Medical Device Trials Research Articles

A Framework for In Silico Clinical Trials for Medical Devices Using Concepts From Model Verification, Validation, and Uncertainty Quantification

Abstract The rising costs of clinical trials for medical devices in recent years has led to an increased interest in what are called in silico clinical trials, where simulation results are used to supplement or to replace those obtained from human patients. Here we present a framework for executing such a trial. This framework relies heavily on ideas already developed for model verification, validation, and uncertainty quantification. The framework uses results from an initial cohort of human patients as model validation data, recognizing that the best model credibility evidence usually comes from real patients. The validation exercise leads to an assessment of the model's suitability based on predefined acceptance criteria. If the model meets these criteria, then no additional human patients are required and the study endpoints that can be addressed using the model are met using the simulation results. Conversely, if the model is found to be inadequate, it is abandoned, and the clinical study continues using only human patients in a second cohort. Compared to other frameworks described in the literature based on Bayesian methods, this approach follows a strict model build-validate-predict structure. It can handle epistemic uncertainties in the model inputs, which is a common trait of models of biomedical systems. Another idea discussed here is that the outputs of engineering models rarely coincide with measures that are the basis for clinical endpoints. This article discusses how the link between the model and clinical measure can be established during the trial.

ПРОГАЛИНИ У РЕГУЛЯЦІЇ ПРОВЕДЕННЯ КЛІНІЧНИХ ДОСЛІДЖЕНЬ МЕДИЧНИХ ВИРОБІВ ТА МЕДИЧНИХ ВИРОБІВ ДЛЯ IN VITRO ДІАГНОСТИКИ В УКРАЇНІ

The article summarizes the arguments and counterarguments within the scientific debate on the issue of gaps in the regulation of clinical research of medical devices and medical devices for in vitro diagnostics in Ukraine. The main goal of the conducted research is to identify an exhaustive list of such gaps and develop recommendations for improving the mentioned regulations. The systematization of literary sources and approaches to solving the problem of gaps in the regulation of clinical research of medical devices and medical devices for in vitro diagnostics in Ukraine proved that the scientific discussion on this topic is not conducted in Ukraine, despite the presence of WHO recommendations on the revision of relevant legal acts . The urgency of solving this scientific problem lies in the fact that filling the gaps in the relevant regulations and harmonizing the regulations with the relevant regulations of the European Union is an integral part of the recognition of clinical evidence on the effectiveness and safety of medical devices obtained during research in Ukraine by European regulatory authorities. Filling these gaps could potentially lead to increased demand for clinical trials of medical devices and medical devices for in vitro diagnostics in Ukraine. The results of the empirical analysis of the market of clinical research of medical products in Ukraine, in comparison with clinical research of medicinal products in Ukraine, proved that Ukraine is more attractive for conducting clinical research of medicinal products. This trend is explained, in particular, by the presence of specialized regulation of clinical trials of medicinal products in Ukraine, the presence of a body responsible for supervision, audit, and evaluation of the results of such clinical trials. The study empirically confirms and theoretically proves that the regulation of this area is insufficient, which leads to the need for additional examination of research materials abroad, and therefore to lower interest in conducting clinical research of medical devices in Ukraine. The results of the conducted research may be useful to regulatory bodies for the development of a regulatory framework for conducting clinical trials of medical devices and products for in vitro diagnostics in Ukraine, sponsors of such trials and contractor companies performing such trials in Ukraine

Badania kliniczne wyrobów medycznych wykorzystujących inteligentne algorytmy – wstęp do dyskusji

The authors of the paper carry out a preliminary assessment of the new regulation on clinical trials of medical devices in the context of software based on intelligent algorithms (so-called AI systems). The primary source of law here is the EU Medical Device Regulation (MDR). The study highlights the need to take into account the regulations on artificial intelligence systems when conducting clinical trials. It is justified by their close relationship with the EU provisions on medical devices. The main difficulty in making a legal and ethical assessment of new solutions used in medical devices is the application of various, sometimes divergent, regulations in the field of new technologies and medical law. The study contains preliminary, necessarily balanced and careful, bearing in mind the need to protect patients - research participants (and other people), conclusions on the application of the above provisions in the conduct of clinical trials.

Брахитерапия локализованного рака предстательной железы отечественными источниками I-125: собственный опыт Национального медицинского исследовательского центра радиологии

Introduction. One of the effective and minimally invasive methods prostate cancer treatment is interstitial radiation therapy, the essence of which is the implantation of radioactive microsources into the tumor tissue. Brachytherapy of prostate cancer is performed in more than 20 clinics in the Russian Federation using mainly foreign microsources, but their high cost does not allow increasing the number of operations and opening new brachytherapy departments in the Russian Federation. Based on the model of foreign microsources such as seed No. 6711 (Nicomed Amersham), a technology for the manufacture of microsources with iodine-125 (IPPE SEED) has been developed at the State Research Center of the Russian Federation - IPPE, as well as a pilot production facility with a capacity of up to 50 thousand items per year. Materials and methods. In order to assess the safety of microsources for medical personnel during brachytherapy, local dosimetric control was carried out. As part of a clinical study in 2015, 36 patients with stage T1 – T2 prostate cancer underwent low-power brachytherapy using domestic microsources. Results. The obtained values of absorbed doses do not differ within the limits of measurement errors from the values of doses determined during the operation with foreign microsources under similar conditions. It follows from the data obtained that even the maximum values of the measured local absorbed doses do not pose a radiation hazard when using IPPE SEED microsources for brachytherapy. Among the treated patients, adverse reactions were in the expected manifestations of grade 1 dysuria according to the RTOG / EORTC classification. No gastrointestinal toxicity has been reported. Patient monitoring was continued in order to obtain long-term results of treatment. PSA disease-free survival at 5-year follow-up was 94.4%. Discussion. Clinical trials of Russian medical devices have demonstrated their safety for patients and medical personnel, which was proved by conducting dosimetry control during the procedure itself, as well as during examination of patients after brachytherapy. The effectiveness of Russian microsources I-125 during low-power brachytherapy is demonstrated by a decrease in PSA level from baseline by 87% at a follow-up period of 6 months. The disease-free survival rate for 5 years was 94.4%. The absence of significant radiation reactions both in the early and in the late postoperative period is important. The low cost of microsources produced by JSC «SSC RF – IPPE» relative to foreign analogs makes it possible to increase the number of operations performed annually, and also gives prospects for opening new divisions performing interstitial radiation therapy operations. Conclusions. Russian microsources «IPPE SEED» have successfully passed clinical trials, during which their effectiveness and safety were proved. The study also demonstrated high rates of relapse-free survival and a low level of adverse reactions in treated patients.

In-silico trial of intracranial flow diverters replicates and expands insights from conventional clinical trials

The cost of clinical trials is ever-increasing. In-silico trials rely on virtual populations and interventions simulated using patient-specific models and may offer a solution to lower these costs. We present the flow diverter performance assessment (FD-PASS) in-silico trial, which models the treatment of intracranial aneurysms in 164 virtual patients with 82 distinct anatomies with a flow-diverting stent, using computational fluid dynamics to quantify post-treatment flow reduction. The predicted FD-PASS flow-diversion success rates replicate the values previously reported in three clinical trials. The in-silico approach allows broader investigation of factors associated with insufficient flow reduction than feasible in a conventional trial. Our findings demonstrate that in-silico trials of endovascular medical devices can: (i) replicate findings of conventional clinical trials, and (ii) perform virtual experiments and sub-group analyses that are difficult or impossible in conventional trials to discover new insights on treatment failure, e.g. in the presence of side-branches or hypertension.

From sandbox to pandemic: Agile reform of Canadian drug regulation

Public health urgency for emerging COVID-19 treatments and vaccines challenges regulators worldwide to ensure safety and efficacy while expediting approval. In Canada, legislative amendments by 2019 Omnibus Bill C-97 created a new "agile" licensing framework known as the "Advanced Therapeutic Pathway" (ATPathway) and modernized the regulation of clinical trials of drugs, vaccines, and medical devices. Bill C-97′s amendments are worthy of attention in Canada and globally, as health product regulation bends to COVID-19. The amendments follow reforms elsewhere to accommodate health product innovation, however, the Canadian ATPathway is broader and more flexible than its counterparts in other jurisdictions. In addition, Bill C-97 informed Canada's COVID-19 response in important ways, particularly in relation to clinical trials. The measures adopted by the drug regulatory authority, Health Canada (HC) during COVID-19 may become the new norm in Canadian regulatory practice insofar as they help achieve the amendments introduced by Bill C-97. Finally, despite government rhetoric of transparency, the agenda-setting, formulation, and implementation of the amendments have occurred with little opportunity for scrutiny or public engagement.

Pressure Relieving Support Surfaces: a Randomised Evaluation 2 (PRESSURE 2): using photography for blinded central endpoint review

BackgroundPRESSURE 2 is a randomised evaluation of the clinical and cost-effectiveness of two types of mattress for the prevention of pressure ulcers (PUs). The primary clinical endpoint was time to development of a category ≥2 PU. The current ‘gold standard’ for PU identification is expert clinical assessment. Due to the mattress appearance, a blinded assessment of the endpoint is not possible. This poses a risk to the internal validity of the study. A possible approach is to use photographs of skin sites, with central blinded review. However, there are practical and scientific concerns including patients’ consent to photographs, burden of data collection, photograph quality, data completeness and comparison of photographs to the current ‘gold standard’. This paper reports the findings of the PRESSURE 2 photographic validation sub-study.MethodWhere consent was obtained, photographs were taken of all category ≥2 PUs on the first presentation to assess over-reporting, and for the assessment of under-reporting, a random sample of 10% patients had an assessment by an independent clinical assessor who also photographed two skin sites. The staff were trained in taking and transferring photographs using standardised procedures and equipment. A card included in the photograph recorded participant details and a ‘greyscale’ for correction of white balance during processing. Three blinded reviewers assessed the photographs and rated how confident they were in their assessment.ResultsThe trial recruited 2029 patients; 85% consented to photography, and 532 photographs were received and used in the blinded central review. The level of confidence varied by skin classification with more confidence observed when the skin was assessed as being less severe than a category ≥2 PU. Overall, there was a very good reliability compared to the gold standard expert clinical assessment (87.8%, kappa 0.82).ConclusionStudy findings have usefully informed the scientific and practical issues of blinded assessment of PU status to reducing the risk of bias in medical device trials. The reliability of central blinded expert photography was found to be ‘very good’ (PABAK). Photographs have been found to be an acceptable method of data validation for participants. Methods to improve the quality of photographs would increase the confidence in the assessments.Trial registrationISRCTN Registry ISRCTN01151335. Registered on 19 April 2013

Development and Effectiveness Testing of “Punsook”: A Smartphone Application for Intermittent Urinary Catheter Users with Spinal Cord Injury

Objective: To develop and evaluate effectiveness of a smartphone application to assist the self-management of intermittent urinary catheter users Methods: This is experimental clinical research as part of a medical device trial. In phase 1, 10 intermittent urinary catheter users were recruited from spinal cord injury (SCI) patients who had been admitted to a rehabilitation ward at Siriraj Hospital. They used the preliminary version of “Punsook”, a web-based application (app) for a smartphone, alongside usual intermittent urinary catheterization (IC), and gave feedback on their experiences. Their qualitative opinions were used to further develop a second version of the “Punsook” app. In phase 2, the new version was used by 35 participants, who were asked to complete an effectiveness questionaire after using the app, including providing details on their history of urinary tract infection (UTI), urinary leakage, and catheterization-related pain. This information was gathered at the end of first and third months in the second phase of the study. Results: More than half the participants agreed at the end of the first month that every part of the app was acceptably pleasant. They liked the simplicity and ease of use of the app, accessibility, ease of return to use, and interest in the program. No statistically significant changes in urinary leakage, UTI, or pain were found. Conclusion: The app was considered effective in terms of the positive user satisfaction with all aspects of the app. However, despite this positive reception, the app may not have contributed to an improvement in participant bladder control.

Silicone adhesive multilayer foam dressings as adjuvant prophylactic therapy to prevent hospital-acquired pressure ulcers: a pragmatic noncommercial multicentre randomized open-label parallel-group medical device trial.

SummaryBackgroundSilicone adhesive multilayer foam dressings are used as adjuvant therapy to prevent hospital‐acquired pressure ulcers (PUs).ObjectivesTo determine whether silicone foam dressings in addition to standard prevention reduce the incidence of PUs of category 2 or worse compared with standard prevention alone.MethodsThis was a multicentre, randomized controlled medical device trial conducted in eight Belgian hospitals. At‐risk adult patients were centrally randomized (n = 1633) to study groups based on a 1 : 1 : 1 allocation: experimental groups 1 (n = 542) and 2 (n = 545) – pooled as the treatment group – and the control group (n = 546). The experimental groups received PU prevention according to hospital protocol, and a silicone foam dressing on the relevant body sites. The control group received standard of care. The primary endpoint was the incidence of a new PU of category 2 or worse at the studied body sites.ResultsIn the intention‐to‐treat population (n = 1605), PUs of category 2 or worse occurred in 4·0% of patients in the treatment group and 6·3% in the control group [relative risk (RR) 0·64, 95% confidence interval (CI) 0·41–0·99, P = 0·04]. Sacral PUs were observed in 2·8% and 4·8% of the patients in the treatment group and the control group, respectively (RR 0·59, 95% CI 0·35–0·98, P = 0·04). Heel PUs occurred in 1·4% and 1·9% of patients in the treatment and control groups, respectively (RR 0·76, 95% CI 0·34–1·68, P = 0·49).ConclusionsSilicone foam dressings reduce the incidence of PUs of category 2 or worse in hospitalized at‐risk patients when used in addition to standard of care. The results show a decrease for the sacrum, but no statistical difference for the heel and trochanter areas.

Medicine-by-wire: Practical considerations on formal techniques for dependable medical systems

• Application of formal methods to commercial medical devices in the UK. • Empirical socio-technical experiment on effective application of formal techniques. • Need for safety-critical mentality and safe automation in medicine. We see the future of medicine as highly automated. Improvement in care-provision will be achieved by both increased clinician efficiency, as well as new computing assisted treatments and diagnoses. In other safety-critical industries, such as avionics and automotive, certification is dependability-driven. In contrast, medical certification is clinical-trial driven, which we argue will become increasingly problematic with increasing medical device and software complexity. By dependability, we mean the dictionary notion: reliable and trustworthy. Thus, failures are either avoided by design, or are accountable to a measured extent. This touches upon the verification (intent) versus validation (outcome) problem. Even though correctness does not imply safety, we do believe from our experiences that, the process of striving for correctness (verification) done right does shed light on safety; on whether the requirements/assumptions were addressed as intended (validation). Medical device trials can lead to adequate assurances of safety, as defined by the local regulatory burden. Nevertheless, the nature of such complex systems means that certain errors may not be detected by trials and so additional efforts to reduce errors is needed. Our intent is, at least for software, to explore the contrast between approaches: correctness-by-construction versus correct-by-trial. Additionally, these levels of safety and effectiveness of systems vary across regulatory domains in different countries. A key challenge is how to achieve a successful interaction between verification tasks using formal methods and system development tasks within engineering teams without prior knowledge of formal techniques. This paper describes a pragmatic process for the application of formal techniques, which is illustrated for three medical devices during pre-clinical development prior to certification. That means, the techniques are not only applied to realistic systems, but are also taken up by development teams themselves ( i.e. cannot be entirely formal expert driven). We demonstrate differences in applying formalisms at the start, midpoint and final development stages. In particular, we describe the underlying socio-technical challenges and how we developed mitigation methods for each exemplar case. This paper is not about a general technique for medical automation, as we do not believe this is practical/possible given the varied/dynamic nature of medical problems.

The Congress of the American College of Cardiology in review

Highlights • The review of the evidences obtained from the recently completed international clinical trials of drugs and medical devices presented at the 69th Congress of the American College of Cardiology is presented. • The Congress meeting was held remotely for the first time due to the COVID-19 pandemic. The American College of Cardiology and the World Heart Federation jointly hosted the 69th Congress of the American College of Cardiology (АСС) that took place in March 28–30, 2020. It was the first remote annual meeting due to the COVID-19 pandemic. However, it didn’t prevent healthcare professionals from 135 countries to participate in the virtual meeting. The employees of the Research Institute for Complex Issues of Cardiovascular Diseases and the Department of Cardiology and Cardiovascular Surgery of the Kemerovo State Medical University took active part in the virtual live sessions and reports in this article novel evidences from recently completed international clinical trials that were presented at the 69th Congress. The Congress organizers opened a free access to the video, abstracts, slides and workshops in 10 main clinical learning pathways till June 2020.

Partnership Between Japan and the United States for Early Development of Pediatric Medical Devices - Harmonization By Doing for Children.

The Harmonization By Doing (HBD) program was established in 2003 as a partnership among stakeholders of academia, industry and regulatory agencies in Japan and the United States, with a primary focus on streamlining processes of global medical device development for cardiovascular medical devices. While HBD has traditionally focused on development of devices intended to treat conditions prevalent in adults, in 2016, HBD established the "HBD-for-Children" program, which focuses on the development of pediatric devices as the development of medical devices for pediatric use lags behind that of medical devices for adults in both countries. Activities of the program have included: (1) conducting a survey with industry to better understand the challenges that constrain the development of pediatric medical devices; (2) categorizing pediatric medical devices into five categories based on global availability and exploring concrete solutions for the early application and regulatory approval in both geographies; and (3) facilitating global clinical trials of pediatric medical devices in both countries. The establishment of the HBD-for-Children program is significant because it represents a global initiative for the introduction of pediatric medical devices for patients in a timely manner. Through the program, academia, industry and regulatory agencies can work together to facilitate innovative pediatric device development from a multi-stakeholder perspective. This activity could also encourage industry partners to pursue the development of pediatric medical devices.

Regulation of Medical Devices and their Clinical Trials Studies in the USA: An Update

Background: Need for Medical devices is very important in the healthcare sector and related processes for global regulation. Medical devices are the apparatus or instruments which are specifically used for diagnostics and therapeutic applications. In the USA, a regulatory body known as FDA (Food and Drug Administration) has its unit called CDRH which looks the manufacture, packaging and use of medical devices in the USA. Objective: In USA, Medical devices are classified into 3 classes: class I which look for the medical devices used for the general control as dental floss and bandages, etc., class II which regulate the medical devices used for the general control as well as special control as powered wheelchairs and pregnancy kits. Class III medical devices look the general control. PMA (Premarket Approval) and Premarket Notification application has been filed to FDA for seeking the market authorization of medical devices. We perform clinical trials for medical device which are quite different from the clinical trials performed for drug analysis. These trials are performed on various age groups such as on paediatrics, adult and old age group commonly called phase 1,2,3,4. Regulatory approval of high-risk medical device is based on clinical studies submitted with pre-market approval. The main objective of this article is to make the researcher aware of the regulation and clinical trials of medical devices in the USA. Conclusion: Every medical device should comply with FDA, QMS and QSR for marketing in the USA. The present article has focused on the regulation of medical devices, clinical trial phases and clinical studies on medical devices.

Eyes on New Product Development.

Eyes on New Product Development.

Study on the Rights and Interests of Subject in Clinical Trials

Clinical trials are essential measures to determine the efficacy and safety of drugs. Clinical trials of new drugs and new medical devices have also received strong support at the national level. In the case of more and more clinical trial cases, how to better protect the rights of the subject becomes a problem that needs to be discussed in more depth. Based on the background of the development of clinical trials, this paper describes the lack of rights protection under the traditional support methods of clinical trial subject and then analyzes the problems of the subject’s right to life, body autonomy, informed consent, privacy and compensation. Problems with current subject rights protection and possible safeguards. The paper believes that the development and application of new life technologies make the clinical trial process more complicated and the results more uncertain. Therefore, the protection of traditional subject rights is not perfect, we need to expand legislative coverage, improve the rights dimension of subject rights protection and the structural dimension analysis of the ethics review committee which are effective measures to protect the rights of subject. Keywords: clinical trial, subject rights, rights protection DOI : 10.7176/PPAR/9-12-01 Publication date: December 31 st 2019

The premature closure of ROMPA clinical trial: mortality reduction in septic shock by plasma adsorption

ObjectivesCoupled Plasma Filtration and Adsorption (CPFA) use in septic shock remains controversial. The objective is to clarify whether the application of high doses of CPFA in addition to the current...

Stakeholders’ views on the Swiss draft ordinances on medical devices

To provide our readers with a good forecast of the changes ahead, the RA Watch editorial team asked different representatives – of the ethics committees umbrella organisation, the industry, and the SCTO network of CTUs – their views about the two ordinances proposed for consultation by the Federal Office of Public Health (FOPH). Their views and opinions refer to the drafted versions of the Medical Devices Ordinance (MedDO) and the ordinance on clinical trials for medical devices (ClinO-MD) as open to comments on 15 May 2019.

Costs of industry-sponsored medical device trials in Canada

Costs of industry-sponsored medical device trials in Canada

The Costs of Industry-Sponsored Medical Device Clinical Trials in Alberta.

ObjectiveOur objective was to describe the costs of industry-sponsored clinical trials for medical devices in Northern Alberta, Canada.MethodsWe used centralized data to identify all industry-sponsored medical device clinical trials initiated in Northern Alberta from 2012 to 2016. For each arm of each trial, we calculated the price of devices provided by the sponsor and the cost of clinical and administrative services that were incurred to clinically operationalize the treatment.ResultsOur sample consisted of 18 device trials initiated between January 2012 and January 2016. The overall cost (Canadian dollars [$Can], year 2018 values) per enrolee was $Can18,243 for the experimental arm and $Can13,827 for the control arm. Devices were the highest cost component, at $Can13,446 per enrollee in the experimental arm. Clinical costs in the control arms were higher on average ($Can7202 vs. 2504) than those in the experimental arms.ConclusionData from industry-sponsored clinical trials can provide important information on the full costs of device-related interventions. As device costs rise, and as policy makers require more evidence on device-related treatments, the cost of medical device-driven interventions should be documented along with their effectiveness.

Drug-Coated Balloon Angioplasty Compared with Uncoated Balloons in the Treatment of Infrapopliteal Artery Lesions: 6-Month Results of a Randomized, Multi-Centers, Single-Blind, and Superiority Trial

Background: Drug-coated balloons (DCBs) have shown promising results in treating femoropopliteal artery lesions while data on infrapopliteal lesions are controversial. We undertook this clinical trial to compare the safety and efficacy of DCBs versus uncoated balloon percutaneous transluminal angioplasty (control) of de novo or recurrent steno-occlusive lesions of the infrapopliteal arteries in patients with critical limb ischemia. Methods: In this prospective multicenter single-blind randomized study, 120 patients were randomized to the DCB group (Litos/Tulip, Acotec Scientific; n=61) or control group treated with uncoated balloons (n=59) in 11 centers in China from May 22, 2014, to June 13, 2018. Follow-up was scheduled at one and six months and included angiographic assessment at six months. Adverse events were assessed by an independent clinical events committee, angiographic parameters by an independent core laboratory. The study is registered at ClinicalTrials.gov, number NCT02137577. Findings: Regarding the primary safety endpoint (composite of all-cause mortality, target extremity major amputation, and target lesion revascularization at 30 days), there was one event (1·6%) in the DCB group and none in the control group (p=0·33). The primary efficacy endpoint-primary patency (defined as absence of target vessel occlusion, major amputation, or target lesion revascularization) at six months was accomplished in 77·1% [95% Cl 65·2%-89%] of the DCB group and 28·3% [95% Cl 15·3%-41·3%] of control group (p<0·001). Freedom from clinically driven target lesion revascularization was 95·1% [95% Cl 89·5%-100%] versus 79·7% [95% Cl 69·7%-90·1%] (p < 0·01) and late lumen loss 0·35±0·74mm [95% Cl 0·14-0·56mm] versus 1·08±0·62mm [95% Cl 0·90-1·26mm] (p<0·001). Interpretation: The Litos/Tulip DCBs are safe and effective in treating infrapopliteal artery lesions, resulting in improved angiographic and clinical outcomes compared with uncoated balloon PTA. Trial Registration Number: The study is registered at ClinicalTrials.gov, number NCT02137577. Funding: Acotec. Declaration of Interest: We declare no competing interests. Ethical Approval: The trial was conducted in conformity with the Declaration of Helsinki and the provisions for the conduct of clinical trials of medical devices issued by the China Food and Drug Administration. It was approved by the Chinese PLA General Hospital Ethics Committee and other ten local ethics committees of participating hospitals in China. All patients gave written informed consent prior to any study procedure.