Elsevier

Seminars in Nuclear Medicine

Volume 40, Issue 5, September 2010, Pages 364-384
Seminars in Nuclear Medicine

Food and Drug Administration Requirements for Testing and Approval of New Radiopharmaceuticals

https://doi.org/10.1053/j.semnuclmed.2010.05.002Get rights and content

In March 2004, the Food and Drug Administration (FDA) published a report entitled Challenge and Opportunity on the Critical Path to New Medical Products in which it explained the critical path to medical product development and called for a nationwide effort to modernize the critical-path sciences with the aim of moving medical product development and patient care into the 21st century. The report identified medical imaging and imaging biomarkers as potential clinical development tools to facilitate medical product development and to help minimize drug attritions and development timelines. Also, in recent years, basic research on receptor-based imaging has led to an increase in the new investigational radiopharmaceuticals, many of which are in basic research stages in academic institutions. It is therefore an opportune time to review the FDA requirements for testing and approval of new radiopharmaceuticals to further the cause of development and approval of newer medical imaging and therapeutic agents. Although the radiopharmaceutical-development process aligns well with the drug-development process for conventional pharmaceuticals, it has its own challenges and unique considerations. For example, unique issues surrounding short-lived positron emission tomography drugs have necessitated revisions and refinements to the existing regulations. The FDA Modernization Act mandate has finally resulted in the publication of new cGMPs (current good manufacturing practice) for positron emission tomography drugs. Often, the radiopharmaceutical community is not well-informed about the regulatory pathways and scientific basis for the regulations they are subjected to. Questions, such as (1) “Do I need an investigational new drug (IND) or can I do my investigation under an RDRC (radioactive drugs research committee) oversight?” (2) “What type of information on radiopharmaceutical product quality is needed for an IND?” (3) “What level of cGMPs I am expected to operate under?” (4) “Do I need a traditional IND or can I perform studies under an exploratory IND?” (5) “What are the IND-enabling pharmacology and toxicology studies?” (6) “Is my practice consistent with pharmacy compounding or do I need to file an application with the FDA?”, for example, are a source of confusion to the radiopharmaceutical community. This review provides an overview of FDA's drug development and approval process with special emphasis on radiopharmaceuticals and attempts to clarify many regulatory issues and questions by providing appropriate discussion and FDA references.

Section snippets

Drug-Development Process

The drug-development process is about connecting a proper linkage between discovery, development, FDA review and approval for marketing, and postmarketing safety surveillance of an approved drug to assure its continued safety and efficacy. Through the discovery phase, lead drug candidates are identified for further assessment in humans. Extensive preclinical testing is conducted in animal models to establish proof of concept. Safety pharmacology and toxicology profiles are established and an

FDA's Critical Path Initiatives Pertaining to Medical Imaging and Imaging Biomarkers

In March 2004, the FDA published a report entitled Challenge and Opportunity on the Critical Path to New Medical Products in which it explained the critical path to medical product development and called for a nationwide effort to modernize the critical path sciences with the aim of moving medical product development and patient care into the 21st century. The report identified medical imaging and imaging biomarkers as potential clinical development tools to facilitate medical product

Regulatory Framework for Investigational Radiopharmaceuticals

It is well known that extensive human research is performed in academic institutions by the use of radiolabeled chemicals, and these institutions often lack adequate regulatory support to determine the appropriate pathways available for the investigations in human subjects. There are 2 pathways available for the clinical studies in which investigational radiopharmaceuticals are used, (1) the Radioactive Drug Research Committee (RDRC) and (2) an IND. The code of federal regulation 21 part 361

Regulatory Framework for Radiopharmaceutical Approvals Under NDAs, BLAs, and Abbreviated NDAs (ANDAs)

Radiopharmaceuticals based on small and well-characterized molecules are submitted as NDAs or ANDAs, whereas those containing biologics, such as monoclonal antibodies and other macromolecules are submitted as BLAs. Since 2005, when all the monoclonal antibodies and therapeutic proteins were moved over from CBER to CDER, all radiopharmaceutical applications are now submitted to CDER regardless of whether they are NDAs or BLAs.

cGMPs for Radiopharmaceutical RDRC Studies, INDs, NDAs, BLAs, and ANDAs

The Food, Drug and Cosmetics Act Section 501(a)(2)(B) states that all drugs, including investigational drugs for human administration, must be manufactured under cGMPs. However, it provides for incremental approach to cGMP expectations during IND stages and enforcement discretion to the FDA. Keeping this in mind, FDA published a cGMP guidance for phase 1 INDs19 in July 2008. The guidance recommends quality control principles to the production of investigational drugs with well-defined written

Radiopharmaceutical Drug Master Files

A drug master file (DMF) is a submission to the FDA of confidential information by a DMF holder and it allows a reference to be made to the proprietary information contained in a DMF in support of an IND, NDA, ANDA, or a BLA. The regulation 21CFR part 314.420(a) provides for a regulatory basis for submitting a DMF. It is submitted under a different cover, separate from a typical regulatory submission and helps prevent proprietary information from being disclosed to sponsors of INDs or to

Radiopharmaceuticals Pharmacy and Physician Compounding

Section 127 of the Food and Drug Administration Modernization Act of 1997 (Pub. L 105-115) added section 503A to the Food, Drug, and Cosmetic Act (21 USC 353a). Section 503A of the Federal Food, Drug, and Cosmetic Act (the Act) (21 USC 353a) describes the circumstances under which compounded drugs may qualify for exemption from three requirements of the Act:1 that a drug be manufactured according to current good manufacturing practice;2 that a drug have adequate directions for use; and3 that a

Conclusions

Since the publication of FDAs Critical Path Initiative in March 2004, progress has been made in facilitating radiopharmaceutical development. FDA's recognition of medical imaging biomarkers as critical to medical product development is a testimony to the enormous potential of medical imaging agents, particularly the radiopharmaceuticals in the diagnosis, monitoring, and treatment of diseases.

The 1999 FDA Modernization Act mandate has finally resulted in the publication of new cGMP rule for PET

Acknowledgments

The author thanks the following colleagues for their help and constructive feedback during the development of the review article: Ravi Kasliwal, PhD, Senior CMC Reviewers, Office of New Drug Quality Assessment, CDER FDA. Eldon Leutzinger, PhD, Pharmaceutical Assessment lead, Office of New Drug Quality Assessment, CDER FDA. George Q. Mills, MD, Vice-President of Medical Imaging, PAREXEL Consulting and Former director of the Division of Medical Imaging and Hematologic Products (DMIHP), CDER, FDA.

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