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
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.
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.
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.
An Institute of Medicine (IOM) committee report, recommends that the FDA take proactive steps to continue monitoring drug safety after initial approval and throughout the market lifecycle. Post-market evidence is far greater than what the FDA has when deciding upon initial approval. The IOM recommendation is that the initial approval is viewed as just one early step in a process that requires continuous, long-term monitoring (the “lifecycle approach”). The report makes recommendations about how post-market research should be conducted. The committee found that while randomized controlled trials remain the gold standard for studying drug effectiveness, observational studies have ethical and practical benefits over clinical trials post-approval. Safety results can be obtained more quickly, therefore regulatory action can be initiated earlier. One of the key report recommendations is that upon approval, each drug will have a single, publicly available Benefit and Risk Assessment Management Plan (BRAMP) to serve as a central, evolving repository of side effects and other information. As a centralized comprehensive record, the BRAMP will include a description, a benefit/risk assessment of any safety questions that exist when a drug is approved as well as any that emerge over the course of its market lifecycle, and details on any regulatory actions taken and their results. Furthermore, it was recommended that the FDA’s drug surveillance systems could be improved through use of various technological and methodological advances (e.g., use of natural language processing for review of electronic medical records). The possibility was also raised that with a more robust post-approval monitoring process, the more flexible regulatory authorities could be in the pre-approval stage.
Source: Medical News Today, and HealthCanal.com
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.
In the FDA’s effort to make both its decisions and clinical trial data more transparent to the public, Agency decisions have become more available for public debate. Sophisticated analyses (increasingly by third parties) of publically available data may present to the FDA a more complex picture of drug safety, as not all posted clinical trials fit standard regulatory paradigms, are sufficiently powered, have similar patient selection criteria, or collect and analyze similar parameters. Changes made in the interest of public health, therefore, may further complicate regulatory assessment of potential changes to drug status. For these reasons, among others, drug safety decisions are rarely “black and white.” To its credit, the “new” FDA seems more open to try a middle path (e.g., the diabetes medicine Avandia will remain on the market under a restricted access program [risk evaluation and mitigation strategy, or REMS]). Even more unusual, however, was public admission by the FDA of disagreement about Avandia within its own scientific ranks. Furthermore, 3 top FDA officials co-authored a New England Journal of Medicine article explaining their rationale. Interpretation of clinical trial data, however, is relatively easy compared to analyses of post-market safety data, where patient populations and indications are even more diverse. It will be interesting to see how public access to evolving data (e.g., the anticipated FDA post-marketing drug safety (public) website) will affect Agency decisions, the timing of those decisions, and how much influence third-party analyses will have on regulatory outcomes. The upside to the ensuing debate may be heightened public awareness of the importance of risk management, as all drugs have risk. With the down-spiral of new drugs both coming to and remaining on the market, an outstanding question is whether the public and subsequently the regulatory environment will become more or less risk adverse as our perception of drug safety and risk management evolves.
Source: The New York Times
Despite greater emphasis on safety as a result of attrition, the application of toxicology (~6% of the total R&D budget) to the preclinical drug development process has remained largely unchanged for over 30 years! For this reason, the impetus to reduce safety risks early has been slow to evolve, with limited resources specifically dedicated to this endeavor. Revolutionizing the way that toxicology is applied, such as moving from a hazard identification and risk assessment preclinical paradigm to one that reduces or eliminates risk prior to major expenditures, may provide a means of narrowing the productivity gap within the biopharmaceutical industry. This paper suggests a strategy for the integration of toxicology into early drug development (discovery phase) through identification of potential safety issues related to therapeutic use, target selection, and compound selection, with a primary emphasis on new chemical entities. Information gained may also guide the appropriate selection of the toxicological species used to support clinical trials. Assays predictive of target organ effects (insufficiently discussed, in my opinion, in the present article) vs. assays designed to look at specific mechanisms of drug-induced toxicities at the intracellular level are presented relative to the need for development of high throughput safety screens.
In conclusion, the preclinical toxicology strategy needs to accommodate the unique attributes of the target, the compound, and the therapeutic application, along with assays that are “fit-for-purpose” for that specific project. This paper provides an overview of safety issues for initial exploration and cites possible techniques available to address them in the preclinical space.
Source: Pharmaceutical Outsourcing