Clinical Data For Medical Devices - Cromsource
White PaperClinical Data for Medical DevicesPreparing for increased requirements in the EU
Clinical Data for Medical DevicesTable of Contents1. Regulation of medical devices in the EU: on the cusp of change . 32. Traditional differences between medical device and drug clinical studies . 43. Proposal adopted by the European Parliament introduces new requirements . 5New device definitions introduce the concept of clinical benefits . 6Failure to prove equivalence may necessitate a clinical investigation . 6The range of devices requiring clinical investigations will be extended . 6Efficacy, not performance, will need to be verified in a clinical investigation . 7Aim is randomised controlled clinical trials with well-chosen controls . 74. Conclusion . 85. Why use a CRO? . 96. How CROMSOURCE can assist . 107. About the Author . 118. About CROMSOURCE . 11March 2015Page 2
Clinical Data for Medical Devices1. Regulation of medical devices in the EU: on the cusp of changeTo market a medical device in the EU, a manufacturer must demonstrate that the device is safe, thatit performs as intended, and that the risks associated with the use of the device are acceptable whenweighed against the benefits to patients. Clinical evaluation is the assessment and analysis of clinicaldata pertaining to a medical device to verify its clinical safety and performance. It may be based on aliterature review and/or clinical experience and/or clinical investigations. While some medicaldevices do require data generated from a clinical investigation, it is often possible, for low- tomedium-risk devices (Class I, IIa, and IIb), to rely on a literature review and/or clinical experience tosupport the device’s intended use.The Medical Devices Directives (MDDs) form the foundation of Europe’s regulatory framework formedical devices. The relevant EU legislation addressing the clinical evaluation of medical devices isthe Medical Device Directive 93/42/EEC, as amended (March 2010) and the Active ImplantableMedical Device Directive 90/385/EEC, as amended (March 2010). This legislation was transposedinto national law in all concerned countries.European regulation of medical devices is undergoing significant revision. On 26 September 2012,the European Commission published aproposal for regulation of medical devices1and a separate proposed regulation of IVDdevices (which will not be discussed here).On 22 October 2013, the EuropeanParliamentvotedtoaccept347amendments to the Commission’s MedicalDevices Regulation Proposal. The formallegislative vote was held on 2 April 2014,which resulted in the Parliament’s adoptionof the amended Proposal2.This actionclosed the first reading of the ordinary legislature procedure. On 5 November 2014, the Committeeon the Environment, Public Health and Food Security of the European Parliament mandated therapporteurs to enter into negotiations with the Council of the EU aiming to reach an agreement onthese proposals.A comprehensive discussion of the proposed changes to Medical Device Regulation can be found inthe CROMSOURCE white paper “EU Recast of the Medical Device Directives: The Rocky Road to thenew Medical Device Regulation”.This white paper focuses on the regulatory changes set to erode the traditional differences betweenmedical device and pharmaceutical clinical studies. A significant aspect of The Medical DevicesRegulation Proposal is that it represents a bid to raise the regulatory bar on clinical evidencerequirements, exposed as inadequate by the scandal of defective breast implants produced by theFrench Poly Implant Prothèse (PIP). CROMSOURCE’s companion white paper on “Clinical ces/files/revision docs/proposal 2012 542 do?type TA&language EN&reference P7-TA-2013-428March 2015Page 3
Clinical Data for Medical DevicesReports: Meeting the demands of a more stringent regulatory environment” discusses howincreased demands placed on medical device notified body performance are leading to morerigorous inspections of manufacturers’ clinical evaluation documentation ahead of theimplementation of new regulations.2.Traditional differences between medical device and drug clinical studiesThe Good Clinical Practice (GCP) standard for medical device investigation is laid down in EN ISO14155 (2010). European legislation also explicitly requires adherence to the Declaration of Helsinki,which defines the ethical principles to be respected when performing investigations on humansubjects.As a rule, all clinical investigations need to be approved by Ethics Committees and notified to thecompetent authorities of involved countries. Other regulatory institutions may need to be involvedin the regulatory process depending on national law.The essential documents for a medical device investigation are similar to the ones required for apharmaceutical study. The term Clinical Investigation Plan is generally used to refer to the studyprotocol in the case of a clinical investigation of a medical device. There is a requirement to include asection on risk management in the Clinical Investigation Plan.Regulatory requirements for clinical investigations of medical devices are different topharmaceuticals and this has an impact on the design of their clinical investigations3. There is nolegal requirement to demonstrate the efficacy of the device to obtain CE marking. The objective ofthe clinical investigation is to demonstrate the safety and performance (conformity with claims) of amedical device. In a pharmaceutical study the objective is to demonstrate the safety and efficacy ofthe medicinal product. One consequence is that case numbers in a medical device investigation areusually lower than in pharmaceutical studies. The stage of a clinical investigation which needs to besatisfactorily completed for CE marking may therefore be likened to Phase II in drug development,where evidence of clinical activity of a drug is sought, rather than Phase III. Since efficacy does notneed to be demonstrated, randomised controlled trial designs for medical devices are rarelynecessary and therefore proof of statistical significance may not be necessary. Interim analysis ofstudy data may be feasible, provided it has been written into the investigation plan.In comparative pharmaceutical studies the most robust comparator is a placebo control, which isoften applied and generally required by authorities. In a medical device investigation, a placebocontrol is usually not feasible. This is particularly the case with implantable devices, where placebocontrol groups (involving sham surgery) are not possible. However, studies comparing a medicaldevice with standard therapy are possible, although in some cases there may be no standardtherapy available which is similar enough to warrant comparison, especially for novel devices. Inaddition the user (usually a healthcare professional) often cannot be blinded to the ion-2-april-2008.pdfMarch 2015Page 4
Clinical Data for Medical DevicesA specific feature of medical deviceinvestigations is that product performancemay be influenced by user. Furthermore, theuse of a medical device may sometimes beassociated with a learning curve for the user,where the outcomes improve withexperience.Another feature is that adverse events, inparticular adverse device effects, may notonly concern the investigation subjects butalso third parties, such as users of the device.In contrast, adverse events in pharmaceuticalstudies are only monitored for the clinical study subjects.Due to the wide range of types of device, testing methodologies vary widely. Some performancedata might simply require user handling feedback; other data might be more analytical. Medicaldevices often create large amounts of data that are transmitted, processed and stored via specificsoftware interfaces. For such data sets, specific monitoring rules have to be established focusing onsupervising data processing rather than individual data points.Moreover, medical devices are subject to frequent incremental innovation. Results from long-termclinical studies with predicate devices may no longer be relevant to improved products and medicalprocedures.3. Proposal adopted by the European Parliament introduces newrequirementsWith EU action pending, the European Commission’s proposal, including the proposedamendments from the European Parliament, outlines new clinical data requirements for theregulations for medical devices. Key initiatives in this area will be highlighted in this section.The reach of the regulation is also being extended to manufacturers of products nothitherto considered to be medical devices. The Proposal states (Article 2, paragraph 1, point1; amendments in bolded italics): “The implantable or other invasive products, as well asproducts using external physical agents, intended to be used for human beings, which arelisted on a non-exhaustive basis in Annex XV, shall be considered medical devices for thepurposes of this Regulation regardless of whether or not they are intended by themanufacturer to be used for a medical purpose”. The following types of products are listedAnnex XV: contact lenses; implants for modification or fixation of body parts; facial or otherdermal or mucous membrane fillers; equipment for liposuction; invasive laser equipmentintended to be used on the human body; intense pulsed light equipment.March 2015Page 5
Clinical Data for Medical DevicesNew device definitions introduce the concept of clinical benefitsThe amended Proposal introduces the concept of “clinical benefit” of medical devices. It willno longer be sufficient to demonstrate safety and claimed performance; medical devices willneed to show actual clinical benefit for patients. Failure to do so using available clinical datamay require a clinical investigation to be performed.Location in theCommission’s ProposalArticle 2: Definitions,paragraph 1Quotation (European Parliament’s amendments in bolded italics)(31a) ‘performance’ means any technical characteristics, any effects and anybenefit of the device when used for the intended purpose and in accordancewith the instructions of use(31b) ‘benefit’ means the positive health impact of a medical device based onclinical and non-clinical data(32) ‘clinical evaluation’ means the assessment and analysis of clinical datapertaining to a device in order to verify the safety, performance and clinicalbenefits of the device when used as intended by the manufacturerFailure to prove equivalence may necessitate a clinical investigationIn Annex XIII “Clinical evaluation and post-market clinical follow-up” the Proposal states that existingclinical evidence with comparable devices can be used for the clinical evaluation, provided deviceequivalence can be demonstrated. This instruction is similar to the current medical device directive;however, the criteria will be stricter and it will be more difficult to convincingly prove equivalence.Without clinical evidence to demonstrate performance and safety, a clinical investigation will beneeded.It should be noted that in 2011 the Institute of Medicine in the US called for a revamp of the 510(k)clearance process warning that "reliance on substantial equivalence cannot assure that devicesreaching the market are safe and effective."Location in theCommission’s ProposalAnnex XIII “Clinicalevaluation and postmarket clinical followup”, Part A: ClinicalEvaluationQuotation(4) Equivalence can only be demonstrated when the device that is subject toclinical evaluation and the device to which the existing clinical data relates havethe same intended purpose and when the technical and biological characteristicsof the devices and the medical procedures applied are similar to such an extentthat there would be not a clinically significant difference in the safety andperformance of the devices.The range of devices requiring clinical investigations will be extendedUnder the amended Proposal, the range of high-risk devices that will require clinicalevidence collected via a clinical investigation is being extended to include: Class IIb devicesintended to administer and/or remove a medicinal product and devices manufacturedutilising tissues or cells of human or animal origin, or their derivatives, which are non-viableor are rendered non-viable. These devices are listed in Article 43a(1) along with: implantabledevices; devices incorporating a substance; and all other class III devices. Special notifiedMarch 2015Page 6
Clinical Data for Medical Devicesbodies will be involved in the conformity assessment procedures of these devices. The rulewill not apply to devices intended for short term use (up to 30 days).Location in theCommission’s ProposalAnnex XIII “Clinicalevaluation and postmarket clinical followup”, Part A: ClinicalEvaluationQuotation (European Parliament’s amendments in bolded italics)(5) In the case of devices falling within Article 43a(1), with the exception ofthose used for a short term, clinical investigations shall be performed unless it isduly justified to rely on existing clinical data alone. Demonstration ofequivalence ( ) shall generally not be considered as sufficient justification withinthe meaning of the first sentence of this paragraph.Efficacy, not performance, will need to be verified in a clinical investigationChapter VI (which has been amended to Chapter V) and Annex XIV “Clinical Investigations” of theProposal introduces the requirement for the demonstration of “efficacy” of the device in a clinicalinvestigation.It should be noted that objections have been raised to this requirement by Eucomed4 on thebasis that, unlike pharmaceuticals, the efficacy of devices often relies on the skills andexperience of the healthcare professional, the quality of the hospital, and many otherfactors.Location in theCommission’s ProposalChapter VI (amended V)“Clinical evaluation andclinical investigations”,Article 50: Generalrequirements regardingclinical investigations,paragraph 1Annex XIV “ClinicalInvestigations”, Part I:General requirements,section 2: MethodsQuotation (European Parliament’s amendments in bolded italics)[regarding purpose of clinical investigations] (b) to verify the clinical safety andefficacy of the device, including the intended benefits to the patient, when usedfor the intended purpose, in the target population and in accordance with theinstructions of use(2.1) Clinical investigations shall be performed on the basis of an appropriateplan of investigation reflecting the latest scientific and technical knowledge anddefined in such a way as to confirm or refute the technical performance of thedevice, the clinical safety and efficacy of the device when used for the intendedpurpose in the target population and in accordance with the instructions ofuse, and the manufacturer's claims for the device as well as the safety,performance and benefit/risk related aspects referred to in Article 50(1); theseinvestigations shall include an adequate number of observations to guaranteethe scientific validity of the conclusions.Aim is randomised controlled clinical trials with well-chosen controlsEarly on in the Proposal, the requirement for clinical investigations to be appropriatelytargeted and controlled is stated. Annex XIV to the Proposal “Clinical Investigations” dictatesthe use of randomised controlled investigations and states that the use of any other designwould need to be justified. The amendment specifically references the control therapy andthe involvement of independent experts in relation to randomised controlled March 2015Page 7
Clinical Data for Medical DevicesAs pointed out by Eucomed5, it is not clear how randomised controlled designs will beimplemented in cases where it would be hard randomise devices due to strong ethical andpractical issues in the choice of the “comparator” (for example, it would be impossible touse a comparator for an implantable cardiac defibrillator). Furthermore, standards of careand therefore the control therapies differ depending on a specific country and healthcareexpert.Location in theCommission’s ProposalArticle 2: Definitions,paragraph 1Annex XIV “ClinicalInvestigations”, Part II:Documentationregarding the applicationfor clinical investigationQuotation (European Parliament’s amendments in bolded italics)(33) Clinical investigations for medical devices, where made compulsory inaccordance with this Regulation, shall include clinical investigations in theappropriate target population and well-controlled investigations.(1.11) Summary of the clinical investigation plan (objective(s) of the clinicalinvestigation, number and gender of subjects, criteria for subject selection,subjects under 18 years of age, design of the investigation such as controlledand/or randomised studies, planned dates of commencement and of completionof the clinical investigation). As randomised controlled investigations usuallygenerate a higher level of evidence for clinical efficacy and safety, the use ofany other design or study has to be justified. Also the choice of the controlintervention shall be justified. Both justifications shall be provided byindependent experts with the necessary qualifications and expertise.4. ConclusionThe amended Medical Devices Regulation Proposal aims to ensure more solid clinical datato support medical device CE marking applications. Clinical evaluation requirements will bemore stringent, and there will be a requirement to demonstrate clinical benefits of thedevice and provide a rigorous proof of equivalence if the evaluation is based on comparabledevices.In a move that is likely to have the greatest impact on manufacturers of medical devices, theamended Proposal has introduced a requirement for efficacy into the European medicaldevice regulatory system, which, since its inception, has been based upon essentialrequirements for safety and performance. Demonstration of efficacy is best achieved with arandomised controlled investigation. Although a randomised controlled study design maynot be feasible or ethical with some implantable devices, such a study design provides clearpotential advantages. Large, multi-centre randomised controlled clinical trials allow reliablegeneral conclusions to be drawn from results while enabling the detection of small, clinicallysignificant effects that smaller trials might miss. This evidence is currently lacking for mostmedical devices.The proposal, as amended, would result in an increased need for randomised controlledclinical studies to gain and maintain CE approval for high-risk devices, a classification which5http://www.emedical evices-pharmaceuticalsMarch 2015Page 8
Clinical Data for Medical Deviceshas been extended and now includes some class IIb devices. In addition, the requirement fordemonstrating clinical benefit will bring more randomised study designs regardless theclassification. For lower risk devices, clinical investigations would have to be performed toachieve CE approval, if rely
The Medical Devices Directives MDDs form the foundation of Europes regulatory framework for medical devices. The relevant EU legislation addressing the clinical evaluation of medical devices is the Medical Device Directive 93/4
Bruksanvisning för bilstereo . Bruksanvisning for bilstereo . Instrukcja obsługi samochodowego odtwarzacza stereo . Operating Instructions for Car Stereo . 610-104 . SV . Bruksanvisning i original
10 tips och tricks för att lyckas med ert sap-projekt 20 SAPSANYTT 2/2015 De flesta projektledare känner säkert till Cobb’s paradox. Martin Cobb verkade som CIO för sekretariatet för Treasury Board of Canada 1995 då han ställde frågan
service i Norge och Finland drivs inom ramen för ett enskilt företag (NRK. 1 och Yleisradio), fin ns det i Sverige tre: Ett för tv (Sveriges Television , SVT ), ett för radio (Sveriges Radio , SR ) och ett för utbildnings program (Sveriges Utbildningsradio, UR, vilket till följd av sin begränsade storlek inte återfinns bland de 25 största
Hotell För hotell anges de tre klasserna A/B, C och D. Det betyder att den "normala" standarden C är acceptabel men att motiven för en högre standard är starka. Ljudklass C motsvarar de tidigare normkraven för hotell, ljudklass A/B motsvarar kraven för moderna hotell med hög standard och ljudklass D kan användas vid
LÄS NOGGRANT FÖLJANDE VILLKOR FÖR APPLE DEVELOPER PROGRAM LICENCE . Apple Developer Program License Agreement Syfte Du vill använda Apple-mjukvara (enligt definitionen nedan) för att utveckla en eller flera Applikationer (enligt definitionen nedan) för Apple-märkta produkter. . Applikationer som utvecklas för iOS-produkter, Apple .
och krav. Maskinerna skriver ut upp till fyra tum breda etiketter med direkt termoteknik och termotransferteknik och är lämpliga för en lång rad användningsområden på vertikala marknader. TD-seriens professionella etikettskrivare för . skrivbordet. Brothers nya avancerade 4-tums etikettskrivare för skrivbordet är effektiva och enkla att
Den kanadensiska språkvetaren Jim Cummins har visat i sin forskning från år 1979 att det kan ta 1 till 3 år för att lära sig ett vardagsspråk och mellan 5 till 7 år för att behärska ett akademiskt språk.4 Han införde två begrepp för att beskriva elevernas språkliga kompetens: BI
**Godkänd av MAN för upp till 120 000 km och Mercedes Benz, Volvo och Renault för upp till 100 000 km i enlighet med deras specifikationer. Faktiskt oljebyte beror på motortyp, körförhållanden, servicehistorik, OBD och bränslekvalitet. Se alltid tillverkarens instruktionsbok. Art.Nr. 159CAC Art.Nr. 159CAA Art.Nr. 159CAB Art.Nr. 217B1B