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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. [ABSTRACT FROM AUTHOR]

Advances in cheminformatics, bioinformatics, and pharmacology in the context of biological systems are now at a point that these tools can be applied to mechanism-based drug safety assessment and prediction. The development of such predictive tools at the US Food and Drug Administration (FDA) will complement ongoing efforts in drug safety that are focused on spontaneous adverse event reporting and active surveillance to monitor drug safety. This effort will require the active collaboration of scientists in the pharmaceutical industry, academe, and the National Institutes of Health, as well as those at the FDA, to reach its full potential. Here, we describe the approaches and goals for the mechanism-based drug safety assessment and prediction program. [ABSTRACT FROM AUTHOR]

The article offers information on the U.S. Orphan Drug Act of 1983 which aims to increase orphan drug development. It informs that the ratio of new molecular entities (NME) is growing in the market. The U.S. Food and Drug Administration is dealing with orphan drug development program in a flexible manner. It further informs that there are other development programs also that target a subset of a broader disease.

The article discusses several aspects of the development of drugs. In 2004, the U.S. Food and Drug Administration (FDA) published a white paper that cited the productivity problems and argued for rapid uptake of biomarkers and clinical trial methods. Since 2004, the costs of drug development have increased while industry productivity has not. It is stated that the importance to produce high-value, innovative drugs will intensify and create a higher performance hurdle for new therapeutics.

As the fourth wave of the SARS-CoV-2 pandemic encircles the globe, there remains an urgent challenge to identify safe and effective treatment and prevention strategies that can be implemented in a range of health care and clinical settings. Substantial advances have been made in the use of anti-SARS-CoV-2 antibodies to mitigate the morbidity and mortality associated with COVID-19. On 15 June 2021, the National Institutes of Health, in collaboration with the U.S. Food and Drug Administration, convened a virtual summit to summarize existing knowledge on anti-SARS-CoV-2 antibodies and to identify key unanswered scientific questions to further catalyze the clinical development and implementation of antibodies.

A 2001 U.S. Government Accountability Office (GAO) report indicated 8 of 10 drugs withdrawn from the U.S. market between 1997 and 2000 posed greater risk to women than men. We examined drugs withdrawn from the market for safety-related reasons from January 1, 2001, to January 1, 2018. To be included, drugs must be listed as discontinued on Drugs@FDA and either listed in the Federal Register or cited in literature as being withdrawn for safety-related reasons. Biologics, over-the-counter products, and medical devices were excluded. During the 17-year time span, 19 drugs were withdrawn from the market for safety-related reasons, fewer drugs per year compared to the 3-year period examined in the GAO report. Food and Drug Administration (FDA) has not recommended the market removal of any drug approved since 2005 due to the time from the start of the Q wave to the end of the T wave (QT) interval prolongation resulting in torsades de pointes (TdP) or other abnormal heart rhythms. Furthermore, no drugs approved after the implementation of FDA's 2009 guidance on drug-induced liver injury (DILI) have been withdrawn because of hepatoxicity. All, but one of the drugs discontinued from the market for safety-related reasons during the period examined were approved between 1957 and 2002. TdP and DILI are two relevant examples of drug-induced adverse events posing greater risk to women than men. FDA has made measurable progress incorporating consideration of sex and gender differences into drug trial development and FDA review of these data, supporting inclusion of women in clinical trials, providing a comprehensive drug safety review, and advancing postmarket surveillance and risk assessment, thus strengthening FDA's ability to protect public health.

The COVID-19 pandemic is causing mass disruption to our daily lives. We integrate mobility data from mobile devices and area-level data to study the walking patterns of 1.62 million anonymous users in 10 metropolitan areas in the United States. The data covers the period from mid-February 2020 (pre-lockdown) to late June 2020 (easing of lockdown restrictions). We detect when users were walking, distance walked and time of the walk, and classify each walk as recreational or utilitarian. Our results reveal dramatic declines in walking, particularly utilitarian walking, while recreational walking has recovered and even surpassed pre-pandemic levels. Our findings also demonstrate important social patterns, widening existing inequalities in walking behavior. COVID-19 response measures have a larger impact on walking behavior for those from low-income areas and high use of public transportation. Provision of equal opportunities to support walking is key to opening up our society and economy.

In response to a rapid increase in drug development activity during the past two decades, the Food and Drug Administration's Center for Drug Evaluation and Research launched a multi-year effort in 2017 to modernize the program by which new drug products are regulated, known as the New Drugs Regulatory Program. Following a detailed analysis of FDA activities in new drug development, premarket review, and postmarket monitoring, the Office of New Drugs was restructured to therapeutically align its clinical offices and to add new cross-functional offices for regulatory support. An interdisciplinary review process for new drug and biologics applications was rolled out to reduce redundancy and produce review documents that effectively communicate the scientific basis for the regulatory decision. The investigational new drug (IND) review process was also streamlined. During the next 2 years, the modernization initiative will seek to attract and retain new scientific and regulatory staff, improve postmarket safety monitoring, increase efficiency of drug review via technology-enabled workflows, and standardize the capture and use of scientific data to inform future regulatory decisions. The modernization effort will position the New Drugs Regulatory Program to continually improve and adapt to innovations in science, technology, and drug development.

Importance: Health care practitioners and patients must have information to support their confidence in the quality of prescription pharmaceuticals., Objective: To determine whether there were clear and substantive differences in major quality attributes between difficult-to-make solid oral dosage form pharmaceutical products marketed in the US., Design, Setting, and Participants: This quality improvement study analyzed US Food and Drug Administration-collected samples of 252 drug products marketed in the US and manufactured in the US, Canada, Europe, India, and the rest of Asia. These drug products were immediate-release solid oral dosage forms considered difficult to make on the basis of product quality history. This sampling included 35 innovator and 217 generic drug samples manufactured by 46 different firms containing 17 different active ingredients. Statistical analysis was performed from February to November 2019., Main Outcomes and Measures: All products were tested within their shelf life on the basis of the legally recognized tests of the US Pharmacopeia for the major quality attributes of dosage unit uniformity and dissolution. These tests measure dosage consistency and drug release, respectively. The consistency of either attribute was used to calculate a process performance index to describe the variability in manufacturing., Results: All 252 drug product samples met the US market standards for dosage unit uniformity and dissolution, although the process performance index (Ppk) for dissolution fell below the level of 4-sigma capability (ie, <1 error per 1600) for 11 different manufacturers and for generics in 4 of 5 regions, including the US. As part of a retrospective analysis, manufacturers performing above the median Ppk for either dissolution or dosage unit uniformity submitted fewer product quality defect reports (mean field alert reports of 0.22 and 0.63, respectively) than those falling at or below the median Ppk for these attributes (mean field alert reports of 2.1 and 1.7, respectively)., Conclusions and Relevance: All samples met the US market standards for dosage unit uniformity and dissolution, indicating acceptability for use by patients regardless of manufacturer or region. To our knowledge, this is the largest sampling study of pharmaceutical manufacturers for the US market and these data provide objective insight into the quality of prescription drugs with high manufacturing risks.

Background: The opioid crisis highlights the need to increase access to naloxone, possibly through regulatory approval for over-the-counter sales. To address industry-perceived barriers to such access, the Food and Drug Administration (FDA) developed a model drug facts label for such sales to assess whether consumers understood the key statements for safe and effective use., Methods: In this label-comprehension study, we conducted individual structured interviews with 710 adults and adolescents, including 430 adults who use opioids and their family and friends. Eight primary end points were developed to assess user comprehension of each of the key steps in the label. Each of these end points included a prespecified target threshold ranging from 80 to 90% that was evaluated through a comparison of the lower boundary of the 95% exact confidence interval., Results: The results for performance on six primary end points met or exceeded thresholds, including the steps "Check for a suspected overdose" (threshold, 85%; point estimate [PE], 95.8%; 95% confidence interval [CI], 94.0 to 97.1) and "Give the first dose" (threshold, 85%; PE, 98.2%; 95% CI, 96.9 to 99.0). The lower boundaries for four other primary end points ranged from 88.8 to 94.0%. One exception was comprehension of "Call 911 immediately," but this instruction closely approximated the target of 90% (PE, 90.3%; 95% CI, 87.9 to 92.4). Another exception was comprehension of the composite step of "Check, give, and call 911 immediately" (threshold, 85%; PE, 81.1%; 95% CI, 78.0 to 83.9)., Conclusions: Consumers met thresholds for sufficient understanding of six of eight components of the instructions in the drug facts label for naloxone use and came close on two others. Overall, the FDA found that the model label was adequate for use in the development of a naloxone product intended for over-the-counter sales., (Copyright © 2020 Massachusetts Medical Society.)

Drug regulators such as the US Food and Drug Administration (FDA) make decisions about drug approvals based on benefit-risk analysis. In this work, a quantitative benefit-risk analysis approach captures regulatory decision making about new drugs to treat renal cell carcinoma (RCC). Fifteen FDA decisions on RCC drugs based on clinical trials whose results were published from 2005 to 2018 were identified and analyzed. The benefits and risks of the new drug in each clinical trial were quantified relative to comparators (typically the control arm of the same clinical trial) to estimate whether the benefit-risk was positive or negative. A sensitivity analysis was demonstrated using pazopanib to explore the magnitude of uncertainty. FDA approval decision outcomes for the clinical trials assessed were consistent and logical using this benefit-risk framework., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

Drug regulators seek to make decisions regarding drug approvals based on analysis of the relevant benefits and risks. In this work, 25 US Food and Drug Administration (FDA) decisions on melanoma drugs were identified and analyzed based on clinical trial results published between 1999 and 2017. In each case, the benefits and risks of the new drug in each clinical trial relative to a comparator (typically the control arm of the same clinical trial) were quantified. The benefits and risks were analyzed using a common scale to allow for direct comparison. A sensitivity analysis was conducted using vemurafenib to explore the magnitude of uncertainty in the quantitative assessments. The associated FDA decision outcomes of the new drugs were consistent with the benefits and risks quantified in this work., (© 2019 The Authors Clinical Pharmacology & Therapeutics © 2019 American Society for Clinical Pharmacology and Therapeutics.)

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., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

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., (Published 2018. This article is a U.S. Government work and is in the public domain in the USA.)

The FDA's "abstinence" outcome measure for approval of new medications to treat opioid-use disorders has been difficult to achieve; developing and validating alternative meaningful outcomes could facilitate drug development., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Diabetes is highly prevalent in the Caribbean, associated with a high morbidity and mortality and is a recognised threat to economic and social development. Heads of Government in the Caribbean Community came together in 2007 and declared their commitment to reducing the burden of non-communicable diseases (NCDs), including diabetes, by calling for a multi-sectoral, systemic response. To facilitate the development of effective policies, policymakers are being engaged in the development and use of a system dynamics (SD) model of diabetes for Caribbean countries., Methods: Previous work on a diabetes SD model from the United States of America (USA) is being adapted to a local context for three countries in the region using input from stakeholders, a review of existing qualitative and quantitative data, and collection of new qualitative data. Three country models will be developed using one-on-one stakeholder engagement and iterative revision. An inter-country model will also be developed following a model-building workshop. Models will be compared to each other and to the USA model. The inter-country model will be used to simulate policies identified as priorities by stakeholders and to develop targets for prevention and control. The model and model-building process will be evaluated by stakeholders and a manual developed for use in other high-burden developing regions., Discussion: SD has been applied with success for health policy development in high-income country settings. The utility of SD in developing countries as an aid to policy decision-making related to NCDs has not been tested. This study represents the first of its kind.

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?, (Published 2015. This article is a U.S. Government work and is in the public domain in the USA.)

The launch of the Center for Drug Evaluation and Research (CDER) Office of Pharmaceutical Quality (OPQ) is a milestone in FDA's efforts to assure that quality medicines are available to the American public. As a new super-office within CDER, OPQ is strategically organized to streamline regulatory processes, advance regulatory standards, align areas of expertise, and originate surveillance of drug quality. Supporting these objectives will be an innovative and systematic approach to product quality knowledge management and informatics. Concerted strategies will bring parity to the oversight of innovator and generic drugs as well as domestic and international facilities. OPQ will promote and encourage the adoption of emerging pharmaceutical technology to enhance pharmaceutical quality and potentially reinvigorate the pharmaceutical manufacturing sector in the United States. With a motto of "One Quality Voice," OPQ embodies the closer integration of review, inspection, surveillance, policy, and research for the purpose of strengthening pharmaceutical quality on a global scale., (Copyright © 2015. Published by Elsevier B.V.)

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., (© 2015 American Society for Clinical Pharmacology and Therapeutics.)

The US Food and Drug Administration (FDA) has directed considerable effort towards modernizing its regulatory processes over the past decade to address the challenges in the drug development sector. Through partnerships and input from stakeholders, multiple initiatives are under way, many projects have been launched, several have resulted in tangible results, and many are ongoing and under discussion. We are learning that collaborative efforts can better inform and leverage existing knowledge, that the challenges of data sharing and intellectual property can be overcome, and that there is wide interest in partnering to address key public health regulatory science issues. It is crucial that we continue to build on these initial efforts to facilitate drug development., (© 2015 American Society for Clinical Pharmacology and Therapeutics.)

Narrow therapeutic index drugs are defined as those drugs where small differences in dose or blood concentration may lead to serious therapeutic failures and/or adverse drug reactions that are life-threatening or result in persistent or significant disability or incapacity. The US Food and Drug Administration proposes that the bioequivalence of narrow therapeutic index drugs be determined using a scaling approach with a four-way, fully replicated, crossover design study in healthy subjects that permits the simultaneous equivalence comparison of the mean and within-subject variability of the test and reference products. The proposed bioequivalence limits for narrow therapeutic index drugs of 90.00%-111.11% would be scaled based on the within-subject variability of the reference product. The proposed study design and data analysis should provide greater assurance of therapeutic equivalence of narrow therapeutic index drug products., (© 2014 American Society for Clinical Pharmacology and Therapeutics.)

Improving the science of drug development and regulation is important in fulfilling the public health mission of the US Food and Drug Administration (FDA). A decade on from the launch of the Critical Path Initiative, the FDA's Center for Drug Evaluation and Research (CDER) is now participating in more than 20 science-driven consortia to achieve this goal.

There is broad agreement among health-care stakeholders that more must be done to ensure that patients have timely access to new and innovative medicines. Assuming that industry will continue to develop such medicines at a sustainable rate, regulators and payers become the gatekeepers. Regulators, starting in the late 1980s/early 1990s, and, more recently, payers have implemented a variety of early-access pathways or initiatives, and this practice is continuing even today. This article describes the specific approaches that have been taken in four economically developed regions, reviews their success rates, and suggests possible new directions.

The US Food and Drug Administration Safety and Innovation Act (FDASIA) was signed on 9 July 2012. This law created a new "breakthrough therapy" (BT) designation program for investigational drugs and biologics intended to treat a serious disease and having "preliminary clinical evidence [that] indicates that the drug may demonstrate substantial clinical improvement over existing therapies on one or more clinically significant endpoints."(1) Many questions have been posed about the impact of this new program on drug development.

The FDA's new "breakthrough therapy" designation for investigational drugs adds to the agency's portfolio of expedited programs for serious conditions. The designation requires preliminary clinical evidence demonstrating substantial improvement over existing therapies.

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.

For more than a decade, industry analysts and policy makers have raised concerns about declining pharmaceutical innovation, citing declining numbers of new molecular entities (NMEs) approved in the United States each year. Yet there is little consensus on whether this is the best measure of "innovation." We examined NME approvals during 1987-2011 and propose the three distinct subcategories of NMEs--first-in-class, advance-in-class, and addition-to-class--to provide more nuanced and informative insights into underlying trends. We found that trends in NME approvals were largely driven by addition-to-class, or "me too," drug approvals, while first-in-class approvals remained fairly steady over the study period. Moreover, the higher proportion of first-in-class drug approvals over the most recent decade is an encouraging sign of the health of the industry as a whole.

For a new therapy to qualify for the accelerated approval pathway, it must treat a serious disease for which there is "unmet medical need"--defined as providing a therapy where none exists or providing a therapy that may be potentially superior to existing therapy. The increasing number of available therapies, coupled with the lack of accepted endpoints considered "reasonably likely to predict clinical benefit" and the lack of clarity early in development about circumstances in which a new product will qualify for accelerated approval, is pushing developers to pursue accelerated approval in heavily pretreated patients to fulfill an unmet need. To optimize the accelerated approval pathway, we propose here a reevaluation of what constitutes "unmet medical need" and "available therapy" in oncology. We also discuss ways for new endpoints to become qualified for use in supporting accelerated approval, and propose a structured process for pursuing accelerated approval., (©2013 AACR)

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.

In 2010, the US Food and Drug Administration (FDA) approved a generic low-molecular-weight heparin without clinical safety or efficacy data under the Abbreviated New Drug Application (ANDA) pathway. To enable a determination of active ingredient sameness of generic and innovator enoxaparin products, the FDA developed a scientifically rigorous approach based on five criteria: first, equivalence of physicochemical properties; second, equivalence of heparin source material and mode of depolymerization; third, equivalence in disaccharide building blocks, fragment mapping and sequence of oligosaccharide species; fourth, equivalence in biological and biochemical assays; and finally, equivalence of in vivo pharmacodynamic profile. In addition to fulfillment of these criteria, FDA also used in vitro, ex vivo and model animal data to ensure there was no increased immunogenicity risk of the generic enoxaparin product relative to the brand name product. The approval of the highly complex enoxaparin product using this framework under the ANDA pathway represents a major development. It also suggests that analytical and scientific advancements may in certain cases allow the elimination of unnecessary in vivo testing in animals and humans.