Highlights of FDA Oncology Approvals in 2023: Bispecific T-cell Engagers, Pediatric Indications, and Inclusive Drug Development.

SUMMARY: Cancer drug development remained robust in 2023. Highlights of U.S. drug approvals this year include new immunotherapies and targeted drug development in adult and pediatric patients as well as patients with rare diseases.

National survey findings on law enforcement agency drug response practices, overdose victim outcomes, and Good Samaritan Laws.

BACKGROUND: The United States continues to experience unprecedented rates of overdose mortality. Addressing the overdose epidemic has been challenging for policy makers given the lack of effectiveness of existing drug control policy measures. More recently, the implementation of harm reduction-based policies such as Good Samaritan Laws has led to increasing scholarly attention aimed at evaluating their effectiveness at reducing the likelihood of criminal justice-related sanctions for individuals following an overdose incident. The results of these studies, however, have been mixed. METHODS: This study utilizes data from a nationally representative survey of law enforcement agencies designed to provide national information on services, policies, practices, operations, and resources of law enforcement drug response around overdoses to assess whether state Good Samaritan Laws reduce the likelihood of overdose victims being cited or being jailed following an overdose incident. RESULTS: In general, findings indicate that although most agencies reported that overdose victims were not incarcerated or cited following an overdose incident, that this did not vary by whether agencies were in a state that had a GSL arrest protection for possession of controlled substances. CONCLUSIONS: GSLs are often written in complex and confusing language that officers and people who use drugs do not fully understand, which may deter their being used for their intended purpose. Although GSLs are well-intentioned, these findings highlight the need for training and education for law enforcement and people who use drugs around the scope of these laws.

The Impact of Improved Treatments on Survival of Adult U.S. Leukemia Patients: 1990-2018.

INTRODUCTION: Molecularly targeted therapies such as tyrosine kinase inhibitors (TKI) are effective treatments for B-cell receptor (BCR)-ABL-bearing leukemias. We evaluated the impact of TKIs on historical chronic myeloid leukemia (CML) mortality trends compared with acute lymphoblastic leukemia (ALL) and chronic lymphoblastic leukemia (CLL). METHODS: Because mortality trends reflect combined effects of leukemia incidence and survival, we also evaluated the contribution of incidence and survival trends to mortality trends by subtypes. We used data from 13 U.S. (SEER) registries (1992-2017) among U.S. adults. We utilized histology codes to identify cases of CML, ALL, and CLL and death certificate data to calculate mortality. We used Joinpoint to characterize incidence (1992-2017) and mortality (1992-2018) trends by subtype and diagnosis year. RESULTS: For CML, mortality rates started declining in 1998 at an average rate of 12% annually. Imatinib was approved by the FDA for treating CML and ALL in 2001, leading to clear benefits for patients with CML. Five-year CML survival increased dramatically over time, especially between 1996 to 2011, 2.3% per year on average. ALL incidence increased 1.5% annually from 1992 to 2017. ALL mortality decreased 0.6% annually during 1992 to 2012 and then stopped declining. CLL incidence fluctuated during 1992 to 2017 while mortality decreased 1.1% annually during 1992 to 2011 and at a faster rate of 3.6% per year from 2011. Five-year survival increased 0.7% per year on average during 1992 to 2016. CONCLUSIONS: Survival benefit from TKIs and other novel therapies for treating leukemia subtypes has been demonstrated in clinical trials. IMPACT: Our study highlights the impact of molecularly targeted therapies at the population level.

Minimal Residual Disease Data in Hematologic Malignancy Drug Applications and Labeling: An FDA Perspective.

Minimal residual disease (MRD) is increasingly used as a prognostic biomarker, a measure of clinical efficacy, and a guide for treatment decisions in various hematologic malignancies. We sought to characterize MRD data in registrational trials in hematologic malignancies submitted to the U.S. Food and Drug Administration (FDA) with the ultimate goal of expanding the utility of MRD data in future drug applications. We descriptively analyzed MRD data collected in registrational trials, including the type of MRD endpoint, assay, disease compartment(s) assessed, and the acceptance of MRD data in the U.S. prescribing information (USPI). Of 196 drug applications submitted between January 2014 and February 2021, 55 (28%) included MRD data. Of the 55 applications, MRD data was proposed by the Applicant for inclusion in the USPI in 41 (75%) applications but was included in only 24 (59%). Despite an increasing number of applications that proposed to include MRD data in the USPI, the acceptance rate decreased over time. Although MRD data have the potential to expedite drug development, our analysis identified challenges and specific areas for improvement, including assay validation, standardization of collection methods to optimize performance, and considerations in trial design and statistical methodology.

Post-overdose follow-up in the community with peer recovery specialists: The Lake Superior Diversion and Substance Use Response Team.

Background: As the overdose epidemic continues to worsen, nonfatal overdose calls for service represent a critical touchpoint for intervention. While most studies have focused on law enforcement led post-overdose follow-up, the current study describes the programmatic characteristics and outcomes of a non-law enforcement post overdose program comprised of peer specialists embedded within a local police department. Methods: We examined information on 341 follow-up responses occurring over a 16-month study period using administrative data. We assessed programmatic characteristics including demographic information on clients, referral source, engagement type, and goal completion. Results: The results indicate that over 60% of client referrals ended in the goal of in-person contact. Of those, about 80% went on to complete an engagement goal with the peer specialist. We found no significant variation in client demographics and referral source or follow-up engagement (in-person or not); however, client referrals from law enforcement first responders, the most common source, are significantly less likely to result in an in-person contact, though, if contact is made, similarly likely to complete an engagement goal. Conclusions: Post overdose response programs that do not involve law enforcement are exceedingly rare. Given that some research has shown that police involvement in post overdose response can have unexpected, associated harms, it is important to assess the effectiveness of post overdose programs that do not involve the police. Findings here suggest that this type of program is successful at locating and engaging community members into recovery support services who have experienced an overdose.

The statistical fragility of the distal fibula fracture literature: A systematic review of randomized controlled trials.

BACKGROUND: The purpose of this study was to apply both the fragility index (FI) and fragility quotient (FQ) to evaluate the degree of statistical fragility in the distal fibular fracture (DFF) literature. We hypothesized that the dichotomous outcomes within the DFF literature are statistically fragile. METHODS: We performed a PubMed search for distal fibular fractures clinical trials from 2000 to 2022 reporting dichotomous outcomes. The FI of each outcome was calculated through the reversal of a single outcome event until significance was reversed. The FQ was calculated by dividing each fragility index by study sample size. The interquartile range (IQR) was also calculated for the FI and FQ. RESULTS: Of the 1158 articles screened, 23 met the search criteria, with six RCTs included for analysis. Forty-five outcome events with 5 significant (p < 0.05) outcomes and 40 nonsignificant (p ≥ 0.05) outcomes were identified. The overall FI and FQ was 5 (IQR 4-6) and 0.089 (IQR 0.061-0.107), respectively. CONCLUSIONS: The randomized controlled trials in the peer-reviewed distal fibular fracture literature may not be as robust as previously thought, as incorporating statistical analyses solely on a P value threshold is misleading. Standardized reporting of the P value, FI and FQ can help the clinician reliably draw conclusions based on the fragility of outcome measures.

A national survey of law enforcement post-overdose response efforts.

Background: Law enforcement agencies in the US have provided naloxone to officers and developed initiatives to follow-up after a non-fatal overdose. However, the prevalence and characteristics of these efforts have yet to be documented in research literature.Objectives: We sought to understand the national prevalence of naloxone provision among law enforcement and examine the implementation of post-overdose follow-up.Methods: We administered a survey on drug overdose response initiatives using a multimodal approach (online and mail) to a nationally representative sample of law enforcement agencies (N = 2,009; 50.1% response rate) drawn from the National Directory of Law Enforcement Administrators database. We further examine a subsample of agencies (N = 1,514) that equipped officers with naloxone who were also asked about post-overdose follow-up.Results: We found 81.7% of agencies reported officers were equipped with naloxone; among these, approximately one-third (30.3%) reported follow-up after an overdose. More than half (56.8%) of agencies indicated partnership in follow-up with emergency medical services as the most common partner (68.8%). There were 21.4% of agencies with a Quick Response Team, a popular national post-overdose model, and were more likely to indicate partnership with a substance use disorder treatment provider than when agencies were asked generally about partners in follow-up (74.5% and 26.2% respectively).Conclusion: Many law enforcement agencies across the US have equipped officers with naloxone, and about one-third of those are conducting follow-up to non-fatal overdose events. Post-overdose follow-up models and practices vary in ways that can influence treatment engagement and minimize harms against persons who use drugs.

Neuronal cilia in energy homeostasis.

A subset of genetic disorders termed ciliopathies are associated with obesity. The mechanisms behind cilia dysfunction and altered energy homeostasis in these syndromes are complex and likely involve deficits in both development and adult homeostasis. Interestingly, several cilia-associated gene mutations also lead to morbid obesity. While cilia have critical and diverse functions in energy homeostasis, including their roles in centrally mediated food intake and peripheral tissues, many questions remain. Here, we briefly discuss syndromic ciliopathies and monogenic cilia signaling mutations associated with obesity. We then focus on potential ways neuronal cilia regulate energy homeostasis. We discuss the literature around cilia and leptin-melanocortin signaling and changes in ciliary G protein-coupled receptor (GPCR) signaling. We also discuss the different brain regions where cilia are implicated in energy homeostasis and the potential for cilia dysfunction in neural development to contribute to obesity. We close with a short discussion on the challenges and opportunities associated with studies looking at neuronal cilia and energy homeostasis. This review highlights how neuronal cilia-mediated signaling is critical for proper energy homeostasis.

Mobilizing the clinical trial ecosystem to drive adoption of master protocols.

Master protocol studies typically use an overarching protocol to answer several questions by guiding a variety of sub-studies. These sub-studies can incorporate multiple diseases, therapies, or both. Although this innovative approach offers many benefits, including the ability to deliver clinical research that is more patient-centric and efficient, several common barriers curtail widespread adoption. The Clinical Trials Transformation Initiative (CTTI) convened industry representatives, regulatory agencies, patient groups, and academic institutions to identify emerging best practices and develop resources designed to help sponsors and other stakeholders overcome these challenges. We first identify some broad changes needed in the clinical trials ecosystem to facilitate mainstream adoption of master protocol studies, and we subsequently summarize CTTI's resources designed to support this effort.

FDA approval summary: Crizotinib for pediatric and young adult patients with relapsed or refractory systemic anaplastic large cell lymphoma.

In January 2021, the U.S. Food and Drug Administration (FDA) approved crizotinib for pediatric patients 1 year and older and young adults with relapsed or refractory systemic anaplastic large cell lymphoma (sALCL). This is the first approval for pediatric sALCL. Approval was based on a single-arm trial of crizotinib monotherapy that included 26 patients, aged 1-20 years, with previously treated sALCL. Efficacy was based on centrally assessed objective response rate (88%) and duration of response. Herein, we highlight unique aspects of the regulatory review, including extension of the indication to young adults, postmarketing safety, and dose optimization strategies.

Association between law enforcement seizures of illicit drugs and drug overdose deaths involving cocaine and methamphetamine, Ohio, 2014-2019.

BACKGROUND: The United States continues to experience a crisis of mounting opioid overdose deaths involving cocaine and methamphetamine (hereafter illicit stimulants). Law enforcement drug seizure data present a unique opportunity to examine the association between illicit-stimulant-involved overdose deaths (ISODs) and the illicit drug supply. Our objective is to better understand correlations between illicit drug market trends and increases in ISODs in Ohio in 2014-2019. METHODS: This observational study analyzes the universe of ISODs and drug seizures in Ohio from 2014 to 2019. We use graphs and descriptive statistics to characterize trends over time and estimate a time series model of their association. ISODs were summed to yield monthly statewide counts of seizures containing methamphetamine, cocaine, illicitly manufactured fentanyl (IMF), and other non-IMF opioids (e.g., heroin). All rates were calculated per 100,000 persons. RESULTS: Roughly 80% of ISODs in Ohio from 2014 to 2019 involved an opioid, with IMF co-occurring in 90% of ISODs by 2019. Methamphetamine and cocaine seizures containing IMF were associated with 0.439 (p < .01) and 0.457 (p < .01) additional deaths per 100,000 persons per month, respectively. IMF seizures not containing cocaine nor methamphetamine were also associated with additional ISODs (0.119, p < .01) and seizures of illicit stimulants not containing IMF were not associated with ISODs. CONCLUSIONS: The number of ISODs was extremely high when IMF was co-involved and relatively low without IMF involvement. By demonstrating how supply-side trends correspond with ISOD rates, the current study bolsters the analytical utility of law enforcement seizures and complements growing literature in the field.

The Association of Traumatic Brain Injury, post-traumatic stress disorder, and criminal recidivism.

BACKGROUND: The purpose of the study was to assess the prevalence of traumatic brain injury (TBI) and post-traumatic stress disorder (PTSD) and to determine whether TBI or PTSD is associated with an increase in general or violent criminal recidivism among a representative sample of released prisoners. In-person interviews were conducted with a stratified random sample of individuals incarcerated with the South Carolina Department of Corrections approximately 90 days prior to the prisoners' releases. In addition to a variety of items and scales, respondents were screened for TBI and were asked whether they had received a current diagnosis of PTSD. Data were merged with arrest data that provided measures of past criminal involvement and indicators of post-release recidivism (arrest). Arrests were coded as "general" for any arrest charge and "violent" for any violent offense charge. RESULTS: Survival analyses indicate that neither TBI nor PTSD predicts time to general recidivism. PTSD (p < 0.01) and age at first arrest (p < 0.01) are significant predictors for violent recidivism and TBI is non-significant at p = 0.09. Results from the negative binomial models indicate that TBI (p < 0.05) and PTSD (p < 0.05) are significantly associated with more post-release violent arrests, but not general arrests. CONCLUSIONS: TBI and PTSD were found to predict violent offending but not general criminal behavior. These findings demonstrate the need for prison officials to identify individuals with a history of TBI and PTSD and to develop appropriate interventions that could be provided during incarceration to reduce the post-release likelihood of violence.

Perspectives from law enforcement officers who respond to overdose calls for service and administer naloxone.

BACKGROUND: Many law enforcement agencies across the United States equip their officers with the life-saving drug naloxone to reverse the effects of an opioid overdose. Although officers can be effectively trained to administer naloxone, and hundreds of law enforcement agencies carry naloxone to reverse overdoses, little is known about what happens on scene during an overdose call for service from an officer's perspective, including what officers perceive their duties and responsibilities to be as the incident evolves. METHODS: The qualitative study examined officers' experiences with overdose response, their perceived roles, and what happens on scene before, during, and after an overdose incident. In-person interviews were conducted with 17 officers in four diverse law enforcement agencies in the United States between January and May 2020. RESULTS: Following an overdose, the officers described that overdose victims are required to go to a hospital or they are taken to jail. Officers also described their duties on scene during and after naloxone administration, including searching the belongings of the person who overdosed and seizing any drug paraphernalia. CONCLUSION: These findings point to a pressing need for rethinking standard operating procedures for law enforcement in these situations so that the intentions of Good Samaritan Laws are upheld and people get the assistance they need without being deterred from asking for future help.

The Hallux Metatarsophalangeal Capsule: An Anatomic Study With Respect to Percutaneous Hallux Valgus Correction.

BACKGROUND: Minimally invasive surgery for the treatment of hallux valgus deformities has become increasingly popular. Knowledge of the location of the hallux metatarsophalangeal (MTP) proximal capsular origin on the metatarsal neck is essential for surgeons in planning and executing extracapsular corrective osteotomies. A cadaveric study was undertaken to further study this anatomic relationship. METHODS: Ten nonpaired fresh-frozen frozen cadaveric specimens were used for this study. Careful dissection was performed, and the capsular origin of the hallux MTP joint was measured from the central portion of the metatarsal head in the medial, lateral, dorsal, plantarmedial, and plantarlateral dimensions. RESULTS: The ten specimens had a mean age of 77 years, with 5 female and 5 male. The mean distances from the central hallux metatarsal head to the MTP capsular origin were 15.2 mm dorsally, 8.4 mm medially, 9.6 mm laterally, 19.3 mm plantarmedially, and 21.0 mm plantarlaterally. CONCLUSION: The MTP capsular origin at the hallux metatarsal varies at different anatomic positions. Knowledge of this capsular anatomy is critical for orthopaedic surgeons when planning and performing minimally invasive distal metatarsal osteotomies for the correction of hallux valgus. TYPE OF STUDY: Cadaveric Study.

Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: ACCELERATE in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration.

The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.

FDA Approval Summary: Selinexor for Relapsed or Refractory Diffuse Large B-Cell Lymphoma.

In June 2020, the U.S. Food and Drug Administration granted accelerated approval to selinexor for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), not otherwise specified, including DLBCL arising from follicular lymphoma, after at least two lines of systemic therapy. Approval was based on SADAL, a multicenter trial of selinexor monotherapy in patients with DLBCL after two to five systemic regimens. Efficacy was based on independent review committee-assessed objective response rate (ORR) and duration of response using Lugano criteria. In 134 patients treated with the approved dosage (60 mg orally on days 1 and 3 of each week), the ORR was 29% (95% confidence interval, 22-38), with complete response in 13% and with 38% of responses lasting at least 6 months. Gastrointestinal toxicity developed in 80% of patients, hyponatremia in 61%, central neurological toxicity (such as dizziness and mental status changes) in 25%, and ocular toxicity in 18%. New or worsening grade 3 or 4 thrombocytopenia, lymphopenia, neutropenia, anemia, or hyponatremia developed in ≥15%. Adverse reactions led to selinexor dose interruption in 61% of patients, dose reduction in 49%, and permanent discontinuation in 17%, with thrombocytopenia being the leading cause of dose modifications. Postmarketing studies will evaluate reduced dosages of selinexor and further evaluate clinical benefit in patients with relapsed or refractory DLBCL. IMPLICATIONS FOR PRACTICE: Selinexor is a new potential option for adults with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, in the third-line setting or beyond. Toxicities are typically manageable but can be difficult to tolerate and necessitate close monitoring and supportive care.

Comparison study of patient demographics and risk factors for surgical site infections following open reduction and internal fixation for lateral malleolar ankle fractures within the medicare population.

BACKGROUND: The purpose of this study was to analyze a comprehensive database to 1) compare patient demographic profiles; and 2) identify patient-related risk factors for surgical site infections (SSIs) following open reduction and internal fixation (ORIF) for lateral malleolar ankle fractures. METHODS: Patients treated with ORIF for lateral malleolar ankle fractures that developed SSIs within 1-year following the procedure were identified. Study group demographics were compared to a control cohort and risks for developing SSI were calculated using multivariate logistic regression analysis. RESULTS: There were statistically significant differences between the control group and patients with SSIs. The study showed that morbidly obese patients, peripheral vascular disease, and electrolyte/fluid imbalance were the greatest risk factors for developing SSIs following ORIF for lateral malleolar fractures. CONCLUSION: The study is useful as it can allow orthopaedists to optimize these high-risk patients to potentially mitigate this adverse event.

FDA approval summary: Dalteparin for the treatment of symptomatic venous thromboembolism in pediatric patients.

On May 16, 2019, the U.S. Food and Drug Administration (FDA) approved dalteparin sodium for the treatment of symptomatic venous thromboembolism (VTE) to reduce the risk of recurrence in pediatric patients 1 month of age and older. Approval was primarily based on FDA review of a single-arm trial evaluating dalteparin administered subcutaneous twice daily in 38 pediatric patients with symptomatic VTE. Efficacy was based on the achievement of therapeutic plasma anti-Xa levels. The FDA concluded that dalteparin has efficacy and acceptable safety for pediatric patients.

FDA Approval Summary: Brentuximab Vedotin in First-Line Treatment of Peripheral T-Cell Lymphoma.

In November 2018, the U.S. Food and Drug Administration (FDA) approved brentuximab vedotin (BV) for the treatment of adult patients with previously untreated systemic anaplastic large cell lymphoma or other CD30-expressing peripheral T-cell lymphomas (PTCL), including angioimmunoblastic T-cell lymphoma and PTCL not otherwise specified, in combination with cyclophosphamide, doxorubicin, and prednisone (CHP). Approval was based on ECHELON-2, a randomized, double-blind, actively controlled trial that compared BV+CHP with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) in 452 patients with newly diagnosed, CD30-expressing PTCL. Efficacy was based on independent review facility-assessed progression-free survival (PFS). The median PFS was 48.2 months with BV+CHP versus 20.8 months with CHOP, resulting in a hazard ratio (HR) of 0.71 (95% confidence interval [CI]: 0.54-0.93). The trial also demonstrated improvement in overall survival (HR 0.66; 95% CI: 0.46-0.95), complete response rate (68% vs. 56%), and overall response rate (83% vs. 72%) with BV+CHP. The most common adverse reactions (incidence ≥20%) observed ≥2% more with BV+CHP were nausea, diarrhea, fatigue or asthenia, mucositis, pyrexia, vomiting, and anemia. Peripheral neuropathy rates were similar (52% with BV+CHP, 55% with CHOP). Through the Real-Time Oncology Review pilot program, which allows FDA early access to key data, FDA granted this approval less than 2 weeks after official submission of the application. IMPLICATIONS FOR PRACTICE: This is the first U.S. Food and Drug Administration approval for treatment of patients with newly diagnosed peripheral T-cell lymphomas (PTCL). Improvement in progression-free and overall survival over cyclophosphamide, doxorubicin, vincristine, and prednisone chemotherapy, which has been the standard of care for decades, is unprecedented. The new regimen represents a major advance for the frontline treatment of patients with CD30-expressing PTCL.