Considerations for licensure of influenza vaccines with pandemic and prepandemic indications.

With over 409 human cases of avian influenza and over 256 deaths worldwide resulting from infection with avian influenza (H5N1), an influenza pandemic is still a real threat, especially with H5N1 continuing to evolve into antigenically distinct clades. The Food and Drug Administration (FDA) along with other national regulatory authorities (NRAs) recognize the important role that safe and effective vaccines will play in protecting the public health from the threat of an influenza pandemic. The challenges to the FDA and other NRAs are significant as regulatory agencies pursue the development of new scientific and regulatory criteria to evaluate vaccines against pandemic influenza strains for licensure. To this end, the FDA is actively utilizing current regulatory processes such as accelerated approval and priority review as well as developing the regulatory pathways needed to speed the availability of vaccines against pandemic influenza. In May of 2007, the FDA issued two final guidance documents, one describing the clinical data recommended to support the licensure of annual influenza vaccines, and the other describing the clinical data recommended to support the licensure of pandemic influenza vaccines. These guidances contain specific approaches outlined by the FDA to assist manufacturers in developing new vaccines to increase the supply of safe and effective influenza vaccines for both annual and pandemic use. In this article we define the nomenclature "pandemic" and "prepandemic," describe the regulatory pathway for licensing new influenza vaccines for pandemic and prepandemic use, and outline considerations for evaluating pandemic/prepandemic vaccines that have been formulated using new approaches such as cell culture and non-aluminum salt adjuvants.

Quantitative determination of cesium binding to ferric hexacyanoferrate: Prussian blue.

Ferric hexacyanoferrate (Fe4III[FeII(CN)6]3), also known as insoluble Prussian blue (PB) is the active pharmaceutical ingredient (API) of the drug product, Radiogardase. Radiogardase is the first FDA approved medical countermeasure for the treatment of internal contamination with radioactive cesium (Cs) or thallium in the event of a major radiological incident such as a "dirty bomb". A number of pre-clinical and clinical studies have evaluated the use of PB as an investigational decorporation agent to enhance the excretion of metal cations. There are few sources of published in vitro data that detail the binding capacity of cesium to insoluble PB under various chemical and physical conditions. The study objective was to determine the in vitro binding capacity of PB APIs and drug products by evaluating certain chemical and physical factors such as medium pH, particle size, and storage conditions (temperature). In vitro experimental conditions ranged from pH 1 to 9, to cover the range of pH levels that PB may encounter in the gastrointestinal (GI) tract in humans. Measurements of cesium binding were made between 1 and 24h, to cover gastric and intestinal tract residence time using a validated atomic emission spectroscopy (AES) method. The results indicated that pH, exposure time, storage temperature (affecting moisture content) and particle size play significant roles in the cesium binding to both the PB API and the drug product. The lowest cesium binding was observed at gastric pH of 1 and 2, whereas the highest cesium binding was observed at physiological pH of 7.5. It was observed that dry storage conditions resulted in a loss of moisture from PB, which had a significant negative effect on the PB cesium binding capacity at time intervals consistent with gastric residence. Differences were also observed in the binding capacity of PB with different particle sizes. Significant batch to batch differences were also observed in the binding capacity of some PB API and drug products. Our results suggest that certain physiochemical properties affect the initial binding capacity and the overall binding capacity of PB APIs and drug products during conditions that simulated gastric and GI residence time. These physiochemical properties can be utilized as quality attributes to monitor and predict drug product quality under certain manufacturing and storage conditions and may be utilized to enhance the clinical efficacy of PB.

Effectiveness of Risk Evaluation and Mitigation Strategies (REMS) for Lenalidomide and Thalidomide: Patient Comprehension and Knowledge Retention.

INTRODUCTION: The effectiveness of patient education activities conducted within the lenalidomide and thalidomide risk evaluation and mitigation strategies (REMS) programs was evaluated by measuring understanding of serious risk and safe-use messages. METHODS: Results from mandatory knowledge, attitude, and behavior surveys and voluntary patient surveys completed between June 2012 and June 2013 were analyzed, and responses to questions relating to compliance with birth control measures and understanding of safe-use messages are presented by patient risk category. RESULTS: In total, 73,645 patients were enrolled into the REMS programs for lenalidomide and thalidomide and completed mandatory surveys prior to medication dispense. Of these, 2790 (3.8%) completed an additional voluntary survey. Among voluntary survey participants, for all patient pregnancy risk categories, reported compliance with birth control requirements was above 90% when starting therapy and at follow-up. At the beginning of therapy, complete compliance was 96.3%; 3 months later it was 96.4%. Patient understanding of safe-use messages was very high in all pregnancy risk groups, notably for messages repeated at each physician visit. Overall, 98.2% of patients knew that lenalidomide and thalidomide could cause birth defects, which is part of the repeated educational messaging. In contrast, 87.1% recalled that unused product should be returned to their healthcare professional, which is not included in repeated messaging. CONCLUSION: The lenalidomide and thalidomide REMS programs enhance patient understanding of safe-use messages, resulting in high levels of compliance with the birth control precautions essential to prevent fetal exposure to these known and potential human teratogens. Overall compliance was maintained after 3 months of follow-up and throughout therapy.

The radioactive drug research committee: Background and retrospective study of reported research data (1975-2004).

In the United States, human research involving radioactive drugs must be conducted under a Food and Drug Administration (FDA) investigational new drug (IND) application, unless specifically exempt from IND requirements, or under the direct oversight of a Radioactive Drug Research Committee (RDRC) as long as certain conditions are met. Research overseen by RDRCs is considered basic science research when its purpose is to advance scientific knowledge and not to determine a radioactive drug's safety and effectiveness as a therapeutic, diagnostic, or preventive medical product in humans. We retrospectively reviewed and analyzed available study data from annual reports submitted to the FDA dating back to 1976. In 1976, there were 18 studies involving 531 subjects compared with 2003, when there were 284 RDRC studies involving 2,797 subjects. In 1976, RDRC subjects were imaged 5% of the time using positron-emitting nuclides and 77% of the time with conventional gamma-emitting nuclides. In 2003, this was reversed with 77% using positron emitters and 5% using conventional gamma-emitters. In 1976, pediatric studies comprised 7.3% of all RDRC subjects; today pediatric RDRC studies are rarely conducted. Today the RDRC is used primarily by large medical research institutions. Although the program has a very good safety record, RDRC's 30-y-old regulations need to be revised to be consistent with current scientific knowledge and health policy.

Teratogenic Drugs and Risk Management: An Implementation Assessment.

About half of all pregnant women are prescribed medication during their pregnancy, including drugs with teratogenic potential. There is a need to manage teratogenic risk and prevent fetal harm. In the US, risk management strategies may range from product labeling to the US Food and Drug Administration requiring a risk evaluation and mitigation strategy, including elements to assure safe use. The resources of these risk management controls on the health care system must be weighed against the benefits of preventing embryo-fetal exposure and birth defects. This article describes considerations for determining which risk mitigation strategies to use with teratogenic drugs and the challenges and opportunities to balance restrictions and burdens with the benefit of access to important drugs.

Managing the teratogenic risk of thalidomide and lenalidomide: an industry perspective.

Celgene has developed and operated pregnancy prevention programs since 1998 with the first approval of thalidomide in the US. With the development and marketing of lenalidomide, an analog of thalidomide, the company further advanced its risk management activities, which now cover several territories across the globe. To date, the program is a success in as much as it has minimized the risk of fetal exposure and subsequent development of fetal malformations. Nonetheless, the company understands the need to provide a mechanism for intervention and remediation when at-risk behaviors are identified, and this forms an integral part of the risk management processes. The implementation of the thalidomide and lenalidomide pregnancy prevention program partners patients, healthcare professionals, regulators and the company in a spirit of shared responsibility. This paper also presents the authors' experience and perspective on the challenges of managing a pregnancy prevention program, which at its core aims at ensuring that the product's benefits outweigh the risk of fetal exposure.

Screening mammography: clinical image quality and the risk of interval breast cancer.

OBJECTIVE: We evaluated the association between clinical image quality and breast cancer occurrence within 24 months of a negative mammogram. MATERIALS AND METHODS: We identified women with breast cancer who were younger than 40 years old and older and screened from January 1, 1988, through December 31, 1993. We retrospectively assigned Breast Imaging Reporting and Data System (BI-RADS) assessments to their screening mammogram. We classified cancers (invasive or ductal in situ) as "screen-detected" when found after positive assessments (BI-RADS codes 3, 4, and 5) and "interval-detected" when found after negative assessments (BI-RADS codes 1 and 2). One reviewer evaluated mediolateral oblique and craniocaudal views for all cancer cases using a 3-point scale (failure, borderline, pass) for each measure of clinical image quality (positioning, breast compression, contrast, exposure, noise, sharpness, artifacts, overall quality). We used separate logistic regression models and evaluated the odds of interval invasive cancer or invasive plus in situ cancer as a function of each measure of quality using "pass" as the referent group. RESULTS: We found 492 screen-detected and 164 interval-detected cancers that met study criteria. Cancer detection (sensitivity) was highest (84%) among patients with proper breast positioning, but when images failed this measure (33.4%), sensitivity fell to 66.3%. After adjustment for age, film date, and breast density, interval-detected invasive cancers were more likely after images failing positioning (odds ratio, 2.57; 95% confidence interval, 1.28-5.52%). Failures in overall quality were also associated with interval cancers when cases of ductal carcinoma in situ (p = 0.037) were included. CONCLUSION: Invasive breast cancer detection by mammography may be improved through attention to correct positioning.