Trends in the Quality of Evidence Supporting FDA Drug Approvals: Results from a Literature Review.

CONTEXT: New drug approvals in the United States must be supported by substantial evidence from "adequate and well-controlled" trials. The Food and Drug Administration (FDA) has flexibility in how it applies this standard. METHODS: The authors conducted a systematic literature review of studies evaluating the design and outcomes of the key trials supporting new drug approvals in the United States. They extracted data on the trial characteristics, endpoint types, and expedited regulatory pathways. FINDINGS: Among 48 publications eligible for inclusion, 30 covered trial characteristics, 23 covered surrogate measures, and 30 covered regulatory pathways. Trends point toward less frequent randomization, double-blinding, and active controls, with variation by drug type and indication. Surrogate measures are becoming more common but are not consistently well correlated with clinical outcomes. Drugs approved through expedited regulatory pathways often have less rigorous trial design characteristics. CONCLUSIONS: The characteristics of trials used to approve new drugs have evolved over the past two decades along with greater use of expedited regulatory pathways and changes in the nature of drugs being evaluated. While flexibility in regulatory standards is important, policy changes can emphasize high-quality data collection before or after FDA approval.

New Drug Postmarketing Requirements and Commitments in the US: A Systematic Review of the Evidence.

INTRODUCTION: After the approval of a new drug, the Food and Drug Administration (FDA) may issue postmarketing requirements (PMRs), studies that the law requires manufacturers to conduct for drugs approved under certain conditions, and postmarketing commitments (PMCs), studies that the FDA and manufacturers agree should be conducted as a condition of approval. OBJECTIVE: With regulators' increasing reliance on gathering important evidence after initial product approval, we sought to assess the track record of PMRs and PMCs by synthesizing information about postmarketing study completion rates, timeliness, study types, and results reporting. METHODS: A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was conducted. Studies published in academic journals or government reports that reported original data about the characteristics of PMRs or PMCs were included. Studies of post-approval trial mandates issued by regulators outside the USA were excluded, as were those that addressed post-approval research without mentioning either PMCs or PMRs or a specific approval pathway associated with statutorily required PMRs. Two investigators independently screened and extracted data from studies and reports. Data sources included the Federal Register from 2003 to 2020, FDA backlog reviews from 2008 to 2020, PubMed from January 2006 to April 2021, and the US Government Accountability Office (GAO) database for reports from January 2006 to April 2021. PMR/PMC characteristics (e.g., completion rates, timeliness, results reporting, outcomes) were not meta-analyzed due to the heterogeneity in study designs. RESULTS: Twenty-seven peer-reviewed articles from PubMed, five GAO reports, 17 annual Federal Register notices, and 12 annual backlog reviews were included. Among the 27 studies, 13 reviewed PMRs and PMCs, one reviewed only PMCs, and 13 reviewed only PMRs. A majority of new drugs were approved with at least one PMR or PMC. PMCs were completed at higher rates than PMRs, although delays were common and neither was found to be completed more than two-thirds of the time. Over two-thirds of PMRs and PMCs reported their findings in publications and trial registries. Over half of PMCs and PMRs produced novel information for clinical practice or leading to regulatory action, such as confirmation of benefit or a labeling change. CONCLUSION: PMRs and PMCs are common for new drugs and can lead to worthwhile outcomes, but are often delayed or incomplete. Greater attention is needed to timely completion, improving transparency of findings, and ensuring that PMRs and PMCs produce optimally useful information for prescribers and patients.

Analysis of Supportive Evidence for US Food and Drug Administration Approvals of Novel Drugs in 2020.

Importance: In recent years, drug approvals have been based on fewer, smaller, and less rigorous pivotal trials. Less robust preapproval testing raises questions about the efficacy and clinical value of these drugs. Objective: To assess the regulatory context, pivotal design characteristics, and postmarket requirements (PMRs) and postmarket commitments (PMCs) of novel 2020 drug approvals to characterize the state of evidence at the time of approval. Design, Setting, and Participants: This cohort study identified novel drugs approved by the US Food and Drug Administration's (FDA) Center for Drug Evaluation and Research in 2020. The Drugs@FDA database was used to extract key characteristics of each drug's pivotal trials. Drug approval packages provided regulatory information. The prevalence of key trial design features was compared between oncology and nononcology drugs. Exposures: Drug names, date of approval, indication on labeling, and clinical and regulatory details. Main Outcomes and Measures: Number of pivotal trials, pivotal trial design (randomization, masking, groups), trial comparator, trial hypothesis, trial end points, results, number and type of expedited pathway designations, and number and type of PMRs and PMCs. Results: The 49 novel therapeutics approved in 2020 were supported by 75 pivotal trials. More than half of drugs (28 [57.1%]) were supported by a single pivotal trial. Trial sizes ranged from 19 to 2230 participants. More than three-fourths of trials (57 [76.0%]) had a randomization component, and nearly two-thirds (46 [61.3%]) were double-masked. Most used a superiority approach. Roughly half (39 [52.0%]) compared the novel therapeutic with a placebo or vehicle control; 13 (17.3%), an active control; 2 (2.7%), both a placebo and active control; and 21 (28.0%), a historical, external, or other control. Nearly half of pivotal trials (34 [45.3%]) used a surrogate measure as a primary end point. Pivotal trials supporting oncology approvals were much more likely to have historical controls than nononcology approvals (13 of 18 [72.2%] vs 8 of 57 [14.0%]; P < .001) and to use at least 1 surrogate measure as a primary end point (17 [94.4%] vs 17 [29.8%]; P < .001). Forty drugs had at least 1 PMR or PMC, accounting for 178 PMRs and PMCs across the cohort. Conclusions and Relevance: These findings suggest that the increased flexibility in the characteristics of acceptable preapproval evidence can be partially explained by the increase in trials of drugs for rare and other serious conditions that require flexible testing strategies as well as the associated regulatory changes that have accumulated over time. The FDA and consumers may benefit from a revised approach that better balances time to market with ensuring that approved drugs show evidence of efficacy.

Something is amiss in Denmark: a comparison of preventable hospitalisations and readmissions for chronic medical conditions in the Danish Healthcare system and Kaiser Permanente.

BACKGROUND: As many other European healthcare systems the Danish healthcare system (DHS) has targeted chronic condition care in its reform efforts. Benchmarking is a valuable tool to identify areas for improvement. Prior work indicates that chronic care coordination is poor in the DHS, especially in comparison with care in Kaiser Permanente (KP), an integrated delivery system based in the United States. We investigated population rates of hospitalisation and readmission rates for ambulatory care sensitive, chronic medical conditions in the two systems. METHODS: Using a historical cohort study design, age and gender adjusted population rates of hospitalisations for angina, heart failure, chronic obstructive pulmonary disease, and hypertension, plus rates of 30-day readmission and mortality were investigated for all individuals aged 65+ in the DHS and KP. RESULTS: DHS had substantially higher rates of hospitalisations, readmissions, and mean lengths of stay per hospitalisation, than KP had. For example, the adjusted angina hospitalisation rates in 2007 for the DHS and KP respectively were 1.01/100 persons (95%CI: 0.98-1.03) vs. 0.11/100 persons (95%CI: 0.10-0.13/100 persons); 21.6% vs. 9.9% readmission within 30 days (OR = 2.53; 95% CI: 1.84-3.47); and mean length of stay was 2.52 vs. 1.80 hospital days. Mortality up through 30 days post-discharge was not consistently different in the two systems. CONCLUSIONS: There are substantial differences between the DHS and KP in the rates of preventable hospitalisations and subsequent readmissions associated with chronic conditions, which suggest much opportunity for improvement within the Danish healthcare system. Reductions in hospitalisations also could improve patient welfare and free considerable resources for use towards preventing disease exacerbations. These conclusions may also apply for similar public systems such as the US Medicare system, the NHS and other systems striving to improve the integration of care for persons with chronic conditions.

Delivery system reform tracking: a framework for understanding change.

The health care delivery system is changing rapidly, with providers forming patient-centered medical homes and exploring the creation of accountable care organizations. Enactment of the Affordable Care Act will likely accelerate these changes. Significant delivery system reforms will simultaneously affect the structures, capabilities, incentives, and outcomes of the delivery system. With so many changes taking place at once, there is a need for a new tool to track progress at the community level. Many of the necessary data elements for a delivery system reform tracking tool are already being collected in various places and by different stakeholders. The authors propose that all elements be brought together in a unified whole to create a detailed picture of delivery system change. This brief provides a rationale for creating such a tool and presents a framework for doing so.

Addressing health care market reform through an insurance exchange: essential policy components, the public plan option, and other issues to consider.

HEALTH INSURANCE EXCHANGE: This Issue Brief examines issues related to managed competition and the use of a health insurance exchange for the purpose of addressing cost, quality, and access to health care services. It discusses issues that must be addressed when designing an exchange in order to reform the health insurance market and also examines state efforts at health reform that use an exchange. RISK VS. PRICE COMPETITION: The basic component of managed competition is the creation an organized marketplace that brings together health insurers and consumers (either as individuals or through their employers). The sponsor of the exchange would set "rules of engagement" for participating insurers and offer consumers a menu of choices among different plans. Ultimately, the goal of a health insurance exchange is to shift the market from competition based on risk to competition based on price and quality. ADVERSE SELECTION AND AFFORDABILITY: Among the issues that need to be addressed if an exchange that uses managed competition has a realistic chance of reducing costs, improving quality, and expanding coverage: Everyone needs to be in the risk pool, with individuals required to purchase insurance or face significant financial consequences; effective risk adjustment is essential to eliminate risk selection as an insurance business model--forcing competition on costs and quality; the insurance benefit must be specific and clear--without standards governing cost sharing, covered services, and network coverage there is no way to assess whether a requirement to purchase or issue coverage has been met; and subsidies would be necessary for low-income individuals to purchase insurance. THE PUBLIC PLAN OPTION: The public plan option is shaping up to be one of the most contentious issues in the health reform debate. Proponents also believe of a public plan is necessary to drive private insurers toward true competition. Opponents view it as a step toward government-run health care and are wary of cost shifting from the public plan to private insurers. FUTURE OF EMPLOYMENT-BASED COVERAGE: The availability of a health insurance exchange may have implications for the future of the employment-based health benefits system and raises major questions for workers. Will employers provide a fixed contribution for the purchase of insurance through an exchange? Would that be large enough to purchase coverage? Would it be flat or vary by such factors as worker health status, age, and/or marital status or the presence of children? Would it be taxed? For both employers and workers, the implications are enormous.

Cost and economic benefit of clinical decision support systems for cardiovascular disease prevention: a community guide systematic review.

OBJECTIVE: This review evaluates costs and benefits associated with acquiring, implementing, and operating clinical decision support systems (CDSSs) to prevent cardiovascular disease (CVD). MATERIALS AND METHODS: Methods developed for the Community Guide were used to review CDSS literature covering the period from January 1976 to October 2015. Twenty-one studies were identified for inclusion. RESULTS: It was difficult to draw a meaningful estimate for the cost of acquiring and operating CDSSs to prevent CVD from the available studies ( n = 12) due to considerable heterogeneity. Several studies ( n = 11) indicated that health care costs were averted by using CDSSs but many were partial assessments that did not consider all components of health care. Four cost-benefit studies reached conflicting conclusions about the net benefit of CDSSs based on incomplete assessments of costs and benefits. Three cost-utility studies indicated inconsistent conclusions regarding cost-effectiveness based on a conservative $50,000 threshold. DISCUSSION: Intervention costs were not negligible, but specific estimates were not derived because of the heterogeneity of implementation and reporting metrics. Expected economic benefits from averted health care cost could not be determined with confidence because many studies did not fully account for all components of health care. CONCLUSION: We were unable to conclude whether CDSSs for CVD prevention is either cost-beneficial or cost-effective. Several evidence gaps are identified, most prominently a lack of information about major drivers of cost and benefit, a lack of standard metrics for the cost of CDSSs, and not allowing for useful life of a CDSS that generally extends beyond one accounting period.

Risk segmentation related to the offering of a consumer-directed health plan: a case study of Humana Inc.

OBJECTIVE: To determine whether the offering of a consumer-directed health plan (CDHP) is likely to cause risk segmentation in an employer group. STUDY SETTING AND DATA SOURCE: The study population comprises the approximately 10,000 people (employees and dependents) enrolled as members of the employee health benefit program of Humana Inc. at its headquarters in Louisville, Kentucky, during the benefit years starting July 1, 2000, and July 1, 2001. This analysis is based on primary collection of claims, enrollment, and employment data for those employees and dependents. STUDY DESIGN: This is a case study of the experience of a single employer in offering two consumer-directed health plan options ("Coverage First 1" and "Coverage First 2") to its employees. We assessed the risk profile of those choosing the Coverage First plans and those remaining in more traditional health maintenance organization (HMO) and preferred provider organization (PPO) coverage. Risk was measured using prior claims (in dollars per member per month), prior utilization (admissions/1,000; average length of stay; prescriptions/1,000; physician office visit services/1,000), a pharmacy-based risk assessment tool (developed by Ingenix), and demographics. DATA COLLECTION/EXTRACTION METHODS: Complete claims and administrative data were provided by Humana Inc. for the two-year study period. Unique identifiers enabled us to track subscribers' individual enrollment and utilization over this period. PRINCIPAL FINDINGS: Based on demographic data alone, there did not appear to be a difference in the risk profiles of those choosing versus not choosing Coverage First. However, based on prior claims and prior use data, it appeared that those who chose Coverage First were healthier than those electing to remain in more traditional coverage. For each of five services, prior-year usage by people who subsequently enrolled in Coverage First 1 (CF1) was below 60 percent of the average for the whole group. Hospital and maternity admissions per thousand were less than 30 percent of the overall average; length of stay per hospital admission, physician office services per thousand, and prescriptions per thousand were all between 50 and 60 percent of the overall average. Coverage First 2 (CF2) subscribers' prior use of services was somewhat higher than CF1 subscribers', but it was still below average in every category. As with prior use, prior claims data indicated that Coverage First subscribers were healthier than average, with prior total claims less than 50 percent of average. CONCLUSIONS: In this case, the offering of high-deductible or consumer-directed health plan options alongside more traditional options caused risk segmentation within an employer group. The extent to which these findings are applicable to other cases will depend on many factors, including the employer premium contribution policies and employees' perception of the value of the various plan options. Further research is needed to determine whether risk segmentation will worsen in future years for this employer and if so, whether it will cause premiums for more traditional health plans to increase.

Gaps in residency training should be addressed to better prepare doctors for a twenty-first-century delivery system.

Many observers have been concerned about a mismatch between the knowledge, skills, and professional values of newly trained physicians and the requirements of current and future medical practice. We surveyed and interviewed Kaiser Permanente's clinical department chiefs for internal medicine, pediatrics, general surgery, and obstetrics/gynecology to ascertain their views of the perceived gaps in the readiness of newly trained physicians. Nearly half of those surveyed reported deficiencies among new physicians in managing routine conditions or performing simple procedures often encountered in office-based practice. A third of the chiefs noted deficiencies in coordinating care for patients. Filling these and other training gaps will require changes at many levels-from residency programs to Medicare reimbursement policies-to better prepare new physicians for the challenges of working in a health care system evolving to emphasize accountability, quality outcomes, cost control, and information technology.

Consumer-directed health care: it's not whether the glass is half-empty, but why.

Analyses of consumer-directed health plans often focus on how use of services under such a plan compares with what use would have been under a more comprehensive benefit design. That's a natural perspective for analysts who observe movement from a world of rich coverage to one of more limited coverage. But the comparison may confuse the message with the messenger. In a world where employers are seeking any port in a storm of unsustainable cost growth, it might be more useful to compare offering a consumer-directed plan to other options that employers could have chosen in constraining health costs.