Fragility of randomized trials supporting cancer drug approvals stratified by approval pathway and review designations.

BACKGROUND: It has been suggested that the results from fragile trials are less likely to translate into benefit in routine clinical practice. METHODS: We searched the Food and Drug Administration (FDA) archives to identify drug approvals for solid organ malignancies between 2010 and 2019. We calculated the Fragility Index (FI) supporting each approval, using methods to account for time-to-event. We compared FI and trial and approval characteristics using Mann-Whitney U and Kruskal-Wallis test. Using logistic regression, we examined study characteristics associated with withdrawal of consent or lost to follow-up (WCLFU) exceeding the calculated FI. RESULTS: The median FI among 125 included studies was 23 (range 1-322). The FI was ≤10 in 35 studies (28%), 11-20 in 21 (17%), and >20 in 69 (55%). The median FI/Nexp was 7.7% (range 0.1-51.7%). The median FI was significantly lower among approvals processed through the accelerated vs regular pathway (5.5 vs 25, p = 0.001), but there was no difference in median FI/Nexp. The WCLFU exceeded FI in 42% of studies. Overall survival endpoints were more likely to have a WCLFU exceeding FI (OR 3.16, p = 0.003). WCLFU exceeding FI was also associated with a lesser magnitude of effect (median HR 0.69 vs 0.55, p < 0.001). In a sensitivity analysis including only studies with 1:1 randomization, 51% of studies had WCLFU >FI. CONCLUSION: The median FI among all trials was 23, and WCLFU exceeded FI in 42%. Comparative trials in solid tumors supporting approval through the accelerated pathway are more fragile compared to trials approved through the regular pathway, an observation likely explained by a lower sample size in the experimental arm.

Evaluation of length and complexity of written consent forms in English and Hebrew for participation in clinical trials authorized in one medical institution in Israel: A descriptive study.

Informed consent forms (ICFs) in clinical trials are the only objective testimony whether the information provided to participants is comprehensive and presented in an accessible language. We evaluated the length of Hebrew ICFs and their English translations and evaluated the readability of the latter. In fifteen clinical trials (5 with pharmacogentic sub-study), the median number (IQR) of pages and words were: English clinical ICFs - 16 pages (13,18) and 7360 words (6959,8289); Hebrew clinical ICFs - 12 pages (10,14), 5807 words (5258,6403); English pharmacogenetics ICFs - 7 pages (4,11), 2930 words (2234,5100); Hebrew pharmacogenetics ICFs - 5 pages (4,8.5), 2273 words (1663,3889); the two English ICFs combined - 23 pages (18;29.5), 10,820 words (9515,15,600); and the two Hebrew ICFs combined - 19 pages (16,23), 8258 words (7340,10,515). Differences between the Hebrew clinical trial ICFs and their English translations were significant (p < 0.001). Median (IQR) Flesch Reading Ease scores for the clinical and the pharmacogenetics ICFs were 48.4 (42.7, 49.9) and 42.2 (41.7,42.65), respectively. Thirteen studies were multinational. Twelve were conducted simultaneously in the United States, where an assessment of readability scores is customary. In conclusion, the consent forms evaluated in this study were long, and readability scores were low.

Factors associated with organ donation by trauma patients in Nova Scotia.

BACKGROUND: Trauma patients represent a significant pool of potential organ donors (PODs), and previous research suggests that this population is underutilized for organ donation (OD). Our objective was to assess factors associated with OD in the trauma population. METHODS: We retrospectively analyzed OD in Nova Scotia over a 7-year period (2009-2016) using data from the Nova Scotia Trauma Registry and Nova Scotia Legacy of Life Donor Registry. All trauma patients who died in the hospital were included. Multiple logistic regression was used to assess factors associated with donation. We also evaluated characteristics, donation types, and reasons for nondonation among trauma PODs. RESULTS: There were 689 trauma-related deaths in all hospitals in NS during the study period, of which 39.8% (274 of 689) met the Nova Scotia Trauma Registry definition of a POD. Data on OD were available for 108 of these patients who were referred to the Legacy of Life Program. The conversion rate was 84%. Compared with nondonors, organ donors were significantly younger, had a higher Abbreviated Injury Scale head score and a lower scene Glasgow Coma Scale score, were more likely to suffer ischemia from drowning or asphyxia and to require air transport, and were less likely to have comorbidities. Regression analysis showed that donation was associated with younger age (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.95-0.99) and lower Glasgow Coma Scale score at the scene (OR, 0.76; 95% CI, 0.66-0.88). Odds of donation were increased with air transport compared with land ambulance (OR, 8.27; 95% CI, 2.07-33.08) and injury within Halifax Regional Municipality compared with injury outside Halifax Regional Municipality (OR, 4.64; 95% CI, 1.42-15.10). Among the 60 referred PODs who did not donate, family refusal of consent was the most common reason (28 [46.7%] of 60). CONCLUSION: Younger age, greater severity of injury, and shorter time to tertiary care were associated with OD in trauma patients. LEVEL OF EVIDENCE: Prognostic and Epidemiological, Level III.

Variability in Informed Consent Practices for Non-Emergent Procedures in Pediatric Emergency Departments.

Although informed consent is a cornerstone of medical ethics, it is unclear if the practice for obtaining informed consent is consistent among pediatric emergency departments. This study's goal is to describe the current practice for written informed consent in academic pediatric emergency departments for non-emergent procedures. A questionnaire distributed to pediatric emergency medicine fellowship directors queried whether written informed consent was standard of care for 15 procedures and assessed departmental consent policies and use of "blanket" consent-to-treat forms. Response rate was 80% (n = 64). Institutions obtained written consent for a mean of 4.4 procedures. Written informed consent was most commonly obtained for procedural sedation (82.5%), blood transfusion (72.9%), and lumbar puncture (66.5%). Twenty-one institutions (32.8%) had policies specifying procedures requiring written consent. Thirty-five institutions (54.7%) used "blanket" consent-to-treat forms. Our results suggest that there is variability in the use of written informed consent for non-emergent procedures among academic pediatric emergency departments.

Opioid prescription and postoperative outcomes in pediatric patients.

OBJECTIVES/HYPOTHESIS: To determine if the amount of opioid prescribed and postoperative outcomes after adenotonsillectomy changed following implementation of mandated opioid consent forms. STUDY DESIGN: Retrospective cohort study. METHODS: Patients undergoing adenotonsillectomy 6 months before and after implementation of mandated opioid consent forms at a tertiary-care pediatric hospital were studied. Demographics, operative data, weight-based opioid dosage, and postoperative outcome measures, including nursing calls, emergency department (ED) visits, hospital readmission, and bleed rates, were collected and analyzed. RESULTS: Of 300 patients, opioid prescription was provided for 211 patients (70.3%), 112 preconsent (74.7%) and 99 postconsent (66.0%). Mean (standard deviation) total opioid prescribed (milligrams/kilogram) was significantly higher preconsent 4.8 (5.6) than postconsent 3.2 (4.7), (P = .003). There were no differences between number of nursing calls (P = .134) or ED visits (P = .083). Interestingly, preconsent patients had more hospital readmission for pain/dehydration (odds ratio OR: 368, P = .016) and bleeding concerns (OR: 244, P = .003). CONCLUSIONS: A mandated consent form prior to opioid prescription was associated with decreased overall opioid prescription without resultant increase in postoperative complications in pediatric patients. These data provide support for minimizing opioid prescription on a systems-based level. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:1477-1481, 2019.

Current use of procedure specific consent forms for laparoscopic cholecystectomy.

Introduction Procedure specific consent forms (PSCFs) have been shown to improve consenting practice for a standardised list of complications. The aim of this study was to assess the current usage and quality of PSCFs in the National Health Service (NHS) for cholecystectomy, specifically comparing the listed complications with those mentioned on the NHS website. Methods A freedom of information request was sent to all NHS trusts asking whether they perform laparoscopic cholecystectomy and whether they have a PSCF for this. A copy of the PSCF was also requested. Complications stated on these forms were compared with those on the NHS Choices website. Results Overall, 162 (88%) of the 185 trusts responded, with 121 of these performing cholecystectomies. Among these, 20 (17%) currently use PSCFs; all provided a copy. Five (25%) of the PSCFs contained all eight risks mentioned on the NHS website. The number of risks listed varied from 4 to 18 per form. Only bile duct injury was listed on every PSCF. The least frequently mentioned complication (45% of forms) was the risk from general anaesthetic. Conclusions This study suggests that too few trusts are using PSCFs and that those PSCFs that are in use contain too little detail on the risks of cholecystectomy. The listed risks and incidences on each PSCF were highly variable. More trusts should begin to use PSCFs during the informed consent process and each PSCF should include a nationally standardised list of potential complications to act as a prompt for discussion (and documentation) of risk.

Improving consent in patients undergoing surgery for fractured neck of femur.

Background Neck of femur fractures and their subsequent operative fixation are associated with high rates of perioperative morbidity and mortality. Consenting in this setting is suboptimal with the Montgomery court ruling changing the perspective of consent. This quality improvement project assessed the adequacy of consenting against British Orthopaedic Association-endorsed guidance and implemented a series of changes to improve the documentation of risks associated with surgery for fractured neck of femur. Methods Seventy consecutive patients who underwent any operative fixation of a neck of femur fracture were included over a 6-month period at a single centre. Patients unable to consent or without electronic notes were excluded. Consent forms were analysed and the documented potential risks or complications associated with surgery were compared to British Orthopaedic Association-endorsed guidance. A series of changes (using the plan, do study, act (PDSA) approach) was implemented to improve the adequacy of consent. Results Documentation of four out of 12 potential risks or complications was recorded in <50% of cases for patients with intracapsular fractures (n=35), and documentation of seven out of 12 potential risks or complications was recorded in <50% of cases for patients with extracapsular fractures (n=35). Re-audit following raising awareness and attaching consent guidance showed 100% documentation of potential risks or complications in patients with intracapsular and extracapsular fractures (n=70). A neck of femur fracture-specific consent form has been implemented which will hopefully lead to sustained improvement. Conclusions Consenting patients with fractured neck of femur for surgery in the authors' unit was suboptimal when compared to British Orthopaedic Association-endorsed consent guidance. This project has shown that ensuring such guidance is readily available has improved the adequacy of consent. The authors hope that introduction of a neck of femur fracture-specific consent form within their unit will lead to sustained adequate documentation of risks associated with surgery.

Videoconferenced Telebehavioral Health Referral Process Adherence.

Background: In 2015, the Army mandated 100% digital storage of telehealth consent forms (DA4700) in the Health Artifact and Image Management Solution (HAIMS) system, and a telebehavioral health (TBH) hub clinic set an aim to accomplish this by improving adherence to referral procedures essential to expanding patient access to videoconferenced (VC) behavioral health care. Methods: The Knowledge-to-Action (KTA) planned action framework underpinned development of a two-phase, PDSA (Plan-Do-Study-Act) quality improvement project to increase the rates of TBH new intake consent form completeness and upload adherence. First, a provider education initiative addressed form uploads. Second, TBH consultants prepared (signed and sent) intake forms to referring sites for their patients to finalize during the initial VC encounter. A chart review of consecutive new intake encounters compared data extracted from CY2015 Q1 baseline records (n = 65) with data from CY2016 Q1 improvement period records (n = 40). A total of 352 forms were reviewed. Results: Referrals (N = 118) that resulted in kept new VC TBH intake visits (n = 105), originated from three military behavioral health clinic referral sites. In CY2016 Q1, all DA4700 consent forms were uploaded to HAIMS. Telehealth treatment and medication consent form upload adherence increased from 94% and 68%, respectively, to 100% (p > 0.05). Form completeness increased from 36% to 95% (p < 0.001), and multiple linear regression analysis predicted an average 59% increase across the three referral sites (sr2 = 0.54). Conclusion: Consultant preparation of telehealth new intake consent forms effectively improved form completeness and increased adherence to new intake referral processes essential to this hub clinic expanding patient access to TBH care.

Pre-made consent for elective inguinal hernia repair: the need for standardisation-a survey of all UK NHS Trusts.

PURPOSE: Elective inguinal hernia repair (IHR) is one of the most commonly performed operations in the UK. As with all procedures, informed consent is essential. Pre-made consent forms have been suggested to improve consenting practice. This study aimed to assess the usage and quality of pre-made hernia-specific consent forms (PCF) in the UK. METHODS: A freedom of information request was sent to all UK NHS Trusts asking: (1) does the trust perform IHRs; (2) do they have a PCF; and (3) to send a copy. Complications lists on received forms were reviewed and compared to those listed on the British Hernia Society (BHS) "patient information" webpage. RESULTS: 157/185 Trusts (85%) responded. 117/157 (75%) perform IHRs; 16/117 (14%) use PCFs. The number of reported risks was variable (range 4-18), as was the content of each form (28 different risks were listed). Quoted percentage risks were inconsistent (e.g. recurrence range < 1-5%). The frequency of each BHS-quoted risk was (open/laparoscopic): Bleeding 62/75%; infection 85/92%; seroma 31/42%; damage to testicular blood supply 69/75%; damage to abdominal contents NA/25%; haematoma 62/67%; venous thromboembolism 54/50%; recurrence 85/83%; chronic pain 77/58%; mesh infection 23/8%. Zero forms contained all BHS-quoted risks. CONCLUSIONS: Whilst the consent form only provides documentation of the consent process, this study suggests that PCFs do not improve the quality of consent as both the type and likelihood of quoted complications were highly variable between Trusts. As follow-up for elective procedures is rare, it is unlikely that this variability reflects actual measured outcomes.

Improving the Consent Process in Foot and Ankle Surgery With the Use of Personalized Patient Literature.

A patient-specific letter was introduced to the consent process to observe the effect, if any, on information recall and satisfaction for patients undergoing elective foot and ankle surgery. The patients attending the clinic were written a personalized letter-this was a simple personalized letter that outlined their treatment options, the proposed management plan, likely treatment course, and the benefits, risks, and likely period required for recovery. The personalized letter system was compared with the 2 existing methods of consent process: signing for consent at their outpatient encounter at which they were scheduled for surgery and a separate consent clinic without the personalized letter. A total of 111 patients (87 females, 24 males) undergoing elective foot and ankle surgery were assessed on the day of surgery for recall of the procedure, risks, postoperative course, and satisfaction with the consent process. Patients receiving a personalized letter recalled more than those who had attended a routine preoperative consent clinic visit and significantly more than those who had provided consent at their last clinic visit. Patient satisfaction with the consent process was also greater in the personalized group. Our results suggest that the consent process is improved using routine preoperative consent clinics and, most notably, with patient-specific information to improve patient recall and satisfaction.

Informed Consent to Study Purpose in Randomized Clinical Trials of Antibiotics, 1991 Through 2011.

Importance: Potential research participants may assume that randomized trials comparing new interventions with older interventions always hypothesize greater efficacy for the new intervention, as in superiority trials. However, antibiotic trials frequently use "noninferiority" hypotheses allowing a degree of inferior efficacy deemed "clinically acceptable" compared with an older effective drug, in exchange for nonefficacy benefits (eg, decreased adverse effects). Considering these different benefit-harm trade-offs, proper informed consent necessitates supplying different information on the purposes of superiority and noninferiority trials. Objective: To determine the degree to which the study purpose is explained to potential participants in randomized clinical trials of antibiotics and the degree to which study protocols justify their selection of noninferiority hypotheses and amount of "clinically acceptable" inferiority. Design and Setting: Cross-sectional analysis of study protocols, statistical analysis plans (SAPs), and informed consent forms (ICFs) from clinical study reports submitted to the European Medicines Agency. The ICFs were read by both methodologists and patient investigators. Main Outcomes and Measures: Protocols and SAPs were used as the reference standard to determine prespecified primary hypothesis and record rationale for selection of noninferiority hypotheses and noninferiority margins. This information was cross-referenced against ICFs to determine whether ICFs explained the study purpose. Results: We obtained trial documents from 78 randomized trials with prespecified efficacy hypotheses (6 superiority, 72 noninferiority) for 17 antibiotics conducted between 1991 and 2011 that enrolled 39 407 patients. Fifty were included in the ICF analysis. All ICFs contained sections describing study purpose; however, none consistently conveyed study hypothesis to both methodologists and patient investigators. Methodologists found that 1 of 50 conveyed a study purpose. Patient investigators found that 11 of 50 conveyed a study purpose, 7 accurately and 4 inaccurately compared with the reference standard. Seventy-one of 72 noninferiority trial protocols or SAPs provided no rationale for selection of noninferiority hypothesis. None provided a clinical rationale for the chosen amount of decreased efficacy. Conclusions and Relevance: Patients were not accurately informed of study purpose, which raises questions regarding the ethics of informed consent in antibiotic trials. Noninferiority and superiority trials entail different benefit-harm trade-offs that must be conveyed for ethical informed consent.

An updated assessment of postpartum sterilization fulfillment after vaginal delivery.

OBJECTIVE: To describe sterilization completion rates after vaginal delivery and indications for unfulfilled procedures. STUDY DESIGN: We used labor and delivery operating room and delivery logs to identify all women over 20years of age with a completed live vaginal birth beyond 24weeks gestation over a 33-month period (March 1, 2012 to November 30, 2014). We reviewed the electronic medical records of all of these patients and identified those who requested a sterilization procedure as indicated in a physician's admission note or antenatal record. RESULTS: We identified 3514 live vaginal births beyond 24weeks gestation during the study period of which 219 requested postpartum sterilization. Sterilization occurred in 114 (52%). The most common reason for unfulfilled procedures was lack of valid federally mandated consent (n=46 [44%]). Fifty-nine percent (27 of 46) of these women had little or no prenatal care. Only one (0.5%) woman had documented completion of consent with the required time elapsed prior to delivery and no consent form available. Of the women with valid consent documentation, the most common indication for an unfulfilled procedure was patient refusal (n=30 [51%]). Body mass index was an independent predictor of an unfulfilled procedure (p<.001) among women with adequate consent. CONCLUSIONS: Inability to complete federally mandated consent is a principal cause of unfulfilled postpartum sterilization and primarily affects women desiring sterilization who lack sufficient prenatal care. Of women who meet consent criteria, the primary reason women eligible for sterilization did not undergo the procedure was due to withdrawing their request. IMPLICATIONS: Because women commonly do not undergo a requested sterilization after vaginal deliveries, antepartum counseling should include alternate contraception choices. Documented consent that fulfills all federally mandated criteria remains the most common barrier to requested sterilization after vaginal delivery; providers and policymakers should work together to help unburden women from this mandate.

Experiencia con la hoja de información de «epilepsia en la infancia» / Experience with the information sheet of «epilepsy in infancy»

Introducción. En la sección de neuropediatría, se trabaja con hojas de información que pretenden explicar de forma rigurosa los problemas y su seguimiento. La de «la epilepsia en la infancia» se entrega cuando existe sospecha o diagnóstico certero de epilepsia. Método. Se analiza, a través de unas encuestas, el grado de satisfacción y las percepciones de los padres o tutores que recibieron dicha hoja. Resultados. 658 pacientes recibieron la hoja de información desde febrero de 2012 hasta diciembre de 2014. La tasa de respuesta es del 56,8%. El 63,10% de los pacientes que recibieron la hoja de información tenían un diagnóstico definitivo de epilepsia. Un 92,7% está satisfecho de haber recibido la hoja. Solo un 0,3% de los pacientes hubiera preferido no recibir la hoja de información. Conclusiones. La mayoría de padres o tutores de los pacientes con sospecha o diagnóstico de epilepsia se mostraron satisfechos por recibir la hoja de información. La hoja de información de «epilepsia en la infancia» mejora la información y la satisfacción percibida y su evaluación para corregir y mejorar, es necesaria en el proceso de mejora que no tiene punto final (AU)

Introduction. In the Pediatric Neurology service, we work with fact sheets that aim to rigorously explain the problems and their follow—up. The «epilepsy in childhood» fact sheet is given when there is suspicion or accurate diagnosis of epilepsy. Methods. The degree of satisfaction and the perceptions of the parents or guardians who received this sheet were analyzed through surveys. Results. 658 patients received the fact sheet from February 2012 to December 2014. The response rate was 56.8%. 63.10% of the patients who received the information sheet had a definitive diagnosis of epilepsy. 92.7% are satisfied to have received the sheet. Only 0.3% of the patients would have preferred not to receive the fact sheet. Conclusion. The majority of parents or guardians of patients with suspected or diagnosed epilepsy were satisfied by receiving the fact sheet. The «epilepsy in childhood» fact sheet improves information and perceived satisfaction, and its evaluation (to correct and improve it) is necessary in the continua] improvement process (AU)

Completion of hand-written surgical consent forms is frequently suboptimal and could be improved by using electronically generated, procedure-specific forms.

INTRODUCTION: Completion of hand-written consent forms for surgical procedures may suffer from missing or inaccurate information, poor legibility and high variability. We audited the completion of hand-written consent forms and trialled a web-based application to generate modifiable, procedure-specific consent forms. METHODS: The investigation comprised two phases at separate UK hospitals. In phase one, the completion of individual responses in hand-written consent forms for a variety of procedures were prospectively audited. Responses were categorised into three domains (patient details, procedure details and patient sign-off) that were considered "failed" if a contained element was not correct and legible. Phase two was confined to a breast surgical unit where hand-written consent forms were assessed as for phase one and interrogated for missing complications by two independent experts. An electronic consent platform was introduced and electronically-produced consent forms assessed. RESULTS: In phase one, 99 hand-written consent forms were assessed and the domain failure rates were: patient details 10%; procedure details 30%; and patient sign-off 27%. Laparoscopic cholecystectomy was the most common procedure (7/99) but there was significant variability in the documentation of complications: 12 in total, a median of 6 and a range of 2-9. In phase two, 44% (27/61) of hand-written forms were missing essential complications. There were no domain failures amongst 29 electronically-produced consent forms and no variability in the documentation of potential complications. CONCLUSION: Completion of hand-written consent forms suffers from wide variation and is frequently suboptimal. Electronically-produced, procedure-specific consent forms can improve the quality and consistency of consent documentation.

Do Chinese Researchers Conduct Ethical Research and Use Ethics Committee Review in Clinical Trials of Anti-Dementia Drugs? An Analysis of Biomedical Publications Originating from China.

BACKGROUND: Medical research using human participants must conform to the basic ethical principles found in the Declaration of Helsinki (DoH) of the World Medical Association. OBJECTIVE: The purpose of this review was to assess whether journals in China have improved in regard to the fulfillment of ethical disclosure procedures for clinical trials of anti-dementia drugs. METHODS: Four medical databases were searched for articles reporting clinical trials of oral anti-dementia drugs published in China in 2003, 2009, and 2014. The frequencies of reporting of informed consent from participants (ICP), approval of a regional ethical committee (REC), reference to DoH, and study registration were estimated respectively. Statistical analyses were conducted with SPSS v21 software. RESULTS: Among those randomized controlled trials published in 2003, 2009, and 2014, disclosure of REC approval was present for 2.67%, 1.15%, and 6.84%; statements of ICP were included in 9.33%, 7.76%, and 17.34%; reference to DoH was found for 4.00%, 1.44%, and 7.45%; and study registration reporting was included in 2.67%, 2.59%, and 9.28%, respectively. Improvements to reporting rates between 2009 and 2014 were seen, with more than twice as many trials reporting REC approval, ICP, reference to DoH, and study registration compared with 2009. CONCLUSION: Compared with 2003 and 2009, reporting rates for REC approval, ICP, reference to DoH, and study registration for clinical trials of anti-dementia drugs were enhanced in 2014 in the major medical journals of China. However, biomedical publications without definite statements of ethical considerations remain common, and this continues to be seen in Chinese journals. It is imperative that measures are taken to reinforce the ethical protection in clinical trials in China.