Post-approval studies in France, challenges facing medical devices.

Medical devices are characterized notably by a wide heterogeneity (from tongue depressors to hip prostheses, and from non-implantable to invasive devices), a short life cycle with recurrent incremental innovations (from 18 months to 5 years), and an operator-dependent nature. The objective of the current round table was to develop proposals and recommendations concerning the prerequisites needed in order to meet the French health authorities expectations concerning requests for post-approval studies for medical devices, required in cases where short and long-term consequences are unknown. These studies, which are the responsibility of the manufacturer or the distributor of the medical device, are designed to confirm the role of the medical device in the therapeutic management strategy in a real-life setting. There are currently approximately 150 post-approval studies underway, mainly concerning class III devices, and the majority face difficulties implementing the study or meeting the study objectives. In light of this, the round table endeavored to clearly identify the conditions for implementation of post-approval studies specific to the characteristics of medical devices. Various areas of progress have been envisaged to improve the performance of these studies, and by consequence, the efficiency of reimbursement of medical devices by the national health insurance. These include providing manufacturers with the opportunity to better anticipate post-approval requirements, defining a study-specific primary objective, integrating a phase allowing dialogue between the manufacturer, the health authorities and the scientific committee, and increasing awareness and training of health professionals on the impact of post-approval clinical studies in terms of the reimbursement of medical devices by the national insurance.

Specific barriers to the conduct of randomised clinical trials on medical devices.

BACKGROUND: Medical devices play an important role in the diagnosis, prevention, treatment and care of diseases. However, compared to pharmaceuticals, there is no rigorous formal regulation for demonstration of benefits and exclusion of harms to patients. The medical device industry argues that the classical evidence hierarchy cannot be applied for medical devices, as randomised clinical trials are impossible to perform. This article aims to identify the barriers for randomised clinical trials on medical devices. METHODS: Systematic literature searches without meta-analysis and internal European Clinical Research Infrastructure Network (ECRIN) communications taking place during face-to-face meetings and telephone conferences from 2013 to 2017 within the context of the ECRIN Integrating Activity (ECRIN-IA) project. RESULTS: In addition to the barriers that exist for all trials, we identified three major barriers for randomised clinical trials on medical devices, namely: (1) randomisation, including timing of assessment, acceptability, blinding, choice of the comparator group and considerations on the learning curve; (2) difficulties in determining appropriate outcomes; and (3) the lack of scientific advice, regulations and transparency. CONCLUSIONS: The present review offers potential solutions to break down the barriers identified, and argues for applying the randomised clinical trial design when assessing the benefits and harms of medical devices.

Evaluation of the safety and tolerability of rasagiline in the treatment of the early stages of Parkinson's disease.

OBJECTIVE: Rasagiline is a second-generation, irreversible MAO-B inhibitor (MAOB-I) previously shown to be efficacious and well-tolerated compared to placebo in the treatment of early Parkinson's disease (PD). ACTOR (ACceptabilité TOlérance Rasagiline) was a 15-week, multi-center, randomized, double-blind study aimed to assess the safety and tolerability of rasagiline compared to the dopaminergic agonist pramipexole in the treatment of early PD. METHODS: Patients with early, untreated idiopathic PD were randomized to receive 1 mg rasagiline (n = 53) or 1.5 mg pramipexole (n = 56) daily. The primary outcome was the number of patients experiencing a 'clinically important adverse event' (classified as a serious adverse event, an event leading to withdrawal or severe according to the patient). Safety outcomes were evaluated by the investigator and the patient. Analysis of the primary criterion was a comparative analysis using the chi-squared test. The Wilcoxon Mann-Whitney test was conducted to test the severity of patient-reported adverse events. Other tests performed include a covariance analysis and Student's t-tests. RESULTS: Mean disease duration was 3.4 months, and mean age was 62.6 years. Of patients taking pramipexole, 44.6% reported at least one 'clinically important' adverse event compared to 32.1% of patients taking rasagiline; non-inferiority of rasagiline was reached, with a difference in proportions of -12.6% [confidence interval of -27.8%; 2.6%]. There were no significant differences in clinical effectiveness between the treatments, measured by clinical and patient global impression of improvement (CGI-I, PGI-I) and PDQ-8 scales. A significant decrease in the incidence of gastrointestinal symptoms (p = 0.015) and sleep disorders (p = 0.027) was reported by physicians in the rasagiline group compared to the pramipexole group; the propensity to sleepiness improved significantly in the rasagiline group (p = 0.020), and worsened in the pramipexole group (p = 0.042). LIMITATIONS: Limitations of this study include the limited sample size due to the lower than anticipated recruitment and the accidental inclusion of a patient who had taken contraindicated medication. CONCLUSIONS: In this study, the safety profile of rasagiline had clinically favorable differences in gastrointestinal and sleep adverse events compared to pramipexole, whilst showing comparable clinician and patient-rated clinical effectiveness as a monotherapy for the treatment of early idiopathic PD.

Effects of dimethylaminoethanol pyroglutamate (DMAE p-Glu) against memory deficits induced by scopolamine: evidence from preclinical and clinical studies.

RATIONALE: Dimethylaminoethanol pyroglutamate (DMAE p-Glu) is a compound resulting from the reaction between dimethylaminoethanol (an indirect precursor of acetylcholine) and pyroglutamic acid (a cyclic derivative of glutamic acid having procholinergic properties and promnesic effects in both animals and man). OBJECTIVES: The present study undertook preclinical and clinical evaluations to test a potential therapeutic utility for DMAE p-Glu in cognitive impairments related to central cholinergic deficit. MATERIALS AND METHODS: In preclinical study, DMAE p-Glu was studied in rats by intracerebral microdialysis in conscious freely moving animals, on performance of rats in the Morris water maze test of spatial memory, and on the deficit in passive avoidance behavior induced by scopolamine. The clinical study examined the effect of DMAE p-Glu on cognitive deficits induced by an intravenous injection of scopolamine in healthy young male subjects. RESULTS: In rat experiments, DMAE p-Glu increased the extracellular levels of choline and acetylcholine in the medial prefrontal cortex, as assessed by intracerebral microdialysis, improved performance in a test of spatial memory, and reduced scopolamine-induced memory deficit in passive avoidance behavior. Clinical study results show that scopolamine induced a memory deficit and that DMAE p-Glu produced a significant positive effect on scores in the Buschke test, as well as a slight but significant difference on choice reaction time. CONCLUSION: These results indicate that DMAE p-Glu reduces the deleterious effect of scopolamine on long-term memory in healthy volunteers and suggest that DMAE p-Glu might be effective in reducing memory deficits in patients with cognitive impairment.

Effect of ascorbic acid in patients with Charcot-Marie-Tooth disease type 1A: a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Charcot-Marie-Tooth disease type 1A (CMT1A) is a hereditary peripheral neuropathy that affects roughly one in 5000 births. No specific therapy currently exists for this degenerative disorder, which is characterised by distal progressive muscle atrophy and sensory loss, although ascorbic acid has been shown to reduce demyelination and improve muscle function in a transgenic mouse model of CMT1A. We tested the safety and efficacy of ascorbic acid in adults with CMT1A. METHODS: This 12-month, randomised, double-blind, placebo-controlled study was undertaken between September, 2005, and October, 2008. Patients diagnosed with CMT1A according to clinical examination and confirmation by genotyping were randomly assigned in a 1:1:1 ratio to receive 1 g ascorbic acid per day, 3 g ascorbic acid per day, or placebo. Treatment allocation was based on a computer-generated list of random numbers in blocks of 12, with stratification according to study site and sex; all investigators and participants were unaware of treatment allocation. The primary outcome was the Charcot-Marie-Tooth disease neuropathy score (CMTNS) at 12 months. Analysis was by intention to treat. This study is registered with the Orphanet Database, number ORPHA60779. FINDINGS: The median change in CMTNS from baseline to 12 months was 0.5 points (95% CI -0.3 to 1.4) for the placebo group (n=62), 0.7 points (0.0 to 1.4) for the 1 g ascorbic acid group (n=56), and -0.4 points (-1.2 to 0.4) for the 3 g ascorbic acid group (n=61). We did not find any significant difference in these changes between the groups (p=0.14). The occurrence of adverse events did not differ between the groups (p=0.74). INTERPRETATION: Ascorbic acid at both doses was safe and well tolerated in adults with CMT1A over 12 months. However, there were no significant differences between the groups and the efficacy of ascorbic acid was not shown.

At low doses, a gamma-linolenic acid-lipoic acid conjugate is more effective than docosahexaenoic acid-enriched phospholipids in preventing neuropathy in diabetic rats.

A deficiency in essential fatty acid metabolism has been reported in diabetes. Nutritional supplementations with (n-6) or (n-3) PUFA have differential efficiency on parameters of diabetic neuropathy, including nerve conduction velocity (NCV) and nerve blood flow (NBF). The aim of this study was to compare the neuroprotective effects of gamma-linolenic acid (GLA)-lipoic acid (LA) conjugate (GLA-LA) and docosahexaenoic acid (DHA)-enriched phospholipids (PL) supplementations on NCV and NBF. Streptozotocin-induced diabetic (D) and control (C) rats were supplemented for 8 wk with either DHA-enriched PL at a dose of 30 mg.kg-1.d-1 (DDHA and CDHA) or with corn oil enriched with GLA-LA at a dose of 30 mg.kg-1.d-1 (DGLA and CGLA). Moreover, a C and D group received no supplementation. After 8 wk, NCV (-30%) and NBF (-50%) were lower in the D group than in the C group. Supplementation with GLA-LA totally prevented the decrease in NCV and NBF in the DGLA group, in which values did not differ from group C. Supplementation with DHA only partially prevented the decrease in NCV in the DDHA group, in which value was different from groups C and D and did not affect NBF. We conclude that at the low doses used, supplementation with GLA-LA is more effective than supplementation with DHA in preventing experimental diabetic neuropathy. The difference could be due in part to an antioxidant protective effect of LA on GLA.