Consortia collaborations offer a fast and efficient way to develop methods and scientific understanding in principal areas of research. This survey, conducted with the support of the Safety Pharmacology Society, had several objectives: to identify ongoing consortia projects probing areas in the field of safety pharmacology, and to make available to the SPS’s members, information about these programs.

Lessons learned, in terms of managing and contributing in such projects will be presented. The potential role of the SPS as a facilitator of such projects will also be explored.

This will hopefully kick off a discussion about the value of collaborative programs and their potential benefits to the participants.

A survey was e-mailed to members of the SPS. Responseswere collected online. 14 projects involving more than 30 companies were identified. The projects covered the areas of drug-induced pro-arrhythmia (4), drug-induced cardiotoxicity (2), drug dependence and abuse liability (2), cardiovascular genomics (1), study of human ion channels (1), comparative biology and scaling of results across different species (1), and zebra fish as a pre-clinical model (1).

The SPS is in a unique position to take the lead by collecting and disseminating information about consortia projects (both completed and in-progress) and identifying new areas where further research is needed. Creation of Special Working Groups around specific topics under the auspices of the SPS could serve to facilitate consortia projects to the benefit of patients, safety pharmacologists, the society, and regulatory bodies alike.

Prior to candidate recommendation from discovery, most groups conduct some sort of “ancillary” cardiovascular study. The question is in what model?

Could folks share the in vivo model or models that are typically used (eg. dog, monkey, rat, conscious/anesthetized, etc) to support the advancement of a compound into the toxicology phase of development.  Also, if any models used are established in the company, or outsourced.

The electrocardiogram is taken routinely in conjunction with toxicological studies in larger animal species including the dog, primate or pig. They have been used in the past to document heart rate as well as to identify gross electrocardiographic changes that might occur over time due to such things as myocardial ischemia or myocardial hypertrophy.

Due to the recent attention to the detection of drug-induced effects on ventricular repolarization, there is an increased interest in analyzing ECGs more thoroughly to include the standard intervals and wave form durations. Of particular note is the meausrement of the QT interval for detecting hERG-induced delays in ventricular repolarization. The ICHS7a guideline suggests that in vivo evaluation of the potential for drugs to prolong the QT interval might be addressed in toxicological studies.

Over the past years there has been an increased awareness of the challenges involved in doing a high quality preclinical, in vivo evaluation of potential effects on ventricular repolarization. The important role of heart rate-induced effects on repolarization must be taken into account. We know now that various physiolgoical factors can affect the QT interval. Furthermore, the sensitivity of a given test system to pick up a given change in the QT interval is dependent upon the variability of the measured parameter. Above all, a robust evaluation of the potential effects of a drug on ventricular repolarization requires a high quality ECG, at best recorded frequently enough to allow for a thorough analysis of time-dependent effects.

The question posed here is whether or not the quality of ECGs, as have been taken routinely in the past (and still presently) are adequate for a reliable assessment of drug-induced prolongation of the QT interval?

Have you evaluated ECGs from toxicological studies and been satisfied with their quality?

Is the amount of data collected in “traditional” tox studies sufficent to base such an assessment?

Are the animals used in a tox study in an acceptable physiological state to consider them for use in a “non-clinical QT study?”

Do you know of anyone who has done a power analysis on ECG data coming from a tox study? What size of effect on QT can one reasonably detect with the number of animals typicllyused for tox studies?

What is feasible to improve quality of ECGs in tox studies and what are the associated costs and efforts needed to affect an increased quality? Would most sponsors be willing to invest to improve this readout?

We would appreciate hearing about your experiences and opinions on this matter!

Do you have questions or comments about various topics in Safety Pharmacology, but did not know how to get feedback?  Or share ideas with other safety pharmacologists?  What can you do to get a timely answer to your question, or issue?  The new  Safety Pharmacology Society blog (aka SPeak) may be an ideal way to post your question, and get comments from members of the safety pharmacology community.

Have you blogged before?  If not, do not be afraid!  “Blog” is an abbreviation for “web log” or “weblog”, which is a term to describe a website that maintains or chronicles information.  How many safety pharmacology blogs are there?  That is unknown, but SPeak is the official blog established by the Safety Pharmacology Society for the benefit of its members.

So, do you have a question, topic or issue that needs to be discussed?  Consider posting your item (aka content) to this blog, and take advantage of the collective wisdom and experience of the membership.  We could all learn something.

If you have participated in a blog previously, especially a science-based forum, please post a comment and share your experience.

What makes a blog successful?  Good content and participation….so, SPeak UP!!