According to a commentary by former Institute of Medicine (IOM) committee members, published this week in the New England Journal of Medicine, increased “fast-tracking” of drug approvals (i.e., for medical conditions with no effective treatment) necessitates a counterbalance of enhanced postmarket surveillance and ethical governance throughout the lifecycle of a drug.  The authors of the report argue that the FDA, when requiring that a postmarked study be initiated, has a unique ethical obligation to research participants, which “cannot be handed off to contractors or the industry sponsor.”  Furthermore, “because some postmarked trials are required specifically to address mounting concerns that the drug’s risks may outweigh its benefits, there are heightened obligations to ensure that potential research participants understand the risks of enrollment.”  Because the volume of postmarked studies is increasing – due not only to FDA-mandated research, but also to increased emphasis on comparative-effectiveness – the benefit-risk balance for comparable study designs can vary depending upon the purpose for which a specific study is being conducted.  The challenges, therefore, for ensuring truly informed consent by study participants can vary widely.

Source:  Science Codex

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

The authors – CM Wittich, CM Burkle, and WL Lanier – offer a concise review of the topic of off-label drug use including its definition, prevalence, and implications for drug safety.   The article format addresses 10 common questions and their answers about off-label drug use.  The breadth of application, its acceptance, and the liabilities of off-label use are explored.  A history of FDA regulations surrounding the practice is presented, which helps to put its evolution into proper perspective.  Off-label use, which occurs in every medical specialty, is more common in patient populations not likely to be included in clinical trials (e.g., pediatric, pregnant, or psychiatric patients).  Once a medication is marketed, the FDA does not limit or control how the medication is prescribed by physicians. The pros and cons of the distribution of information regarding the off-label use of medications by pharmaceutical companies, the use of informed consent, and the liability of prescribing physicians are discussed.

Source:  Mayo Clinic Proceedings  – pdf of full article.

Linguamatics, the leader in natural language processing (NLP)-based text mining, announced that the Federal Drug Administration’s (FDA) Center for Drug Evaluation and Research (CDER) has licensed its 12E text mining platform as a discovery and decision support tool to supplement laboratory research efforts on drug safety.  The FDA will use the platform to review published literature and drug product labels to address key biomedical issues, including mechanisms of drug toxicity and disease processes.  In addition to document retrieval, the 12E platform can identify, extract, synthesize, and analyze relevant facts and relationships (e.g., between genes and diseases, drugs and side effects).  Customers include top tier commercial, academic, and governmental organizations, including 9 of the top 10 global pharmaceutical companies.  The 12E platform is available both as an in-house or cloud-based system.

Typical applications in pharmaceutical, biotechnology, and healthcare include:
•    Mapping gene-disease relationships and identifying potentially novel therapeutic targets
•    Biomarker discovery
•    Drug repurposing
•    Drug safety
•    Patent analysis
•    Clinical trial site selection and study design
•    Mining electronic medical records to improve prediction of health outcomes
•    Translational medicine
•    Competitive intelligence
•    Social media mining
•    Subjective data mining (sentiment analysis, key opinion mining)

Sources:  BioSpace and Business Weekly

The objective of a recent survey by Cambridge Health Associates was to identify trends in safety biomarkers and their utilization in drug development.  Regardless of company size, recurrent themes for assessing drug safety in early preclinical development were noted.

• Greater knowledge of safety biomarkers improved mechanistic understanding and helped to determine the relevance of nonclinical findings for clinical risk assessment.

• Preclinical inclusion of systems or pathway modeling was deemed important for the selection and interpretation of biomarkers of organ toxicity.

• Physical chemical prediction software or other forms of genetic or developmental and reproductive toxicity (DART) prediction software (e.g., DEREK, M-CASE, Leadscope) were being incorporated into early preclinical development by most companies.  All 3 software companies have Cooperative Research and Development Agreements (CRADA) with the FDA.

• For cellular parameter screens, most companies are using image-based multi-parametric approaches of cellular analysis and cytotoxicity at the single-cell and subcellular level (via High Content Analysis [HCA])

• Off-target screening (usually a CEREP panel) was performed by most companies early in preclinical development.

As might be expected to “slow the burn,” smaller companies ran fewer preclinical screens to predict drug safety and  performed these screens later in the drug development process.  Given that larger companies expect to have this information sooner than later, companies wanting to partner and/or be acquired may consider including more screens for drug safety earlier in their preclinical development programs.

Source:  DSEC Drug Safety Executive Blog

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)

Analysis and overview of new drug reviews from 1993 through present by an over 20-year-active FDA veteran of drug approvals, Dr. John Jenkins (Director, Office of New Drugs, Center for Drug Evaluation and Research).  The presentation includes review times and comparison to global approvals.  Of note, median approval times for New Molecular Entities (NME) applications are 10 months, a 47% reduction from calendar year 1993.  A status update on CDER compliance with past PDUFA goals is given, with information on forward planning to comply with PDUFA V goals.  In accordance with the enhanced emphasis on benefit-risk analysis in PDUFA V, discussion of the anticipated framework and balance of stakeholder concerns is detailed.   The PDUFA V program for NME review is presented, with key elements and projected timelines detailed.

This slide presentation gives excellent perspective of past and future trends for the global pharmaceutical market, with emphasis on FDA approvals of NME.

Source Slide Show (pdf hyperlink):  FDA

Pharmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose. Drug labels may contain information on genomic biomarkers and can describe:

• Drug exposure and clinical response variability
• Risk for adverse events
• Genotype-specific dosing
• Mechanisms of drug action
• Polymorphic drug target and disposition genes

This resource table lists FDA-approved drugs with pharmacogenomic information / biomarkers in their labels.

Source:  FDA

What is new about PDUFA V?   Congress, the media, and the public have a history of boiling down the issue to whether drugs are safe or not safe.  In reality the issue is benefit versus risk.   In addition, this judgement needs to be aligned with that of the patients who take the medication.  Emphasis on this risk-benefit framework is a landmark difference in the pending PDUFA V legislation.

Source:  Nature

Ever wanted to know the ins and outs of almost every drug approved by the Food and Drug Administration since 1939?

By using the Drugs@FDA database, you can search for information about FDA-approved brand name and generic drugs and therapeutic biological products.  The database includes most of the drug products approved since 1939 and has drug labels, patient information, approval letters, and other information for most drug products approved since 1998.

Source:  FDA