The new National Center for Advancing Translational Sciences planned for the US National Institutes of Health intends to help transform biological findings into new therapeutic products. But if ...taxpayer funding of risky biomedical research translates into lucrative new medicines, the public should share in the economic benefits as well.
Importance Spending in Medicare Part D continues to increase. Yet, studies of Medicare Part D are plagued by a common limitation: none can fully account for confidential rebates and other discounts ...that drug manufacturers and pharmacies pay to Medicare Part D plans. Objectives To review existing methods and to propose an approach for estimating rebates and other discounts received by Medicare Part D. Evidence Review Publicly available data from the Boards of Trustees of the Federal Hospital Insurance and Federal Supplementary Medical Insurance Trust Funds, the Centers for Medicare & Medicaid Services, the Medicare Payment Advisory Commission, the Congressional Budget Office, the Government Accountability Office, and the Office of Inspector General. Findings Existing methods for estimating rebates and other discounts in Medicare Part D have several limitations. This analysis used an approach that aims to improve on those methods. Based on this approach, estimated discounts on brand-name drugs increased in Medicare Part D from 25.4% of gross brand-name spending in 2014 to 37.3% in 2018. There was substantial variation between classes, with estimated 2016 discounts surpassing 50% for some drugs (eg, ophthalmologic and gastrointestinal tract agents) while remaining below 10% for others (eg, antineoplastic and immunologic agents). Between 2014 and 2018, estimated net Medicare Part D spending on prescription drugs increased by 21% from $99 billion to $119 billion. With increasing enrollment, estimated annual net spending per beneficiary remained stable, increasing by just 3% from $2622 to $2694, which was below the 6% rate of inflation during the same period. Conclusions and Relevance Models that fail to properly account for increasing rebates and other discounts will overestimate Medicare Part D expenditures. Rigorous and transparent methods for estimating discounts are critical for understanding patterns in spending and developing new cost-containment strategies.
In this issue of CMAJ, Becker and colleagues provide an in-depth look at another potential source of the covert promotion of pharmaceuticals: the free ("controlled-circulation") medical journal.8 The ...authors focus on publications from Germany, but there are versions of these journals in virtually every other major medical marketplace. In the United States, these publications may be sent to the membership lists of the American Medical Association (AMA) or a specialty society. Controlled-circulation publications are disseminated without subscription because they are funded entirely by advertising revenue. Many provide summaries of previously published peerreviewed research in easily read formats that may appeal to busy physicians. Some articles are specifically intended for CME purposes and may provide physicians with the opportunity to apply for the credits required by regulatory authorities that show their ability to absorb the information contained in the articles. For many physicians, obtaining CME credits in this manner may be less expensive and more convenient than attending a course or conference. Becker and colleagues provide valuable empirical data to inform the discussion over the role these publications play in medical education. 8 In a cohort of 11 German periodicals, the authors systematically examined pharmaceutical advertisements and CME articles discussing certain heavily marketed drugs or drug classes.8 Five of these publications were distributed to physicians for free (i.e., the publications were supported entirely by advertising revenue), one relied on a revenue model that combined subscription fees and paid advertisements, and five journals were available by subscription only and included no advertisements.8 The authors found a greater number of articles that mentioned the selected drugs in the free publications than in the subscription publications.8 The authors also found that nearly all of the articles in the free publications depicted the drugs in a positive light. In two of the free publications, logistic regression analysis helped the authors to conclude that the presence of an advertisement for a specific drug more than doubled the odds of an article appearing in the same issue that made a positive recommendation for the use of the drug.8 Becker and colleagues suggest addressing the public health issue by encouraging physicians to rely mainly on journals supported by subscription fees for their CME.8 This suggestion is reminiscent of that of Rennie and Bero, who proposed in 1990 that physicians return free publications, at cost, to the publishers.13 Twenty years later, however, free publications are still prominent. Reducing their influence will require increasing the awareness among physicians of the bias that can be contained in the pages of these publications. It will also require competition from high-quality alternatives that meet the physicians' demand for readable summaries of recent medical literature, as well as updates on evidence-based prescribing and the management of certain clinical conditions. Further funding from governments or other sources not affiliated with the pharmaceutical industry for the development of such information would promote rational prescribing and better outcomes while reducing the need for prescription fees. Most physicians would be happy to receive additional information about the proper use of drugs that is both effective and free of bias, but the medical community needs to do a better job of creating and disseminating this information without the influence of pharma ceutical advertising.
Background Regulators increasingly rely on registries for decision making related to high-risk medical devices in the United States. However, the limited uniform standards for registries may create ...substantial variability in registry implementation and utility to regulators. We surveyed the current landscape of US cardiovascular device registries and chart the extent of inconsistency in goals, administration, enrollment procedures, and approach to data access. Methods and Results A systematic review using Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines identified studies (1995-2017) referencing cardiovascular device registries with a US-based institution. Registries were then evaluated by reviewing associated articles and websites. Extracted data included device type, primary scientific aim(s), funding, stewardship (eg, administration of registry procedures), enrollment procedures, informed consent process, and mechanisms to access data for research. The 138 cardiovascular device registries in the cohort covered devices addressing interventional cardiology (65.9%), arrhythmias (15.2%), heart failure (10.1%), and valvular disease (10.1%). While the majority (55.8%) were industry-funded, stewardship was predominantly overseen by academic centers (74.0%). Most registry participation was voluntary (77.5%), but a substantial minority (19.7%) were required as a condition of device implantation. Informed consent requirements varied widely, with written consent required in only 55.1% of registries. Registry data were primarily accessible only to stewards (84.1%), with 13.8% providing pathways for external applications. Conclusions The majority of cardiovascular device registries were funded privately under the auspices of academic institutions, which set the rules for data access. The substantial variation between cardiovascular device registries suggests a role for regulators to further strengthen guidelines to improve quality, consistency, and ethical standards.
The US Food and Drug Administration (FDA) created the exception from informed consent (EFIC) pathway in 1996 to allow some emergency trials to enroll patients without informed consent. To protect ...individual autonomy and preserve public trust, the FDA requires that EFIC trial investigators consult with community members before a trial may begin.
To analyze data from surveys conducted as part of community consultation ahead of EFIC trials and assess levels of public approval.
All trials granted an EFIC must submit documentation of compliance with EFIC regulations to a publicly available docket at the FDA. Submissions between November 1, 1996, and October 23, 2017, were reviewed.
Trials with survey data were included.
Data were extracted between January 2018 and June 2018 and were analyzed between June 2018 and August 2018. The quality and validity of data were assessed according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. A random-effects metaregression was used to assess the association of demographic characteristics with EFIC approval.
The primary study outcome was EFIC approval.
The FDA docket contained 15 958 pages of material with survey data for 42 448 individuals submitted by 27 trials. Public approval of EFIC varied by question type, with more people willing to approve initiation of EFIC trials in their community (86.5%) than personal enrollment (73.0%), enrollment of a family member (68.6%), or the principle of enrollment without consent (58.4%) (P < .001 for all comparisons). In the United States, African American individuals made up 29.3% of those enrolled in EFIC trials that reported data on race (5064 of 17 302) but only 16.7% of those surveyed as part of community consultation. In the United States and Canada, men made up 42.9% of the surveyed population but 65.6% of those eventually enrolled in EFIC trials (29 961 of 45 694). Groups surveyed with higher proportions of African American and male respondents had lower rates of EFIC approval.
Public approval of EFIC trials varied by question type and by the respondents' reported race and sex. The demographic characteristics of those surveyed did not match the demographic characteristics of EFIC enrollees. The FDA could strengthen community consultation by standardizing survey instruments and reporting, requiring broader inclusion of African American and male respondents, clarifying the function of surveys in the development and modification of trial protocols, and building more public consensus around the acceptable use of EFIC.
To review the clinical evidence, regulatory background, and cost of antibiotics approved by the US Food and Drug Administration (FDA), 2016-19.
Cohort study of FDA approved drugs.
FDA databases, ...ClinicalTrials.gov, and drug labelling. Launch prices were extracted from IBM Micromedex Red Book.
Antibiotics approved by the FDA from October 2016 to December 2019 were identified, and key features of their clinical development were extracted from publicly available FDA databases, ClinicalTrials.gov, and drug labelling. Launch prices were extracted from IBM Micromedex Red Book to evaluate the cost of treatment against comparators.
15 new antibiotics received at least one special regulatory designation and were supported by a median of two pivotal trials. More than half of the pivotal trials used an active control non-inferiority design. All drugs were approved based on surrogate outcome measures. 52 postmarketing requirements and commitments were included across the cohort (median 3 for each drug). From January 2021, 27 postmarketing requirements and commitments were listed as pending, seven as ongoing, three as delayed, one as submitted, eight as released, and four as fulfilled. The most expensive new antibiotic was pretomanid at $36 399 (£29 618; €34 582) for a course of treatment, and the least expensive was rifamycin ($176). Cost ratios between study drugs and comparators ranged from 0.48 to 134.
New antibiotics have been approved by the FDA in recent years mostly based on fewer, smaller, and non-inferiority pivotal trials that often used surrogate outcome measures but were commonly more costly. Efforts to incentivise the development of antibiotics should balance growing the antibiotic development pipeline with ensuring that clinical trials provide clinically relevant evidence of effectiveness in showing added benefits for the patient.
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.
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.
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.
Drug names, date of approval, indication on labeling, and clinical and regulatory details.
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.
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.
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.
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