CHAPTER § 1.03 FDA Approval of New Drug Applications and Supplemental New Drug Applications

• Jurisdiction: United States

§ 1.03 FDA Approval of New Drug Applications and Supplemental New Drug Applications

[1] FDA Approval of NDA and Drug Labeling

Congress, through the FDCA,²⁵⁰ gave FDA the authority and responsibility to regulate every aspect of the safety, effectiveness, labeling, marketing, and promotion of prescription drugs.²⁵¹ Most prescription drugs are "new drugs" that cannot be commercially marketed in the United States without FDA review and approval.²⁵²

[a] The Drug Approval Process

To obtain approval, a pioneer manufacturer must submit a new drug application ("NDA").²⁵³ An NDA must provide data that demonstrate to FDA that the drug is safe and effective for its intended use.²⁵⁴ Extensive material, data, and information must be submitted in an NDA, including but not limited to the following:

(1) comprehensive information about the development, manufacturing, packaging, labeling, and clinical experience;
(2) detailed documentation describing physical, chemical, pharmacological, and biological characteristics;
(3) methods of preparation;
(4) methods of ensuring identity, strength, quality, and purity;
(5) manufacturing processes;
(6) prior toxicology and pharmacological data from pre-clinical testing; and
(7) comprehensive information regarding NDA clinical studies.²⁵⁵

An NDA also includes the proposed labeling, appearing in a format prescribed by FDA's regulations, and correspondence to or from FDA concerning the proposed labeling.²⁵⁶

Upon receipt of an NDA, FDA conducts a comprehensive scientific review of the cumulative safety and efficacy data and proposed labeling. The purpose of this safety review is to identify potential safety risks posed by the drug to determine whether:

(1) the drug is sufficiently safe for commercial use; and
(2) there are contraindications, warnings, precautions, or adverse events that should be disclosed in the prescribing information.²⁵⁷

FDA carefully reviews the NDA and identifies the actual and potential safety risks that the drug poses and decides how these risks should be disclosed in the prescribing information. FDA also considers other critical elements relating to a prescription drug, such as risk management and postmarketing study commitments.²⁵⁸

FDA approves the NDA only after it concludes that a prescription drug is both safe and effective under the conditions of use specified in the proposed prescribing information. FDA must disapprove an NDA if it finds that: (a) investigations conducted to establish safety and effectiveness were not adequate; (b) the prescription drug is not safe for use under the conditions provided in the proposed labeling; or (c) the proposed labeling is false or misleading.²⁵⁹

[b] Regulation of the Content of Drug Labeling and Warnings

When FDA concludes that the NDA data shows the drug is "safe and effective" for use, it establishes the precise conditions of use that must be stated in the prescription drug's approved prescribing information. This information is the "official" labeling for a prescription drug. By regulation, the prescribing information must be a compendium of all the information physicians require to safely and effectively prescribe drugs to treat patients.²⁶⁰ The prescribing information is the principal mechanism by which FDA and the manufacturer communicate the risks and benefits of the drug to health care professionals.²⁶¹

Because all drugs carry some risk, FDA's regulation of prescription drug labeling, including warnings, is extensive.²⁶² Drug labeling must include specific information under mandated section headings, including contraindications, warnings, precautions, and adverse reactions.²⁶³ The "warnings" section must describe any "serious adverse reactions and potential safety hazards, limitations in use imposed by them, and steps that should be taken if they occur."²⁶⁴ These mandated warnings must be based on "reasonable evidence of an association of a serious hazard with a drug; a causal relationship need not have been proved."²⁶⁵

A critical objective of any NDA review by FDA is to ensure that the approved labeling accurately reflects the medication's risks and benefits so that physicians, in consultation with their patients, can make optimal treatment choices. FDA will not approve an NDA until the drug's labeling accurately describes its indications, effects, dosages, routes, methods, frequency and duration of administration, and any relevant warnings, hazards, contraindications, side effects, or precautions.²⁶⁶

Based on the existing and reliable scientific evidence, FDA carefully develops warnings to express known risks through discussions with the manufacturer. At the same time, FDA avoids mention of unsubstantiated risks that may unnecessarily deter use of the drug, thereby depriving patients of beneficial treatment. FDA explained its longstanding risk-based and balanced approach to prescription drug labeling:

This amendment is intended to clarify FDA's existing policies and is intended to ensure that scientifically valid and appropriately worded warnings will be provided in the approved labeling for medical products, and to prevent overwarning, which may deter appropriate use of medical products, or overshadow more important warnings.²⁶⁷

FDA communicates its decision to approve the NDA through an approval letter that sets out FDA's terms for approving both the prescription drug and its labeling. These approvals are inextricably intertwined. FDA approval of a NDA is expressly conditioned on the development and use of "final printed labeling" (prescribing information) that is identical—in every material respect—to the labeling that accompanies the approval letter.²⁶⁸ Use of the FDA-approved prescribing information is mandatory, and failure to comply may lead to civil and criminal enforcement. A prescription drug's labeling²⁶⁹ is the "centerpiece of risk management."²⁷⁰ It "reflects thorough FDA review of the pertinent scientific evidence and communicates to health care practitioners the Agency's formal, authoritative conclusions regarding the conditions under which the product can be used safely and effectively."²⁷¹

Following approval, a drug is "misbranded" if its labeling is false or misleading,²⁷² lacks "adequate information for use,"²⁷³ or omits material facts.²⁷⁴ Therefore, departing from the FDA-approved prescribing information, failing to include a scientifically valid warning that FDA believes is necessary, or including warning information not based on reliable scientific evidence of known risks, causes the medication's labeling to be "false and misleading" and lacking "adequate directions for use," and renders the drug misbranded—in violation of the FDCA.²⁷⁵ The FDCA prohibits the distribution of misbranded drugs.²⁷⁶ If FDA believes a medication is misbranded, FDA, through the Department of Justice, is authorized to seek an in rem forfeiture action against the drug, or an injunction against, and/or criminal prosecution of the drug's manufacturer or responsible persons.²⁷⁷ FDA may also seek to withdraw the approval of the NDA.²⁷⁸

[2] Integrated Summary of Safety and Integrated Summary of Efficacy

The Integrated Summary of Safety ("ISS") and an Integrated Summary of Effectiveness ("ISE") are detailed integrated analyses of all the relevant data from the clinical study reports. FDA considers the ISS and ISE "critical components of the clinical efficacy and safety portions" of a marketing application.²⁷⁹ As such, the ISS and ISE must be submitted in an NDA.

[a] Integrated Summary of Safety

The ISS is an overall integrated analysis of all the available information about the safety of the drug product.²⁸⁰ The ISS should include data from animal studies, demon-strated or potential adverse effects of the drug, clinically significant drug interactions, data from epidemiological studies of related drugs, and any additional safety considerations.²⁸¹ The manufacturer should analyze the safety data and present the data in the ISS by gender, age, racial subgroups, and, when appropriate, other subgroups of the population of patients treated with the drug product.²⁸² In addition, the manufacturer should include any statistical analyses it used in analyzing the safety data.²⁸³

A pending NDA should be updated periodically with any new safety information learned about the drug that "may reasonably affect the statement of contraindications, warnings, precautions, and adverse reactions in the draft labeling."²⁸⁴ An updated ISS must be submitted: (1) 4 months after the initial submission; (2) in a resubmission following the receipt of a complete response letter from FDA; and (3) as requested by FDA.²⁸⁵

The updated ISS should include similar information submitted in the original ISS— animal studies data, adverse effects of the drug, and clinically significant drug interactions.²⁸⁶ In addition, the updated ISS should also include case report forms for each patient who died during a clinical study and for each patient who did not complete a clinical study because of an adverse event.²⁸⁷

[b] Integrated Summary of Effectiveness

The ISE is an overall integrated analysis that comprehensively examines the effectiveness data from clinical studies.²⁸⁸ The ISE includes the adequate and well-controlled studies submitted as a basis for approval, any other controlled trials (e.g., incomplete trials or those trials that do not support the claim), and the results of any other studies of which the applicant is aware.²⁸⁹ The ISE should include the following:

(1) an integrated summary of the data demonstrating substantial evidence of effectiveness for each claimed indication;
(2) evidence that supports the dosage and administration section of the labeling, including support for the recommended dosage and dose interval;
(3) effectiveness data analyzed by gender, age, and racial subgroups, identifying any modifications of dosing for specific subgroups; and
(4) evidence that is pertinent to individualization of dosing and the need for modifications of

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