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:
• Endocrine Disruption Potential of Drugs: Non Clinical Evaluation
• Integrated Summary of Safety
• Food-Effect Bioavailability and Fed Bioequivalence Studies—Bioavailability and Bioequivalence Studies for Orally Administered Drug Products Submitted in New Drug Applications General Consideration
• 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 10 drugs with the largest numbers of reports sent directly to the FDA by healthcare practitioners and consumers in 2011 in order of frequency are Pradaxa, Coumadin, Levaquin, Carboplatin, Zestril, Cisplatin, Zocor, Cymbalta, Cipro and Bactrim. It is interesting to note that just two of these drugs were first introduced in the last decade (Pradaxa and Cymbalta), and only one in the previous year (Pradaxa), suggesting that major drug safety issues are not confined to recently approved drugs. On one hand, this shows that FDA and manufacturer safety surveillance programs have identified these significant safety risks. On the other, it illustrates that placing warnings in product information only begins the process of managing drug safety risks. Relative rates vs. report expectations are detailed.
These data come from QuarterWatch™ an Institute for Safe Medication Practices surveillance program that monitors all serious and fatal adverse drug events (ADEs) reported to the Food and Drug Administration through MedWatch, its adverse event reporting system. The goal is to identify signals that may represent important new drug safety issues.
High throughput (HT) Absorption, Distribution, Metabolism, and Excretion (ADME) screening technology is the current push from Big Pharma to be outsourced through contract research organizations (CROs). Shifting also is the ADME regulatory emphasis; the FDA has released a draft guidance (17 Feb 2012) that includes specific wording around what needs to be done with respect to transporter drug-drug interactions (both efflux and influx). The guidance will start to drive significant changes in how ADME screening is performed. Two assays that are routinely being utilized in pharma are the Caco-2 cell-based assay and the PAMPA (parallel artificial-membrane permeation) assay. As currently practiced, predictive ADME screening is made even more difficult given the variety of transport mechanisms available. In toxicology screens (ADME-tox), however, one is not looking for altered aspects of the drug, which is generally initially unknown, but changes in known, endogenous parameters. Thus ADME-tox lends itself more easily to HT platforms. New platforms for high throughput ADME screening are available, and discussed in this article.
Source: Drug Discovery and Development
To make best use of its limited resources, the Institute of Medicine (IOM) concludes that the US Food and Drug Administration (FDA) should direct resources to improve the regulatory systems of developing nations to better ensure the safety of the global pharmaceutical supply chain. Rather than try to inspect all foreign establishments itself, the FDA and its technologically advanced counterparts in the European Union, Canada, Japan, Norway, Iceland, Switzerland, Australia, and New Zealand are encouraged to plan a system for mutual recognition of inspections, which would eliminate the wasteful duplication of effort. Along these lines, an active pharmaceutical ingredient (API) inspection program involving many of the world’s premiere global regulatory bodies (FDA, the European Medicines Agency (EMA), Australia’s Therapeutic Goods Administration (TGA), the World Health Organization (WHO), the European Directorate for the Quality of Medicines & Healthcare (EDQM), and the Council of Europe (CE)) has formed to facilitate international collaboration and information sharing to enhance inspection capacity. Since data review and interpretation is already being shared between some global regulatory authorities in the nonclinical safety arena, it will be interesting to see if such global harmonization efforts extend to nonclinical safety inspections in the near future.
RAPS – Regulatory Focus: IOM – Boost Foreign Regulatory Capacity and Global API Inspection Scheme
In order to keep our competitive edge, the Federal Drug Administration (FDA) is placing increased emphasis on strengthening both the field and application of regulatory science relative to pharmaceutical research, development, review, and post-market surveillance. The FDA also has a mandate to recognize areas of unmet public health need and try to galvanize action to move appropriate new products through the pipeline and into the market. The FDA has the responsibility, therefore, not just to review and approve products if the data support that decision, but also to follow these products once marketed to answer critical questions about efficacy and safety. Examination of products across their life cycle enables not only the identification and analysis of emerging safety signals, but also facilitates the continual balancing of risks and benefits.
Research studies, both preclinical and clinical, that form the basis for approval of medical products are increasingly being performed in other countries and often in networks of other countries. For this reason, international recognition of both the scientific appropriateness and ethical conduct of those studies becomes increasingly important to global regulatory bodies. A key understanding is that if a safety concern develops for an approved drug, it does not necessarily reflect that a mistake was made. It may instead reflect new emerging knowledge about that drug in practical use. Regulatory safety has to be a dynamic process. The desire is to proactively ensure that the right studies are done so that the best possible decisions result. However, there isn’t always an absolute, clear decision to be made; resolution, therefore, requires a dynamic balancing of risks and benefits. Questions need to be asked about whether certain subpopulations of patients may benefit from targeted use of a drug, or whether the safety concerns are sufficient to mean a more active withdrawal of a product from the market. Advances in science and technology need to be better incorporated into the regulatory process, with a key area being safety science. To continue to strengthen the science of regulatory safety, the need is to broaden not only the kinds of preclinical and clinical studies that can be done to deepen our understanding of safety, but also to broaden our understanding of how to apply and weight that data to further the science of risk management.
Source: Interview between Dr. Eli Adashi, Professor of Medical Science at Brown University and host of Medscape One-on-One, and Dr. Margaret Hamburg, Commissioner of the US Food and Drug Administration. MedScape Today.