Withdrawn accelerated approvals for cancer indications in the USA: what is the marketing authorisation status in the EU?

As of April, 2023, 23 accelerated approvals for cancer indications granted by the US Food and Drug Administration (FDA) since 1992 have been withdrawn from the US market, with 17 (74%) of 23 withdrawn in the past 3 years. The marketing authorisation status of these indications in the EU has not been reported. A review of relevant documents from the FDA and the European Medicines Agency (EMA) was done to investigate whether the accelerated approvals for cancer indications withdrawn by the FDA have a marketing authorisation in the EU to date, and to compare the approval history of these indications by the EMA and FDA. We found that, as of April 20, 2023, nine (39%) of 23 withdrawn accelerated approvals for cancer indications in the USA have a marketing authorisation in the EU for a similar indication. By comparison, only two conditional marketing authorisations for cancer indications have been withdrawn from the EU; both are no longer approved in the USA. These findings indicate a discrepancy in the approval policies between the FDA and EMA and imply either that some patient groups in the USA do not get access to relevant medical treatment, or that some patient groups in the EU are treated with medicine without a positive benefit-risk balance. These discrepancies could potentially be reduced by increased collaboration and information sharing between the two agencies.

Treatment outcome at 1 year did not differ between use of cast or walker in the first 3 weeks after an acute Achilles tendon rupture. A registry study of 1304 patients from the Danish Achilles tendon database.

BACKGROUND: The best choice of orthosis in the treatment of acute Achilles tendon rupture is still under debate. OBJECTIVE: To investigate if choice of orthosis in the first 3 weeks of treatment affected patient reported outcome (Achilles tendon Total Rupture Score (ATRS)), tendon elongation (Achilles Tendon Resting Angle (ATRA) and Heel Rise Height (HRH)) and re-rupture. METHODS: Registry study in the Danish Achilles tendon Database. Patients treated with cast and patients treated with walker in the first 3 weeks of treatment were compared using a linear mixed-effects model adjusted for potential confounders. RESULTS: 1304 patients were included in the study. No clinically relevant difference was found: Adjusted mean difference (using walker the whole period as reference)(95% CI) ATRS after 1 year = 0.1(-3.0; 4.1), ATRS after 6 months = 2.0(-4.5; 5.8), ATRS after 2 years = 3.0(-0.7; 7.0), HRH difference = 0.6(-6.6; 8.2), ATRA difference = 0.03°(-1.5; 1.6), re-rupture(odds ratio) = 0.812(0.4; 1.61). CONCLUSION: Patients treated with cast the first 3 weeks after acute Achilles tendon rupture did not have better treatment outcome than patients treated with walker.

Estimation of Patient Acceptable Symptom State (PASS) and Treatment Failure (TF) Threshold Values for the Achilles Tendon Total Rupture Score (ATRS) at 6 Months, 1 Year, and 2 Years After Acute Achilles Tendon Rupture.

Interpretation of the Achilles tendon Total Rupture Score (ATRS) is challenging because limited knowledge exists about at which score the patients consider the outcome of treatment as satisfactory. The aims of the study were (1) to describe the proportion of patients who find their symptom levels to be satisfactory, to reflect treatment failure or neither after acute Achilles tendon rupture (ATR), and (2) to estimate the Patient Acceptable Symptom State (PASS) and the Treatment Failure (TF) threshold values for the ATRS at 6 months, 1 year, and 2 years after ATR. The study was based on data extracted from the nationwide Danish Achilles tendon Database which includes patients treated operatively or nonoperatively after ATR. The PASS and TF threshold values for ATRS were estimated using the adjusted predictive modeling method. One hundred and sixty-six patients were included at 6 months, 248 patients at 1 year, and 287 patients at 2 years after ATR. The proportion of patients who considered their symptom level to be satisfactory was 61% at 6 months, 50% at 1 year, and 66% at 2 years, while 5% at 6 months, 11% at 1 year, and 10% at 2 years considered their symptom level to reflect treatment failure. The PASS threshold value for ATRS (95% confidence interval) was 49 (46-52) at 6 months, 57 (54-60) at 1 year, and 52 (49-55) at 2 years. The TF threshold value for ATRS was 30 (23-36) at 6 months, 33 (26-40) at 1 year, and 35 (29-39) at 2 years. The calculated PASS and TF threshold values can help interpret the outcome of ATR when measured with the ATRS. About 50% to 66% of the patients had a satisfactory symptom level after ATR.

Genetic contribution to the etiology of Achilles tendon rupture. A Danish nationwide register study of twins.

BACKGROUND: It is unknown if genetics contribute to the etiology of acute Achilles tendon rupture (ATR). The aims of the present study were, 1) To calculate the concordance rate for monozygotic (MZ) twins and same-sex dizygotic (SSDZ) twins and 2) to estimate the heritability of ATR. METHODS: The study was performed as a registry study using the Danish Twin Registry and the Danish National Patient Registry. RESULTS: The study sample consisted of 85,534 twins born from 1895 to 1995. Of these, 572 (0.67%) were registered with ATR in the period from 1994 to 2014. The concordance rate was 8.1% (95% CI 1.4-14.7%) for MZ twins and 4.3% (95% CI 0.7-7.9%) for SSDZ twins. The heritability of ATR was 47% (95% CI 31-62%). CONCLUSION: This study found that genetics contribute substantially to the etiology of ATR with an estimated heritability of the liability to ATR of approximately 50%. The finding generates the hypothesis that genetics play a role in the pathological changes that occur in the Achilles tendon before a rupture. The risk of ATR for a twin within a 20 year period, if the co-twin has had an ATR, was 8% for MZ twins and 4% for SSDZ twins.

Neither heel-rise Height (HRH) nor Achilles tendon resting angle (ATRA) show strong correlations to patient limitations and return to previous activities one year after acute Achilles tendon rupture.

BACKGROUND: Knowledge is limited about how Achilles tendon elongation following acute Achilles tendon rupture (ATR) affects the ability to return to work and return to sport. This study aimed to examine if the indirect length measures, the heel-rise height (HRH) and the Achilles tendon resting angle (ATRA), correlated with patient limitations and return to previous activities one year after ATR. METHODS: The study was performed as a registry study in the Danish Achilles tendon Database (DADB). The analyses investigated if HRH (limb symmetry index (LSI)) and relative ATRA one year after rupture, correlated with return to the same type of work, return to the same type of sport and the Achilles tendon total rupture score (ATRS) at the same time point. RESULTS: 477 patients were included in the study. HRH (LSI) showed fair correlation to ATRS (r = 0.35, p < 0.001), poor correlation to same type of work (r = 0.29, p < 0.001) and did not statistically significantly correlate with return to the same type of sport. Relative ATRA showed poor correlation to ATRS (r = 0.09, p = 0.04) and did not correlate statistically significantly with return to same type of work or sport. CONCLUSIONS: Neither relative ATRA nor HRH (LSI) showed strong correlations to return to work, return sport or ATRS. When comparing the relative ATRA and HRH (LSI), HRH (LSI) seems to be a better outcome in reflecting patient limitations and return to previous activities one year after ATR.

No clinically relevant difference between operative and non-operative treatment in tendon elongation measured with the Achilles tendon resting angle (ATRA) 1 year after acute Achilles tendon rupture.

PURPOSE: Studies have shown that elongation of the injured Achilles tendon after acute Achilles tendon rupture (ATR) is negatively associated with clinical outcomes. The difference between operative and non-operative treatment on the length of the Achilles tendon is only sparsely investigated. The aim of the study was to investigate if the operative and non-operative treatment of ATR had different effects on tendon elongation. METHODS: The study was performed as a registry study in the Danish Achilles tendon database (DADB). The primary outcome of the study was an indirect measure of Achilles tendon length: the Achilles tendon resting angle (ATRA) at 1-year follow-up. The variable of interest was treatment (operative or non-operative). RESULTS: From August 2015 to January 2019, 438 patients (154 operatively treated and 284 non-operatively treated) were registered with full baseline data and had their ATRA correctly registered at 1-year follow-up in DADB. The analysis did not show a clinically relevant nor statistically significant difference in ATRA between operative and non-operatively treated patients at 1-year follow-up (mean difference - 1.2°; 95% CI - 2.5; 0.1; n.s) after adjustment for potential confounders. CONCLUSION: There were neither clinically relevant nor statistically significant differences in terms of the ATRA at 1-year follow-up between the operative and non-operatively treated patients. This finding suggests that operative treatment does not lead to a clinically relevant reduction in tendon elongation compared to non-operative treatment and it should therefore not be used as an argument in the choice of treatment. LEVEL OF EVIDENCE: Level III.

Diabetes and treatment with orally administrated corticosteroids negatively affect treatment outcome at follow-up after acute Achilles tendon rupture.

PURPOSE: Studies investigating the influence of comorbidities on patient-reported outcomes after acute Achilles tendon ruptures (ATR) are lacking. In this study, the aim was to investigate the effect of comorbidity and medical treatment on the patient-reported outcome measure Achilles tendon total rupture score (ATRS). METHODS: The study was performed as a registry study from the Danish Achilles tendon Database (DADB). In the DADB, ATRS was registered at baseline (prior to rupture), at 3-6 month, 1-year and 2-year follow-ups. The outcomes were ATRS at follow-up and the change in ATRS from baseline to follow-up. Variables of interest were diabetes, hypertension, rheumatic disease and treatment with orally administrated corticosteroids. Linear mixed-effects models including all follow-up time points in the same model were used adjusting for sex, age group, treatment (operative or non-operative) and the investigated comorbidities. RESULTS: Data were collected from 2012 to 2019. Two thousand and four patients with ATR were included. Patients with the investigated comorbidities and treatment with orally administrated corticosteroid scored 10.6-19.1 points lower in mean ATRS at baseline (prior to rupture) compared to patients without the respective disease or treatment. At follow-up, patients with diabetes (mean difference, [95% CI]) (- 6.2, [- 11.7; - 0.8]; P = 0.03) and patients in treatment with orally administrated corticosteroids (- 10.9, [- 16.2; - 5.7]; P < 0.01) had a statistically significantly worse ATRS than patients without the respective disease. However, change in ATRS from baseline to follow-up was not affected. Hypertension and rheumatic disease did not affect ATRS at follow-up but had a positive effect on change in ATRS (4.3, [0.5; 8.1]; P = 0.03) and (12.0, [5.0; 19.9]; P < 0.01), respectively. No other statistically significant differences were found. CONCLUSION: This study showed that patients with diabetes, hypertension, rheumatic disease and patients in treatment with orally administrated corticosteroids had a lower ATRS at baseline (prior to the rupture) when compared to patients without the respective disease or treatment. Diabetes and treatment with orally administrated corticosteroids did negatively affect ATRS at follow-up, but none of the investigated comorbidities or treatment with orally administrated corticosteroids did negatively affect change in ATRS from baseline to follow-up. LEVEL OF EVIDENCE: Level III.

Outcome after acute Achilles tendon rupture is not negatively affected by female sex and age over 65 years.

PURPOSE: Studies suggest that women have worse treatment outcome than men after acute Achilles tendon rupture (ATR). The aim of this study was to investigate if sex and age affect treatment outcome after ATR. METHODS: The study was performed as a registry study in the Danish Achilles tendon Database. The primary outcome was change in the Achilles tendon Total Rupture Score (ATRS) from baseline to 4 months, 1 year and 2 years follow-up. Variables of interest were sex and age group (< 40 years, 40-65 years and > 65 years). RESULTS: Data were collected from April 2012 to March 2018. Five-hundred and sixteen patients (416 men, 100 women) were included in the study population. At baseline, women scored 4.3 points lower in ATRS compared to men. No statistically significant difference between the sexes regarding change in ATRS were found. Women scored statistically significantly less in absolute ATRS at 1 year follow-up (mean difference 9.4; 95% CI 3.8, 14.9; P = 0.03). Patients older than 65 years scored statistically significantly more in ATRS change compared to patients between 40-65 years (mean difference 12.8; 95% CI 6.1-19.5; P < 0.001). CONCLUSION: This study did not show a statistically significant or clinically relevant difference between the sexes in ATRS change from baseline to follow-up. The mean difference in ATRS change between patients older than 65 years and patients between 40-65 years was clinically relevant with better outcome for patients older than 65 years. When comparing ATRS between groups with an unequal sex distribution, the findings of a baseline difference and a difference in absolute ATRS at 1 year follow-up between the sexes, advocate for reporting of sex-specific data or for use of change in ATRS from baseline to follow-up instead of absolute ATRS. LEVEL OF EVIDENCE: Level III.

Sources of drug information.

Modern healthcare requires clinicians to navigate through complex drug treatments. This review offers an overview of sources of drug information which can be used for general medication prescription and for challenging patient populations. Key considerations for pregnant or breastfeeding patients, those with renal impairment, and those with liver dysfunction are discussed. We also touch on adverse drug reactions and drug interactions. Finally, information about services from independent regional drug information centers, that can be used by clinicians, are provided.

Achilles Tendon Tissue Turnover Before and Immediately After an Acute Rupture.

BACKGROUND: An Achilles tendon rupture (ATR) is a frequent injury and results in the activation of tendon cells and collagen expression, but it is unknown to what extent turnover of the tendon matrix is altered before or after a rupture. PURPOSE/HYPOTHESIS: The purpose of this study was to characterize tendon tissue turnover before and immediately after an acute rupture in patients. It was hypothesized that a rupture would result in pronounced collagen synthesis in the early phase (first 2 weeks) after the injury. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: The study included patients (N = 18) eligible for surgery after an ATR. At the time of inclusion, the patients ingested deuterium oxide (2H2O) orally, and on the day of surgery (within 14 days of the injury), they received a 3-hour flood-primed infusion of an 15N-proline tracer. During surgery, the patients had 1 biopsy specimen taken from the ruptured part of the Achilles tendon and 1 that was 3 to 5 cm proximal to the rupture as a control. The biopsy specimens were analyzed for carbon-14 (14C) levels in the tissue to calculate long-term turnover (years), incorporation of 2H-alanine (from 2H2O) into the tissue to calculate the fractional synthesis rate (FSR) of proteins in the short term (days), and incorporation of 15N-proline into the tissue to calculate the acute FSR (hours). RESULTS: Both the rupture and the control samples showed consistently lower levels of 14C compared with the predicted level of 14C in a healthy tendon, which indicated increased tendon turnover in a fraction (48% newly synthesized) of the Achilles tendon already for a prolonged period before the rupture. Over the first days after the rupture, the synthesis rate for collagen was relatively constant, and the average synthesis rate on the day of surgery (2-14 days after the rupture) was 0.025% per hour, irrespective of the length of time after a rupture and the site of sampling (rupture vs control). No differences were found in the FSR between the rupture and control samples in the days after the rupture. CONCLUSION: Higher than normal tissue turnover in the Achilles tendon before a rupture indicated that changes in the tendon tissue preceded the injury. In addition, we observed no increase in tendon collagen tissue turnover in the first 2 weeks after an ATR. This favors the view that an increase in the formation of new tendon collagen is not an immediate phenomenon during the regeneration of ruptured tendons in patients. REGISTRATION: NCT03931486 (ClinicalTrials.gov identifier).

Involvement of Bacteria in the Pathological Changes Before Achilles Tendon Rupture: A Case Series Investigating 16S rDNA in 20 Consecutive Ruptures.

Background: The source of the pathological changes that occur before an acute Achilles tendon rupture (ATR) is not fully understood. Bacterial DNA has previously been detected in samples from ruptured Achilles tendons, suggesting a pathogenic role of bacteria in ATR. Purpose/Hypothesis: The purpose of this study was to investigate if DNA from bacteria was present in acutely ruptured Achilles tendons. We hypothesized that 20% to 30% of the samples from the rupture site and no samples from healthy tissue would be positive for bacterial DNA. Study Design: Case series; Level of evidence, 4. Methods: This study included 20 consecutive patients scheduled for surgical repair of an acute ATR. Tendon biopsy specimens were taken from the rupture site and from the healthy tendon tissue proximal to the rupture to act as a control. Samples were blinded to the technician and analyzed using polymerase chain reaction targeted to the bacterial 16S rDNA gene and Sanger sequencing to identify the bacterial species present. McNemar test for paired proportions was performed to test for statistically significant differences in the number of samples positive for bacterial DNA between the ruptured and control regions of the Achilles tendon. Results: Of the 20 patients, 1 (5%) had a positive sample with bacterial DNA from the ruptured part of the Achilles tendon. The same patient also had a positive control sample, although with different bacterial DNA. An additional patient had a positive control sample. There was no statistically significant difference in the number of bacterial DNA-positive samples between the ruptured and control regions of the Achilles tendon. The bacteria found (Staphylococcus sp, Micrococcus sp, and Staphylococcus epidermidis) were normal commensal organisms on the human skin. Conclusion: Bacterial DNA was infrequent in tissue from ruptured Achilles tendons and, if identified, likely was a result of contamination. This suggests that bacteria are not involved in the pathological changes occurring before rupture of the Achilles tendon.

Validity of sports-related diagnosis codes in the Danish National Patient Register.

INTRODUCTION The diagnosis codes for sports-related injuries in the Danish National Patient Register (DNPR) are frequently used for research. Even so, their validity remains unknown. The aim of this study was to establish the validity of sports-related diagnosis codes in the DNPR. METHODS The study was conducted as a registry study in the DNPR investigating the diagnosis codes for acute Achilles tendon rupture, Achilles tendinitis, anterior cruciate ligament (ACL) rupture, dislocation of the patella, traumatic tear of the meniscus and degenerative meniscal lesion. For each diagnosis code, patient records were retrieved. We considered a positive predictive value (PPV) of 80% or higher to be satisfying. RESULTS A total of 523 patients were included. The PPV for acute Achilles tendon rupture was 98% (95% confidence interval (CI): 92-100%), for Achilles tendinitis 85% (95% CI: 74-92%), for ACL rupture 96% (95% CI: 88-99%) and for dislocation of the patella 96% (95% CI: 90-99%). Depending on the diagnosis definition used, the PPVs were 56-72% for traumatic tear of the meniscus and 53-77% for degenerative meniscal lesion. CONCLUSIONS This study documented an acceptable validity allowing for epidemiological research of the diagnosis codes for acute Achilles tendon rupture, Achilles tendinitis, ACL rupture and dislocation of the patella. The diagnosis codes for traumatic tear of the meniscus and degenerative meniscal lesion showed a lower validity, and thus caution should be taken when using these codes. FUNDING none. TRIAL REGISTRATION The study was approved by the Danish Data Protection Agency and the Danish Patient Safety Authority.

Completeness and data validity in the Danish Achilles tendon Database.

INTRODUCTION: Acute Achilles tendon rupture is a severe injury causing functional deficits and sick leave. Data from the Danish Achilles tendon Database (DADB) can help us monitor and optimise treatment. The aim of this study was to investigate the completeness and data validity in the DADB. METHODS: The study was performed as a registry study comparing data in the DADB with data from patient records. Data were collected from three of 11 hospitals registered in the DADB. The study was conducted from 1 January to 31 December 2016. A completeness of 80% was considered satisfactory, and a parameter was valid if there was agreement between the DADB and the patient record in 80% of the cases. RESULTS: Overall, completeness was 77% (155/201); for the non-operated patients 81% (150/185) and the operated patients 31% (5/16). The seven investigated parameters all showed a validity of 83-100%. CONCLUSIONS: This study documented a satisfactory completeness of data on the non-operated patients registered in the DADB and an unsatisfactory completeness of data on operated patients. All investigated parameters were valid. These results suggest that data in the DADB on non-operated patients can contribute to research within the field. Due to a limited sample on operated patients, conclusions should be made with caution. The logistics concerning data collection among operated patients warrants optimisation. FUNDING: not relevant. TRIAL REGISTRATION: The study was approved by the Danish Data Protection Agency and the Danish Patient Safety Authority.