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Advances in our understanding of the molecular underpinnings of disease have spurred the development of targeted therapies and the use of precision medicine approaches in patient care. While targeted therapies have improved our capability to provide effective treatments to patients, they also present additional challenges to drug development and benefit-risk assessment such as identifying the subset(s) of patients likely to respond to the drug, assessing heterogeneity in response across molecular subsets of a disease, and developing diagnostic tests to identify patients for treatment. These challenges are particularly difficult to address when targeted therapies are developed to treat diseases with multiple molecular subtypes that occur at low frequencies. To help address these challenges, the US Food and Drug Administration recently published a draft guidance entitled "Developing Targeted Therapies in Low-Frequency Molecular Subsets of a Disease." Here we provide additional information on specific aspects of targeted therapy development in diseases with low-frequency molecular subsets.

Drug regulators around the world make decisions about drug approvability based on qualitative benefit-risk analyses. There is much interest in quantifying regulatory approaches to benefit and risk. In this work the use of a quantitative benefit-risk analysis was applied to regulatory decision-making about new drugs to treat advanced non-small cell lung cancer (NSCLC). Benefits and risks associated with 20 US Food and Drug Administration (FDA) decisions associated with a set of candidate treatments submitted between 2003 and 2015 were analyzed. For benefit analysis, the median overall survival (OS) was used where available. When not available, OS was estimated based on overall response rate (ORR) or progression-free survival (PFS). Risks were analyzed based on magnitude (or severity) of harm and likelihood of occurrence. Additionally, a sensitivity analysis was explored to demonstrate analysis of systematic uncertainty. FDA approval decision outcomes considered were found to be consistent with the benefit-risk logic.

The discovery, development, and use of biomarkers for a variety of drug development purposes are areas of tremendous interest and need. Biomarkers can become accepted for use through submission of biomarker data during the drug approval process. Another emerging pathway for acceptance of biomarkers is via the biomarker qualification program developed by the Center for Drug Evaluation and Research (CDER, US Food and Drug Administration). Evidentiary standards are needed to develop and evaluate various types of biomarkers for their intended use and multiple stakeholders, including academia, industry, government, and consortia must work together to help develop this evidence. The article describes various types of biomarkers that can be useful in drug development and evidentiary considerations that are important for qualification. A path forward for coordinating efforts to identify and explore needed biomarkers is proposed for consideration.

Our nation's ongoing prescription opioid abuse crisis, amounting to over 78 billion dollars in health and social costs annually,1 is a critical priority for the US Food and Drug Administration (FDA). As a part of our mission to support the safe and effective use of prescription medicines, the FDA is taking a fresh look at potential scientific and regulatory actions we can take to address this crisis.

The concept of precision medicine has entered broad public consciousness, spurred by a string of targeted drug approvals, highlighted by the availability of personal gene sequences, and accompanied by some remarkable claims about the future of medicine. It is likely that precision medicines will require precision drug development programs. What might such programs look like?

In September 2012, the President's Council of Advisors on Science and Technology (PCAST) released the report "Propelling Innovation in Drug Discovery, Development and Evaluation." A product of discussions with many stakeholders, the report reiterates current problems in drug development, including diminished return on basic biomedical research. The report calls for doubling the current annual output of innovative new medicines--an ambitious goal. Recommendations and resulting initiatives will probably affect the FDA's drug regulatory programs.

The "regulatory paradox" is a tension between aversion to uncertainty and willingness to accept unknowns about a drug before its approval. Finding the right balance may mean the difference between fostering and stifling innovation. Clinical pharmacology applied in the drug development and regulatory contexts can bridge mechanistic reasoning and empiricism to help reconcile the regulatory paradox. Here, we propose that the discipline of clinical pharmacology, in the regulatory setting, is well positioned to build on its past successes in the advancement and acceleration of drug development.

There is an ongoing debate over the evidentiary standards that should be applied for introduction of new diagnostics into routine clinical practice. Many call for evidence of "clinical utility," i.e., a positive impact on patient outcomes. A diagnostic, when used with a medicine, has clinical utility if it improves the outcomes of drug therapy. Improved outcomes may be defined broadly, including benefits, harm reduction, and patient-reported outcomes. Much of the controversy centers around the methods of demonstrating clinical utility. For instance, are randomized prospective trials the only acceptable source of data? Practically speaking, many sources of evidence-mechanistic, pharmacologic, and observational-can contribute to a finding of clinical utility, depending on the circumstances. Clinical utility is highly indication specific, and achieving it is dependent on good analytical and diagnostic test performance.

There has been much recent discussion about the advent of "personalized medicine," but controversy exists over its exact definition; how, when, and whether it will be brought about, and what means could be used to measure its attainment. In fact, the concept of "personalized medicine" is a sort of shorthand used to represent the logical next steps in progression of medical science toward greater mechanistic understanding of health, disease, and treatment. This shorthand is attractive to the public because of its intuitive appeal, and irritating to the biomedical community because it glosses over the very real scientific and implementation challenges. This paper evaluates the trajectory and promise of these next steps for the currently problematic states of both drug development and therapy.

Integrating molecular medicine into clinical practice will create many challenges. But the existing genetic testing paradigm may not be the right model for introducing these new technologies. Clinical Pharmacology & Therapeutics (2007) 82, 376–378. doi:10.1038/sj.clpt.6100349

Over the past few years, an increasing number of critically needed medicines have been in short supply. Using economic theory to frame the drug-shortage problem, this paper explores why and how manufacturing-quality problems could combine with other economic and technological factors to result in shortages of generic sterile injectable drugs. The fundamental problem we identify is the inability of the market to observe and reward quality. This lack of reward for quality can reinforce price competition and encourage manufacturers to keep costs down by minimizing quality investments. The US Food and Drug Administration's (FDA's) need to use its regulatory flexibility, on behalf of patients, to avoid shortages of medically necessary drugs may further strengthen the incentive to "push the envelope" on quality. These dynamics may have produced a market situation in which quality problems have become sufficiently common and severe to result in drug shortages.