BackgroundIn situations of unmet medical need or in the interests of public health, expedited approval pathways, including conditional marketing authorisation (CMA) and accelerated assessment (AA), speed up European Medicines Agency (EMA) marketing authorisation recommendations for medicinal products. CMAs are based on incomplete benefit-risk assessment data and authorisation remains conditional until regulator-imposed confirmatory postmarketing measures are fulfilled. For products undergoing AA, complete safety and efficacy data should be available, and postauthorisation measures may include only standard requirements of risk management and pharmacovigilance plans. In the pivotal trials supporting products assessed by expedited pathways, surrogate endpoints reduce drug development time compared with waiting for the intended clinical outcomes. Whether surrogate endpoints supporting products authorised through CMA and AA pathways reliably predict clinical benefits of therapy has not been studied systematically. Our objectives were to determine the extent to which surrogate endpoints are used and to assess whether their validity had been confirmed according to published hierarchies.Methods and findingsWe used European Public Assessment Reports (EPARs) to identify the primary endpoints in the pivotal trials supporting products authorised through CMA or AA pathways during January 1, 2011 to December 31, 2018. We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame. Where pivotal trials reported surrogate endpoints, we conducted PubMed searches for evidence of validity for predicting clinical outcomes. We used 2 published hierarchies to assess validity level. Surrogates with randomised controlled trials supporting the surrogate-clinical outcome relationship were rated as ‘validated’. Fifty-one products met the inclusion criteria; 26 underwent CMAs, and 25 underwent AAs. Overall, 26 products were for oncology indications, 10 for infections, 8 for genetic disorders, and 7 for other systems disorders. Five products (10%), all AAs, were authorised based on pivotal trials reporting clinical outcomes, and 46 (90%) were authorised based on surrogate endpoints. No studies were identified that validated the surrogate endpoints. Among a total of 49 products with surrogate endpoints reported, most were rated according to the published hierarchies as being ‘reasonably likely’ (n = 30; 61%) or of having ‘biological plausibility’ (n = 46; 94%) to predict clinical outcomes. EPARs did not consistently explain the nature of the pivotal trial endpoints supporting authorisations, whether surrogate endpoints were validated or not, or describe the endpoints to be reported in the confirmatory postmarketing studies. Our study has limitations: we may have overlooked relevant validation studies; the findings apply to 2 expedited pathways and may not be generalisable to products authorised through the standard assessment pathway.ConclusionsThe pivotal trial evidence su...

AimsTo review the ECGs of all patients referred to MAT services over the preceding 5 year period.BackgroundNeurodegenerative conditions such as Alzheimer's Disease can be treated with Acetylcholinesterase Inhibitors (AChEI) to slow down cognitive decline. Side effects of AChEIs include bradycardia, syncope and cardiac conduction disorders. An electrocardiograms (ECG) is completed prior to memory assessment team (MAT) medical assessments to screen for those who may be at risk of the cardiac side effects of AChEIs. ECGs may be included in the initial referral to the service or completed by the MAT. Given the predominantly elderly population referred to the MATs service, other incidental abnormalities are to be expected. Not all MAT referrals that are screened by memory nurses reach the threshold to be reviewed by the medical team and therefore not all ECGs are routinely reviewed, potentially missing clinically significant abnormalities.ResultA total of 1795 patients were identified as being referred to a single mental health unit in the North West on England over a five-year period. 781 (44%) of the patients had an ECG completed by the MAT, of which 452 (58%) showed an abnormality. Significant abnormalities that were previously unknown to the patients’ primary care provider include eight cases of Atrial Fibrillation (AF), four cases of Trifasciular Block, and 19 cases of Left Ventricular Hypertrophy (LVH). 64 (8%) of patients who had an ECG by the MAT had a bradycardia.ConclusionIn addition to identifying abnormalities that could interfere with memory medication, this audit showed that over half of the ECGs completed by the MAT had an atypical trace. Cardiology was consulted to identify which abnormalities were considered clinically significant and if not already known, the general practitioner (GP) was informed. A change in the local service means that all ECGs completed by the MAT are now screened at point of filling into the notes, so any future abnormalities are identified and followed up immediately.