News from the FDA

The FDA has issued a guidance for industry titled “Botanical Drug Products,” which is intended to encourage the clinical study and submission for marketing approval of such products. The guidance explains the circumstances under which FDA regulations require approval of an NDA submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(b)) before marketing a botanical drug and explains when such a drug may be marketed under an OTC drug monograph. The document also provides scientific and regulatory guidance to sponsors about conducting initial and expanded clinical investigations of botanical drugs, including those botanical products currently lawfully marketed as foods and dietary supplements in the United States.

The agency received a number of comments on the botanical drugs draft guidance issued in 2001 that prompted it to make a few substantive changes to the final draft. For example, the guidance now emphasizes the importance of maintaining batch-to-batch consistency in the drug substance and drug product used throughout the clinical development process. For further information, go to: http://a257.g.akamaitech.net/7/257/2422/06jun20041800/edocket.access.gpo.gov/2004/04-13031.htm.

Clarifications Made Concerning Bioequivalence and Bioavailability Studies

The FDA has issued a guidance for industry that provides recommendations for study sponsors and/or drug manufacturers, contract research organizations, site management organizations, clinical investigators, and independent third parties on the procedure for handling reserve samples from bioavailability (BA) and bioequivalence (BE) studies. The guidance, titled “Handling and Retention of BA and BE Testing Samples,” will clear up questions concerning how to distribute test articles and reference standards to testing facilities, how to randomly select reserve samples and how to retain reserve samples.

The guidance was issued in response to problems that developed following the generic drug crisis in the 1980s, when the FDA issued regulations to prevent possible bias and fraud in BA and BE testing by study sponsors and/or drug manufacturers. In the preamble to the final rule then issued, the agency stated that a study's sponsor should not separate out the reserve samples of the test article and reference standard prior to sending the drug product to the testing facility, in order to ensure that the reserve samples are in fact representative of the batches provided by the study sponsor for testing. Despite this, the FDA's inspectors still find that reserve samples are often not retained, as they should be, at testing facilities. For further information, go to: http://a257.g.aka maitech.net/7/ 257/2422/14mar20010800/edocket.access.gpo.gov/2004/04-11828.htm.

Reprocessed Single-Use Medical Device Guidance Revised

A revised guidance for industry on premarket notification submissions for reprocessed single-use medical devices to include the procedures and timeframes that the agency intends to follow in its review of the validation data required by the Medical Device User Fee and Modernization Act of 2002 (MDUFMA) is available for certain reprocessed single-use devices The revisions, which can be found in the document “Guidance for Industry and FDA Staff; Medical Device User Fee and Modernization Act of 2002, Validation Data in Premarket Notification Submissions (510(k)s) for Reprocessed Single-Use Medical Devices,” includes updated references to relevant Federal Register notices and a section addressing the Paperwork Reduction Act of 1995 (the PRA). This guidance document, which is now in effect, outlines the agency's current position on validation data regarding the cleaning, sterilization, and functional performance of reprocessed SUDs, as well as the procedures and review times that should be used by the FDA in evaluating these validation data. To download the document, visit the CDRH Web site at http://www.fda.gov/ cdrh/guidance.html. The docket number is 2003D-0309.

Comment Period Reopened on Consumer-Directed Communications Issues

The FDA is reopening until August 10 the comment period for the draft guidances “Brief Summary: Disclosing Risk Information in Consumer-Directed Print Advertisements,” “Help-Seeking and Other Disease Awareness Communications by or on Behalf of Drug and Device Firms,” and “Consumer-Directed Broadcast Advertising of Restricted Devices.” The initial comment period closed on May 10, but the agency received requests for an extension because of the importance of the subject matter to be commented on and the need for time to complete research in order to prepare comments. Copies of the draft guidances are available on the Internet at http:// www. fda.gov/cder/guidance/index.htm, http://www.fda.gov/ cber/guidelines, or http://ww.fda.gov/ ohrms/dockets/ default.htm. Submit written comments on the draft guidances to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

For more information, see http://a257.g.akamaitech.net/7/257/2422/14mar20010800/edocket.access.gpo.gov/2004/04-12270.htm. The docket number is 2003D-0309.

Requests for Inspections By Accredited Persons

The Medical Device User Fee and Modernization Act of 2002 (Public Law 107-250) (MDUFMA) added a provision in section 704(g) to the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 374(g)) to permit third-party inspections of eligible establishments that market class II or class III devices in the United States and who also market or plan to market such devices in foreign countries. The inspections by accredited persons program (AP program) generally enables manufactures to better manage their inspection schedules since they will schedule the AP inspections themselves, provided the FDA has approved their request to use an AP. The new law defines the qualifying criteria that a manufacturer must meet in order to participate in the AP program (section 704(g)(6)(A) of the act). A draft guidance to help manufacturers determine whether they are eligible to participate in this inspectional program, titled “Requests for Inspection by an Accredited Person Under the Inspections by Accredited Persons Program Authorized by Section 201 of the Medical Device User Fee and Modernization Act of 2002,” is now available. It identifies the information manufacturers should submit to the FDA when requesting permission to use an AP. To download the document, go to: www.fda.gov/cber/ gdlns/inspectaccred.pdf.

Guidance on the M4 Common Technical Document

A guidance titled “M4: The CTD – Quality: Questions and Answers/ Location Issues,” has been issued by the FDA under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). This guidance provides further clarification for preparing the quality components of an application in the CTD-Q format. The guidance addresses the relationship between linked sections for certain parameters, such as polymorphism and particle size, and also addresses location issues by indicating the section in which to place requested information. The guidance is intended to ease the preparation of paper and electronic submissions, facilitate regulatory reviews, and simplify the exchange of regulatory information among regulatory authorities. The document (docket number 2002D-0509) can be obtained at: http://www.fda.gov/cber/ publications.htm, or http://www.fda. gov/ohrms/dockets/default.htm.

New Rules On Development of Veterinary Drugs That Can Affect Food Supplies

Of interest to veterinary medicine manufacturers is a final guidance document issued by the FDA titled “Studies to Evaluate the Safety of Residues of Veterinary Drugs in Human Food: Carcinogenicity Testing” (VICH GL28). The guidance was adapted for veterinary use by the International Cooperation on Harmonisation of Technical Require-ments for Registration of Veterinary Medicinal Products (VICH) from a guidance regarding pharmaceuticals for human use. It's intended to help ensure that residues of veterinary drugs in animal products for human consumption are not too carcinogenic and applies to food in the European Union, Japan, and the United States. Copies of the document may be obtained on the Internet from the CVM home page at http://www.fda.gov/cvm. For more information, see Docket No. 2001D-0357 at http://a257.g.akamaitech.net/ 7/257/2422/14mar20010800/edocket.access.gpo.gov/2004/04-11781.htm

Botanical Drug Product Approval Process Outlined

The FDA has issued a guidance for industry titled “Botanical Drug Products,” which is intended to encourage the clinical study and submission for marketing approval of such products. The guidance explains the circumstances under which FDA regulations require approval of an NDA submitted under section 505(b) of the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 355(b)) before marketing a botanical drug and explains when such a drug may be marketed under an OTC drug monograph. The document also provides scientific and regulatory guidance to sponsors about conducting initial and expanded clinical investigations of botanical drugs, including those botanical products currently lawfully marketed as foods and dietary supplements in the United States.

The agency received a number of comments on the botanical drugs draft guidance issued in 2001 that prompted it to make a few substantive changes to the final draft. For example, the guidance now emphasizes the importance of maintaining batch-to-batch consistency in the drug substance and drug product used throughout the clinical development process. For further information, go to: http://a257.g.akamaitech.net/7/257/2422/06jun20041800/edocket.access.gpo.gov/2004/04-13031.htm.

Clarifications Made Concerning Bioequivalence and Bioavailability Studies

The FDA has issued a guidance for industry that provides recommendations for study sponsors and/or drug manufacturers, contract research organizations, site management organizations, clinical investigators, and independent third parties on the procedure for handling reserve samples from bioavailability (BA) and bioequivalence (BE) studies. The guidance, titled “Handling and Retention of BA and BE Testing Samples,” will clear up questions concerning how to distribute test articles and reference standards to testing facilities, how to randomly select reserve samples and how to retain reserve samples.

The guidance was issued in response to problems that developed following the generic drug crisis in the 1980s, when the FDA issued regulations to prevent possible bias and fraud in BA and BE testing by study sponsors and/or drug manufacturers. In the preamble to the final rule then issued, the agency stated that a study's sponsor should not separate out the reserve samples of the test article and reference standard prior to sending the drug product to the testing facility, in order to ensure that the reserve samples are in fact representative of the batches provided by the study sponsor for testing. Despite this, the FDA's inspectors still find that reserve samples are often not retained, as they should be, at testing facilities. For further information, go to: http://a257.g.aka maitech.net/7/ 257/2422/14mar20010800/edocket.access.gpo.gov/2004/04-11828.htm.

Reprocessed Single-Use Medical Device Guidance Revised

A revised guidance for industry on premarket notification submissions for reprocessed single-use medical devices to include the procedures and timeframes that the agency intends to follow in its review of the validation data required by the Medical Device User Fee and Modernization Act of 2002 (MDUFMA) is available for certain reprocessed single-use devices The revisions, which can be found in the document “Guidance for Industry and FDA Staff; Medical Device User Fee and Modernization Act of 2002, Validation Data in Premarket Notification Submissions (510(k)s) for Reprocessed Single-Use Medical Devices,” includes updated references to relevant Federal Register notices and a section addressing the Paperwork Reduction Act of 1995 (the PRA). This guidance document, which is now in effect, outlines the agency's current position on validation data regarding the cleaning, sterilization, and functional performance of reprocessed SUDs, as well as the procedures and review times that should be used by the FDA in evaluating these validation data. To download the document, visit the CDRH Web site at http://www.fda.gov/ cdrh/guidance.html. The docket number is 2003D-0309.

Comment Period Reopened on Consumer-Directed Communications Issues

The FDA is reopening until August 10 the comment period for the draft guidances “Brief Summary: Disclosing Risk Information in Consumer-Directed Print Advertisements,” “Help-Seeking and Other Disease Awareness Communications by or on Behalf of Drug and Device Firms,” and “Consumer-Directed Broadcast Advertising of Restricted Devices.” The initial comment period closed on May 10, but the agency received requests for an extension because of the importance of the subject matter to be commented on and the need for time to complete research in order to prepare comments. Copies of the draft guidances are available on the Internet at http:// www. fda.gov/cder/guidance/index.htm, http://www.fda.gov/ cber/guidelines, or http://ww.fda.gov/ ohrms/dockets/ default.htm. Submit written comments on the draft guidances to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.

For more information, see http://a257.g.akamaitech.net/7/257/2422/14mar20010800/edocket.access.gpo.gov/2004/04-12270.htm. The docket number is 2003D-0309.

Requests for Inspections By Accredited Persons

The Medical Device User Fee and Modernization Act of 2002 (Public Law 107-250) (MDUFMA) added a provision in section 704(g) to the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 374(g)) to permit third-party inspections of eligible establishments that market class II or class III devices in the United States and who also market or plan to market such devices in foreign countries. The inspections by accredited persons program (AP program) generally enables manufactures to better manage their inspection schedules since they will schedule the AP inspections themselves, provided the FDA has approved their request to use an AP. The new law defines the qualifying criteria that a manufacturer must meet in order to participate in the AP program (section 704(g)(6)(A) of the act). A draft guidance to help manufacturers determine whether they are eligible to participate in this inspectional program, titled “Requests for Inspection by an Accredited Person Under the Inspections by Accredited Persons Program Authorized by Section 201 of the Medical Device User Fee and Modernization Act of 2002,” is now available. It identifies the information manufacturers should submit to the FDA when requesting permission to use an AP. To download the document, go to: www.fda.gov/cber/ gdlns/inspectaccred.pdf.

Guidance on the M4 Common Technical Document

A guidance titled “M4: The CTD – Quality: Questions and Answers/ Location Issues,” has been issued by the FDA under the auspices of the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). This guidance provides further clarification for preparing the quality components of an application in the CTD-Q format. The guidance addresses the relationship between linked sections for certain parameters, such as polymorphism and particle size, and also addresses location issues by indicating the section in which to place requested information. The guidance is intended to ease the preparation of paper and electronic submissions, facilitate regulatory reviews, and simplify the exchange of regulatory information among regulatory authorities. The document (docket number 2002D-0509) can be obtained at: http://www.fda.gov/cber/ publications.htm, or http://www.fda. gov/ohrms/dockets/default.htm.