| Title of guidance | Type and level of guidance | About the guidance | Source |
|---|---|---|---|
| E2C(R2) Periodic Benefit-Risk Evaluation Report – Questions and Answers | Final guidance | The ICH E2C(R2) IWG has prepared this Q&A document to support implementation of the guidance in practice. The Q&A document is intended to facilitate practical implementation of the PBRER, including points to consider in addressing some of the more novel aspects of the new periodic safety report. | FDA |
| E2C(R2) Periodic Benefit-Risk Evaluation Report (PBRER) | Final guidance | This guidance: • defines the recommended format and content of a Periodic Benefit-Risk Evaluation Report (PBRER), and provides an outline of points to be considered in the preparation and submission of the PBRER. The PBRER described in this guidance is intended to be a common standard for periodic benefit-risk evaluation reporting on marketed products (including approved drugs that are under further study) among the ICH regions. • revises, combines, and replaces two ICH guidances: E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs (ICH E2C guidance) and Addendum to E2C Clinical Safety Data Management: Periodic Safety Update Reports for Marketed Drugs (ICH E2C addendum). | FDA |
| M11 Template: Clinical Electronic Structured Harmonised Protocol | Draft guidance | This template is intended for interventional clinical trials of drugs, vaccines, and drug/device combinations intended to be registered as drugs. The template is suitable for all phases of clinical research and all therapeutic areas. Existing ICH Guidelines and ISO 14155 were considered in its development. The template is designed to enable modification suitable for the particular trial. Refer to the sections in the guidance for additional details and conventions related to flexibility. | FDA |
| M11 Technical Specification: Clinical Electronic Structured Harmonised Protocol | Draft guidance | The purpose of this document is to serve as a technical representation of the ICH M11 protocol template. This Technical Specification (TS) is to be aligned with the latest version of the ICH M11 Guideline and protocol template, but with flexibility in addressing data exchange needs per ICH and those of regional authorities. | FDA |
| M11 Clinical Electronic Structured Harmonised Protocol | Draft guidance | The purpose of this guideline is to describe the general protocol design principles and approach used to develop the separate associated documents, the ICH M11 Clinical Electronic Structured Harmonised Protocol Template [Template] and the Technical Specification that are acceptable to all regulatory authorities of the ICH regions. The Template presents the format and structure of the protocol, including the table of contents, common headers, and contents. The Technical Specification presents the conformance, cardinality, and other technical attributes that enable the interoperable electronic exchange of protocol content. Conformance with this Template and Technical Specification should ensure that protocols are provided in a harmonised data exchange format acceptable to the regulatory authorities. The Template and Technical Specification have been developed with built-in flexibility and are ICH M11 Guideline versioned documents. As clinical protocol requirements evolve and technology advances, they may be revised subject to a change control process. | FDA |
| Controlled Correspondence Related to Generic Drug Development | Draft guidance | This guidance: • provides information regarding the process by which generic drug manufacturers and related industry or their representatives can submit to FDA controlled correspondence requesting information related to generic drug development. • also describes the Agency’s process for providing communications related to such correspondence. • revises the guidance for industry Controlled Correspondence Related to Generic Drug Development issued in December 2020. When final, this guidance will replace the December 2020 guidance. The December 2020 guidance was issued as part of FDA’s implementation of the Generic Drug User Fee Amendments of 2017 (GDUFA II). • is being issued to incorporate program enhancements related to the review of controlled correspondence to which FDA committed, and industry agreed, as part of their negotiations relating to the reauthorization of the Generic Drug User Fee Amendments (GDUFA) (GDUFA III), as described in “GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027” (GDUFA III commitment letter). Other significant changes from the 30 December 2020 version include providing additional recommendations for specific types of inquiries in controlled correspondence. | FDA |
| Hypertension Indication: Drug Labeling for Cardiovascular Outcome Claims | Final guidance | This guidance is intended to assist applicants in developing labeling for cardiovascular outcome claims for drugs that are indicated to treat hypertension. With few exceptions, current labeling for antihypertensive drugs includes only the information that these drugs are indicated to reduce blood pressure; the labeling does not include information on the clinical benefits related to cardiovascular outcomes expected from such blood pressure reduction. However, blood pressure control is well established as beneficial in preventing serious cardiovascular events, and inadequate treatment of hypertension is acknowledged as a significant public health problem. The FDA believes that the appropriate use of these drugs can be encouraged by making the connection between lower blood pressure and improved cardiovascular outcomes more explicit in labeling. This guidance recommends standard labeling for antihypertensive drugs except where differences in labeling are supported by clinical data. The FDA encourages applicants to submit labeling supplements containing the new language. | FDA |
| Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug or Device Inspection | Draft guidance | This guidance covers facilities that are subject to inspection under section 704 of the FD&C Act. This guidance defines the types of behaviors (actions, inactions, and circumstances) that FDA considers to constitute delaying, denying, or limiting inspection, or refusing to permit entry or inspection for the purposes of section 501(j) of the FD&C Act. The examples used in this guidance are not intended to serve as an exhaustive list; rather, they illustrate the most common situations that FDA has encountered in preparing for and conducting inspections as well as situations that FDA anticipates may occur. FDA does not interpret the four terms describing prohibited behavior (delay, deny, limit, refuse) necessarily to be mutually exclusive. Therefore, the behaviors described in the scenarios in the guidance may be examples of more than one type of prohibited behavior. Also note that, for purposes of this guidance, the term “facility” is intended to include all establishments, factories, and warehouses covered by section 501(j). Once finalized, this draft guidance is intended to supersede the October 2014 FDA final guidance for industry entitled, “Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection.” However, until this draft guidance is finalized, the October 2014 FDA guidance remains in effect until it is withdrawn and will continue to reflect FDA’s current thinking on this issue. | FDA |
| Failure to Respond to an ANDA Complete Response Letter Within the Regulatory Timeframe Guidance for Industry | Final Level 2 guidance | This guidance is intended to assist applicants of abbreviated new drug applications (ANDAs), which are submitted under section 505(j) of the FD&C Act (21 U.S.C. 355(j)), in responding to complete response letters (CRLs) from FDA. As described in regulation, ANDA applicants are required to take action after receiving a CRL. The guidance revises the guidance of the same title issued in July 2022. This revision is being issued to incorporate the performance goals outlined in the Generic Drug User Fee Amendments Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027 (GDUFA III commitment letter). This guidance provides information and recommendations regarding potential courses of action for an ANDA applicant after issuance of a CRL, as well as the actions that FDA may take if the applicant fails to respond to that CRL. | FDA |
| Small Volume Parenteral Drug Products and Pharmacy Bulk Packages for Parenteral Nutrition: Aluminum Content and Labeling Recommendations | Draft guidance | Aluminum toxicity in parenteral nutrition (PN) represents a major safety concern, necessitating that PN products meet the requirements in 21 CFR 201.323 for aluminum content and labeling. Per the regulation, aluminum content of large volume parenteral (LVP) drug products used in total parenteral nutrition (TPN) therapy must not exceed 25 micrograms per liter (mcg/L). In contrast, the limits for the aluminum content of small volume parenteral (SVP) drug products and pharmacy bulk packages (PBPs) used in PN are not specified by statute or regulation. Further, the International Council for Harmonisation (ICH) has not established a permitted daily exposure (PDE) for aluminum. To address this lack of information, this guidance clarifies the key factors in determining the aluminum content in an SVP drug product and/or a PBP intended as a component of PN and provides FDA’s recommendations regarding the aluminum concentration limits in SVP drug products and PBPs for PN. Additionally, this guidance is intended to assist applicants in determining the appropriate content and placement of information on aluminum in SVP and PBP human prescription drug product labeling, including the Prescribing Information and container label and carton labeling. The intent of this guidance is to help assure that the information is clear and accessible to health care practitioners and guides the safe and effective use of the drug product. The recommendations in this guidance apply to the evaluation of aluminum content and establishment of a recommended aluminum concentration limit in an SVP drug product or PBP for PN. The guidance does not alter labeling considerations or recommended concentration limits for aluminum content in LVP drug products for TPN as those are already addressed in 21 CFR 201.323. However, because LVP and SVP drug products can be used together in PN therapy, this guidance does consider the aluminum content in LVP drug products when calculating the recommended aluminum concentration limit in an SVP drug product. | FDA |
| Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial | Final guidance | The purpose of this guidance is to provide recommendations to sponsors interested in studying multiple versions of a cellular or gene therapy product in an early-phase clinical trial2 for a single disease. Sponsors have expressed interest in gathering preliminary evidence of safety and activity using multiple versions of a cellular or gene therapy product in a single clinical trial. Although multiple versions of a product can be studied together in a single clinical trial, each version of the product is distinct and is generally submitted to FDA in a separate investigational new drug application (IND). The objective of these early-phase clinical studies is to guide which version(s) of the product to pursue for further development in later-phase studies. Thus, these studies are not intended to provide primary evidence of effectiveness to support a marketing application and generally are not adequately powered to demonstrate a statistically significant difference in efficacy between the study arms. In this guidance, we, FDA, provide recommendations for studies that evaluate multiple versions of a cellular or gene therapy product, including how to organize and structure the INDs, submit new information, and report adverse events. This guidance finalizes the draft guidance of the same title dated September 2021. | FDA |
| E19 A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval or Post-Approval Clinical Trials | Final guidance | This guidance is intended to provide internationally harmonized guidance on the use of selective safety data collection that may be applied in specific pre-approval or post-approval late-stage clinical trials. Selective safety data collection refers to the reduced collection of certain types of data in a clinical trial after thorough consideration of factors that would justify such an approach. By tailoring the method and streamlining the approach to safety data collection, it may be possible to carry out clinical trials with greater efficiency. This may facilitate the conduct of large-scale efficacy and safety clinical trials with large numbers of participants and long-term follow-up. In all circumstances in which the use of selective safety data collection is considered, it is important that the welfare of every trial participant is safeguarded. | FDA |
| Statistical Approaches to Establishing Bioequivalence | Draft guidance | Requirements for submitting bioavailability (BA) and bioequivalence (BE) data in INDs, NDAs, ANDAs, and supplements; the definitions of BA and BE; and the types of in vitro and in vivo studies that are appropriate to measure BA and establish BE are set forth in part 320 (21 CFR part 320). This guidance provides recommendations on how to meet provisions of part 320 for all drug products. | FDA |
| ANDAs: Pre-Submission Facility Correspondence Related to Prioritized Generic Drug Submissions | Draft guidanc | The FDA is issuing this revised draft guidance to incorporate program enhancements related to the content, timing, and assessment of a pre-submission facility correspondence (PFC) within the abbreviated new drug application (ANDA) assessment program agreed upon by the Agency and industry as part of the reauthorization of the GDUFA III, as described in GDUFA Reauthorization Performance Goals and Program Enhancements, Fiscal Years 2023 through 2027 (GDUFA III commitment letter). This guidance replaces the November 2017 draft guidance for industry on ANDAs: Pre-Submission of Facility Information Related to Prioritized Generic Drug Applications (Pre-Submission Facility Correspondence). | FDA |
| In Vitro Permeation Test Studies for Topical Drug Products Submitted in ANDAs | Draft guidance | This guidance: • is intended to assist applicants who are submitting abbreviated new drug applications (ANDAs) for liquid-based and/or other semisolid products applied to the skin, including integumentary and mucosal (e.g., vaginal) membranes, which are hereinafter called “topical products.” Because of the complex route of delivery associated with these products, which are typically locally acting, and the potential complexity of certain formulations, topical products (other than topical solutions) are classified as complex products. • provides recommendations for in vitro permeation test (IVPT) studies comparing a proposed generic (test) topical product and its reference standard (RS) for the purpose of supporting a demonstration of bioequivalence (BE) to the reference listed drug (RLD). The reference standard ordinarily is the RLD. • does not address drug products that are administered via ophthalmic, otic, nasal, inhalation, oral, or injection-based routes, or that are transdermal or topical delivery systems (including products known as patches, topical patches, or extended release films). | FDA |
| Charging for Investigational Drugs Under an IND – Questions and Answers | Final guidance | This guidance provides information for industry, researchers, physicians, institutional review boards (IRBs), and patients about the implementation of FDA’s regulation on charging for investigational drugs under an IND for the purpose of either clinical trials or expanded access for treatment use (21 CFR 312.8), which went into effect on October 13, 2009. Since 2009, FDA has received a number of questions concerning its implementation of the charging regulation. As a result, FDA is providing guidance in a Q & A format, addressing the most frequently asked questions. | FDA |
| Oversight of Clinical Investigations — A Risk-Based Approach to Monitoring | FinalLevel 2 revised guidance | This guidance: • assists sponsors of clinical investigations in developing risk-based monitoring strategies and plans for investigational studies of medical products, including human drug and biological products, medical devices, and combinations thereof. The overarching goal of this guidance is to enhance human subject protection and the quality of clinical trial data by focusing sponsor oversight on the most important aspects of study conduct and reporting. • makes clear that sponsors can use a variety of approaches to fulfill their responsibilities for monitoring clinical investigator (CI) conduct and performance in investigational new drug (IND) studies conducted under 21 CFR part 312 or investigational device exemption (IDE) studies conducted under 21 CFR part 812. The guidance describes strategies for monitoring activities that reflect a modern, risk-based approach that focuses on critical study parameters and relies on a combination of monitoring activities to oversee a study effectively. For example, the guidance specifically encourages greater use of centralized monitoring methods where appropriate. | FDA |
| Q5A(R2) Viral Safety Evaluation of Biotechnology Products Derived From Cell Lines of Human or Animal Origin | Draft guidance | This guideline concerns the testing and evaluation of the viral safety of biotechnology products, and it outlines what data should be submitted in marketing application and registration packages for those products. Biotechnology products include biotherapeutics and certain biological products derived from cell cultures initiated from characterised cell banks of human or animal origin (e.g., mammalian, avian, insect). In this document, the term “virus” excludes non-conventional transmissible agents like those associated with mammalian prions (e.g., bovine spongiform encephalopathy, scrapie). Applicants are encouraged to discuss bovine spongiform encephalopathy-associated issues with the appropriate regulatory authorities. | FDA |
| E6(R2) Good Clinical Practice: Integrated Addendum to ICH E6(R1) | Final guidance | The objective of this ICH GCP guidance is to provide a unified standard for the European Union, Japan, and the United States to facilitate the mutual acceptance of clinical data by the regulatory authorities in these jurisdictions. The guidance was developed with consideration of the current good clinical practices of the European Union, Japan, and the United States, as well as those of Australia, Canada, the Nordic countries, and the World Health Organization. This guidance should be followed when generating clinical trial data that are intended to be submitted to regulatory authorities. The principles established in this guidance may also be applied to other clinical investigations that may have an impact on the safety and well-being of human subjects. | FDA |
| Individual Patient Expanded Access Applications: Form FDA 3926 | Final guidance | This guidance describes Form FDA 39262 (Individual Patient Expanded Access – Investigational New Drug Application (IND)), which is available for licensed physicians to use for expanded access requests for individual patient INDs. The terms compassionate use and preapproval access are also occasionally used in the context of the use of an investigational drug to treat a patient; however, these terms are not defined or described in FDA regulations. Individual patient expanded access allows for the use of an investigational new drug outside of a clinical investigation, or the use of an approved drug where availability is limited by a risk evaluation and mitigation strategy (REMS), for an individual patient who has a serious or immediately life- threatening disease or condition and there is no comparable or satisfactory alternative therapy to diagnose, monitor, or treat the disease or condition. Form FDA 3926 provides a streamlined alternative for submitting an IND under 21 CFR 312.23 for use in cases of individual patient expanded access, including for emergency use. This guidance and Form FDA 3926 do not apply to other types of expanded access requests, including requests for expanded access for medical devices. | FDA |
| Cross Labeling Oncology Drugs in Combination Regimens Guidance for Industry | Final, Level 1 guidance | The purpose of this guidance is to describe the FDA’s current recommendations about including relevant information in labeling for oncology drugs approved for use in a combination regimen, including important considerations for cross labeling of these drugs. This guidance does not address all issues that might arise relating to labeling for oncology drugs for use in a combination regimen. Applicants proposing cross labeling for oncology drug combination regimens should contact the review division for information on cross labeling of their individual products. This guidance also does not address circumstances in which a drug product and a biological product packaged separately constitute a cross-labeled combination product as defined in 21 CFR 3.2(e). | FDA |
| Expanded Access to Investigational Drugs for Treatment Use: Questions and Answers | Draft guidance | This guidance provides information for industry, researchers, physicians, institutional review boards (IRBs), and patients about the implementation of FDA’s regulations on expanded access to investigational drugs for treatment use under an investigational new drug application (IND) (21 CFR part 312, subpart I), which went into effect on October 13, 2009. FDA received numerous questions concerning implementation of the regulatory requirements for expanded access. As a result, FDA issued the guidance for industry Expanded Access to Investigational Drugs for Treatment Use — Questions and Answers (June 2016, updated October 2017) (the 2017 guidance), providing recommendations in a question-and answer format, addressing the most frequently asked questions. Since 2017, FDA has received additional questions concerning implementation of the regulatory and statutory requirements of expanded access to investigational drugs, including those added by the 21st Century Cures Act (Cures Act) and the FDA Reauthorization Act of 2017 (FDARA). When finalized, this guidance will replace the 2017 guidance. Significant changes from the 2017 version include additional recommendations related to IRB review, informed consent, and new requirements established by the Cures Act and FDARA related to sponsors making their policies for evaluating and responding to expanded access requests (i.e., expanded access policy) public and readily available. | FDA |
| S1B(R1) Addendum to S1B Testing for Carcinogenicity of Pharmaceuticals | Final, Level 1 guidance | This Addendum is to be used in close conjunction with the ICH guidances for industry S1A The Need for Long-term Rodent Carcinogenicity Studies of Pharmaceuticals (March 1996), S1B Testing for Carcinogenicity of Pharmaceuticals (July 1997), and S1C(R2) Dose Selection for Carcinogenicity Studies (September 2008). The Addendum is complementary to the ICH S1 guidances for industry. More on this guidance here. | FDA |
| Regulation of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) – Small Entity Compliance Guide | Final guidance | The FDA has prepared this guidance in accordance with section 212 of the Small Business Regulatory Enforcement Fairness Act (Public Law 104-121). It is intended to help small entity establishments that manufacture human cells, tissues, or cellular or tissue-based products (HCT/Ps) better understand the comprehensive regulatory framework for HCT/Ps, set forth in Title 21 of the Code of Federal Regulations, part 1271 (21 CFR 1271). Section 21 CFR 1271.3 provides definitions for important terms used in 21 CFR 1271. | FDA |
| Measuring Growth and Evaluating Pubertal Development in Pediatric Clinical Trials; Draft Guidance for Industry; Availability | Draft guidance | This guidance: • is intended to assist sponsors in monitoring growth and, when appropriate, pubertal development in clinical trials that enroll pediatric participants with rare and common diseases. • provides recommendations for the most appropriate methods for measuring and recording growth and evaluating pubertal development for evaluation of safety. • does not address use of growth or pubertal development data to support primary evidence of efficacy in growth disorders (e.g., primary growth deficiency, disorders of pubertal development such as precocious puberty or delayed puberty). Sponsors should further discuss with the appropriate review division how to establish efficacy for such drugs. • does not address evaluation of nutritional status. • does not address statistical methods for analyzing growth or pubertal developmental data. | FDA |
| Crohn’s Disease: Developing Drugs for Treatment | Draft, Level 1 guidance | The purpose of this guidance is to help sponsors in the clinical development of drugs to treat adults with Crohn’s disease (CD). This draft guidance addresses the Food and FDA’s current recommendations on clinical trials for drugs being developed under section 505 FD&C Act (21 U.S.C. 355), section 351 of the PHS Act (42 U.S.C. 262) and 21 CFR parts 312, 314, and 601 for treating CD. Specifically, this guidance addresses FDA’s current thinking about the necessary attributes of clinical trials for drugs being developed for treating CD, including trial population, trial design, efficacy considerations, and safety assessments. This guidance does not address extraintestinal manifestations of CD, stricturing or fistulizing disease, pediatric drug development, or the treatment or prevention of long-term complications of CD. | FDA |
| Topical Dermatologic Corticosteroids: In Vivo Bioequivalence | Draft guidance | This guidance: • is intended to assist applicants who submit ANDAs for topical dermatologic corticosteroid products of all potency groups, hereinafter referred to as topical corticosteroids. • describes recommendations for in vivo studies to demonstrate the bioequivalence of topical corticosteroids. • provides recommendations for the study design, method qualification, data analysis, and data reporting for the pilot dose-duration vasoconstrictor response study and pivotal vasoconstrictor bioequivalence study used to demonstrate bioequivalence of topical corticosteroids. • also discusses considerations and approaches for estimating key study parameters (e.g., dose corresponding to half the maximal vasoconstrictor response (ED50)) and sample size for the pivotal vasoconstrictor bioequivalence study). When finalized, this guidance will replace the guidance for industry Topical Dermatologic Corticosteroids: In Vivo Bioequivalence that was issued in June 1995. Revising this guidance will provide clarity for potential ANDA applicants on the appropriate pilot and pivotal studies and other recommendations for pharmacodynamic approach to assess the bioequivalence of topical dermatologic corticosteroids. These recommendations have evolved since the original guidance was issued in 1995. | FDA |
| Physicochemical and Structural (Q3) Characterization of Topical Drug Products Submitted in ANDAs | Draft guidance | This guidance: • is intended to assist applicants who are submitting ANDAs for liquid-based and/or other semisolid products applied to the skin, including integumentary and mucosal (e.g., vaginal) membranes, which are hereinafter called topical products. Because of the complex route of delivery associated with these products which are typically locally acting, and the potential complexity of certain formulations, topical products (other than topical solutions) are classified as complex products. • provides recommendations for physicochemical and structural (collectively, Q3) characterizations that can be used (1) to identify the dosage form of a proposed generic (test) topical product and (2) to describe properties of the drug product that may be critical to its performance (to support a demonstration of bioequivalence (BE). When comparing the Q3 attributes of two topical products (e.g., to support a demonstration of BE), we generally advise that applicants conduct a comparative Q3 characterization of their proposed generic product against the reference standard, which ordinarily is the reference listed drug (RLD). • does not address Q3 characterization of topical products for purposes of product quality control. Basic Q3 characterization of a topical product can be used to describe its dosage form (e.g., an emulsion). See section III of this guidance for more information on (1) a characterization of appearance and texture, (2) a characterization of phase states, and (3) a characterization of the structural organization of matter. These three types of characterizations typically constitute a basic Q3 characterization of a topical product. | FDA |
| In Vitro Permeation Test Studies for Topical Drug Products Submitted in ANDAs | Draft guidance | This guidance is intended to assist applicants who are submitting abbreviated new drug applications (ANDAs) for liquid-based and/or other semisolid products applied to the skin, including integumentary and mucosal (e.g., vaginal) membranes, which are hereinafter called “topical products.” Because of the complex route of delivery associated with these products which are typically locally acting, and the potential complexity of certain formulations, topical products (other than topical solutions) are classified as complex products. This guidance provides recommendations for in vitro permeation test (IVPT) studies comparing a proposed generic (test) topical product and its reference standard (RS) for the purpose of supporting a demonstration of bioequivalence (BE) to the reference listed drug (RLD). The reference standard ordinarily is the RLD. This guidance does not address drug products that are administered via ophthalmic, otic, nasal, inhalation, oral, or injection-based routes, or that are transdermal or topical delivery systems (including products known as patches, topical patches, or extended release films). | FDA |
| In Vitro Release Test Studies for Topical Drug Products Submitted in ANDAs | Draft guidance | This guidance is intended to assist applicants who are submitting ANDAs for liquid-based and/or other semisolid products applied to the skin, including integumentary and mucosal (e.g., vaginal) membranes, which are hereinafter called topical products. Because of the complex route of delivery associated with these products, which are typically locally acting, and the potential complexity of certain formulations, topical products (other than topical solutions) are classified as complex products. This guidance provides recommendations for in vitro release test (IVRT) studies that can be used to compare a proposed generic (test) topical product and its reference standard (RS) for the purpose of supporting a demonstration of bioequivalence (BE) to the reference listed drug (RLD). The reference standard ordinarily is the RLD. This guidance does not address drug products that are administered via ophthalmic, otic, nasal, inhalation, oral, or injection-based routes, or that are transdermal or topical delivery systems (including products known as patches, topical patches, or extended-release films). | FDA |
| Multiple Endpoints in Clinical Trials Guidance for Industry | Final guidance | This guidance provides sponsors and review staff with the Agency’s thinking about the problems posed by multiple endpoints in the analysis and interpretation of study results and how these problems can be managed in clinical trials for human drugs, including drugs subject to licensing as biological products. Most clinical trials performed in drug development contain multiple endpoints to assess the effects of the drug and to document the ability of the drug to favorably affect one or more disease characteristics. When more than one endpoint is analyzed in a single trial, the likelihood of making false conclusions about a drug’s effects with respect to one or more of those endpoints could increase if there is no appropriate adjustment for multiplicity. The purpose of this guidance is to describe various strategies for grouping and ordering endpoints for analysis of a drug’s effects and applying some well-recognized statistical methods for managing multiplicity within a study to control the chance of making erroneous conclusions about a drug’s effects. Basing a conclusion on an analysis where the risk of false conclusions has not been appropriately controlled can lead to false or misleading representations regarding a drug’s effects. More information about the guidance is available here. Here you can listen to the guidance recap podcast and/or read the podcast transcript here. Here you can view the guidance snapshot. | FDA |
| Acute Myeloid Leukemia: Developing Drugs and Biological Products for Treatment | Final, Level 1 guidance | The purpose of this guidance is to assist sponsors in the clinical development of drugs and biological products for the treatment of acute myeloid leukemia (AML). Specifically, this guidance addresses FDA’s current thinking regarding the overall development program and clinical trial designs for the development of drugs to support an indication of treatment of AML, including indications limited to an individual phase of treatment (e.g., maintenance, transplantation preparative regimen, etc.). | FDA |
| Characterizing, Collecting, and Reporting Immune-Mediated Adverse Reactions in Cancer Immunotherapeutic Clinical Trials | Draft, Level 1 guidance | Cancer immunotherapeutic drugs and biological products (hereafter referred to as cancer immunotherapeutic drugs) can modulate (i.e., stimulate or suppress) the endogenous immune system to produce an anticancer effect. Adverse events that are consistent with an autoimmune etiology should be evaluated as potential immune-mediated adverse reactions (imAR) to guide patient management and inform the drug labeling or investigator brochure, as applicable. For the purpose of this guidance, the term imAR refers to adverse reactions that occurred in the context of exposure to a cancer immunotherapeutic drug and are consistent with the development of an autoimmune reaction, and are not attributable to another cause (e.g., infection, trauma, other drugs). While corticosteroids and other immunosuppressive drugs are regularly used to manage imARs in cancer clinical trials, the absence of a history of immunosuppressive treatment for an adverse reaction does not preclude its characterization as an imAR, especially for low grade imARs that result in dose interruption. This guidance: • is intended for sponsors of cancer immunotherapeutic drugs that modulate the endogenous immune system and may disrupt immunologic tolerance to normal organs and tissues. Examples of such cancer immunotherapeutic drugs include monoclonal antibodies, anticancer vaccines, and cytokines. Adoptively transferred cell-based cancer immunotherapeutics that target a tumor-associated antigen (TAA) and directly exert an anticancer effect (e.g., a TAAdirected genetically modified T-cell immunotherapy) are outside the scope of this guidance. • provides recommendations regarding the data that should be collected and evaluated to assess whether adverse events qualify as imARs and the data on imARs that should be included in a new drug application (NDA) or biologics license application (BLA) for a cancer immunotherapeutic drug. | FDA |
| Tissue Agnostic Drug Development in Oncology | Draft, Level 1 guidance | This guidance provides recommendations to sponsors regarding considerations for tissue agnostic drug development in oncology. For the purpose of this guidance, the term tissue agnostic oncology drug refers to a drug that targets a specific molecular alteration(s) (a kind of biomarker) across multiple cancer types as defined, for example by organ, tissue, or tumor type. A tissue agnostic oncology drug can therefore be used to treat multiple types of cancer (e.g., colorectal, thyroid, and breast cancers) with the targeted molecular alteration (e.g., either the same targeted molecular alteration or targeted molecular alterations affecting a single pathway). Although applications for a tissue agnostic oncology drug are reviewed for safety and effectiveness under the same legal and regulatory standard as drugs indicated for a tissue specific cancer, the development of a tissue agnostic oncology drug raises issues that generally do not arise in more traditional development approaches. This guidance describes the development of tissue agnostic drugs, scientific considerations in determining when tissue agnostic oncology drug development may be appropriate, and, if appropriate, issues to be addressed during such development. This guidance does not address the development of drugs intended to prevent or decrease the incidence of cancer and does not address the treatment of cancer in the adjuvant or neoadjuvant setting. | FDA |
| ANDA Submissions – Prior Approval Supplements Under GDUFA | Final level 2 guidance | This guidance is intended to assist applicants preparing to submit to FDA prior approval supplements (PASs) and amendments to PASs for ANDAs under section 505(j) of the FD&C Act 21 U.S.C. 355(j)). The guidance explains how the Generic Drug User Fee Amendments (GDUFA) relates to PAS submissions. The guidance revises the guidance of the same title issued in October 2017. This revision is being issued to incorporate the performance goals currently outlined in the GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years [Fiscal Years [FYs]] 2023-2027 (GDUFA III commitment letter) that FDA has agreed to meet and clarifies how FDA will handle a PAS and amendments to a PAS for an ANDA subject to the performance goals in the GDUFA III commitment letter. Specifically, this guidance describes how the GDUFA performance goals apply to: • A PAS subject to the refuse-to-receive (RTR) standards • A PAS that requires an inspection3 • A PAS for which an inspection is not required • An amendment to a PAS • Other PAS-related matters | FDA |
| Comparability Protocols for Postapproval Changes to the Chemistry, Manufacturing, and Controls Information in an NDA, ANDA, or BLA | Final guidance | This final guidance is intended to assist original applicants and holders of approved NDAs, ANDAs, and BLAs with implementing a CMC postapproval change through the use of a comparability protocol (CP). A CP is a comprehensive, prospectively written plan for assessing the effect of a proposed postapproval CMC change(s) on the identity, strength, quality, purity, and potency of a drug product, including a biological product (i.e., product), as these factors may relate to the safety or effectiveness of the product (i.e., product quality). Submission of a CP in an original application or in a prior approval supplement (PAS) to an approved application allows FDA to review a description of one or more proposed CMC postapproval changes, any supporting information and analysis, including a risk assessment, a plan to implement the change(s), and, if appropriate, a proposed reduced reporting category for the change(s). Approval of the original application or a subsequent PAS containing the CP provides an agreed-upon plan to implement the specified change(s), and in many cases, a justification to report the change(s) in a reduced reporting category, contingent upon your analysis of the data from the implementation of the change(s). In many cases, submission and approval of a CP will facilitate the subsequent implementation and reporting of CMC changes, which could result in moving a product into distribution or facilitating a proactive approach to reinforcing the supply of the product sooner than if a CP were not used. The drivers for such changes include business needs, expanding markets, process improvements, potential for drug shortage, and accelerated manufacturing development that sometimes occurs with drugs eligible for expedited programs. This guidance recommends a framework to promote innovation and continuous improvement in the manufacturing of quality products by encouraging you to employ: • Effective use of knowledge and understanding of the product and manufacturing process • Risk management activities over the life cycle of a product • An effective pharmaceutical quality system This guidance applies to CPs submitted in NDAs, ANDAs, BLAs, and supplements to these applications regulated by CDER and CBER. However, this guidance is not applicable to blood and blood components; biological products that also meet the definition of a device in section 201(h) of the FD&C Act; or human cells, tissues, or cellular or tissue-based products (HCT/Ps) regulated solely under section 361 of the Public Health Service Act and 21 CFR part 1271. | FDA |
| Competitive Generic Therapies | Final, level 1 guidance | The FDA Reauthorization Act of 2017, or FDARA, created a pathway by which FDA may, at the request of the applicant, designate a drug with “inadequate generic competition” as a competitive generic therapy (CGT). At the request of the applicant, FDA may also expedite the development and review of an ANDA for a drug designated as a CGT. This guidance provides a description of the process that applicants should follow to request designation of a drug as a CGT and the criteria for designating a drug as a CGT. It also includes information on the actions FDA may take to expedite the development and review of ANDAs for drugs designated as CGTs. Finally, it provides information on how FDA implements the statutory provision for a 180-day exclusivity period for certain first approved applicants that submit ANDAs for CGTs. This guidance revises the guidance of the same title issued in March 2020. This revision is being issued to incorporate information on the meeting types and performance goals included in the GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027 (GDUFA III commitment letter). | FDA |
| Formal Meetings Between FDA and ANDA Applicants of Complex Products Under GDUFA Guidance for Industry | Final guidance | This guidance describes an enhanced pathway for discussions between FDA and a prospective applicant preparing to submit to FDA or an applicant that has submitted to FDA an ANDA for a complex product, as defined in this guidance. Specifically, this guidance provides information on requesting and conducting product development meetings, pre-submission meetings, mid-cycle review meetings (MCRMs), enhanced mid-cycle review meetings (EMCRMs), and post-complete response letter (CRL) scientific meetings with FDA. This guidance reflects a unified approach to formal meetings between FDA and prospective ANDA applicants or ANDA applicants for complex products under the pre-ANDA program and the ANDA assessment program. This guidance will assist applicants in generating and submitting to FDA a meeting request and the associated meeting package for complex products, as defined in this guidance, that are or will be the subject of ANDAs submitted under section 505(j) of the FD&C Act (21 U.S.C 355(j)), and as contemplated in the GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027 (GDUFA III commitment letter). This guidance revises the guidance of the same title issued in November 2020. This revision is being issued to incorporate information on the complex product meeting types and performance goals included in the GDUFA III commitment letter, including information on requesting these meetings and FDA’s procedures for handling these meetings. | FDA |
| Post-Complete Response Letter Clarification Teleconferences Between FDA and ANDA Applicants Under GDUFA Guidance for Industry | Final guidance | This guidance provides recommendations to industry on post-complete response letter (CRL) teleconferences (post-CRL clarification teleconferences) between FDA and ANDA applicants for the purpose of clarifying deficiencies identified in a CRL to an ANDA submitted under section 505(j) of the FD&C Act (21 U.S.C. 355(j)). For the purposes of this guidance, a post-CRL clarification teleconference is a meeting that is requested in writing by an ANDA applicant pursuant to the procedures described in this guidance following receipt of a CRL. It is important that there are efficient, consistent procedures for the timely and effective conduct of post-CRL clarification teleconferences. This guidance will assist applicants in generating and submitting a request for a post-CRL clarification teleconference and the associated meeting package to FDA as contemplated in the GDUFA of 2022, reauthorizing the GDUFA III for Fiscal Years 2023- This guidance is intended to provide procedures that will promote well-managed post CRL clarification teleconferences and help ensure that such meetings are scheduled and conducted in accordance with the time frames set forth in the GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027 (GDUFA III commitment letter). This guidance revises the guidance entitled Post-Complete Response Letter Meetings Between FDA and ANDA Applicants Under GDUFA issued in December 2018. This revision is being issued to incorporate the performance goals outlined in the GDUFA III commitment letter that FDA has agreed to meet, and clarifies how FDA will conduct post-CRL clarification teleconferences subject to the GDUFA performance goals. | FDA |
| Facility Readiness: Goal Date Decisions Under GDUFA | Draft guidance | This guidance provides information to applicants on how FDA intends to assign a goal date based on a facility’s readiness for inspection as certified on Form FDA 356h submitted as part of an original abbreviated new drug application (ANDA)4 20 under section 505(j) of the FD&C Act (21 U.S.C. 355(j)). This guidance explains how FDA incorporates a program enhancement agreed upon by the Agency and industry as part of the negotiations relating to reauthorization of the GDUFA, described in “GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023-2027” (GDUFA III commitment letter) | FDA |
| Review of Drug Master Files in Advance of Certain ANDA Submissions Under GDUFA | Draft guidance | This guidance is intended for holders of Type II active pharmaceutical ingredient (API) drug master files (DMFs) that will be referenced in an ANDA, or a prior approval supplement (PAS) to an ANDA. This guidance explains how FDA incorporates a program enhancement agreed upon by the Agency and industry as part of the negotiations relating to reauthorization of the GDUFA, as described in “GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2023- 2027” (GDUFA III commitment letter). Specifically, this guidance describes instances when an early assessment, or “DMF prior assessment,” could be requested by a DMF holder and the circumstances under which FDA would commence an early assessment of Type II API DMFs months prior to an ANDA or PAS submission referencing the DMF. It also provides recommendations for such DMF holders when making a request. The guidance does not apply to Type II API DMFs used to support NDAs, submissions related to ANDAs that are not described above, or any other types of DMFs. | FDA |
| Size, Shape, and Other Physical Attributes of Generic Tablets and Capsules | Final, Level 2 revised guidance | Tablets and capsules are widely manufactured and prescribed and may provide a number of advantages over other dosage forms, including ease of storage, portability, ease of administration, and accuracy in dosing. While generic formulations of these drug products are required to be both pharmaceutically and therapeutically equivalent to a reference listed drug (RLD), FDA is concerned that differences in physical characteristics (e.g., size and shape of the tablet or capsule) may affect patient compliance and acceptability of medication regimens or could lead to medication errors. FDA believes these patient safety concerns are important and are recommending that generic drug manufacturers consider physical attributes when they develop quality target product profiles (QTPPs) for their generic product candidates. The recommendations in this guidance apply to abbreviated new drug applications (ANDAs) and their supplements for additional strengths that are submitted to the Office of Generic Drugs (OGD). This guidance: · does not apply to approved ANDAs (generic drugs) already on the market. However, if the Agency determines that an approved product should be modified because the size or shape of a product poses a risk to public health, it will notify the holder of the ANDA. · is not intended to apply to other oral dosage forms (e.g., chewable tablets, oral tablets for suspension/solution, orally disintegrating tablets, sublingual tablets, troches, gums). · revises the guidance of the same name issued in June 2015 to clarify that the largest dimension of a tablet should not exceed 22 mm and that capsules should not exceed a standard 00 size. This guidance also includes updated references. | FDA |
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