January 2011

The FDA Food Safety Modernization Act (FSMA) (P.L. 111-353), enacted on January 4, 2011, implements some of the most significant changes to food safety regulation in 70 years. The FSMA represents a major reform of the food safety provisions of the Federal Food, Drug, and Cosmetic Act of 1938 (FDCA) and expands the powers of the FDA with respect to food. The new law generally does not apply to meat, poultry, or egg products regulated by the U.S. Department of Agriculture; the expected cost will be $1.4 billion over the next four years.

Topic of the Month:  With the signing of the FDA Food Safety Modernization Act, President Barack Obama and Congress have adopted the first comprehensive overhaul of the food safety program at the FDA. The overhaul will replace the reactive structure under which FDA responded to food safety problems—adulterated or misbranded foods already on the market—with a preventive mandate. The new structure provides the FDA with much greater oversight over the food industry, including requiring facilities to develop new food safety plans, to provide the agency with test results, and to register every two years. The law also gives greater incentives for the industry and importers to implement strong food safety programs. Internet subscribers to the Food, Drug, and Cosmetics Reporter may access a special “FDA Food Safety Modernization Act: Law, Explanations, and Analysis” for complete, practical, and easy-to-understand guidance on every provision of the law designed to make sense and apply the changes enacted in this bill.

I. Agency Developments

Tobacco products equivalence exemptions proposed
A proposed rule would establish procedures for tobacco manufacturers requesting an exemption from the substantial equivalence requirements of the Family Smoking Prevention and Tobacco Control Act (FSPTCA). The proposed rule would describe the process and statutory criteria for requesting an exemption and explain how the FDA would review requests for exemptions. Once finalized, the regulation will satisfy the requirement in the FSPTCA that the FDA issue regulations implementing the exemption provision. Specifically, the rule would provide that the FDA may exempt tobacco products that are modified by adding or deleting a tobacco additive, or increasing or decreasing the quantity of an existing tobacco additive, if the FDA determines that the modification would be a minor modification of a tobacco product that can be sold under the FDC Act. The proposed rule also explains that an exemption request maybe made only by the manufacturer of a legally, commercially marketed tobacco product for a minor modification to that manufacturer’s product. The  FDA is proposing this requirement because it believes that only the manufacturer of the product being modified will have, and be able to provide to the FDA, sufficient and complete information about the product and the proposed modification.  FDA Proposal, ¶46,162

Informed consent documents amended for data bank registry
Effective March 7, 2011, the FDA is amending the informed consent regulations to require that informed consent documents and processes for applicable drug (including biological products) and device clinical trials include a specific statement that clinical trial information will be entered into a data bank. The data bank, a clinical trial registry data bank maintained by the National Institutes of Health/National Library of Medicine was created by statute, along with a requirement regarding the submission of clinical trial information to this data bank. This amendment to the informed consent regulations is required by the Food and Drug Administration Amendments Act of 2007 (FDAAA) and is designed to promote transparency of clinical research to participants and patients. Sixty eight comments were received, including comments objected to adding any statements to informed consent documents about submitting information to the databank for a variety of reasons, including the objection that it lengthens already lengthy informed consent documents, exacerbating potential participants’ confusion and anxiety upon reading consent forms. The agency disagreed, finding that the revised language consisted of four short sentences, which will minimally impact a potential subject’s reaction to a consent form. The cost analysis concluded that the compliance cost of the proposed rule per trial protocol would range from $611 to $1,061. FDA Order, ¶40,414

II. Drug and Biologics Developments

Electronic source documentation in clinical investigations guidance issued
A draft guidance outlining the FDA’s recommended procedures for ensuring the reliability, quality, integrity, and traceability of electronic source data was published by the agency. Titled “Electronic Source Documentation in Clinical Investigations” the document provides guidance to sponsors, contract research organizations (CROs), data management centers, and clinical investigators on capturing, using, and archiving electronic data in FDA-regulated clinical investigations. When paper source documents are available for review, tracing of data in paper-based studies can be easily performed, however, when source data is electronic, the data is traced through complex data capture, transmission, and archival processes. Topics that relate to electronic source data are discussed in the draft guidance, including: (1) the identification of the data element as the basic unit of information in the electronic case report form; (2) the description of a source of each data element; (3) information about the electronic creation, modification, transmission, and storage of source data and documents; and (4) investigator responsibilities with respect to reviewing and archiving electronic data.. FDA Notice, ¶42,081

Reduction in acetaminophen dosage strength implemented
The maximum dosage unit strength of acetaminophen in prescription drug products will be reduced by the FDA to increase the margin of safety to prevent liver damage caused by an overdose of acetaminophen. The FDA will require mandatory safety labeling changes that will include a new boxed warning, for acetaminophen-containing prescription drug products to warn consumers of the potential risk for liver damage. Sponsors of approved prescription drug products that have more than 325 milligrams (mg) of acetaminophen will have until January 14, 2014, to withdraw the approval of the product's application or be subject to sanctions.

The change is based on several reasons including: (1) prescription products contribute to the continued and unacceptably high incidence of acetaminophen- related liver injury; (2) a need to establish an adequate margin of safety based on the inability to identify precise toxicity thresholds and/or specific populations for whom currently recommended dosages are not  safe; (3) a high potential for unintentional overdoses; and (4) a lack of evidence to support the benefit of increased pain relief or dosing convenience from higher acetaminophen strengths outweighs the risk of liver damage from an unintentional overdose.

The changes will apply only to acetaminophen-containing drug products labeled for prescription use and marketed under approved new drug applications or abbreviated new drug applications. The FDA did not change the requirements for over-the-counter acetaminophen drug products. FDA Notice, ¶43,981

Bead sizes in drugs used in sprinkle dosages, guidance issued
A draft guidance titled “Size of Beads in Drug Products Labeled for Sprinkle” for sponsors of new drug applications (NDAs), abbreviated new drug  applications (ANDAs), and biologics licensing applications (BLAs) concerning the appropriate size ranges for beads in drug products that are labeled to be administered via sprinkling (e.g., capsules or packets containing beads) was published by the FDA. There are certain drug products that contain beads within a capsule and the labeling states that the capsule may be broken and the internal beads may be sprinkled on soft foods and swallowed without chewing.

This method is common for drug products that have extended or delayed-release characteristics. According to the FDA, additional assurances may be needed when the label allows for administration via an enteral feeding tube. The FDA recommended a maximum bead size of 2.0 mm for drug products labeled for sprinkle but this recommendation only applies to NDAs, ANDAs, and BLAs of products that are not yet approved. Bead size distribution, including the maximum bead size can be determined through analytical sieving in accordance to USP <786>; or other validated methods.

It was also recommended that enteral feeding tube administration should be demonstrated to show the entire contents can be adequately administered by this method. The FDA recommended that studies be done for NDAs and ANDAs, because of the differences in bead size and coatings that vary between products, will affect the products’ ability to pass through a feeding tube. The FDA had specific recommendations regarding the acceptability of bead size and bead size differences from a bioavailability (BA) or bioequivalence (BE) point of view as directly evaluated in the BE studies. In NDAs, for the labeling to indicate that the drug product can be sprinkled on soft foods, additional in vivo relative BA studies should be performed by administering beads that have been sprinkled on one of the soft foods that are listed in the labeling and comparing the sprinkled products’ BA results to those of the product administered in the intact form. FDA Notice, ¶42,082