Total Hip Arthroplasty or Hemiarthroplasty for Hip Fracture.

BACKGROUND: Globally, hip fractures are among the top 10 causes of disability in adults. For displaced femoral neck fractures, there remains uncertainty regarding the effect of a total hip arthroplasty as compared with hemiarthroplasty. METHODS: We randomly assigned 1495 patients who were 50 years of age or older and had a displaced femoral neck fracture to undergo either total hip arthroplasty or hemiarthroplasty. All enrolled patients had been able to ambulate without the assistance of another person before the fracture occurred. The trial was conducted in 80 centers in 10 countries. The primary end point was a secondary hip procedure within 24 months of follow-up. Secondary end points included death, serious adverse events, hip-related complications, health-related quality of life, function, and overall health end points. RESULTS: The primary end point occurred in 57 of 718 patients (7.9%) who were randomly assigned to total hip arthroplasty and 60 of 723 patients (8.3%) who were randomly assigned to hemiarthroplasty (hazard ratio, 0.95; 95% confidence interval [CI], 0.64 to 1.40; P = 0.79). Hip instability or dislocation occurred in 34 patients (4.7%) assigned to total hip arthroplasty and 17 patients (2.4%) assigned to hemiarthroplasty (hazard ratio, 2.00; 99% CI, 0.97 to 4.09). Function, as measured with the total Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score, pain score, stiffness score, and function score, modestly favored total hip arthroplasty over hemiarthroplasty. Mortality was similar in the two treatment groups (14.3% among the patients assigned to total hip arthroplasty and 13.1% among those assigned to hemiarthroplasty, P = 0.48). Serious adverse events occurred in 300 patients (41.8%) assigned to total hip arthroplasty and in 265 patients (36.7%) assigned to hemiarthroplasty. CONCLUSIONS: Among independently ambulating patients with displaced femoral neck fractures, the incidence of secondary procedures did not differ significantly between patients who were randomly assigned to undergo total hip arthroplasty and those who were assigned to undergo hemiarthroplasty, and total hip arthroplasty provided a clinically unimportant improvement over hemiarthroplasty in function and quality of life over 24 months. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT00556842.).

High Return to Play and Low Reinjury Rates in National Collegiate Athletic Association Division I Football Players Following Anterior Cruciate Ligament Reconstruction Using Quadrupled Hamstring Autograft.

PURPOSE: The purpose of this study was to examine the outcomes of anterior cruciate ligament (ACL) reconstruction using quadrupled hamstring (QH) autograft in a cohort of National Collegiate Athletic Association (NCAA) Division I football players. METHODS: A retrospective analysis was performed on NCAA Division I football players at a single institution who had transtibial ACL reconstruction using QH autograft between 2001 and 2016. Primary outcomes were ACL reinjury and return to play (RTP). Secondary outcomes were position, percent of eligibility used after surgery, graft diameter, Tegner-Lysholm scores, concomitant injuries/surgeries, and postcollegiate professional play. RESULTS: Between 2001 and 2016, 34 players had QH autograft ACL reconstruction, and 29 players achieved RTP. Of the 29, 2 (6.9%) sustained ACL reinjuries. The average RTP was 318 days (range 115-628) after surgery. Players used 79.5% of their remaining collegiate eligibility after surgery. Nine players sustained multiligamentous knee injuries. This did not have a significant effect on RTP (P = 0.709; mean 306±24 days for isolated ACL, mean of 353±51 for 2 ligaments, mean of 324±114 for 3 + ligaments) and none sustained reinjury. Associated meniscal injuries were sustained by 28, and 8 sustained chondral injuries. The mean postoperative Tegner-Lysholm score was 90.7 of 100, with mean follow-up of 102 months. Of these players, 18 went on to play professionally, with 17 joining National Football League rosters and 1 an arena team roster. CONCLUSION: QH demonstrated an ACL reinjury and RTP rates similar to those in previously published, predominantly bone-patella tendon-bone ACL reinjury data in elite athletes. This study demonstrates that QH autograft may be a viable option in elite athletes. LEVEL OF EVIDENCE: IV, case series.

Low intensity pulsed ultrasound (LIPUS) use for the management of instrumented, infected, and fragility non-unions: a systematic review and meta-analysis of healing proportions.

BACKGROUND: Non-union occurs in approximately 5 to 10% of fracture patients, with certain bones at greater risk of failing to heal. Non-unions have a significant impact on socioeconomic costs and the patients short and long-term quality of life. Low intensity pulsed ultrasound (LIPUS) is a non-invasive therapy for non-union treatment that can improve the long-term outcome. The purpose of this study is to summarize the available literature assessing LIPUS potential to improve the union rate in instrumented, infected, and fragility non-unions. METHODS: A literature search was conducted in the MEDLINE, EMBASE, and CINAHL databases for all relevant literature on the healing rates of LIPUS utilized in instrumented, infected, and fragility non-unions. Study characteristics were summarized for each of the included studies. The percentage of healed patients (healing rate), for instrumented, infected, and fragility fracture non-union patients were pooled from each included study. RESULTS: The literature search identified a total of 326 articles, while searching reference lists and grey literature identified an additional 3 articles. There was a total of 29 articles included in this review, with 20 articles included within the quantitative synthesis of healing rates. The most common design of included studies was case series (17 articles), followed by case reports (9 articles). Studies were primarily retrospective (18 studies), with an additional 10 prospective studies. Non-union healing rates were 82% (95% CI: 76 to 87%) in instrumented, 82% (95% CI: 70 to 95%) in infected, and 91% (95% CI: 87 to 95%) in fragility fracture patients with non-unions. CONCLUSION: This study has provided a thorough overview of the current literature on LIPUS treatment for instrumented, infected, and fragility fracture non-unions. The healing rates for non-unions in these subgroups were comparable to healing rates observed with LIPUS use in general non-union literature. LIPUS treatment should be considered as a conservative non-surgical treatment option to potentially reduce the socioeconomic impact and improve the quality of life of these unfortunate patients. LEVEL OF EVIDENCE: 4 (systematic review of primarily case series data).

Gunshot Wounds to the Hip: Doomed to Failure?

The purpose is to evaluate hip fractures due to gunshot wounds (GSW) to the hip, which are treated surgically, and the complications. Patients who sustained a low velocity GSW with fracture to the femoral head/neck and intertrochanteric/peritrochantric region at three Level 1 Trauma Centers were eligible. There were 69 patients (63 males-91%), with an average age of 29 (18-60). Nine patients had orthopaedic surgical site infections. There were 6 nonunions, 4 patients with hardware failure, 2 cases of avascular necrosis (AVN), 3 patients with post traumatic arthritis (PTA) and 20 patients with heterotopic ossification (HO). There was no significant difference found regarding fracture site or type of fixation with regards to complications. This represents the largest study of surgically treated GSW to the hip. Of patients studied, 61% sustained additional GSW. These injuries are not benign; the main complications being infection and heterotopic ossification. (Journal of Surgical Orthopaedic Advances 29(3):135-140, 2020).

Healing, nonunion, and re-operation after internal fixation of diaphyseal and distal femoral fractures: a systematic review and meta-analysis.

PURPOSE: Nonunion is a highly morbid complication that exacerbates the pain, disability and financial burden of distal and diaphyseal femur fractures. This study examined the modern rates of healing, nonunion, and other complications requiring reoperation of different fixation methods for distal and diaphyseal femur fractures. METHODS: A systematic review and meta-analysis of all records from PubMed, Embase and the Cochrane Review system was performed. Included studies had >20 acute, non-pathologic distal or diaphyseal femur fractures treated with primary internal fixation. Excluded were studies on abnormal patient/fracture populations, external fixation, or cement/bone graft use. RESULTS: Thirty-eight studies with 2,829 femoral shaft fractures and 11 studies with 505 distal femur fractures were included. Distal fractures had a lower healing rate (86.6% vs. 93.7%) and a higher re-operation rate (13.4% vs 6.1%) than shaft fractures (p < 0.00001), primarily due to higher rates of mechanical failure (p < 0.00001). Nonunion was the most frequent complication, occurring in 4.7% of distal fractures and 2.8% of shaft fractures. There was no difference between plate and nail fixation of distal fractures in healing, nonunion, or other causes of re-operation. Shaft fractures developed nonunion in 6.6% of unreamed nails and 2.1% of reamed nails (p = 0.002). Nonunion occurred in 2.3% of antegrade nailed fractures and 1.5% of retrograde nailed fractures (p = 0.66). CONCLUSIONS: Approximately one out of every eight distal fractures and one of every 16 shaft fractures requires re-operation. The most common cause of fixation failure is nonunion. Further research is needed to improve outcomes, particularly in distal femur fractures.

Novel Technique for Treatment of Calcaneal Tuberosity Fractures.

Calcaneal tuberosity fractures comprise only 1% to 2% of all calcaneal fractures. Treatment of these injuries has traditionally included open reduction and internal fixation with various means including lag screws, suture anchors, and K-wires. This article reports on a series of cases treated with excision of the tuberosity fragment with repair of the Achilles tendon supplemented by a flexor hallucis longus tendon transfer.

A cohort study of 4,190 patients treated with low-intensity pulsed ultrasound (LIPUS): findings in the elderly versus all patients.

BACKGROUND: Patient age is one of many potential risk factors for fracture nonunion. Our hypothesis is that older patients (≥ 60) with fracture risk factors treated with low-intensity pulsed ultrasound (LIPUS) have similar heal rate (HR) to the population as a whole. We evaluate the impact of age in conjunction with other risk factors on HR in LIPUS-treated patients with fresh fracture (≤ 90 days old). METHODS: The Exogen Bone Healing System is a LIPUS device approved in 1994 to accelerate healing of fresh fracture. After approval, the FDA required a Post-Market Registry to assess performance. Patient data collected from October 1994 until October 1998 were individually reviewed and validated by a registered nurse. Four distinct data elements were required to report a patient: date fracture occurred; date treatment began; date treatment ended; and a dichotomous outcome of healed v. failed, by clinical and radiological criteria. Data were used to calculate two derived variables; days to treatment (DTT) and days on treatment (DOT). Every validated fresh fracture patient with DTT, DOT, and outcome is reported. RESULTS: The validated registry had 5,765 patients with fresh fracture; 73% (N = 4,190) are reported, while 13% of patients were lost to follow-up, 11% withdrew or were non-compliant, and 3% died or are missing outcome. Among treatment-compliant patients, HR was 96.2%. Logistic estimates of the odds ratio for healing are equivalent for patients age 30 to 79 years and all age cohorts had a HR > 94%. Open fracture, current smoking, diabetes, vascular insufficiency, osteoporosis, cancer, rheumatoid arthritis, and prescription NSAIDs all reduced HR, but older patients (≥ 60) had similar HRs to the population as a whole. DTT was significantly shorter for patients who healed (p < 0.0001). CONCLUSIONS: Comorbid conditions in conjunction with aging can reduce fracture HR. Patients with fracture who used LIPUS had a 96% HR, whereas the expected HR averages 93%. Time to treatment was significantly shorter among patients who healed (p < 0.0001), suggesting that it is beneficial to begin LIPUS treatment early. Older patients (≥ 60) with fracture risk factors treated with LIPUS exhibit similar heal rates to the population as a whole.

Medicaid and Indigent Patients Experience Delayed Fixation of Distal Radius Fractures, Resulting in Worse Consequential Radiographic Outcomes.

Distal radius fractures are the most common upper extremity injury. Patients referred to safety-net tertiary facilities following a fracture experience significant delays in treatment because of financial and language barriers as well as poor access to care at outlying community hospitals. This delay in treatment can affect postoperative functional outcomes and complication rates because of failure to restore anatomic alignment. The purpose of this multicenter study was to assess for risk factors associated with delayed fixation of distal radius fractures and evaluate the impact of delayed treatment on radiographic alignment. Patients with a distal radius fracture treated surgically during a 2-year period were identified. Measures included time from injury to surgery, demographic information, fracture classification, and radiographic parameters. The effect of surgery delay on radiographic outcomes was assessed with delayed surgery defined as 11 or more days out from injury. A total of 183 patients met study inclusion criteria. Medicaid and indigent patients were more likely to experience a delay in surgical treatment. Specifically, 70% of these patients were treated in a delayed fashion. Delayed treatment of 11 days or more was associated with worse radial height and inclination on postoperative radiographic imaging. Medicaid and indigent patients are more likely to experience delayed fixation in the treatment of distal radius fractures. This delayed surgery negatively affects postoperative radiographic outcomes. These findings suggest a need to improve access to care for Medicaid and indigent patients and to proceed with operative intervention within 10 days for distal radius fractures. [Orthopedics. 2024;47(2):e93-e97.].

Outcomes of Humerus Nonunion Surgery in Patients With Initial Operative Fracture Fixation.

OBJECTIVES: To describe outcomes following humerus aseptic nonunion surgery in patients whose initial fracture was treated operatively and to identify risk factors for nonunion surgery failure in the same population. DESIGN: Retrospective case series. SETTING: Eight, academic, level 1 trauma centers. PATIENTS SELECTION CRITERIA: Patients with aseptic humerus nonunion (OTA/AO 11 and 12) after the initial operative management between 1998 and 2019. OUTCOME MEASURES AND COMPARISONS: Success rate of nonunion surgery. RESULTS: Ninety patients were included (56% female; median age 50 years; mean follow-up 21.2 months). Of 90 aseptic humerus nonunions, 71 (78.9%) united following nonunion surgery. Thirty patients (33.3%) experienced 1 or more postoperative complications, including infection, failure of fixation, and readmission. Multivariate analysis found that not performing revision internal fixation during nonunion surgery (n = 8; P = 0.002) and postoperative de novo infection (n = 9; P = 0.005) were associated with an increased risk of recalcitrant nonunion. Patient smoking status and the use of bone graft were not associated with differences in the nonunion repair success rate. CONCLUSIONS: This series of previously operated aseptic humerus nonunions found that more than 1 in 5 patients failed nonunion repair. De novo postoperative infection and failure to perform revision internal fixation during nonunion surgery were associated with recalcitrant nonunion. Smoking and use of bone graft did not influence the success rate of nonunion surgery. These findings can be used to give patients a realistic expectation of results and complications following humerus nonunion surgery. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Protein modification by deamidation indicates variations in joint extracellular matrix turnover.

As extracellular proteins age, they undergo and accumulate nonenzymatic post-translational modifications that cannot be repaired. We hypothesized that these could be used to systemically monitor loss of extracellular matrix due to chronic arthritic diseases such as osteoarthritis (OA). To test this, we predicted sites of deamidation in cartilage oligomeric matrix protein (COMP) and confirmed, by mass spectroscopy, the presence of deamidated (Asp(64)) and native (Asn(64)) COMP epitopes (mean 0.95% deamidated COMP (D-COMP) relative to native COMP) in cartilage. An Asp(64), D-COMP-specific ELISA was developed using a newly created monoclonal antibody 6-1A12. In a joint replacement study, serum D-COMP (p = 0.017), but not total COMP (p = 0.5), declined significantly after replacement demonstrating a joint tissue source for D-COMP. In analyses of 450 participants from the Johnston County Osteoarthritis Project controlled for age, gender, and race, D-COMP was associated with radiographic hip (p < 0.0001) but not knee (p = 0.95) OA severity. In contrast, total COMP was associated with radiographic knee (p < 0.0001) but not hip (p = 0.47) OA severity. D-COMP was higher in soluble proteins extracted from hip cartilage proximal to OA lesions compared with remote from lesions (p = 0.007) or lesional and remote OA knee (p < 0.01) cartilage. Total COMP in cartilage did not vary by joint site or proximity to the lesion. This study demonstrates the presence of D-COMP in articular cartilage and the systemic circulation, and to our knowledge, it is the first biomarker to show specificity for a particular joint site. We believe that enrichment of deamidated epitope in hip OA cartilage indicates a lesser repair response of hip OA compared with knee OA cartilage.

Distal femoral locking plates and the posterolateral corner.

The purpose of this study was to evaluate the effect of minimally invasive submuscular placement of a distal femoral locking plate on the posterolateral structures of the knee. Eight fresh-frozen cadaveric knees were dissected after application of a lateral distal femoral locking plate through a minimally invasive submuscular approach. The lateral collateral ligament and popliteus tendon were identified and inspected for injury. Distances from the plate to the lateral collateral ligament and popliteus insertions were determined.Neither the lateral collateral ligament nor the popliteus tendon was disrupted by the minimally invasive submuscular application of distal femoral periarticular locking plates. The mean distances to the lateral collateral ligament and popliteus tendon insertions were 2.5 and 6.6 mm, respectively.Distal femoral locking plates can be applied in a minimally invasive manner without disrupting the posterolateral structures of the knee.

Predictors of length of hospital stay in elderly hip fracture patients.

The purpose of this study was to assess the relationship between prefracture characteristics and length of stay (LOS) at the authors' institution. Three hundred eighty-nine consecutive elderly hip fracture patients' preoperative characteristics, comorbidities, fracture type, and surgical and hospital course were retrospectively reviewed. Multiple regression was used to determine which subset of potential independent variables would be good predictors of LOS. Predictors of increased LOS included cerebral vascular disease (+1.28 days, p <.0352), chronic renal insufficiency (+1.17 days, p < .0363), and American Society of Anesthesiologists (ASA) score (+1.27 days per ASA class, p < .0005). For each increase in age by 1 year, LOS decreased by a mean of 0.085 days (p < .0041). Fracture type, prefracture mobility, or other examined comorbidities were found not to be significant predictors of LOS. Identifying high-risk patients in the preoperative period and minimizing certain perioperative events will be important to optimize care of patients who fracture their hip and to minimize future costs.

Relation between prefracture characteristics and perioperative complications in the elderly adult patient with hip fracture.

BACKGROUND: The exact relation among patient prefracture characteristics such as age, American Society of Anesthesiologists (ASA) class, fracture type, and prefracture mobility status with perioperative complications in elderly adult patients with hip fracture is still unclear. The aim of the study was to assess the relations among patient prefracture characteristics and perioperative complications. METHODS: Patients 65 years old and older admitted to our institution between January 2006 and May 2010 with the diagnosis of a low-energy hip fracture were retrospectively reviewed. A total of 389 patients met the inclusion criteria and were analyzed in this investigation. Patient prefracture characteristics, comorbidities, and surgical and hospital courses were reviewed. RESULTS: Using logistic regression analysis, ASA class was found to be the only significant predictor of a patient having at least one or more perioperative complications (odds ratio [OR] 2.007). In addition to ASA class, prefracture mobility status was a significant predictor of delirium (OR 1.39) and pneumonia (OR 1.77), advanced age was a significant predictor of congestive heart failure (OR 1.73), and fracture type was a significant predictor of pneumonia (OR 1.6). None of the examined prefracture characteristics was found to be a significant predictor of pulmonary embolus, deep venous thrombosis, surgical wounds, transfusions, urinary tract infection, or death. CONCLUSIONS: At our institution, certain patient prefracture characteristics, particularly high ASA class, are related to certain perioperative complications. Recognition of patients who possess these risk factors can be used to alert the caregiving team about a potentially complicated hospital course.

Computer-assisted reduction method for periprosthetic distal femur fracture.

The purpose of this case report is to describe a novel use of computer assistance in identifying and restoring the mechanical axis in the treatment of a periprosthetic distal femur fracture in a 76-year-old female patient with a total knee arthroplasty.

Risk factors for nonunion following surgically managed, traumatic, diaphyseal fractures: a systematic review and meta-analysis.

Background: There are several studies on nonunion, but there are no systematic overviews of the current evidence of risk factors for nonunion. The aim of this study was to systematically review risk factors for nonunion following surgically managed, traumatic, diaphyseal fractures. Methods: Medline, Embase, Scopus, and Cochrane were searched using a search string developed with aid from a scientific librarian. The studies were screened independently by two authors using Covidence. We solely included studies with at least ten nonunions. Eligible study data were extracted, and the studies were critically appraised. We performed random-effects meta-analyses for those risk factors included in five or more studies. PROSPERO registration number: CRD42021235213. Results: Of 11,738 records screened, 30 were eligible, and these included 38,465 patients. Twenty-five studies were eligible for meta-analyses. Nonunion was associated with smoking (odds ratio (OR): 1.7, 95% CI: 1.2-2.4), open fractures (OR: 2.6, 95% CI: 1.8-3.9), diabetes (OR: 1.6, 95% CI: 1.3-2.0), infection (OR: 7.0, 95% CI: 3.2-15.0), obesity (OR: 1.5, 95% CI: 1.1-1.9), increasing Gustilo classification (OR: 2.2, 95% CI: 1.4-3.7), and AO classification (OR: 2.4, 95% CI: 1.5-3.7). The studies were generally assessed to be of poor quality, mainly because of the possible risk of bias due to confounding, unclear outcome measurements, and missing data. Conclusion: Establishing compelling evidence is challenging because the current studies are observational and at risk of bias. We conclude that several risk factors are associated with nonunion following surgically managed, traumatic, diaphyseal fractures and should be included as confounders in future studies.

A scoping review of operative and non-invasive management in the treatment of non-unions.

INTRODUCTION: Non-union occurs when a fracture fails to adequately heal, and requires additional intervention to achieve union. The purpose of this scoping review is to provide a high-level overview of the existing non-union management literature. This review aims to highlight the current literature on non-union management, as well as identify key areas that require future research to provide a better understanding of potential non-union management strategies. METHODS: This study utilized the scoping review framework from Arksey and O'Malley All relevant literature on non-union management was systematically searched for within the OVID Medline, OVID Embase, and Web of Science databases. As a scoping review, this study aimed to identify the high-level trends in non-union literature. This was assessed through a visual and numerical summary of the general themes in non-union literature, as well as the timeline in which these trends have occurred. RESULTS: The literature search identified 8081 articles, of which 2210 articles were included. There is a large body of evidence for various surgical treatment options for non-union. The literature suggests healing rates between 80 and 100 percent for commonly utilized surgical procedures, such as plating with bone graft for long bones. Despite these beneficial healing rates, the requirement of a surgery creates a large socioeconomic burden. The possibility for bone growth stimulator (BGS) options to achieve non-union healing rates in a similar realm as surgical options suggests that the use of a BGS may be a beneficial option prior to surgical intervention, as this would potentially reduce the number of patients who would otherwise require surgery. CONCLUSION: A large body of evidence exists on non-union management, which is largely comprised of case series and reports. The most commonly assessed non-unions include the tibia, wrist, and femur. Bone grafting, plating, and nailing are the most investigated treatment options. BGS are a non-operative treatment options for non-union that provide similar healing rates to surgical options in certain indications within initial observational data. BGS are a potential option for non-operative management of non-unions to reduce socioeconomic burdens of surgical intervention, with a need for further high-quality investigation in this therapeutic area.

Case report: lead toxicity associated with an extra-articular retained missile 14 years after injury.

Lead toxicity associated with extra-articular retained missiles (EARMs) is an uncommon yet potentially devastating complication of gunshot wounds. While the risk of lead toxicity with intra-articular retained missiles is well-known, EARMs are routinely permitted to remain in tissues indefinitely without surveillance for lead toxicity. We present a 34 year-old man who was found to have symptomatic lead toxicity 14 years after sustaining a gunshot-associated femoral fracture with retention of lead bullet fragments. A fluid-filled cyst containing two large lead bullet fragments was identified intraoperatively. Whole-blood lead concentration decreased after removal of the lead-filled cyst. Cyst formation and concomitant bone fracture are two of the risk factors for lead toxicity in patients with EARMs after gunshot wounds. Recognizing risk factors for EARM-associated elevation in lead levels is important as the adverse effects of increased lead burden may be asymptomatic and difficult to diagnose, yet debilitating and potentially lethal.

Randomized Clinical Trial or Real-World Evidence: How Historical Events, Public Demand, and the Resulting Laws and Regulations Shaped the Body of Medical Evidence.

SUMMARY: The signing of the 21st Centuries Cures Act in 2016 was a confirmational step in a long journey toward an understood use and need for real-world evidence (RWE), even though the Food and Drug Administration (FDA) had the legislative authority to accept RWE since 1962 to demonstrate efficacy. The 21st Century Cures Act, as well as the subsequent FDA guidance published in 2017 and other supporting guidance, documents that since are opening the doors for the clinical and research community. They specifically allow for labeling changes and indication expansion based on RWE. The legislative discussion of efficacy requirements started in the late 1950s, when evidence of effectiveness was not required in the United States before the marketing of a drug or medical device, and calls for the real-world comparative effectiveness research were being made by Senator Estes Kefauver. When the thalidomide tragedy stuck, Congress and the Kennedy Administration rushed to pass a new law to require that drugs be "effective in use." The regulations subsequently drafted by the FDA to enforce the law often required placebo-controlled, randomized clinical trials (RCTs). In the 1980s, some started to label the RCT as the gold standard for medical evidence. The use of real-world data for new indication approval was not specifically prohibited by the 1962 law, but the new 2016 law sent a clear mandate to FDA, requiring the agency to review new forms of evidence such as RWE.