Centre for Trials Research<\/a> staff, including representation from trial managers, senior trial managers, pharmacovigilance and safety, and quality assurance attended the medical devices training day hosted by Health Care Research Wales and presented by Professor Pete Wall in March 2019. This is reflective of our need to understand and develop knowledge of the regulations around clinical investigations and evaluations of medical devices as the Centre Trials Research\u2019s research portfolio expands to include research of this type.<\/p>\n\n\n\nThe day was split into two halves: the morning session covering clinical investigations and the afternoon session covering clinical evaluation. Clinical investigations are defined as a systematic investigation involving one or more human participants, undertaken to assess the safety or performance of a device. A clinical evaluation is a systematic and planned process to continually generate, collect, analyse and assess the clinical data pertaining to a device in order to verify safety and performance, including clinical benefits of the device when used as intended by the manufacturer. This blog only talks about clinical investigations, I hope to follow-up with a second blog on clinical evaluations soon.<\/p>\n\n\n\n
Medical Devices Defined<\/h2>\n\n\n\n
The clinical investigations session defined a medical device\nand discussed the differences between medical device and drug trials and the\ncurrent regulations that apply. The\ncurrent regulatory framework in the EU (Medical Devices Directive \u2013 93\/42\/EEC)\nis to be replaced by the Medical Devices Regulation (MDR) in 2020. We are currently in a transition phase from\nthe Directive to the Regulation. Both\nthe Directive and the Regulation define a medical device as:<\/p>\n\n\n\n
Any instrument or\napparatus, appliance, material or other article, whether used alone or in\ncombination, including the software necessary for its proper application\nintended by the manufacturer to be used on human beings for the purposes of:<\/em><\/p>\n\n\n\n- Diagnosis,\nprevention, monitoring, treatment or alleviation of disease,<\/em><\/li>
- Diagnosis,\nmonitoring, treatment, alleviation or compensation for an injury or handicap,<\/em><\/li>
- Investigation,\nreplacement or modification of the anatomy or of a physiological process<\/em><\/li>
- Control of\nconception<\/em><\/li>
- And which\ndoes not achieve its principal intended action in or on the human body by\npharmacological, immunological or metabolic means, but which may be assisted in\nits function by such means.<\/em><\/li><\/ul>\n\n\n\n
Clinical Investigations<\/h2>\n\n\n\n
Clinical investigations can be split into 3 categories:<\/p>\n\n\n\n
- Pilot (feasibility studies)<\/li>
- Pivotal (objective evidence of the effectiveness\nof a device via single or multiple clinical outcomes \u2013 frequently the only\nclinical trial that medical device manufacturers will undertake)<\/li>
- Post-marketing<\/li><\/ul>\n\n\n\n
The practicalities of a clinical investigation are like drug\ntrials, with respect to the essential documentation and approvals that are\nrequired. The protocol is defined as a\n\u201cclinical investigational plan\u201d (CIP) and the trial documentation (CIP,\nparticipant information sheet, consent form and advertising) require approval\nby an Ethics committee. Regulatory\napproval may also be required \u2013 this is dependent on the involvement of a\ncommercial device company. Where a\ncommercial device company is involved regulatory approval is required. The MHRA website provides some guidance on\nspecific scenarios. Other documentation,\nsuch as the CRF and statistical analysis plan should be drafted prior to\nsubmission for approval, since they are sometimes requested as part of the\nregulatory approval process. Following\nthe notice of receipt of an application by the MHRA, the 60-day clock\nstarts. The application is reviewed by 2\nassessors and questions usually begin around day 14, at which point the clock\nwill stop and you will be given 10 days to respond. Following approval, any amendments to the\ntrial (e.g. device, investigator, site, safety information) will require\nEthical and where applicable Regulatory approval. Manufacturers are required to report all\nSerious Adverse Events occurring in the UK to the MHRA. The definition of an SAE in device trials is\ndifferent to that in drug trials and they must be reported to the MHRA within\n24 hours of receipt.<\/p>\n\n\n\n
Regulatory and Marketing Approval<\/h2>\n\n\n\n
The standard for regulatory and marketing approval for\nmedical devices (CE marking) is significantly different from the marketing\napproval of drugs. Proof of efficacy is\nnot a fundamental requirement for medical device registration \u2013 demonstration\nof safety and performance only is required. \nMost devices in clinical use have no evidence for their efficacy, and\nthose that have are usually more recent introductions to the market or devices\nthat have been comparatively tested in post-marketing clinical trials. Regulatory and marketing approval of drugs\nrequire multiple trials and replication of clinical findings and trials may\ninvolve tens of thousands of patients. \nDevices frequently require a single pivotal study and studies rarely involve\ngreater than 100 participants.<\/p>\n\n\n\n
From a regulatory perspective, medical devices are\ndistinguished from drugs by their mechanism of action. Devices operate via physical or mechanical\nmeans and are not dependent on metabolism to achieve their primary mode of\naction and effect. There are two important\nconsiderations for device trials, the effect of the device on the patient, plus\nthe influence of the person operating the device on the variability of the\nclinical outcome. Being aware of and\ncontrolling for, the user influence on device performance is a critical\nconsideration when designing a device trial. \nTraining in the use of any clinical device used in a clinical trial is a\nfundamental component of any investigation of performance and the eventual marketing\nof the device post registration.<\/p>\n\n\n\n
CE marking is a certification mark which symbols free\nmarketability in the EEA. The need for\nclinical data in the CE marking process arises from the general requirements\nfor demonstrating safety and performance. \nThe CE mark is not a mark of efficacy or effectiveness.<\/p>\n\n\n\n
Essential Requirements<\/h2>\n\n\n\n
The Medical Devices Directive specifies the \u201cEssential\nRequirements\u201d (ER) that must be met prior to any device being sold or used\nclinically. The ERs can be broken down\ninto two groups:<\/p>\n\n\n\n
- General\nrequirements for safety and performance that apply to all devices<\/li>
- Specific\ntechnical requirements regarding design and manufacturing that may or may not\napply depending on the nature of the device (for example the requirement for\nelectrical safety would not apply to a urinary catheter)<\/li><\/ol>\n\n\n\n
Only products complying with the ERs may be placed on the\nmarket and used clinically. To CE mark\nany device, compliance with the ERs must be demonstrated, this will usually\nrequire provision of clinical data via:<\/p>\n\n\n\n
- A critical evaluation of relevant scientific and\nclinical literature covering safety, performance, design characteristics and\nintended purpose to demonstrate:
- Equivalence of the new device to the device data\nused and<\/li><\/ul>