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Pharmacology/Toxicology Corner: Spring retreat eyes drug-device combinations, pediatric issues

The Center's semi-annual retreat for pharmacology/toxicology reviewers included regulatory updates from standing subcommittees of the Pharm/Tox Coordinating Committee, a scientific update on drug-device combinations and an entire afternoon session devoted to pediatric issues during pre-clinical assessment.

These retreats focus on regulatory issues, new technology and integrated education in areas impacting the drug review process. The June 19 retreat was organized and arranged by Fred Alavi, Ph.D., Hanan Ghantous, Ph.D., Pat Harlow, Ph.D., Wafa Harrouk, Ph.D., Elizabeth Hausner, DVM, Tom Papoian, Ph.D., Adele Seifried, M.S., Jui Shah, Ph.D., William Taylor, Ph.D., and Suzanne Thornton, Ph.D.

Dr. Ghantous, the retreat planning committee chair, gave the opening remarks. Dr. Ghantous is from the Division of Anti-Inflammatory, Analgesic and Ophthalmic Drug Products. Supervisors introduced new reviewers. After a team building exercise, Robert Osterberg, Ph.D., the acting deputy associate director for pharmacology/toxicology, gave an update of the current pharm/tox issues. The search for a new associate director is ongoing and hopefully will be completed in a few months.

The pharm/tox group is also trying to be proactive about the projected retirement within the next five years of many senior reviewers. The Education Committee and the associate director are designing multi-faceted programs to mitigate the effects of losing so much historical and institutional memory. Dr. Osterberg also discussed the status of several guidances, MAPPs and the good review practices format.

Several of the standing pharm/tox sub-committees provided summaries of their most recent activities in a session organized by Pat Harlow, Ph.D., from the Division of Cardio-Renal Drug Products. Additional committees will present their updates at the fall retreat. The committees represented and those presenting were:

• PTCC Educational Committee, Robin Huff, Ph.D., (Division of Pulmonary and Allergy Drug Products).
• Genetic Toxicology Committee, Anita Bigger, Ph.D., (Division of Anti-Viral Drug Products).
• Inactive Ingredients Committee, Bob Osterberg, Ph.D., (Division of Anti-Infective Drug Products).
• Information Technology Subcommittee, Tom Papoian, Ph.D., (Division of Cardio-Renal Drug Products).
• Safety Pharmacology Subcommittee, John Koerner, Ph.D., (DCRDP).

A corollary to the safety pharmacology update came afterwards when Dr. Koerner discussed the Draft ICH S-7B guidance, Safety Pharmacology Studies for Assessing Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals. The goal of this guidance is to protect clinical-trial participants and patients from lethal drug-induced arrhythmias. This combined regulatory and scientific update emphasizes the importance of careful non-clinical assessment of cardiac repolarization. Recommendations on study types and general principles are provided to help in designing a non-clinical program for the identification of potential hazards.

Investigational devices that also provide localized drug delivery are the motivating force behind a collaborative intercenter effort involving the Center for Devices and Radiological Health and CDER. This effort involves from CDRH: Jonette Foy, Ph.D., John Hyde, M.D., Ph.D., Donald Jensen, DVM, M.S., John Stuhlmuller, M.D., and Carolyn Vaughan, M.S. Those from CDER include Albert DeFelice, Ph.D., Kasturi Srinivasachar, Ph.D., Shari Targum, M.D., Belay Tesfamariam, Ph.D. and Douglas Throckmorton, M.D.

Dr. Tesfamariam, from DCRDP, discussed the scientific rationale behind the drug-eluting stents used for reducing restenosis in coronary arteries following revascularization.

Drug elution from the polymer that coats a stent depends on multiple factors including biocompatibility, the amount of drug loaded, rate and duration of release and the residual drug.

The safety assessment of these devices includes three separate components: the stent, the drug, the carrier polymer and the summation of those components. The assessment of toxicity involves local vascular, regional myocardial and systemic effects and includes quantitative angiograms and histomorphometry. Several issues under consideration include the long-term efficacy (once the drug is completely eluted), long-term safety, appropriate duration of a preclinical study and relevance to clinical cases.

The afternoon was devoted to a workshop on pediatric issues. The speakers were: Karen Davis-Bruno, Ph.D., from the Division of Metabolic and Endocrine Drug Products and co-chair of the PTCC Pediatric Working Group; Mark Hurtt, Ph.D., from Pfizer Global Research and Development; Rosemary Roberts, M.D., from CDER's Office of Counter-Terrorism and Pediatric Drug Development; and Tim Link, Ph.D., from DCRDP.

It is estimated that there is inadequate information regarding pediatric use of approximately 75 percent of prescription medications. Data is not accrued in a systematic fashion to learn how to administer drugs in a safe and efficacious manner, so every use is essentially an experiment. A history of tragedies led to the current regulatory position that careful study in clinical trials may be a better method of pediatric drug development.

There were points of commonality in the three presentations. The species differences in development were stressed as important considerations in designing both safety and efficacy studies. Pharmacokinetics and pharmacodynamics influence growth and development while concurrently growth and development also influence PK/PD. Age and physiology differences preclude simply scaling down adult dosages for pediatric use. Examples were given of age-related differences in drug metabolism and interspecies differences in organ system development.

The mechanics of working with juvenile animals must also be considered. The nuts and bolts of different routes of drug administration were discussed as well as some of strengths and limitations of each. Study design for litter-bearing and nonlitter-bearing animals was an issue also. The current database is limited but indicates that juvenile studies are technically possible to conduct and can provide useful safety data.

Dr. Roberts presented statistics and the status of pediatric submissions and studies requested up to the present time as well as the impact on labeling. Although the 1998 Pediatric Rule requiring studies in children has been challenged by the Association of American Physicians and Surgeons and the Competitive Enterprise Institute and Consumer Alert, it remains in effect.

At the end of the day, Dr. Link presented a case study: "Endothelin Receptor Antagonists: Class Effects on Fertility and Development." As background, he first discussed the basic biology of endothelin, the isoforms and related peptides, the endothelin receptors and endothelin converting enzyme and progressed to the therapeutic applications of manipulating this system.

The fetal effects of ETA antagonism include fetal death, agnathia to micrognathia, aglossia to microglossia, aplasia of facial and skull bones, cardiac defects, thyroid and thymus abnormalities. Another adverse effect is an increased incidence of tubular dilatation, degeneration and atrophy. It was not clear that the testicular effects were in fact a class effect until the DCRDP made re-evaluation of the existing data a priority. It then became apparent from a focused review of the data that each drug showed the same adverse effect profile. The presentation ended with a series of questions for break-out discussion among the reviewers.

The Spring 2002 Pharm/Tox Retreat was an excellent opportunity for reviewers from different divisions to compare notes. The fall retreat will have a neurotoxicology theme.

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