The problem of wasteful clinical trials has been debated relentlessly in the medical community. To a significant extent, it is attributed to redundant trials - studies that are carried out to address ...questions, which can be answered satisfactorily on the basis of existing knowledge and accessible evidence from prior research. This article presents the first evaluation of the potential of the EU Clinical Trials Regulation 536/2014, which entered into force in 2014 but is expected to become applicable at the end of 2021, to prevent such trials. Having reviewed provisions related to the trial authorisation, we propose how certain regulatory requirements for the assessment of trial applications can and should be interpreted and applied by national research ethics committees and other relevant authorities in order to avoid redundant trials and, most importantly, preclude the unnecessary recruitment of trial participants and their unjustified exposure to health risks.
Adverse reactions and medication errors are complications of drug use. Spontaneous reporting systems and pharmacoepidemiological studies incompletely detect the occurrence of these events in daily ...hospital care. In this study, the frequency and type of drug-related admissions and hospital-acquired adverse drug events (ADE) in Germany were assessed using routinely collected hospital data.
The study was based on aggregated hospital routine data covering the period 2003 to 2007 and annually recorded as part of the further development of the German Diagnosis-Related Groups. The 505 ICD-10-codes indicating an ADE were categorized in seven groups according to their certainty. Primary diagnoses were considered as a proxy for drug-related admissions, and secondary diagnoses as a proxy for hospital-acquired ADE.
Among all hospital admissions, 5% were found to be at least possibly drug-induced and 0.7% very likely drug-induced. There was a significant increase in the overall rate of drug-related admissions over time (p < 0.038). Enterocolitis due to Clostridium difficile infection was the most frequent cause of a drug-related admission. About 4.5% of in-patients had experienced a hospital-acquired ADE. In addition, over the course of the study period, the overall frequency of hospital-acquired ADEs significantly increased (p < 0.001).
In Germany, more than 5% of hospital episodes are either caused or complicated by an ADE. Between 2003 and 2007, there was a statistically significant increase in the overall rate and in some of the subcategories defined by the list of ICD-10-codes suspected to be indicative of an ADE. Before the use of routine data in pharmacovigilance and patient safety can be fully exploited, a further tailoring of both the ICD and the available variable set is needed.
Purpose
Two to seven percent of the German adult population has a renal impairment (RI) with an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73m
2
. This often remains unrecognized and ...adjustment of drug therapy is lacking. To determine renal function in clinical routine, the CKD-EPI equation is used to calculate an indexed eGFR (ml/min/1.73m
2
). For drug dosing, it has to be individualized to a non-indexed eGFR (ml/min) by the patient’s body surface area. Here, we investigated the number of patients admitted to urological wards of a teaching hospital with RI between July and December 2016. Additionally, we correctly used the eGFR
non-indexed
for drug and dosage adjustments and to analyse the use of renal risk drugs (RRD) and renal drug-related problems (rDRP).
Methods
In a retrospective observational study, urological patients with pharmacist-led medication reconciliation at hospital admission and eGFR
indexed
(CKD-EPI) of 15–59 ml/min/1.73m
2
were identified. Indexed eGFR (ml/min/1.73m
2
) was recalculated with body surface area to non-indexed eGFR (ml/min) for correct drug dosing. Medication at admission was reviewed for RRD and based on the eGFR
non-indexed
for rDRP, e.g. inappropriate dose or contraindication.
Results
Of 1320 screened patients, 270 (20.5%) presented with an eGFR
indexed
of 15–59 ml/min/1.73m
2
. After readjustment, 203 (15.4%) patients had an eGFR
non-indexed
of 15–59 ml/min. Of these, 190 (93.6%) used ≥ 1 drugs at admission with 660 of 1209 (54.7%) drugs classified as RRD. At least one rDRP was identified in 115 (60.5%) patients concerning 264 (21.8%) drugs.
Conclusion
Renal impairment is a common risk factor for medication safety in urologic patients admitted to a hospital. Considerable shifts were seen in eGFR-categories when correctly calculating eGFR
non-indexed
for drug dosing purposes. The fact that more than half of the study patients showed rDRP at hospital admission underlines the need to consider this risk factor appropriately.
Deep molecular response (MR(4.5)) defines a subgroup of patients with chronic myeloid leukemia (CML) who may stay in unmaintained remission after treatment discontinuation. It is unclear how many ...patients achieve MR(4.5) under different treatment modalities and whether MR(4.5) predicts survival.
Patients from the randomized CML-Study IV were analyzed for confirmed MR(4.5) which was defined as ≥ 4.5 log reduction of BCR-ABL on the international scale (IS) and determined by reverse transcriptase polymerase chain reaction in two consecutive analyses. Landmark analyses were performed to assess the impact of MR(4.5) on survival.
Of 1,551 randomly assigned patients, 1,524 were assessable. After a median observation time of 67.5 months, 5-year overall survival (OS) was 90%, 5-year progression-free-survival was 87.5%, and 8-year OS was 86%. The cumulative incidence of MR(4.5) after 9 years was 70% (median, 4.9 years); confirmed MR(4.5) was 54%. MR(4.5) was reached more quickly with optimized high-dose imatinib than with imatinib 400 mg/day (P = .016). Independent of treatment approach, confirmed MR(4.5) at 4 years predicted significantly higher survival probabilities than 0.1% to 1% IS, which corresponds to complete cytogenetic remission (8-year OS, 92% v 83%; P = .047). High-dose imatinib and early major molecular remission predicted MR(4.5). No patient with confirmed MR(4.5) has experienced progression.
MR(4.5) is a new molecular predictor of long-term outcome, is reached by a majority of patients treated with imatinib, and is achieved more quickly with optimized high-dose imatinib, which may provide an improved therapeutic basis for treatment discontinuation in CML.
The prognostic relevance of additional cytogenetic findings at diagnosis of chronic myeloid leukemia (CML) is unclear. The impact of additional cytogenetic findings at diagnosis on time to complete ...cytogenetic (CCR) and major molecular remission (MMR) and progression-free (PFS) and overall survival (OS) was analyzed using data from 1151 Philadelphia chromosome–positive (Ph+) CML patients randomized to the German CML Study IV. At diagnosis, 1003 of 1151 patients (87%) had standard t(9;22)(q34;q11) only, 69 patients (6.0%) had variant t(v;22), and 79 (6.9%) additional cytogenetic aberrations (ACAs). Of these, 38 patients (3.3%) lacked the Y chromosome (−Y) and 41 patients (3.6%) had ACAs except −Y; 16 of these (1.4%) were major route (second Philadelphia Ph chromosome, trisomy 8, isochromosome 17q, or trisomy 19) and 25 minor route (all other) ACAs. After a median observation time of 5.3 years for patients with t(9;22), t(v;22), −Y, minor- and major-route ACAs, the 5-year PFS was 90%, 81%, 88%, 96%, and 50%, and the 5-year OS was 92%, 87%, 91%, 96%, and 53%, respectively. In patients with major-route ACAs, the times to CCR and MMR were longer and PFS and OS were shorter (P < .001) than in patients with standard t(9;22). We conclude that major-route ACAs at diagnosis are associated with a negative impact on survival and signify progression to the accelerated phase and blast crisis.
Blood pressure lowering drugs are usually evaluated in short term trials determining the absolute blood pressure reduction during trough and the duration of the antihypertensive effect after single ...or multiple dosing. A lack of persistence with treatment has however been shown to be linked to a worse cardiovascular prognosis. This review explores the blood pressure reduction and persistence with treatment of antihypertensive drugs and the cost consequences of poor persistence with pharmaceutical interventions in arterial hypertension.
We have searched the literature for data on blood pressure lowering effects of different antihypertensive drug classes and agents, on persistence with treatment, and on related costs. Persistence was measured as patients' medication possession rate. Results are presented in the form of a systematic review.
Angiotensin II receptor blocker (ARBs) have a competitive blood pressure lowering efficacy compared with ACE-inhibitors (ACEi) and calcium channel blockers (CCBs), beta-blockers (BBs) and diuretics. 8 studies describing the persistence with treatment were identified. Patients were more persistent on ARBs than on ACEi and CCBs, BBs and diuretics. Thus the product of blood pressure lowering and persistence was higher on ARBs than on any other drug class. Although the price per tablet of more recently developed drugs (ACEi, ARBs) is higher than that of older ones (diuretics and BBs), the newer drugs result in a more favourable cost to effect ratio when direct drug costs and indirect costs are also considered.
To evaluate drugs for the treatment of hypertension several key variables including the blood pressure lowering effect, side effects, compliance/persistence with treatment, as well as drug costs and direct and indirect costs of medical care have to be considered. ARBs, while nominally more expensive when drug costs are considered only, provide substantial cost savings and may prevent cardiovascular morbidity and mortality based on the more complete antihypertensive coverage. This makes ARBs an attractive choice for long term treatment of hypertension.
Treatment of chronic-phase (CP) chronic myeloid leukemia (CML) with imatinib 400 mg/d can be unsatisfactory. Optimization of treatment is warranted.
In all, 1,014 newly diagnosed CP-CML patients were ...randomly assigned to imatinib 800 mg/d (n = 338), imatinib 400 mg/d (n = 325), or imatinib 400 mg/d plus interferon alfa (IFN-α; n = 351). Dose adaptation to avoid higher-grade toxicity was recommended. First primary end point was major molecular remission (MMR) at 12 months.
A higher rate of MMR at 12 months occurred with tolerability-adapted imatinib 800 mg/d than with imatinib 400 mg/d (59% 95% CI, 53% to 65% v 44% 95% CI, 37% to 50%; P < .001) or imatinib 400 mg/d plus IFN-α (59% v 46% 95% CI, 40% to 52%; P = .002). Median dose in the 800-mg/d arm was 628 mg/d with a maximum dose of 737 mg/d during months 4 to 6 and a maintenance dose of 600 mg/d. All three treatment approaches were well tolerated with similar grade 3 and 4 adverse events. Independent of treatment approach, MMR at 12 months showed better progression-free survival (99% v 94%; P = .0023) and overall survival (99% v 93%; P = .0011) at 3 years when compared with > 1% on the international scale or no MMR but showed no difference in 0.1% to < 1% on the international scale, which closely correlates with complete cytogenetic remission.
Treatment of early-phase CML with imatinib can be optimized. Early high-dose therapy followed by rapid adaptation to good tolerability increases the rate of MMR at 12 months. Achievement of MMR by month 12 is directly associated with improved survival.
Prognostic scores support clinicians in selecting risk-adjusted treatments and in comparatively assessing different results. For patients with chronic-phase chronic myeloid leukemia (CML), four ...baseline prognostic scores are commonly used. Our aim was to compare the prognostic performance of the scores and to arrive at an evidence-based score recommendation. In 2949 patients not involved in any score development, higher hazard ratios and concordance indices in any comparison demonstrated the best discrimination of long-term survival with the ELTS score. In a second step, of 5154 patients analyzed to investigate risk group classification differences, 23% (n = 1197) were allocated to high-risk by the Sokal score. Of the 1197 Sokal high-risk patients, 56% were non-high-risk according to the ELTS score and had a significantly more favorable long-term survival prognosis than the 526 high-risk patients according to both scores. The Sokal score identified too many patients as high-risk and relatively few (40%) as low-risk (versus 60% with the ELTS score). Inappropriate risk classification jeopardizes optimal treatment selection. The ELTS score outperformed the Sokal score, the Euro, and the EUTOS score regarding risk group discrimination. The recent recommendation of the European LeukemiaNet for preferred use of the ELTS score was supported with significant statistical evidence.
Optimal adherence to CML therapy is of key importance to maximize treatment effectiveness. Two clinical studies (ADAGIO and Hammersmith) have proven a clear correlation between adherence and ...achieving optimal treatment response and have revealed that non-adherence is common in CML patients (Marin et al. in J Clin Oncol 28(24):2381–2388,
2010
, Noens et al. in Haematologica 99(33):437–447,
2014
). The aim of this study is to assess the extent of suboptimal adherence and to investigate motivations and behavioural patterns of adherence in a worldwide patient sample. Questionnaires were provided by the CML Advocates Network and were filled in by patients online and offline. Patient characteristics, treatment and motivations were collected. Adherence was assessed by the 8-item Morisky Medication Adherence scale. Logistic regression models were fitted to investigate the influence of different factors on adherence. Overall, 2 546 questionnaires from 63 countries and 79 CML patient organisations were evaluable. 32.7% of participants were highly adherent, 46.5% were in the medium and 20.7% in the low adherence group. Factors increasing the probability of being in the high adherence group are older age, male sex, management of side effects, only one tablet per day and feeling well informed about CML by the doctor. More than 2 years since diagnosis were significantly lowering the chance as was the use of reminding tools. Living arrangements, multiple medication and personal payment obligations increased the probability to be at least in the medium adherent group. This is the most comprehensive study conducted to date to gain knowledge about factors causing non-adherence in CML. Better information on the disease, medication and management of side effects, supported by haematologists, is key to improve adherence.
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