjects of NDAs and BLAs.

On 30 June 2003, the premarket review and oversight of certain therapeutic biologics was transferred from the Center for Biologics Evaluation and Research (CBER)'s Office of Therapeutic Research and Review to CDER's Office of New Drugs (OND). In September 2005, OND was reorganized, and the review of CDER's therapeutic biologics was integrated into OND's review divisions based on indication. As discussed on FDA's website for drugs, while both CDER and CBER have regulatory responsibility for therapeutic biological products, CDER is responsible for monoclonal antibodies for in vivo use; cytokines, growth factors, enzymes, immunomodulators and thrombolytics; proteins intended for therapeutic use that are extracted from animals or microorganisms, including recombinant versions of these products (except clotting factors); and other non-vaccine therapeutic immunotherapies. For additional information about therapeutic biological products and each center's regulatory responsibilities, refer to

Some internal processes utilized by CDER and CBER differ due to historical policies and practices, IT infrastructure and organizational structure. This chapter focuses on the processes followed by CDER.

Regulatory Strategy

Compiling a new marketing application is a highly complex activity that requires much preparation and early and effective communication with FDA. A clear and well-laid-out strategy is essential for navigating the prescription drug submission regulatory process and for ultimately obtaining a timely and smooth FDA approval for the drug product. FDA is, in turn, committed to and responsible for bringing healthcare products, particularly innovative healthcare products, to the market as expeditiously as possible. To achieve this common objective, there are several pathways and tools that should be carefully considered when formulating a regulatory strategy. A sound regulatory strategy should underlie the applicant's drug development program, linking the different activities and drug development phases, assessing the challenges along the way and formulating appropriate risk mitigation activities, all with the ultimate goal of obtaining FDA approval for the desired indications within the desired timeframe. Applicants should develop the regulatory strategy years before the actual application is submitted and as early as Phase 1 of the drug development clinical studies. The strategy is often expanded during Phase 2 or Phase 3 of clinical drug development to a global strategy so approval for the drug may be obtained in the major commercial markets. Throughout the drug development process, applicants are highly encouraged to design trials and collect data to ultimately support planned marketing claims as well as product labeling.

Target Product Profile (TPP)

The Target Product Profile (TPP) was developed in the late 1990s as a joint initiative between FDA and industry to improve sponsor-FDA interactions in the drug development process. Pilots were conducted between 1997 and 2003, and a draft guidance was issued in 2007.3

The TPP is a format for a summary of the drug development program described in terms of labeling concepts, i.e., it is organized according to the key sections of the drug's intended labeling. It is prepared by the sponsor, and submission is voluntary.

The TPP links each specific labeling concept to a specific study or other source of data that is intended to support the labeling concept. The TPP is a dynamic summary that will change as knowledge of the drug increases. It is intended to eliminate the need to revisit development issues that have already been discussed with FDA, unless development goals change, and to facilitate final labeling discussions related both to initial approvals and labeling supplements. Moreover, it helps update FDA quickly on revised development goals and facilitates rapid orientation for new personnel. A TPP does not, however, represent a commitment or obligation on the part of either the sponsor or FDA to the drug's development strategy or eventual drug approval.

Drug Development Tools (DDT)

Another critical component of regulatory strategy lies in the use of drug development tools such as animal models, biological markers (biomarkers) and clinical outcomes assessments (COAs) (e.g., patient reported outcome (PRO) measure). A biological marker or biomarker is defined as a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes or biological responses to a therapeutic intervention.4 Thus, a change to a biomarker following treatment with the drug product can predict or identify safety problems related to the drug or reveal a pharmacological activity expected to predict an eventual benefit from treatment. Biomarkers may reduce uncertainty in drug development and evaluation by providing quantitative predictions about drug performance.

While there are several types of COAs, this section will focus on PROs. A PRO is an instrument that captures the outcomes of drug intervention during a clinical trial from the patient's perspective (e.g., change in pain or depression from before the therapy compared over time after therapy). The PRO uses a questionnaire that is self-administered by the patient or through interviews by other parties that report on patient perspectives. The questionnaires measure "characteristics" (or constructs) that should have a sound theoretical basis and be relevant to the patient group in which they are to be used. Questionnaires can be designed to provide data in any disease population and cover a broad aspect of the construct measured, or can be developed specifically to measure those aspects of outcome that are of importance for people with a particular medical condition. In any case, a PRO tool should be thoroughly tested using appropriate methodology and validated in order to justify its use. Results from properly validated PRO instruments can be used to support drug approval and claims in approved medical product labeling. Examples of characteristics that PRO questionnaires can assess include symptoms and other aspects of well-being, functionality (disability) and quality of life (QoL).

In addition to PRO tools, FDA also will consider qualification of other DDTs to support labeling claims, such as clinician rating scales and caregiver rating scales, where a respondent is requested to assign a rating to a concept using a process similar to that used for PROs.

With proper qualification, analytically valid measurements using the DDT can be relied upon to have a specific use and interpretable meaning and can be used broadly in drug development. Once a DDT is qualified for a specific context of use, industry can use the DDT for the qualified purpose during drug development, and reviewers from CDER, and OND's Study Endpoints and Labeling Development Team (SEALD) can be confident in applying the DDT for the qualified use without the need to reconfirm the DDT's utility. 

Programs for Expediting Drug Development and Review

FDA currently uses several approaches to expedite the development and review of new drugs: 1) Accelerated Approval; 2) Fast Track Designation; 3) Priority Review; and, since the enactment of FDASIA, 4) Breakthrough Therapy Designation. An investigational agent may be eligible for any combination of these programs. For example, approximately 80% of applications that were approved under a Fast Track designation were also Priority Review drugs, and sponsors need to apply for these different programs separately. A novel agent with breakthrough designation is subject to the same drug development and review programs as those agents with Fast Track designation. Priority review will be granted if the breakthrough designation is still in place at the time of NDA or BLA submission. Accelerated Approval will apply if appropriate and all the criteria under 21 CFR 314 Subpart H or Subpart E are met.

As discussed at under "Expedited Drug Development Pathway" (, FDA is in the process of developing draft guidance on expedited drug development pathways. Table 11-1 highlights differences and similarities of the respective programs.5

Accelerated Approval

The Accelerated Approval process under Subpart H (drugs, 21 CFR 314) and Subpart E (biologics, 21 CFR 601) was created by FDA in 1992 at the height of the HIV/AIDS crisis. It allows approval of drugs based on surrogate endpoints that are reasonably likely to predict clinical benefit under the following conditions: 1) The disease to be treated must be serious or life-threatening and 2) the treatment must provide meaningful therapeutic benefit over existing treatments. In cancer drug development, a surrogate endpoint could be tumor shrinkage and the clinical benefit increased overall survival.

Approval under these provisions is subject to the requirement that the applicant study the drug further, to verify and describe its clinical benefit, where there is uncertainty as to the relation of the surrogate endpoint to clinical benefit, or of the observed clinical benefit to ultimate outcome. 

More than 80 new products have been approved under Accelerated Approval regulations, including 29 drugs to treat cancer, 32 to treat HIV and 20 to treat other conditions, such as pulmonary arterial hypertension, Fabry disease and transfusion-dependent anemia. Two of the 35 NMEs approved in Fiscal 2012 received Accelerated Approval.6

Fast Track Designation

Fast Track designation is designed to facilitate the development and expedite the review of drugs to treat serious or life-threatening diseases and that have the potential to address unmet medical needs.7 Fast Track designation may apply to drugs or biologics intended to treat a broad range of serious diseases, including AIDS, Alzheimer's disease, cancer, epilepsy and diabetes. Addressing an unmet medical need is defined as providing a therapy where none exists or one that may be potentially superior to an existing therapy. Once a drug receives Fast Track designation, FDA offers the sponsor early and frequent communication to facilitate an efficient development program. The frequency of communications ensures that questions and issues are resolved in a timely manner, often leading to earlier drug approval. Fast Track drug sponsors are also eligible for "Rolling Review" of applications, allowing earlier submission and initiation of review. More than a third (12/35) of the 35 NME drugs approved in Fiscal 12 were granted Fast Track designation. Of the 12 drugs that received a Fast Track designation, nine (75%) were approved in the first review cycle. Of the 10 Fast Track designated drugs for which FDA was able to make comparisons to approvals in other countries, 100% were approved in the US first.8

Sponsors should submit requests for Fast Track designation to FDA in writing. Supporting documentation should clearly demonstrate that the criteria necessary for designation have been met and that the sponsor has a stage-appropriate clinical development plan in place. Fast Track designation applies to both the product and the specific indication for which it is being studied.

The request for Fast Track designation can be submitted simultaneously with the IND, or at any time thereafter prior to receiving marketing approval. To maximize the use of the Fast Track incentives, it is best to include the designation request in the original IND submission or as soon as possible thereafter. Note that the request for Fast Track designation can be granted by FDA only upon submission of an IND.

FDA will respond to a request for Fast Track designation within 60 days of receipt. If FDA determines that Fast Track criteria have been met, the review division will issue a designation letter that will state that Fast Track designation is granted for development of the product for use in treating the specific serious or life-threatening condition. The letter also will request that sponsors design and perform studies that can show whether the product fulfills unmet medical needs. FDA can issue a non-designation letter either because the Fast Track request package was incomplete or because the drug development program failed to meet the criteria for Fast Track designation. The non-designation letter will explain the reasons for FDA's decision. FDA will respond to a subsequent request for Fast Track designation after a non-designation determination within 60 days of receiving the new request. Sponsors must continue to meet the Fast Track criteria throughout product development to retain the designation. The sponsor should expect the appropriateness of continuing the Fast Track designation for the drug development program to be discussed and evaluated at different times during the drug development process, including at the End-of-Phase 2 meeting and the Presubmission Meeting. If FDA determines that a product is no longer eligible, it will notify the sponsor that the product is no longer part of the Fast Track drug development program. Sponsors can appeal FDA's decision through the dispute resolution process (21 CFR 10.75, 312.48 and 314.103).

Rolling Review

FDA may consider reviewing portions of a marketing application before the complete NDA or BLA is submitted (Rolling Review). To qualify for a Rolling Review, Fast Track designation must have been granted. Furthermore, the pivotal study must be complete or near completion.

A sponsor seeking a Rolling Review may simultaneously submit a Rolling Review request with a request for Fast Track designation. The sponsor should provide a schedule for submission of portions of the application. If the Rolling Review request is granted, FDA may review portions of the application as they become available. However, FDA is not obligated to start the review upon receipt of a portion. The PDUFA goal date is determined upon receipt of the final portion of the application, while the user fee is due upon receipt of the first portion. It is recommended that applicants initiate discussion about their plans for submitting a Rolling Review NDA or BLA at the Presubmission Meeting.

Priority Review

In 1992, under PDUFA, FDA agreed to specific goals for improving drug review times using a two-tiered system of review times: Priority Review and Standard Review. Priority Review designation is given to drugs that offer major advances in treatment, or provide a treatment where no adequate therapy exists. FDA reviews priority applications more quickly than standard applications, in six months versus 10 months (in eight months versus 12 months for applications in "the Program"). Twelve of the 35 Fiscal 2012 NME drugs received Priority Review. Of those 12, 11 (92%) were approved on the first cycle, and 10 (83%) were approved in the US before any other country.9 Prior to the enactment of PDUFA, application review in CDER was subject to the 180-day review period described in 21 CFR 314.100 (the "regulatory clock") with review extensions allowed for receipt of major amendments. In addition, prior to 1992, CDER used a three-tier therapeutic-potential classification system (Type A-important therapeutic gain; Type B-modest therapeutic gain; and Type C-little or no therapeutic gain) to determine application review priorities. Potentially eligible for Priority Review are drugs that have the potential to provide significant advances in treatment in at least one of the following instances:

  • provide evidence of increased effectiveness in treatment, prevention or diagnosis of disease
  • eliminate or substantially reduce a treatment-limiting drug reaction
  • provide documented evidence of enhanced patient compliance to treatment schedule and dose
  • provide evidence of safety and effectiveness in a new subpopulation, such as children

An applicant may submit a request for Priority Review to FDA, providing adequate evidence that its drug product meets one of the criteria listed above. While Fast Track products generally are eligible for Priority Review, as they are intended to treat serious or life-threatening conditions and address unmet medical needs, having a Fast Track designation does not automatically convey a Priority Review; the applicant should request the Priority Review with appropriate justification in the cover letter. CDER currently grants Priority Review for drugs that provide a significant improvement, compared to marketed products, in the treatment, diagnosis or prevention of a disease, i.e., eligibility is not limited to drugs for a serious or life-threatening disease. A Fast Track product ordinarily would meet either center's criteria for Priority Review. However, an applicant need not seek Fast Track designation to be eligible for priority review.

FDA determines within 45 days whether a Priority or Standard Review designation will be assigned. If Priority Review is granted, the applicant still must provide the same amount of scientific and medical evidence as required under Standard Review classification in order for FDA to approve the drug.

Breakthrough Therapy Designation

FDASIA gave FDA a new tool to expedite the development of therapies that show substantial promise in early clinical trials. This new authority arose out of discussions between FDA, the National Institutes of Health (NIH), industry, academia and patient groups on how to create a novel pathway for development of breakthrough therapies. A drug company may seek designation of a drug as a "Breakthrough Therapy" if it is for a serious and life-threatening disease, and preliminary clinical evidence shows the drug may offer substantial improvement over existing therapies. Once FDA designates a drug as a Breakthrough Therapy, it will provide advice and interaction throughout the development process to streamline the drug's clinical trials and review (Table 11-2). Not later than 18 months after the date of enactment of FDASIA, FDA will issue draft guidance on implementing the requirements with respect to breakthrough therapies,10 but companies may begin to seek the designation immediately (see Fact Sheet: Breakthrough Therapies,

Risk Evaluation and Mitigation Strategy (REMS)

Title IX, Subtitle A, Section 901 of FDAAA amended the FD&C Act by creating Section 505-1, which authorizes FDA to require applicants of certain prescription drugs products, to submit a proposed REMS if the agency determines one is necessary to ensure that a drug's benefits outweigh its risks. An applicant also may voluntarily submit a proposed REMS without having been required to do so by FDA. FDA can request the REMS at the time of the initial submission of the original application or at any time after its approval (usually, if FDA becomes aware of new safety information and determines that a REMS is necessary). Once the applicant is notified by FDA that a REMS is necessary, the applicant must submit a proposed REMS within 120 days.

The content of the proposed REMS should adequately describe its proposed goals and the specific elements proposed for inclusion in the drug product's approved REMS. The proposed REMS must include, at a minimum, a timetable for the submission of assessments of the strategy by 18 months, three years and seven years after the REMS is approved by FDA. The proposed REMS also may include one or more of the following elements: Medication Guide (21 CFR 208); patient package insert; communication plan to healthcare providers; and Elements to Assure Safe Use (ETASU). The proposed REMS also should contain a thorough explanation of the rationale for, and supporting information about, the content of the proposed REMS, as well as a timetable by which each of the elements will be implemented.

ETASU may be required if a drug has been shown to be effective but is associated with a serious adverse event. In such a case, the drug can be approved only if, or would be withdrawn unless, such elements are included in the REMS to mitigate the specific serious risks listed in the product's labeling. ETASU may be required for approved products when an assessment and Medication Guide, patient package insert or communication plan are not sufficient to mitigate these risks. An example of an ETASU would be a system or process to ensure that certain laboratory test result outcomes are obtained before a drug may be dispensed.

The applicant must reach agreement with FDA on the elements of a REMS submission and the timelines for implementation. FDA will determine which REMS elements are necessary to ensure that the benefits of the drug outweigh its risks and will determine approvability of the REMS. FDA also must approve REMS that are voluntarily submitted. An approved REMS that is submitted voluntarily is subject to the same requirements and enforcement as a required REMS. FDA will notify applicants who voluntarily submit a proposed REMS whether the REMS will be required. If FDA determines that a REMS is not required, an applicant may undertake voluntary risk management measures that would be performed outside of a REMS.

Once FDA approves the REMS, it will serve as the basis for inspection and enforcement. A drug will be considered to be misbranded if the applicant fails to comply with a requirement of the approved REMS. An applicant that violates a REMS requirement also is subject to civil monetary penalties of up to $250,000 per violation, not to exceed $1 million in a single proceeding. These penalties increase if the violation continues more than 30 days after FDA notifies the applicant of the violation. The penalties double for the second 30-day period, and continue to double for subsequent 30-day periods, up to $1 million per period and $10 million per proceeding. In addition, the sponsor may not introduce into interstate commerce an approved drug that is noncompliant with the conditions of an approved REMS. For additional information on REMS, refer to MaPP 6700.6 REMS Questions and Answers.

Presubmission Activities

Many activities need to be completed by the applicant prior to an application submission, including proprietary name submission and review, establishment registration, labeler code assignment and request for a Presubmission Meeting with the review division.

Proprietary Name Submission and Review

One important activity during the drug development phase is crafting a proprietary name (i.e., "brand name") for the product. The proprietary name is one of the product's critical identifiers for healthcare professionals and consumers. Companies expend a vast amount of resources creating the perfect proprietary name. Equally, FDA allocates many resources to review a proposed proprietary name in an attempt to help prevent medication errors.

[media:1684:embed:left]The applicant must submit proposed proprietary names for FDA review as part of the marketing application. The request for proprietary name approval must be submitted no later than when the application is submitted, although applicants may submit  a "request for proprietary name" review prior to application submission (perhaps as early as completion of Phase 2 trials) under the IND. However, to ensure resources are not used to evaluate proposed proprietary names for products that will not be viable candidates for an NDA, ANDA or BLA, or for which proposed indications are not yet sufficiently clear to form the basis of an evaluation of a name for potential medication errors, FDA does not evaluate proprietary names until products have completed Phase 2 trials.

The contents of a proprietary name submission should include the primary and alternate proposed proprietary name, intended pronunciation of the proprietary name, name derivation, intended proprietary name modifier meanings and the name's pharmacologic/therapeutic category.

An FDA review of proprietary names includes an evaluation of both the proposed names' safety and promotional aspects. The safety review focuses primarily on preventing medication errors and evaluating other products that may have similar dosage regimens, overlapping strengths, similar names when said aloud or a similar appearance when written out by hand. The promotional review is to determine whether the name implies superiority, attempts to minimize risk or overstates efficacy.

For a proposed proprietary name submitted during the IND phase, FDA will review and communicate a decision about the name within 180 days of the receipt date of the submission. For a proposed proprietary name submitted with the original NDA or BLA, or as a part of a supplement, FDA will review and communicate a decision within 90 days of the receipt date of the submission. Proprietary names accepted during a pre-review will be re-reviewed 90 days before the action date to ensure they are still acceptable.

Establishment Registration and National Drug Code

A company that manufactures human drugs, certain biological products and animal drugs must register the manufacturing facility before FDA can approve a marketing application. Specifically, owners or operators of all drug establishments, not exempt under Section 510(g) of the act or Subpart B of Part 207, that engage in the manufacture, preparation, propagation, compounding, or processing of a drug or drugs shall register and submit a list of every drug in commercial distribution (21 CFR 207.20(a)).

Prior to 1 June 2009, paper forms for Drug Establishment Registration and Drug Product Listing were completed and submitted to FDA. Changes to the FD&C Act from enactment of FDAAA, require that drug establishment registration and drug listing information be submitted electronically unless a waiver is granted. Therefore, as of 1 June 2009, FDA only accepts electronic submissions for registration and listing unless a waiver is granted.

The National Drug Code (NDC) system is designed to provide drugs in the US with a specific number that describes the product. Per 21 CFR 207.35, the NDC is limited to 10 digits; however, the passing of the Health Insurance Portability and Accountability Act of 1996 (HIPAA) propagated more consistent 11-digit codes to allow for proper billing for reimbursement purposes. The first segment of the NDC is assigned by FDA and identifies the vendor (or labeler) involved with the drug's manufacture, packaging or distribution. The second segment conveys the product codes and comprises the entity, strength, dosage form and formulation. The third segment, or package code, indicates the package forms and sizes. The second and third segments of a given product's code are assigned by the manufacturer.

[media:1685:embed:left]Prior to June 2009, FDA would input the full NDC number and information into a database known as the Drug Registration and Listing System (DRLS). However, with electronic submissions and eDRLS, this is now done automatically. More recently, FDASIA amends the FD&C Act by requiring additional information to be submitted for the registration of domestic or foreign drug facilities. This additional information includes each drug establishment's unique facility identifier and a point of contact email address. Furthermore, as of 1 October 2012, the re-registration period for domestic and foreign drug manufacturers has been changed to 1 October to 31 December of each year, instead of the previously more open-ended period of on or before 31 December of each year. For more direction on how to properly list and register products, please see the link under "Electronic Drug Registration and Listing Instructions" below.

As of June 2009, eDRLS contains Rx products and OTC products as well as finished and unfinished drug products. FDA utilizes information from the eDRLS database to update the NDC directory on a daily basis (see the NDC Directory at Additionally, FDA relies on establishment registration and drug listing information to administer many of its programs, such as postmarketing surveillance (including risk-based scheduling and planning of inspections), protection against bioterrorism, prevention of drug shortages, management of drug recalls and assessment of user fees.

Presubmission Meeting

Sponsors can request meetings with FDA at various stages during the drug development process. A Presubmission Meeting, considered a Type B meeting (see Chapter 4), is highly recommended prior to NDA or BLA submission. It generally is advisable to hold such a meeting four to six months prior to the anticipated submission date. A request for a Presubmission Meeting should be submitted 60 days prior to the desired date. A briefing package must be submitted for review by FDA attendees and should be received by FDA at least four weeks prior to the scheduled meeting. For additional information on meetings with FDA, refer to Guidance for Industry: Formal Meetings with Sponsors and Applicants for PDUFA Products. The Presubmission Meeting allows the sponsor to present data that will be submitted in the application and to provide additional assurance that the sponsor is submitting all the necessary information required by the agency in order to reach a decision on the application's approvability. In addition, for NDAs and BLAs in PDUFA V's "the Program," (i.e., NMEs and original BLAs received on or after 1 October 2012), FDA and the sponsor will agree at the Presubmission Meeting on the content of a complete application for the proposed indication(s) and conduct preliminary discussions on the need for a REMS or other risk management actions.

The NDA or BLA Application


The goals of the NDA or BLA are to provide enough information to permit FDA reviewers to reach key decisions on whether: the drug is safe and effective when used for the indications described in the labeling; the drug's benefits outweigh its risks; the proposed labeling is appropriate; and the drug's manufacturing methods and the controls used to maintain drug quality are adequate to preserve its identity, strength, quality and purity.

Content and Format

An application must provide all information pertaining to the drug's development. The quantity of information can vary from one application to another; however, the application structure is consistent. Per 21 CFR 314.50 and 601 (NDA and BLA respectively), an application must include an application form, an index, a summary, five or six technical sections, case report forms and tabulations, patent information, financial disclosure or certification and labeling. The technical sections may include product quality, nonclinical pharmacology and toxicology, human pharmacokinetics and bioavailability, microbiology, statistical and clinical data. The product quality section should describe the composition, manufacture and specifications of both the drug substance and the drug product, as well as fairly detailed descriptions of all manufacturing controls and stability data. The nonclinical pharmacology and toxicology section should describe any animal and in vitro drug studies that help to define the drug's pharmacologic properties and address toxicity related to its administration. The clinical section should include a description of all clinical investigations completed in support of the drug's efficacy and safety, as well as the study protocols and copies of case report forms for each patient who died during a clinical study or did not complete a study because of an adverse event, regardless of the incident's relationship to the study drug.

Copies of the proposed drug product labeling-including the package insert, carton and container labels and Medication Guide-should be provided in the application. FDA requires that labeling be submitted electronically in a format that the agency can review and process. The content of labeling must utilize the structured product labeling (SPL) format with an extensible markup language (XML) backbone. SPL has several advantages: the exchange of information between computer systems, automation of text comparison by section and exchange of information needed for other submissions (i.e., cross-referencing). SPL allows labeling content to be searched, moved between systems and combined with other data sources and lends itself to the support of electronic healthcare initiatives.

The CTD Format

As outlined above, a huge amount of information is submitted in support of a marketing application. Generally, similar scientific and clinical information is broadly required in countries where a manufacturer (or applicant) plans to market the drug. Because the information is similar-and to allow manufacturers to proceed more quickly and consistently with the submission and application process-the International Conference for Harmonisation (ICH) developed the Common Technical Document (CTD) format. The CTD provides harmonized structure and format for new marketing applications submitted in the US, EU, Japan and to numerous other regulatory authorities.

Per the CTD format, an application is broken up into five modules (Figure 11-1). Module 1 contains documents specific to the region where the file is being submitted, and Modules 2-5 are intended to be common across all regions. Module 1 is region-specific and contains administrative and prescribing information (e.g., application forms, proposed labeling and applicable patent information). Module 2 contains CTD summaries (e.g., a quality overall summary and clinical summary). Module 3 contains quality data or product quality information (e.g., drug substance and drug product data). Module 4 contains nonclinical study reports (e.g., pharmacodynamic and pharmacokinetic data). Module 5 contains clinical study reports (e.g., study protocols, case report forms, integrated safety and efficacy summaries and relevant literature references, including FDA meeting minutes and references cited in the Clinical Overview section).

The eCTD Format

Historically, submissions to FDA have been in paper format. Paper submissions not only require many resources for both the sponsor and FDA, but also require a lot of storage space. FDA attempted to address this issue by creating standards that permit electronic submissions (eSubs). FDA started to accept eCTDs in 2003, and it became the recommended standard in 2008.

The value of electronic submissions is well recognized. Under FDASIA, FDA, working with stakeholders, will issue draft and final guidance on the standards and format of eSubs. Requirements of eSubs will be phased in over the next few years starting with original NDA and BLA submissions and eventually requiring all original commercial INDs and their amendments to be submitted electronically as well.

The formats of the paper CTD and eCTD submissions are different. With an eCTD submission, each document is separate (granular) and named according to ICH specifications. Each submission has its own eCTD XML backbone file, which allows FDA to receive, archive and review the submission. Once an application is submitted in electronic format, all subsequent submissions to the application are also submitted electronically and should include eCTD backbone files (once eCTD, always eCTD). Without these backbone files, FDA will be unable to process subsequent submissions. FDA also recommends that electronic file cover letters include a description of the submission's approximate size (e.g., 4 gigabytes), the type and number of electronic media used (e.g., two DVDs), a regulatory and technical point of contact and a statement that the submission is virus free, with a description of the software used to virus-check the file.

At any time, a sponsor can decide to convert its paper application to an electronic filing. Should a sponsor decide to do so, it is not necessary to provide all previous submissions in electronic format with eCTD backbone files; instead the electronic filing may begin with the planned submission. For ease of conversion, the Comprehensive Table of Contents Headings and Hierarchy maps the application to the eCTD format. When converting and cross-referencing to past submissions, the applicant should be sure to include specific information, such as the date of the previous submission, document name, page numbers, volume numbers and approval dates, or may consider including any items critical for review of the current submission within the electronic format submission so the reviewer can find it more easily.

Types of Applications

There are several types of drug applications: 1) "Traditional" 505(b)(1) NDA (FD&C Act Section 505(b)(1)); 2) 505(b)(2) NDA (FD&C Act Section 505(b)(2)); 3) Abbreviated NDA (ANDA) (FD&C Act Section 505(j)); 4) Original BLA (PHS Act Section 351(a)); and 5) Biosimilar BLA (PHS Act Section 351(k)).

505(b)(1) NDA ("traditional" NDA)

A 505(b)(1) application is a complete NDA that contains all the studies conducted by the applicant necessary to demonstrate a drug's safe and effective use. A 505(b)(1) application contains all information as outlined in 21 CFR 314.50.

505(b)(2) NDA

A 505(b)(2) application also contains information required in a 505(b)(1) application necessary to demonstrate safe and effective use of a drug; however, the applicant can provide some of the information required for approval in the application from studies it did not conduct and for which it has not obtained a right of reference.11

Section 505(b)(2) was added to the FD&C Act by the Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman Act) to allow companies to develop alternative therapies more quickly by relying on existing data. Applicants may rely on published literature that supports approval of an application and/or on FDA's previous finding of safety and effectiveness of an approved drug. For example, a 505(b)(2) application can be submitted if the applicant has changed a product's route of administration from an oral form to an intramuscular injection. In this instance, the applicant can rely on the efficacy data and some of the safety data established for the drug's oral formulation that has already been approved by FDA, but will have to conduct studies showing safety and efficacy that relate to the change to the intramuscular form. In addition, the applicant will have to establish a "bridge" (e.g., via comparative bioavailability data) between the proposed drug and the approved listed drug to demonstrate that reliance on FDA's previous finding of safety and effectiveness is scientifically justified.

Sections 505(b)(2) and 505(j) of the FD&C Act together replaced FDA's "paper NDA policy," which had permitted an applicant to rely on studies published in the scientific literature to demonstrate the safety and effectiveness of duplicates of certain post-1962 pioneer drug products.

(505(j)) Abbreviated NDA (ANDA)

A 505(j) application is considered abbreviated because, generally, the applicant is not required to include preclinical and clinical data necessary to demonstrate safety and effectiveness. Instead, it contains chemistry and bioequivalence data to show that the proposed product is identical in active ingredient, dosage form, strength, route of administration, labeling, quality, performance characteristics and intended use to the previously-approved reference listed drug (RLD). More information on ANDAs is provided in Chapter 13.

(351(a)) BLA (Original BLA)

A 351(a) application is a complete BLA that contains all the studies conducted by the applicant necessary to demonstrate a drug's safe and effective use. A 351(a) BLA contains all information as outlined in 21 CFR 601.2.

For additional information, see Therapeutic Biologic Applications at

(351(k)) BLA (Biosimilar BLA)

A 351(k) application is an abbreviated BLA for a biological product that is demonstrated to be "biosimilar" to or "interchangeable" with an FDA-licensed biological product.

For additional information, see Biosimilars at

This chapter does not discuss the submission or review of ANDAs or Biosimilar BLAs.

Submission of the Marketing Application and Next Steps

Once the application has been compiled and is ready for dispatch, it can be submitted by regular post or express mail to FDA's Document Control Room.

Electronic CTD submissions are submitted either on electronic media or through the FDA Electronic Submissions Gateway (FDA ESG). If submitted on electronic media, it should be sent by regular post or express mail just like the paper submission. The FDA ESG is a centralized, agency-wide communications point for securely receiving electronic regulatory submissions. It electronically receives, acknowledges, routes to and notifies a receiving center of the receipt of an electronic submission. The FDA ESG is a conduit, or "highway," along which submissions travel to reach their final destinations within FDA. FDA ESG staff do not open or review submissions.

Upon receipt of the application, FDA has 60 days to determine whether the application is sufficiently complete to allow for a substantive review. If FDA determines that the application is complete, it will be filed on Day 60. If FDA determines that the application is not complete (see 21 CFR 314.101(d)), FDA may refuse-to-file (RTF) it and, if so, will issue a formal RTF letter by Day 60 that will provide the reasons for the decision. By eliminating incomplete applications from the review queue, FDA is able to focus its resources on complete applications.

Note that FDA tends to be more flexible in accommodating drugs intended for critical diseases, particularly when there is no alternative therapy. In such cases, the agency and applicant will often work together to find a balanced resolution to allow application review to begin as quickly as possible. Note also that FDA may accept some parts of an application and RTF others (e.g., file one of two proposed indications for use and RTF the other). The applicant may resubmit the application after addressing FDA's RTF issues; FDA then determines whether the resubmitted application can be filed.

If an applicant strongly disagrees with FDA's decision to RTF an application, the applicant is given 30 days after receiving the RTF letter to request a meeting with FDA. Following the meeting, the applicant can request that the agency file the application "over protest." In this event, the date of filing will be 60 days after the date the applicant requested the meeting.

For applications that will be filed, FDA performs an "initial filing review" by Day 60 to identify "filing review issues," which are substantive deficiencies or concerns that may have significant impact on FDA's ability to complete the review of or approve the application. Filing review issues are distinct from application deficiencies that serve as the basis for an RTF action. Note that FDA's initial filing review represents a preliminary review of the application and is not indicative of deficiencies that may be identified later in the review cycle.

FDA will then inform the applicant in writing whether or not there are filing review issues by issuing a letter mandated by PDUFA within 14 days of the determination (also called a Day 74 letter). The Day 74 letter states the date the application was received, which is also the date the review clock begins. The Day 74 letter provides the planned review timeline and includes an "action" date, when FDA will provide a decision on the application, as well as dates when the applicant can expect to receive feedback from the review division on proposed labeling and postmarketing requirements/commitments. The Day 74 letter also identifies the review classification granted by FDA (i.e., Standard Review or Priority Review). For applications reviewed under the PDUFA V "Program," the Day 74 letter will also state whether the division is considering convening an Advisory Committee meeting.

For additional information on filing review issues and the Day 74 letter, refer to MaPP 6010.5 NDAs: Filing Review Issues.

During the review period, FDA may ask the applicant for additional information ("solicited" information) or the applicant may submit additional information on its own initiative ("unsolicited" information). If the new information constitutes a major amendment, FDA may determine that an extension to the PDUFA action date is needed to review the new information. Only one three-month extension can be given per review cycle. For a solicited major amendment that extends the PDUFA action date, FDA also will provide a new timeline for feedback on proposed labeling and postmarketing requirements or commitments. Thus, an applicant's strategy for providing information contained in the application should be very carefully planned.

FDA Review Process

Once an application is validated and received, the application is routed to the regulatory project manager (RPM) in the appropriate review division. The RPM will ask supervisory team leaders from appropriate disciplines to assign reviewers. The first review task is to determine, from each specific discipline, whether the application is fileable (see Submission of the Marketing Application and Next Steps above).

The review team consists of various disciplines such as clinical, pharmacology and toxicology, chemistry, clinical pharmacology, etc. 

[media:1686:embed:left]Each disciplinary group completes its review and determines whether the data can support the drug's approval. During the review process, a reviewer may identify a minor deficiency, may need a topic clarified or may need additional information in order to facilitate his or her review. These requests for additional information usually are communicated through an information request (IR) or advice letter (AD), and these letters generally are handled via email, telephone or direct mail. As the regulatory contact for the application, the RPM facilitates these communications. Applicants submit amendments to the application in an attempt to address all additional information requests. If serious deficiencies exist, the review division has the option of notifying applicants via a "discipline review" (DR) letter after each discipline has finished the initial review of its section of the pending application. DR letters had been used sparingly since the release of the 2001 FDA Guidance for Industry Information Request and Discipline Review Letters Under the Prescription Drug User Fee Act (2001).

With PDUFA V, a renewed focus on DR letters was agreed upon for applications in the "Program" as outlined in the PDUFA Reauthorization Performance Goals and Procedures Fiscal years 2013 Through 2017. FDA intends to complete primary and secondary discipline reviews of the application and issue DR letters in advance of the planned late-cycle meeting.

If additional scientific expertise is needed outside the core review team, the review division may consult other parts of the center or beyond (e.g., the Center for Devices and Radiological Health). For certain applications, opinions from outside experts may also be sought through the advisory committee process or by special government employees (SGEs).

As the review proceeds, FDA determines whether any bioresearch monitoring (BIMO) or current Good Manufacturing Practice (CGMP) inspections are required prior to approval. The results of these inspections will allow the agency to determine the credibility and accuracy of the data submitted in the application (see Preapproval Inspections (PAI) below).

FDA will make a determination whether Postmarketing Requirements (PMRs) and/or Postmarketing Commitments (PMCs) are necessary. If so, this is communicated to the applicant, and FDA and the applicant discuss and agree on specific studies, as well as specific milestone dates, including dates for final protocol submission, study or trial completion and final report submission. 

In parallel, with PMR and PMC determinations, FDA reviews the product labeling and determines whether it accurately reflects the product's safety and efficacy and allows physicians, healthcare professionals and consumers to determine whether the drug's benefits outweigh its risks. The agency will then decide if it is ready to take action on the application.

Application review consists of several stages and involves a multidisciplinary team (see Figure 11-2). The primary review staff summarizes their preliminary review findings at a mid-cycle meeting. Discussions at the mid-cycle meeting can include the need for additional information from the applicant, the need for additional scientific expertise within the center, or the need for a REMS, postmarketing commitments or requirements, if the product is approved. During the review, the applicant's proposed labeling is reviewed, and comprehensive comments are conveyed to the applicant. At the wrap-up meeting, discussions can include issues that preclude approvability of the application, and further discussions involving details of the REMS, or postmarketing commitments or requirements, as needed.

If the product is an NME or an original BLA, the signatory authority for the application is the office director; the signatory authority for all other applications, including efficacy supplements, is usually the division director. 

Advisory Committee Meeting

Advisory Committee meetings are discussed in Chapter 5 of this book. Situations that frequently lead FDA to convene an Advisory Committee meeting are described in the relevant draft guidance.12 According to FDAAA (2007), a drug characterized by "…no active ingredient (including any ester or salt of the active ingredient) of which has been approved in any other application under this section or section 351 of the Public Health Service Act" needs13 to be evaluated by an independent FDA Advisory Committee, unless FDA delineates why such a review will be unnecessary.

FDAAA also amended the FD&C Act to limit conflicts of interest and restricted the eligibility criteria for serving on FDA Advisory Committees. It was felt these provisions made the recruitment of suitable individuals for Advisory Committees more difficult. More recently, FDASIA largely eliminated those restrictions. Detailed discussions and analysis of the changes can be found in a number of recent third party newsletters.14

Preapproval Inspections (PAI)

FDA may approve a drug product if, among other requirements, the methods used in, and the facilities and controls used for, the manufacture, processing, packing and testing of the drug are found adequate, and ensure and preserve its identity, strength, quality and purity.

Prior to approving an application, FDA may inspect manufacturing facilities (CGMP inspections), as well as facilities or sites where the drug was tested in nonclinical or clinical studies (BIMO inspections). A PAI is performed to contribute to FDA's assurance that a manufacturing establishment listed in a drug product application is capable of manufacturing a drug and that data are accurate and complete.

Although the risk-based decision is left to the agency's discretion, BIMO and CGMP inspections generally are conducted for most new NDA and original BLA applications. FDA is likely to conduct PAI inspections in the following instances:

  • NMEs or original BLAs
  • priority reviews
  • the first application filed by an applicant
  • for-cause inspections (e.g., if one clinical site had a significantly better trial outcome than other sites)
  • original or supplemental applications, if the CGMP status is unknown (e.g., it has been more than two years since the domestic facility was last inspected, or the establishment is new and has yet to be inspected by FDA or another global regulated authority)

CDER evaluates the adequacy of the applicant's data and relies on the facility inspections to verify the authenticity and accuracy of that data. This ensures that applications are not approved if it is determined that the applicant cannot demonstrate the ability to operate with integrity and in compliance with all applicable requirements.

Per FDASIA, all applicants are expected to include a comprehensive and readily located list of facilities and establishments. FDA will use this list to facilitate the need for potential inspections of foreign and domestic sites that will manufacture a drug for the US market, or that have completed a study to support the approval of a drug that will be marketed in the US.

FDA Decision on the Application

One of two actions may be taken on an application, namely an approval action or a complete response. The latter lists all review deficiencies identified by FDA and identifies steps the applicant should take to address these deficiencies in a future submission before the application can be approved.

Approval letters are issued when FDA has determined that the drug is safe and effective, can be acceptably manufactured and is appropriately labeled. An approval is effective on the date of approval letter issuance, granting authorization to market the drug for sale in the US.

Postmarketing Requirements and Commitments

The approval letter also stipulates any postmarketing requirements and commitments. A postmarketing requirement is a study (e.g., an observational epidemiologic study, an animal study or a laboratory experiment) or clinical trial that the applicant must conduct after the application is approved. It includes studies that may be required under the Pediatric Research Equity Act (PREA) (21 CFR 314.55(b)), the Animal Efficacy Rule (21 CFR 314.610(b)(1)), Accelerated Approval regulations (21 CFR 314.510 and 601.41) or FDAAA (Title IX, Section 901). The applicant must report the status of each postmarketing requirement annually.

A postmarketing commitment is a written commitment by the applicant to FDA to provide additional information after approval of the application. It is not a postmarketing requirement, although 506B-reportable postmarketing commitments require annual status reports to be submitted by the applicant. (506B is the section of the FD&C Act that mandates annual status reports and obligates FDA to make certain information about postmarketing commitments publicly available.)

Maintenance of the Application

After the application is approved, the applicant is expected to continue a number of activities, including the submission of expedited reporting of serious, unexpected adverse events that occur in the postmarketing setting; submission of Periodic Safety Update Reports that provide a review of the drug's safety profile since approval; and submission of Annual Reports. Updated stability data and annual updates to establishment registrations and drug listings also may be necessary. Please refer to Chapter 12 for more information on postmarketing activities.

Special Incentive Programs for Drug Development

Programs under the Orphan Drug Act and PREA are the most well-known special incentive programs and will be discussed in detail in other chapters of this book. This section briefly introduces programs designed to stimulate the development of new antimicrobial drugs, drugs for certain tropical diseases and the Presidential Emergency Plan for AIDS Relief (PEPFAR).


FDASIA contains specific provisions to incentivize development of antibiotics known as Generating Antibiotic Incentives Now (GAIN). GAIN is designed to stimulate development of drugs for the treatment of serious or life-threatening infections caused by bacteria or fungi. Eligible drugs must be designated a "qualified infectious disease product" (QIDP). Benefits of QIDP designation include Fast Track designation, FDA Priority Review and a five-year extension to the marketing exclusivity that is granted at the time of NDA approval (e.g., five-year NCE exclusivity, three-year new product exclusivity, seven-year orphan drug exclusivity). CDER has created an Antibacterial Drug Development Task Force ( As part of its work, the task force will assist in developing and revising guidance related to antibacterial drug development, as required by GAIN.

Tropical Diseases

A guidance that describes the policies and procedures for the tropical disease priority review voucher described in section 524(a)(3) of the FD&C Act (21 79 U.S.C. 360n(a)(3)) is available15 and should be used in conjunction with Guidance for Industry: Neglected Tropical Diseases of the Developing World: Developing Drugs for Treatment or Prevention.16

Briefly, under the law, a sponsor of certain marketing applications approved for the prevention or treatment of a designated tropical disease (examples include malaria, tuberculosis and cholera) receives a Priority Review Voucher for Priority Review from FDA to be used with a product of its choice. The voucher can be transferred to another developer. A PRV entitles the bearer to Priority Review for a future new drug application that would not otherwise qualify for priority review. The PRV holder must pay FDA an additional user fee ($3,559,000 in Fiscal 2013, reduced from $4,582,000 and $5,280,000 in Fiscal 2011 and 2012, respectively) and provide FDA with a one-year notice before redemption. So far, two manufacturers have been granted PRVs: Novartis for the malaria drug Coartem and Johnson & Johnson for the antimycobacterial drug Sirturo. FDASIA includes Section 908, the "Rare Pediatric Disease Priority Review Voucher Incentive Program," which extends the voucher program on a trial basis to rare pediatric diseases.

AIDS Relief

Working with implementing organizations and governments in over 32 countries, PEPFAR has contributed to the rapid acceleration of HIV treatment access, availability of care and support services and HIV prevention interventions. To support PEPFAR's goals, FDA introduced an initiative in 2004 to ensure that antiretroviral drugs produced by manufacturers all over the world could be reviewed rapidly, their quality assessed and their acceptability for purchase with PEPFAR funds supported.

As of 2 July 2012, FDA has approved or tentatively approved a total of 152 antiretroviral drugs in association with PEPFAR. Tentative approval means that although existing patents and/or marketing exclusivity prevent the product from being approved for marketing in the US, FDA has found that the product meets all of the manufacturing quality, safety and effectiveness requirements for marketing in the US.

New Drug Product Exclusivity (Hatch-Waxman Exclusivity)

New Drug Product Exclusivity, under sections 505(c)(3)(E) and (j)(5)(F) of the FD&C Act (Hatch-Waxman Amendments), provides the holder of an approved NDA limited protection from new competition in the marketplace for the innovation represented by its approved drug product. A five-year period of exclusivity is granted for drugs that contain a new chemical entity (NCE). A new chemical entity17 means a drug that contains no active moiety that has been approved by FDA in any other application submitted under section 505(b) of the FD&C Act. An active moiety means the molecule or ion responsible for the physiological or pharmacological action of the drug substance. Excluded from the concept of "active moiety" are those appended portions of the molecule that cause the drug to be an ester, salt (including a salt with hydrogen or coordination bonds), or other noncovalent derivative (such as a complex, chelate, or clathrate) of the molecule (see 21 CFR 314.108).

[media:1687:embed:left]A three-year period of exclusivity may be granted for drug products that contain an active moiety that has been previously approved, but the applications contain reports of new clinical investigations (other than bioavailability studies) that were conducted or sponsored by the applicant and were essential to the approval of the application. For example, the changes in an approved drug product that affect its active ingredient, strength, dosage form, route of administration or conditions of use may be granted exclusivity if the application meets the criteria.


  • A prescription drug is any drug approved or licensed for distribution by FDA that requires a healthcare practitioner's authorization before it can be obtained.
  • The FD&C Act prohibits introduction of a prescription drug product into interstate commerce unless the drug's manufacturer has submitted an application and obtained FDA approval.
  • A well-thought-out regulatory strategy is essential to the ultimate success of an applicant's drug development program and could shave months, or even years, off the product launch timeline.
  • An application is required to contain all information pertaining to the drug's development, including chemistry, manufacturing and controls, nonclinical and clinical data. The ultimate goal of the application is to provide adequate information to allow FDA to complete its review and provide a decision on the drug's safety, effectiveness and quality.
  • There are three different types of NDAs and two different types of BLAs. All of these applications should provide adequate information to allow FDA reviewers to conclude both that the drug is safe and effective when used for the proposed indication and that it can be manufactured consistently under controlled conditions.
  • FDA will take action on a submitted application by issuing either a complete response letter or an approval letter, based upon its assessment of the application. Complete response letters are issued when deficiencies are identified. Approval letters are issued once FDA has determined that the drug is safe, effective, can be acceptably manufactured and is appropriately labeled. FDA can require that a REMS be implemented or that postmarketing studies or clinical trials be conducted after approval.
  • Ongoing maintenance of the application is required for as long as it is active. Maintenance includes, but is not limited to, adverse event reporting, submission of Annual Reports, submission of advertising and promotional labeling.
  • Many incentives and programs are available to expedite drug development, review and approval. Many of these incentives focus on the development, review and approval of drugs intended to treat serious or life-threatening conditions and/or address an unmet medical need.


  1. All references to "drugs" or "drug products" in this chapter include both human drugs and biological drug products regulated by CDER unless otherwise specified.
  2. PDUFA Reauthorization Performance Goals and Procedures Fiscal Years 2013 Through 2017. FDA website. Accessed 26 March 2013.
  3. FDA. Draft Guidance for Industry and Review Staff: Target Product Profile-A Strategic Development Process Tool. FDA website. Accessed 26 March 2013.
  4. Biomarker Definitions Working Group (2001). Clinical Pharmacology and Therapeutics, 69, p. 89-95.
  5. Table modified from Sawyers CL, Haber DA, Horning SJ, Ivy SP and Selig WKD. "Developing Standards for Breakthrough Therapy Designation." Cancer Research (2012). Elsevier website. Accessed 26 March 2013.
  6. FDA. FY 2012 Innovative Drug Approvals. Bringing Life-saving Drugs to Patients Quickly and Efficiently (FDA December 2012). FDA website. Accessed 26 March 2013.
  7. FDA. Guidance for Industry: Fast Track Drug Development Programs-Designation, Development, and Application Review. FDA website. Accessed 26 March 2013.
  8. Op cit. 6.
  9. Ibid.
  10. Food and Drug Administration Safety and Innovation Act (FDASIA) of 2012. GPO website. Accessed 26 March 2013.
  11. As defined in 21 CFR 314.3, "right of reference or use" means the authority to rely upon, and otherwise use, an investigation for the purpose of obtaining approval of an application, including the ability to make available the underlying raw data from the investigation for FDA audit, if necessary.
  12. FDA. Guidance for the Public and FDA Staff on Convening Advisory Committee Meetings. FDA website. Accessed 26 March 2013.
  13. This statutory definition is equivalent to how FDA defines a "New Molecular Entity (NME)." Note that "active ingredient" includes salts and esters. The definition of NME for purposes of convening an Advisory Committee meeting is therefore different from the definition of "New Chemical Entity" for the purpose of determining eligibility for five-year market exclusivity under the Hatch-Waxman Act.
  14. See for example Covington E-alert 10 August 2012, Covington & Burling LLC website,, or Hyman,Phelps & McNamara, P.C. 11 July 2012, Accessed 26 March 2013.
  15. FDA. Guidance for Industry: Tropical Disease Priority Review Vouchers. FDA website. Accessed 26 March 2013.
  16. FDA. Guidance for Industry: Neglected Tropical Diseases of the Developing World: Developing Drugs for Treatment or Prevention. FDA website. Accessed 26 March 2013.
  17. The FD&C Act uses the term "new chemical entity (NCE)" and clearly refers to small molecules. The terms NCE and "new molecular entity (NME)" have very specific meanings to FDA that are distinct.


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