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1.
PLoS Med ; 17(3): e1003058, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32231363

RESUMO

BACKGROUND: Evidence and guidelines do not support use of systemic steroids for acute respiratory tract infections (ARTIs), but such practice appears common. We aim to quantify such use and determine its predictors. METHODS AND FINDINGS: We conducted a cohort study based on a large United States national commercial claims database, the IBM MarketScan, to identify patients aged 18-64 years with an ARTI diagnosis (acute bronchitis, sinusitis, pharyngitis, otitis media, allergic rhinitis, influenza, pneumonia, and unspecified upper respiratory infections) recorded in ambulatory visits from 2007 to 2016. We excluded those with systemic steroid use in the prior year and an extensive list of steroid-indicated conditions, including asthma, chronic obstructive pulmonary disease, and various autoimmune diseases. We calculated the proportion receiving systemic steroids within 7 days of the ARTI diagnosis and determined its significant predictors. We identified 9,763,710 patients with an eligible ARTI encounter (mean age 39.6, female 56.0%) and found 11.8% were prescribed systemic steroids (46.1% parenteral, 47.3% oral, 6.6% both). All ARTI diagnoses but influenza predicted receiving systemic steroids. There was high geographical variability: the adjusted odds ratio (aOR) of receiving parenteral steroids was 14.48 (95% confidence interval [CI] 14.23-14.72, p < 0.001) comparing southern versus northeastern US. The corresponding aOR was 1.68 (95% CI 1.66-1.69, p < 0.001) for oral steroids. Other positive predictors for prescribing included emergency department (ED) or urgent care settings (versus regular office), otolaryngologist/ED doctors (versus primary care), fewer comorbidities, and older patient age. There was an increasing trend from 2007 to 2016 (aOR 1.93 [95% CI 1.91-1.95] comparing 2016 to 2007, p < 0.001). Our findings are based on patients between 18 and 64 years old with commercial medical insurance and may not be generalizable to older or uninsured populations. CONCLUSIONS: In this study, we found that systemic steroid use in ARTI is common with a great geographical variability. These findings call for an effective education program about this practice, which does not have a clear clinical net benefit.

2.
Clin Pharmacol Ther ; 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-32236959

RESUMO

Assessments of clinical evidence vary between regulators and health technology assessment bodies, but precise differences remain unclear. To compare uncertainties raised on the clinical evidence of approved drugs, we analyzed assessments of regulators and health technology assessment (HTA) bodies in the US and Europe. We found that US and European regulators report uncertainties related to safety for almost all drugs (85-94%) whereas HTA bodies reported these less (53-59%). By contrast, HTA bodies raised uncertainties related to effects against relevant comparators for almost all drugs (88-100%) while this was infrequently addressed by regulators (12-32%). Regulators as well as HTA bodies reported uncertainties related to the patient population for 60-95% of drugs. The patterns of regulator-HTA misalignment were comparable between the US and Europe. Our results indicate that increased coordination between these complementary organizations is necessary to facilitate the collection of necessary evidence in an efficient and timely manner.

3.
Lancet ; 395(10228): 986-997, 2020 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-32199486

RESUMO

Fewer than half of new drugs have data on their comparative benefits and harms against existing treatment options at the time of regulatory approval in Europe and the USA. Even when active-comparator trials exist, they might not produce meaningful data to inform decisions in clinical practice and health policy. The uncertainty associated with the paucity of well designed active-comparator trials has been compounded by legal and regulatory changes in Europe and the USA that have created a complex mix of expedited programmes aimed at facilitating faster access to new drugs. Comparative evidence generation is even sparser for medical devices. Some have argued that the current process for regulatory approval needs to generate more evidence that is useful for patients, clinicians, and payers in health-care systems. We propose a set of five key principles relevant to the European Medicines Agency, European medical device regulatory agencies, US Food and Drug Administration, as well as payers, that we believe will provide the necessary incentives for pharmaceutical and device companies to generate comparative data on drugs and devices and assure timely availability of evidence that is useful for decision making. First, labelling should routinely inform patients and clinicians whether comparative data exist on new products. Second, regulators should be more selective in their use of programmes that facilitate drug and device approvals on the basis of incomplete benefit and harm data. Third, regulators should encourage the conduct of randomised trials with active comparators. Fourth, regulators should use prospectively designed network meta-analyses based on existing and future randomised trials. Last, payers should use their policy levers and negotiating power to incentivise the generation of comparative evidence on new and existing drugs and devices, for example, by explicitly considering proven added benefit in pricing and payment decisions.

5.
Drug Saf ; 2020 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-32180134

RESUMO

INTRODUCTION: Clinical practice guidelines recommend co-prescribing naloxone to patients at high risk of opioid overdose, but few such patients receive naloxone. High costs of naloxone may contribute to limited dispensing. OBJECTIVE: The aim of this study was to evaluate rates and costs of dispensing naloxone to patients receiving opioid prescriptions and at high risk for opioid overdose. METHODS: Using claims data from a large US commercial insurance company, we conducted a retrospective cohort study of new opioid initiators between January 2014 and December 2018. We identified patients at high risk for overdose defined as a diagnosis of opioid use disorder, prior overdose, an opioid prescription of ≥ 50 mg morphine equivalents/day for ≥ 90 days, and/or concurrent benzodiazepine prescriptions. RESULTS: Among 5,292,098 new opioid initiators, 616,444 (12%) met criteria for high risk of overdose during follow-up, and, of those, 3096 (0.5%) were dispensed naloxone. The average copayment was US$24.83 for naloxone (standard deviation [SD] 67.66) versus US$9.74 for the index opioid (SD 19.75). The average deductible was US$6.18 for naloxone (SD 27.32) versus US$3.74 for the index opioid (SD 25.56), with 94% and 88% having deductibles of US$0 for their naloxone and opioid prescriptions, respectively. The average out-of-pocket cost was US$31.01 for naloxone (SD 73.64) versus US$13.48 for the index opioid (SD 34.95). CONCLUSIONS: Rates of dispensing naloxone to high risk patients were extremely low, and prescription costs varied greatly. Since improving naloxone's affordability may increase access, whether naloxone's high cost is associated with low dispensing rates should be evaluated.

8.
Clin Infect Dis ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32022228
9.
Nat Rev Clin Oncol ; 17(3): 140-146, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32020042

RESUMO

The traditional regulatory drug approval paradigm comprising discrete phases of clinical testing that culminate in a large randomized superiority trial has historically been predominant in oncology. However, this approach has evolved in the current era of drug development, with multiple other development pathways now being utilized. Indeed, treatment approaches designed on the basis of an improved understanding of cancer biology have led to unprecedented responses in early phase trials, sometimes resulting in drug approvals in the absence of large-scale trials. At the same time, improved molecular diagnostic technologies have led to the identification of ever-smaller patient subgroups for molecularly targeted therapy. Moreover, new FDA regulatory paradigms have enabled the rapid review and accelerated approval of certain drugs in the absence of survival data. Regulatory approvals based on large-cohort trials with surrogate or intermediate clinical end points or on non-inferiority trials, as well as new tumour-agnostic indications, also set important precedents in the field. In this Viewpoint, we asked two leading oncologists involved in clinical drug development, an expert in regulatory science and prescription drug policy and a prominent patient advocate, to provide their opinions on the implications of these changes in regulatory practices for patient care.

12.
JAMA ; 323(2): 164-176, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31935033

RESUMO

Importance: US law requires testing of new drugs before approval to ensure that they provide a well-defined benefit that is commensurate with their risks. A major challenge for the US Food and Drug Administration (FDA) is to achieve an appropriate balance between rigorous testing and the need for timely approval of drugs that have benefits that outweigh their risks. Objective: To describe the evolution of laws and standards affecting drug testing, the use of new approval programs and standards, expansions of the role and authority of the FDA, and changes in the number of drugs approved from the 1980s to 2018. Evidence: Sources of evidence included principal federal laws and FDA regulations (1962-2018) and FDA databases of approved new drugs (1984-2018), generic drugs (1970-2018), biologics (1984-2018), and vaccines (1998-2018); special development and approval programs (Orphan drug [1984-2018], Fast-Track [1988-2018], Priority Review and its predecessors [1984-2018], Accelerated Approval [1992-2018], and Breakthrough Therapy [2012-2018]); expanded access (2010-2017) and Risk Evaluation and Mitigation Strategies (2008-2018); and user fees paid to the FDA by industry (1993-2018). Findings: From 1983 to 2018, legislation and regulatory initiatives have substantially changed drug approval at the FDA. The mean annual number of new drug approvals, including biologics, was 34 from 1990-1999, 25 from 2000-2009, and 41 from 2010-2018. New biologic product approvals increased from a median of 2.5 from 1990-1999, to 5 from 2000-2013, to 12 from 2014-2018. The median annual number of generic drugs approved was 136 from 1970 to the enactment of the Hatch-Waxman Act in 1984; 284 from 1985 to the enactment of the Generic Drug User Fee Act in 2012; and 588 from 2013-2018. Prescription drug user fee funding expanded from new drugs and biologics in 1992 to generic and biosimilar drugs in 2012. The amount of Prescription Drug User Fee Act fees collected from industry increased from an annual mean of $66 million in 1993-1997 to $820 million in 2013-2017, and in 2018, user fees accounted for approximately 80% of the salaries of review personnel responsible for the approval of new drugs. The proportion of drugs approved with an Orphan Drug Act designation increased from 18% (55/304) in 1984-1995, to 22% (82/379) in 1996-2007, to 41% (154/380) in 2008-2018. Use of Accelerated Approval, Fast-Track, and Priority Review for new drugs has increased over time, with 81% (48/59) of new drugs benefiting from at least 1 such expedited program in 2018. The proportion of new approvals supported by at least 2 pivotal trials decreased from 80.6% in 1995-1997 to 52.8% in 2015-2017, based on 124 and 106 approvals, respectively, while the median number of patients studied did not change significantly (774 vs 816). FDA drug review times declined from more than 3 years in 1983 to less than 1 year in 2017, but total time from the authorization of clinical testing to approval has remained at approximately 8 years over that period. Conclusions and Relevance: Over the last 4 decades, the approval and regulation processes for pharmaceutical agents have evolved and increased in complexity as special programs have been added and as the use of surrogate measures has been encouraged. The FDA funding needed to implement and manage these programs has been addressed by expanding industry-paid user fees. The FDA has increasingly accepted less data and more surrogate measures, and has shortened its review times.


Assuntos
Aprovação de Drogas/legislação & jurisprudência , Regulamentação Governamental , Legislação de Medicamentos/tendências , Preparações Farmacêuticas/normas , United States Food and Drug Administration , Aprovação de Drogas/economia , Aprovação de Drogas/estatística & dados numéricos , História do Século XX , Legislação de Medicamentos/história , Estados Unidos
14.
J Natl Compr Canc Netw ; 18(1): 36-43, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31910385

RESUMO

BACKGROUND: Many new targeted cancer drugs have received FDA approval based on durable responses in nonrandomized controlled trials (non-RCTs). The goal of this study was to evaluate whether the response rates (RRs) and durations of response (DoRs) of targeted cancer drugs observed in non-RCTs are consistent when these drugs are tested in RCTs. METHODS: We used the FDA's Table of Pharmacogenomic Biomarkers in Drug Labeling to identify cancer drugs that were approved based on changes in biomarker endpoints through December 2017. We then identified the non-RCTs and RCTs for these drugs for the given indications and extracted the RRs and DoRs. We compared the RRs and median DoR in non-RCTs versus RCTs using the ratio of RRs and the ratio of DoRs, defined as the RRs (or DoRs) in non-RCTs divided by the RRs (or DoRs) in RCTs. The ratio of RRs or DoRs was pooled across the trial pairs using random-effects meta-analysis. RESULTS: Of the 21 drug-indication pairs selected, both non-RCTs and RCTs were available for 19. The RRs and DoRs in non-RCTs were greater than those in RCTs in 63% and 87% of cases, respectively. The pooled ratio of RRs was 1.06 (95% CI, 0.95-1.20), and the pooled ratio of DoRs was 1.17 (95% CI, 1.03-1.33). RRs and DoRs derived from non-RCTs were also poor surrogates for overall survival derived from RCTs. CONCLUSIONS: The RRs were not different between non-RCTs and RCTs of cancer drugs approved based on changes to a biomarker, but the DoRs in non-RCTs were significantly higher than in RCTs. Caution must be exercised when approving or prescribing targeted drugs based on data on durable responses derived from non-RCTs, because the responses could be overestimates and poor predictors of survival benefit.

15.
J Gen Intern Med ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31808127

RESUMO

This paper published with several formatting errors. They have been corrected and the paper has re-published.

17.
Mayo Clin Proc ; 94(12): 2437-2443, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31685265

RESUMO

OBJECTIVE: To evaluate trends in the clinical development of new pain and reformulated pain medications given the ongoing opioid crisis and the public health burden of inadequately controlled pain. METHODS: We conducted a retrospective cohort study of new drugs starting clinical testing between January 1, 2000, and December 31, 2015. We searched two comprehensive commercial databases of global research and development activity. The primary outcomes were trends in new and reformulated pain drugs starting clinical testing, proportion of new pain drugs targeting a novel biological pathway, and rates and reasons for discontinuation of development. RESULTS: The proportion of new pain drugs entering phase 1 testing (relative to all new drug trials) declined from 2.5% between 2000 and 2002 to 1.7% between 2013 and 2015. No significant changes in the proportion of new pain drugs entering phase 2 or phase 3 trials were observed. Most new pain drugs failed to reach late-stage clinical development, with 52% of pain drugs successfully advancing from phase 1 to phase 2 and 11% advancing from phase 2 to phase 3 trials. The number of reformulated products starting clinical testing increased over the study period and was greater than that for new analgesics in 2012 and every year thereafter. CONCLUSION: Pain drug development activity has largely shifted from new therapeutics to reformulated ones. New policies, such as increased funding for basic pain research, may help address the urgent need for new therapies for pain.


Assuntos
Analgésicos Opioides/uso terapêutico , Desenvolvimento de Medicamentos , Transtornos Relacionados ao Uso de Opioides/epidemiologia , Dor/tratamento farmacológico , Humanos , Dor/diagnóstico , Dor/epidemiologia , Estudos Retrospectivos
18.
Circ Cardiovasc Qual Outcomes ; 12(11): e006073, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31707825

RESUMO

BACKGROUND: Recent court decisions have thrown into question the Food and Drug Administration's rules limiting manufacturer promotion of prescription drugs for unapproved uses. We assessed how providing pro forma disclosures or more descriptive evidence context about the data supporting an off-label claim affected physicians' beliefs about drug efficacy. METHODS AND RESULTS: In online and mailed surveys, we randomized national samples of board-certified, clinically active cardiologists, internists, and endocrinologists to receive 1 of 3 information scenarios about a hypothetical drug derived verbatim from excerpts on the website for Vascepa, a prescription fish oil for which Food and Drug Administration specially permitted off-label promotion after a manufacturer lawsuit. The scenarios presented information about the approved on-label indication (severe hypertriglyceridemia), off-label claim + pro forma disclaimers (suggestive but not conclusive evidence for use as an add-on to a statin for patients reaching low-density lipoprotein goal but with persistent moderate hypertriglyceridemia), and off-label claim + evidence context (eg, reports on 3 trials failing to demonstrate cardiovascular benefit of other triglyceride-lowering drugs for such patients). Among 686 respondents (48% response rate), 29% reported receiving off-label information about Vascepa (ie, use as an add-on to a statin) from the manufacturer, and 16% had prescribed it off-label for this purpose. Off-label prescribing was 5 times higher among physicians who received such off-label information (38% versus 7%, P<0.001). For the hypothetical drug, the proportion of physicians endorsing the unproven claim that the drug reduced cardiovascular risk was similar among those randomized to the on-label and off-label claim + pro forma disclaimers scenarios (35% versus 37% [95% CI, -6% to 11%]), but substantially lower among those randomized to the off-label claim + evidence context scenario (21% [95% CI, -24% to 7%]). CONCLUSIONS: Physicians who received company information about the unapproved use of Vascepa were more likely to report prescribing it off-label. Supplementing off-label claims with evidence context improved the prescribers' knowledge and reduced enthusiasm for the unproven, off-label indication of reducing cardiovascular risk.

19.
JAMA Intern Med ; 2019 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-31710344

RESUMO

Importance: Regulatory and scientific guidelines stipulate that indirect, surrogate measures of patient benefit, such as a change in microbial culture status, should be used as primary end points only in pivotal trials of chronic conditions that are serious or life threatening and when the experimental therapy is expected to offer substantial benefit compared with available therapy. However, many recent US Food and Drug Administration (FDA) anti-infective drug approvals for acute and/or non-life-threatening diseases have been based on pivotal trials using surrogate measures as primary end points rather than clinical outcomes, such as symptom resolution or survival. Objectives: To review FDA recommendations for primary end points in pivotal trials of new anti-infective drugs and assess the concordance of those recommendations with the regulatory and scientific conditions for the appropriate use of surrogate measures as primary trial outcomes. Evidence Review: All guidance documents for antimicrobial drug development hosted on the FDA website were searched in November 2017; the search was updated in June 2018. For each document, 2 reviewers independently extracted data on the recommended primary end points for a pivotal or phase 3 trial. Findings: Twenty-two FDA guidance documents met the inclusion criteria, which included recommendations for primary end points in pivotal clinical trials in 27 infectious disease indications. Twenty-one of 27 indications recommended surrogate outcomes as either the sole primary end point or as components of composite end points. None of the recommendations for the use of surrogate measures matched the regulatory and scientific conditions favoring indirect outcomes in place of clinical outcomes. Conclusions and Relevance: The FDA guidance documents for developing new anti-infective agents frequently recommend indirect measures of patient benefit, rather than direct measures of patient benefit, as sole primary end points or components of primary end points. Existing guidance documents should be updated and revised to recommend appropriate clinical outcomes consistent with general scientific and regulatory parameters.

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