Evaluating the Revised National Institutes of Health Clinical Trial Definition Impact on Recruitment Progress.

Background: The National Institutes of Health (NIH) announced a revised, expanded definition of "clinical trial" in 2014 to improve trial identification and administrative compliance. Some stakeholders voiced concerns that the policy added administrative burden potentially slowing research progress. Methods: This quasi-experimental study examined the difference-in-differences impact of the new NIH clinical trial definition policy on participant recruitment progress in grants funded by the National Institute of Mental Health (NIMH). Results: 132 funded clinical trial grants were identified. While more grants were identified as clinical trials under the revised definition, the difference-in-differences in recruitment progress before and after the policy change was not statistically significant. Conclusions: The revised NIH clinical trial definition had no clear effect on recruitment progress in newly-identified NIMH-funded clinical trials as compared to traditionally-identified clinical trials. Concerns that administrative delays and burden could impact study progress may be alleviated by these initial results.

Potential benefits and burdens of National Institutes of Health and National Institute of Mental Health clinical trial policies.

The National Institutes of Health (NIH) and the National Institute of Mental Health (NIMH) have implemented numerous clinical trial policies in recent years. These policies have well-intended goals but concerns of undue burden have been raised by professional societies. This study identified the new and revised NIH and NIMH clinical trial policies from 2005 to 2019 and summarized the publicly-identified potential benefits and burdens of those policies. Five new/revised NIH-wide and four NIMH-only clinical trial policies were identified. Potential benefits were improved identification, review, conduct, and reporting of publicly-funded clinical trials. Potential burdens were loss of researcher time, potential loss of future research funding opportunities for basic behavioral researchers, and researcher confusion resulting from perceived definition overlap between clinical trials and basic science. Future clinical trial policy development may benefit from early engagement of researchers as stakeholders. Policymakers may benefit from publicly incorporating benefit/burden analyses and outcome evaluations into future policy development.

National Institute of Mental Health Recruitment Monitoring Policy and Clinical Trial Impact.

BACKGROUND/AIMS: The National Institutes of Health (NIH) implemented a recruitment milestone and progress reporting policy in fiscal year 2019. While too recent to evaluate, the National Institute of Mental Health (NIMH) previously implemented a similar policy in fiscal year 2006 which may forecast likely effects of the NIH-wide policy. METHODS: An observational, single-group, pre/post evaluation of the association between the NIMH policy and the Relative Citation Ratio was conducted for non-fellowship, competing clinical trial grants funded from fiscal years 2004-2007. RESULTS: 124 clinical trial grants were identified. After adjusting for covariates, the clinical trial grants subject to the NIMH recruitment monitoring policy were associated with a statistically significant mean-per-grant citation ratio (citations relative to the field norm) 1.98 times that of the clinical trial grants that were not subject to the policy (p = 0.005; 95% CI: [1.23, 3.20]). The clinical trial grants subject to the policy were also associated with a non-statistically significant 1.58 times maximum-per-grant citation ratio compared to the clinical trial grants not covered by the policy (p = 0.24; 95% CI: [0.73, 3.44]). CONCLUSIONS: The NIMH recruitment monitoring and reporting policy was associated with a statistically significant increase in the mean-per-grant Relative Citation Ratio. NIMH-specific results suggest that the NIH-wide policy might also be positively associated with improved Relative Citation Ratio.

Race and ethnicity reporting for clinical trials in ClinicalTrials.gov and publications.

Inclusion and subsequent reporting of minority participants in clinical trials are critical for ensuring external validity and detecting differences among subgroups, however reports suggest that ongoing gaps persist. ClinicalTrials.gov began requiring the reporting of race/ethnicity information (if collected) during results submission for trials in April 2017. For this study, we downloaded and compared trial race/ethnicity information from ClinicalTrials.gov submitted before (N = 3540) and after (N = 3542) the requirement date. We found that 42.0% of pre-requirement trials compared to 91.4% of post-requirement trials reported race/ethnicity information in ClinicalTrials.gov; 8.6% of post-requirement trials indicated race/ethnicity information was not collected. Use of NIH/U.S. Office of Management and Budget (OMB) classification categories was slightly higher in the post-requirement (77.1%) compared to pre-requirement (72.8%) samples. Additionally, we examined two 10% random samples of post-requirement trials - one with customized race/ethnicity reporting in ClinicalTrials.gov and the other with corresponding results publications available in PubMed. In the first random sample, 95.9% of customized categories included race information and 52.7% included ethnicity information. In the other random sample, 33.1% had a corresponding results publication, of which 62.4% reported race/ethnicity information in the publication. Among trials without published race/ethnicity information, 90.0% reported race/ethnicity information on ClinicalTrials.gov. This analysis demonstrates that the requirement has advanced public availability of information on the inclusion of minorities in research, but that further work remains to systematically ensure collection and complete reporting of race/ethnicity information.

Frequency and Predictors of Analgesic Prescribing in U.S. Nursing Home Residents with Persistent Pain.

OBJECTIVES: To quantify prescription analgesic use of elderly nursing home (NH) residents with persistent noncancer pain and to identify individual and facility traits associated with no treatment. DESIGN: Cross-sectional study. SETTING: Linked Minimum Data Set (MDS) assessments; Online Survey, Certification and Reporting (OSCAR) records; and Medicare Part D claims. PARTICIPANTS: Individuals aged 65 and older with persistent noncancer pain were identified from a cross-section of all long-stay U.S. NH residents with an MDS assessment and Medicare Part D enrollment in 2008, excluding those who were terminally ill, those with Alzheimer's disease, and those with the most-severe cognitive impairment. MEASUREMENTS: Residents with moderate to severe daily pain on consecutive assessments at least 90 days apart constituted the cohort with persistent pain. Part D dispensing for an opioid or nonsteroidal anti-inflammatory drug (NSAID) within 30 days of persistent pain onset was identified. Information on resident and facility characteristics was obtained from MDS and OSCAR records. Associations between resident and facility attributes and pain treatment were estimated using multilevel mixed-effects logistic regression analyses. RESULTS: Of the study sample of 18,526 residents with persistent pain, 3,094 (16.7%) did not receive prescription analgesics, 12,815 (69.2%) received a prescription opioid, 485 (2.6%) received a prescription NSAID, and 2,132 (11.5%) received a prescription opioid and NSAID. After adjusting for potentially confounding covariates, residents who were older (≥95, odds ratio (OR) = 2.06, 95% confidence interval (CI) = 1.70-2.49), more cognitively impaired (moderately severe cognitive impairment, OR = 2.12, 95% CI = 1.71-2.62), or black (OR = 1.20, 95% CI = 1.03-1.39) or Asian (OR = 1.97, 95% CI = 1.22-3.20) were less likely to receive a prescription analgesic. CONCLUSION: Through 2008, pain remained undertreated in NHs, especially in certain subpopulations, including cognitively impaired and older residents. Changes in pain management practice and policies may be necessary to target these vulnerable residents.

Inappropriate Fentanyl Prescribing Among Nursing Home Residents in the United States.

OBJECTIVE: We quantified transdermal fentanyl prescribing in elderly nursing home residents without prior opioid use or persistent pain, and the association of individual and facility traits with opioid-naïve prescribing. DESIGN: Cross-sectional study. SETTING: Linked Minimum Data Set (MDS) assessments; Online Survey, Certification and Reporting (OSCAR) records; and Medicare Part D claims. PARTICIPANTS: From a cross-section of all long-stay US nursing home residents in 2008 with an MDS assessment and Medicare Part D enrollment, we identified individuals (≥65 years old) who initiated transdermal fentanyl, excluding those with Alzheimer disease, severe cognitive impairment, cancer, or receipt of hospice care. MEASUREMENTS: We used Medicare Part D to select beneficiaries initiating transdermal fentanyl in 2008 and determined whether they were "opioid-naïve," defined as no opioid dispensing during the previous 60 days. We obtained resident and facility characteristics from MDS and OSCAR records and defined persistent pain as moderate-to-severe, daily pain on consecutive MDS assessments at least 90 days apart. We estimated associations of patient and facility attributes and opioid-naïve fentanyl initiation using multilevel mixed effects logistic regression modeling. RESULTS: Among 17,052 residents initiating transdermal fentanyl, 6190 (36.3%) were opioid-naïve and 15,659 (91.8%) did not have persistent pain. In the regression analysis with adjustments, residents who were older (ages ≥95 odds ratio [OR] 1.69, 95% confidence interval [CI] 1.46-1.95) or more cognitively impaired (moderate-to-severe cognitive impairment, OR 1.99, 95% CI 1.73-2.29) were more likely to initiate transdermal fentanyl without prior opioid use. CONCLUSION: Most nursing home residents initiating transdermal fentanyl did not have persistent pain and many were opioid-naïve. Changes in prescribing practices may be necessary to ensure Food and Drug Administration warnings are followed, particularly for vulnerable subgroups, such as the cognitively impaired.

Evidence selection for a prescription drug's benefit-harm assessment: challenges and recommendations.

OBJECTIVES: To describe challenges and make recommendations for researchers in how they select evidence to quantitatively assess a prescription drug's benefits and harms. STUDY DESIGN AND SETTING: These challenges and recommendations are based on our recent experience conducting a benefit-harm assessment for the prescription drug roflumilast. We considered the selection of evidence to quantify (1) the drug's treatment effects in patients, (2) the patient population's baseline risks for beneficial and harmful outcomes without treatment, and (3) the patient population's preferences for these beneficial effects and harms. These are fundamental steps for most benefit-harm assessment methods. RESULTS: We identify critical issues in selecting evidence for each of these steps. We justify in particular the need to incorporate (1) clinical trials for the drug's specific treatment effect; (2) observational studies with the most valid, precise, and applicable effect estimates for the baseline risk; and (3) flexible weighting approaches for balancing the drug benefits and harms. CONCLUSION: We identify challenges and make recommendations for selecting evidence at the critical steps in a prescription drug's benefit-harm assessment. Our findings should assist other researchers conducting these assessments for prescription drugs, which could help regulators, medical professionals, and patients make better decisions about prescription drug use.

Use of surrogate outcomes in US FDA drug approvals, 2003-2012: a survey.

OBJECTIVE: To evaluate, across a spectrum of diseases, how often surrogate outcomes are used as a basis for drug approvals by the US Food and Drug Administration (FDA), and whether and how the rationale for using treatment effects on surrogates as predictors of treatment effects on patient-centred outcomes is discussed. STUDY DESIGN AND SETTING: We used the Drugs@FDA website to identify drug approvals produced from 2003 to 2012 by the FDA. We focused on four diseases (chronic obstructive pulmonary disease (COPD), type 1 or 2 diabetes, glaucoma and osteoporosis) for which surrogates are commonly used in trials. We reviewed the drug labels and medical reviews to provide empirical evidence on how surrogate outcomes are handled by the FDA. RESULTS: Of 1043 approvals screened, 58 (6%) were for the four diseases of interest. Most drugs for COPD (7/9, 78%), diabetes (26/26, 100%) and glaucoma (9/9, 100%) were approved based on surrogates while for osteoporosis, most drugs (10/14, 71%) were also approved for patient-centred outcomes (fractures). The rationale for using surrogates was discussed in 11 of the 43 (26%) drug approvals based on surrogates. In these drug approvals, we found drug approvals for diabetes are more likely than the other examined conditions to contain a discussion of trial evidence demonstrating that treatment effects on surrogate outcomes predict treatment effects on patient-centred outcomes. CONCLUSIONS: Our results suggest that the FDA did not use a consistent approach to address surrogates in assessing the benefits and harms of drugs for COPD, type 1 or 2 diabetes, glaucoma and osteoporosis. For evaluating new drugs, patient-centred outcomes should be chosen whenever possible. If the use of surrogate outcomes is necessary, then a consistent approach is important to review the evidence for surrogacy and consider surrogate's usage in the treatment and population under study.

Markers of Impaired Decision Making in Nursing Home Residents: Assessment by Nursing Home Staff in a Population-Based Study.

INTRODUCTION: Many nursing home residents have cognitive impairment that affects their decision making. In order to identify potential markers of impaired decision making, we investigated the association between a range of nursing home resident characteristics and impaired decision making in a population-based sample. METHODS: Participants were 13,013 residents in the 2004 National Nursing Home Survey. We used logistic regression to determine the association between resident characteristics (ie, gender, age, race, mood, recent pain, falls, fractures, or hospitalizations, length of stay, number of activities of daily living (ADL) requiring help, and diagnoses of dementia, anxiety disorders, and depression) and impaired (vs independent) decision making. RESULTS: After controlling for depression and anxiety diagnoses, as well as gender, age, race, and recent hospitalization or pain, characteristics associated with impaired decision making included depressed, sad, or anxious mood ["mild" odds ratio (OR) = 1.39, 95% confidence interval (CI) = 1.23-1.58; "severe" OR = 2.69, 95% CI = 2.27-3.20); diagnosed dementia or living on a dementia hall (OR = 5.07, 95% CI = 4.52-5.67); number of ADL requiring assistance (with 5 ADL, OR = 10.69, 95% CI = 6.82-16.75); length of nursing home stay [101-365 days (OR = 1.60, 95% CI = 1.36-1.89); 366 days-2 years (OR = 1.60, 95% CI = 1.34-1.90); >2 years (OR = 2.25, 95% CI = 1.92-2.63)]; and history of falls or fractures in the last 6 months (OR = 1.19, 95% CI = 1.07-1.32)]. Residents reporting pain in the last week were less likely to have impaired decision making (OR = 0.58, 95% CI = 0.52-0.66). CONCLUSIONS: We found several independent markers of impaired decision making in nursing home residents, including depressed, sad, or anxious mood (independent of depression or anxiety diagnosis); dementia; and greater need for ADL assistance. Some of these factors, in particular mood, are modifiable and addressing them may help improve decision making. These markers should be explored further to help identify residents with impaired decision making.