Folic acid and primary prevention of neural tube defects: A review.

With 4 mg folic acid daily, it may take 20 weeks to reach red-blood-cell folate levels between 1050 and 1340 nmol/L, optimal for reduction of the neural tube defect risk. Therefore, folic acid supplementation should be started 5-6 months before conception. The residual risk with optimal red-blood-cell folate levels is reportedly 4.5 per 10,000 total births. The residual risk in pooled data from countries with mandatory folic acid fortification is 7.5 per 10,000 pregnancies, regardless of pre-fortification rates. European monitoring of folate intake with questionnaires should be replaced by periodic measurements of red-blood-cell folate. The risk of folate intake >1 mg/day does not outweigh the benefits of folic acid fortification, provided un-metabolized folic acid, RBC folate and vitamin B12 are monitored periodically. A European monitoring system, based on U.S. National Health and Nutrition Examination Surveys, should reside with the European Centre for Disease Prevention and Control.

Value of juvenile animal studies.

The Developmental and Reproductive Toxicology Technical Committee of the ILSI Health and Environmental Sciences Institute has undertaken a project to address the impact of juvenile animal studies on pediatric drug development. A workshop, sponsored and organized by the Health and Environmental Sciences Institute Developmental and Reproductive Toxicity Technical Committee, was held on May 5-6, 2010, in Washington, DC, to discuss the outcome of a global survey and the value of juvenile animal studies in the development of drugs intended for use in pediatric patients. During this workshop, summary data from the 2009-2010 survey were presented, and breakout sessions were used to discuss specific case studies to try to assess the impact of juvenile animal studies performed to support specific pediatric drug development. The objectives of the Workshop on The Value of Juvenile Animal Studies were to (1) provide a forum for scientists representing industry, academia, and regulatory agencies to discuss the impact of juvenile animal studies on pediatric drug development, (2) evaluate summary data from the survey to understand how the juvenile study data are being used and their impact in labeling and risk assessment, (3) discuss selected case studies from the survey to highlight key findings, and (4) identify the areas of improvement for the designs of juvenile animal studies. The take home message that resonated from the workshop discussions was that well-designed juvenile animal studies have demonstrated value in support of certain pediatric drug development programs. However, it was also clear that a juvenile animal study is not always warranted.

Real life juvenile toxicity case studies: the good, the bad and the ugly.

With the growing experience in the conduct of juvenile toxicity studies for multiple classes of compound, the 'case-by-case' approach has become under much more pressure. Instead, a general screen or 'standard design' is now commonly expected by regulatory authorities with more routine inclusion of neurological and reproductive assessments. Minor modifications or additions can be made to the design to address specific questions according to the class of drug or intended clinical use. This drift from a 'case-by-case' approach to a 'standard design' approach is present within certain reviewing divisions of the FDA, often requesting by default a rodent and non-rodent juvenile animal study. However, juvenile animal studies should be designed thoughtfully to fulfil a purpose based on scientific rationale, with each endpoint carefully considered in terms of practicality and interpretability of data generated. Only when using the appropriate strategy and design may juvenile studies add value by (1) identifying potential safety or pharmacokinetic issues for drugs intended for paediatric use, (2) suggesting additional clinical endpoints and (3) adding new information to the product label. As the knowledge from juvenile animal studies in various species grows, a better understanding of the significance/relevance of findings will be achieved.