The FDA has published an updated Guidance Agenda – new and revised draft guidances CDER is planning to publish during calendar year 2012.   Guidances of particular interest to nonclinical pharmaceutical toxicologists may include:

Pharmacology/Toxicology

• Endocrine Disruption Potential of Drugs: Non Clinical Evaluation

Procedural
• Integrated Summary of Safety

Biopharmaceutics

• Food-Effect Bioavailability and Fed Bioequivalence Studies—Bioavailability and Bioequivalence Studies for Orally Administered Drug Products Submitted in New Drug Applications General Consideration

Electronic Submissions
• Providing Regulatory Submissions in Electronic Format – General Considerations
• Providing Regulatory Submissions in Electronic Format – Study Data
• Providing Regulatory Submissions in Electronic Format – Standardized Study Data

Source:  U.S. Food and Drug Administration

An innovative Procedure Cage invented by Dr. Ryoichi Nagata, SNBL USA chairman, is at the center of a comprehensive program designed to significantly raise standards for non-human primate (NHP) care and thereby improve the quality of preclinical data collected.

The Procedure Cage attaches directly to an animal’s home cage allowing animals to enter on their own.  This innovation significantly reduces animal stress by eliminating the need for capture-by-hand or use of other restraints, creating a calmer handling environment.  In addition, the use of this separate cage for study-related procedures allows the animal to always view their home cage as a “safe place.”

The Procedure Cage is currently being tested at six beta test sites including key pharmaceutical industry, government, and university locations.  The results will be presented at the American Association for Laboratory Animal Science (AALAS) National Meeting in Minneapolis on November 4-8, 2012.  The Procedure Cage is available exclusively through SNBL USA.

Procedure Cage Demo:  Click here

Source:  SNBL USA newsletter (18 July 2012)

Many drug hypersensitivity reactions are HLA-linked, meaning that they will occur much more often or even exclusively in individuals who have certain variants of the HLA gene.  A new study elucidates the specific mechanism leading to HLA gene-linked hypersensitivity to the drug abacavir.  These findings are applicable to other drugs and related hypersensitivity reactions.

The findings are discussed in the paper “Drug hypersensitivity caused by alteration of the MHC-presented self-peptide repertoire,” published last week in the scientific journal Proceedings of the National Academy of Sciences.

An interview with the authors is published in the Source cited below.

Source:  Clinical Toxicology

Transgenic and genetically modified animal models are increasingly being used in the study of disease and for the safety assessment of new compounds.  Use of these models enhances understanding of the role that specific genes play in biological pathways.   The primary uses of transgenic mouse models in toxicology have mainly been to screen for genotoxicity and carcinogenicity and to understand the mechanisms of toxicity.   These mouse models can reliably predict the carcinogenic potential of compounds and significantly reduce the number of false positives.  When applied as single assays, however, transgenic models are unable to identify all known human carcinogens.  Use of a short-term transgenic mouse assay in combination with a two-year rat chronic study could eliminate the occurrence of false negatives and increase the overall accuracy of detecting carcinogens and non-carcinogens.  Additional bonuses for use of transgenic assays include reduced duration, conservative use of animals, and decreased cost relative to a traditional two-year rodent chronic toxicity study.

Source:  Life Science Leader

The increased requirement for combined chronic toxicity and fertility assessment of biologics has led to greater use of sexually mature non-human primates.  Older animals have different needs compared to the younger, adolescent animals with which we are used to working.  In addition, the establishment of sexual maturity requires additional parameter measurements, such as assessment of menstrual cycling, hormone analyses, and seminology.  Changes in caging are required to reflect the social hierarchy inherent with the interaction of older primates, especially since subordinate animals mature later than their dominant peers.  Provision of complex environmental stimuli also becomes a greater necessity.  Due to the increased size and weight of older primates, handling becomes more of a potential source of stress and injury, to both animals and their handlers.  Differential criteria for assessment of sexual maturity in primates are discussed.

Source:  Developments in Life Sciences

In the next 2-5 years, large pharmaceutical companies plan to increase outsourcing of preclinical work, with emphasis on Discovery and non-GLP Toxicology.  This trend is driven by the reductions in internal preclinical capability within Big Pharma.  In an apparent reversal of the current trend towards use of a limited number of preferred providers, capacity will necessitate increasing the number of contract research organizations (CRO) involved.  An offshore trend is anticipated despite the rapidly narrowing price differentials between Chinese and Western CROs for nonclinical work.  A survey suggested that the offshore CROs best positioned to secure the early-stage drug development business from large pharmaceutical companies are Covance, WuXi, BioDuro, and ShangPharma.   As an example, ShangPharma recently opened a new facility to accommodate a multi-year contract with Eli Lilly, with emphasis on in vivo pharmacology, oncology, and metabolic disease work.

Sources:  Outsourcing-Pharma.com 11 Jan 2012,  17 Apr 2012, 19 Apr 2012

Growth in demand for nonclinical toxicology services will be weak for the foreseeable future analysts said after the Society of Toxicology (SOT) annual meeting in San Francisco this past week.  “Most agree that the industry is not merely going through a prolonged cyclical slowdown, but has also structurally changed, with less of an emphasis by clients on maximizing the number of drug candidates flowing into preclinical testing,” stated John Kreger, equity analyst at William Blair.  In addition, chronic toxicity testing is being delayed until the later stages of compound development; this reduces preclinical development costs for compounds that fail.  Among other factors, this has led to excess capacity at contract research organizations (CRO), price restrictions, and site closures.  Tim Evans, senior analyst at Wells Fargo, expects the overall nonclinical toxicology market to grow by 2% in 2012 due to higher outsourcing penetration.  In their selection of preferred service providers, global bio/pharmaceutical companies generally favor large CROs with broad capabilities.  These “strategic partnership” deals, which are the cornerstones of global bio/pharmaceutical companies’ current outsourcing strategies, seek to leverage their massive buying power, reduce the cost of overhead, and improve coordination with the CRO.  Sourcing models will continue to evolve, however, and will eventually threaten the business model upon which the recent megadeals are based.

On a related note due in part to ongoing capacity cuts, large pharmaceutical companies are seeking co-development deals with CROs and biotechnology firms to handle excess intellectual property.   Shared risk and reward features are found in some of the more creative models.   CROs that have made major acquisitions in order to leverage capacity, however, could be outmaneuvered by evolving sourcing models.

Sources:  Outsourcing-Pharma.com 12-Mar-2012, 15-Mar-2012; BioPharm International

Zebrafish offer a nonclinical model for the high-throughput screening of drug compounds, including toxicity assessment, with resolution at the cellular level in living vertebrate organisms.  These small, freshwater, tropical fish share genetic and biochemical similarity to humans, in addition to similar organ system development.  Vertebrate disease models (e.g., Parkinson’s, epilepsy, wound repair) are available , as are 3-D image resolution and data analysis capabilities.  Live-imaging options, unparalleled in other vertebrate organisms, are possible using the transparent larvae.  Furthermore, live-cell microscopy can provide views of the inner complexity and workings at the cellular level.  For purposes of disease modeling, researchers can create and screen genetic mutants in the zebrafish that are linked to human immune diseases.  Neurological assessments using the live, transparent, zebrafish larvae allow visualization of the mechanisms of myelination.  In conclusion, the zebrafish preclinical model owes much of its popularity to the transparent nature and relevant ease of imaging of vertebrate larvae.  Optimization of data analyses for these varied indications is ongoing.

Source:  Genetic Engineering and Biotechnology News