The use of validated and nonvalidated surrogate endpoints in two European Medicines Agency expedited approval pathways: A cross-sectional study of products authorised 2011-2018.

BACKGROUND: In 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 FINDINGS: We 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 We excluded products that were vaccines, topical, reversal, or bleeding prophylactic agents or withdrawn within the study time frame.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. CONCLUSIONS: The pivotal trial evidence supporting marketing authorisations for products granted CMA or AA was based dominantly on nonvalidated surrogate endpoints. EPARs and summary product characteristic documents, including patient information leaflets, need to state consistently the nature and limitations of endpoints in pivotal trials supporting expedited authorisations so that prescribers and patients appreciate shortcomings in the evidence about actual clinical benefit. For products supported by nonvalidated surrogate endpoints, postauthorisation measures to confirm clinical benefit need to be imposed by the regulator on the marketing authorisation holders.

Novel stratified medicines approach to manage uncontrolled hypertension due to multiple drug intolerances.

A 61-year-old man with a 30-year history of uncontrolled hypertension was unable to tolerate conventional antihypertensive medications from all classes. At the time of referral to our centre he had discontinued all antihypertensive drugs and felt well. However, his average home blood pressure (HBP) reading was 179/125 mm Hg and echocardiography demonstrated moderate concentric left ventricular hypertrophy. A novel stratified medicines algorithm was used to guide treatment entailing transdermal clonidine patch therapy instead of tablet formulations. Sixteen months later, his average HBP was 147/106 mm Hg with no side effects and the left ventricular hypertrophy had completely regressed. Our experience has taught us that multiple drug intolerance is a common, often overlooked, cause of non-adherence to antihypertensive medication. This case demonstrates the benefit of a novel approach to optimise blood pressure control and emphasises the important role of hypertension specialists in managing complex, high-risk patients unable to tolerate guideline-based therapy.

Childhood constipation: recognition, management and the role of the nurse.

Constipation is a common childhood condition that health professionals will encounter in many different settings. The majority of these cases of childhood constipation are idiopathic in nature. It is considered to exhibit the 'tip of the iceberg' phenomenon as a large number of cases remain undetected due to under-recognition by families, embarrassment regarding the condition, fear of receiving a negative response from health professionals, or parental belief there is actually something more seriously wrong and failure to accept the diagnosis. Prompt evaluation and management is likely to be associated with better outcomes. To ensure this, fast recognition of symptoms, with care taken to exclude any 'red flag' symptoms that could indicate an organic cause and subsequently a different treatment pathway, is essential. Nurses, given their regular contact with families in different settings, are suitably placed to detect these symptoms early and can play a vital role in successful management of the condition. Laxatives are the first line in management of constipation. Polyethylene glycol 3350 is the laxative that evidence-based guidelines from the National Institute for Health and Care Excellence (2010) recommend as the initial pharmacological management. Advice should also be given about supportive measures, including diet and lifestyle changes.