Applying for a CE Mark for a Medical Device - Assignment Example

 Applying for a CE Mark for a Medical Device Per BS EN 30993-6:1995 testing of my polymeric cement is required to assess the ”local effects of an implant material on living tissues, at both the macroscopic and microscopic level” (p. 3) in the long-term application. This is necessary to determine if the unique property of the cement will yield any negative or positive response in contact areas. Living tissue is required in this application to facilitate this evaluation and adequately demonstrate the biological response over time. Per 3.2.2 of the standard testing of the cement is authorized in its intended state, that is the cement may be mixed and set “after varying time periods” prior to application. The use of a PE tube is used to hold the cement after sterilization per prescribed, typical methods contained in the standards. The cement is mixed and inserted into the tube to a level flush with the tube. The cement used in a fresh state prior to implanting is also tested for microbiological contamination. As the testing requires a tube to contain the cement for testing a like size rod of equal diameter and length and sanitized per normal procedures will be used as the control. For long term testing of in bone, which is what is required in test the effects of the cement which will be used long term in actual application, selection of the species for test and control is contained in Figure 1 below: Figure 1: Test Periods and Animals for testing the long-term implanting in bone1 Implantation will be done through normally accepted surgical method including shaving the insertion area and thorough antiseptic cleaning of the area and surgery to implant should be performed to minimize any trauma to the area. After insertion sutures are used to close the site and ensure tubes do not loosen or move. After surgery observation is conducted of the test species at appropriate intervals to note and record per 3.3.4 of the standard “any abnormal findings, including local, systemic and behavioural abnormalities” (p. 5). At the completion of the testing period, in this case 78 weeks the animals will be euthanized humanely in order to determine the biological response of the test area to the prolonged contact with the cement “by grading and documenting the macroscopic and histopathological test responses as a function of time” (p. 5) and comparing it with the control material (the rods) and the surrounding area. The examination will be facilitated by use of a low magnification lens of each test site material. After all of these results have been documented, the test and control tubes and rods and the surround tissue/bone shall be removed for further evaluation. Care must be used in the removal of the samples. Section 3.4.2 details the removal process: When the implant/tissue interface is to be studied, embedding of the intact tissue envelope with the implant in situ using hard plastics is preferred. Appropriate sectioning or grinding techniques are employed for the preparation of histological sections. It shall be demonstrated that the technique of embedding in plastics does not markedly alter the interface tissue (p. 5). All responses noted in the area surrounding the implant is to be documented and measurements taken of distance to unaffected areas and the specific characteristics of the normal tissue in relation to the implant area. It is important to follow protocol and record the location, orientation, geometry of the incision and the number of sections. Biological assessment of the sections include per 3.4.3: a) Extent of fibrosis/fibrous capsule and inflammation; b) Degeneration as determined by changes in tissue morphology; c) number and distribution as a function of distance from the material/tissue interface of the inflammatory cell types, namely polymorphonuclear leucocytes, lymphocytes, plasma cells, eosinophils, macrophages and multinucleated cells; d) Presence of necrosis as determined by nuclear debris and/or capillary wall breakdown; e) Other parameters such as material debris, fatty infiltration, granuloma; f) For porous implant materials, the quality and quantity of tissue ingrowth (p. 6). Of particular interest as this testing involves bone is to examine the area surrounding the bone contact and the surrounding bone and any “the presence of intervening non-calcified tissues” (p. 6) paying particular attention to the bone resorption and formation. The entire procedure should be documented from recording animal species, age, location, number of implants and all procedures in the implantation process and removal and examination. The report must contain detailed findings of both the biological data and the observations of the area surrounding the implants. Since the primary application of the cement will be used in conjunction with devices used in the bone area, testing will evaluate the effect of various responses to the cement as compared to the control (the rod). As rabbits were selected for this study as a 72 week period will suffice to determine the biological response to test material on the bone and surrounding tissue and allows ample time. Per the BS EN 30993-6:1995 four rabbits will be used with implantation into the femur a control and a test for the duration of the 72 week period with documented observations. Additionally the MHRA requires an assessment of “toxicological risks…for the assurance of biological risks safety” (“Guidance on Biological”, 2006, p. 3). These requirements include: 1. The choice of materials used as regards toxicity (Requirement 7.1) 2. the compatibility between the materials used and biological tissues, cells and body fluids, taking account of the intended purpose of the device” (also Requirement 7.1) 3. Minimisation of risk from contaminants and residuals, where particular attention must be paid to the tissues exposed and the duration and frequency of exposure (Requirement 7.2). The concept minimisation rather than acceptable risk is used here because residuals and contaminants are expected to only bring risk and no benefits 4. Safe use of the device with the substances they will enter into contact with during their normal use (Requirement 7.3) 5. risks from substances leaking from the device must be minimised (Requirement 7.5) 6. risks from unintentional ingress from substances into the device must be minimised (Requirement 7.6) 7. Risks from ageing of the materials used in situations where the device cannot be maintained or calibrated (such as implants) should be minimised (Requirement 9.2). From a toxicity point of view, this means that breakdown products of the materials used should be taken into account in the risk assessment of long-term devices (“Guidance on Biological”, 2006, p. 3). Van de Belt et al. (2001) provided data of studies performed to date on the antibiotic additives of cement used in vitro application which should suffice for CE Mark application. Figure 2 provides the study type, study size, researchers, infection rates and follow up period. Figure 2: Antibiotic Additives in Cement Studies Completed for Inclusion in CE Mark Application2 To have the legal authority to CE mark any product or device, the manufacture must have the ability to demonstrate that the product is within the guidelines specified by the Medicines and Healthcare Products Regulatory Agency (MHRA). This is achieved through one of two methods, according to MHRA (2002): “either a compilation of the relevant scientific literature currently available on the intended purpose of the device and the techniques employed, together with, if appropriate, a written report containing a critical evaluation of the compilation; or The results and conclusions of a specifically designed clinical investigation” (p. 4). In short it must be demonstrated to the satisfaction of MHRA that the device, in this case the polymeric biomaterial which will be used in the cement for implanted orthopaedic and dental devices, does what is intended to with no adverse medical consequences in a safe manner. This is done through development of adequate clinical testing by “taking into account any risks associated with the use of the device when weighed against the expected benefits” (MHRA, 2002, p. 4) as the material to be used is new and unique it must conform to specify clinical testing methodology. In general, it must be shown it can do what it is intended to do under normal conditions and to ascertain any potential adverse side effects that may present themselves upon its use. 60 days prior to the intended clinical trials, the manufacturer of the new cement must send a notice of intent to the Secretary of State for Health. If within the 60 days prior to the beginning of the clinical testing process written notice from the Secretary of State for Health or his designated authority objecting to the clinical trials is received by the manufacture, testing may begin. According to MHRA (2002) any objection by the government to the clinical testing will be based on one of two factors: risk of public safety and health concerns or public policy (p. 5). Appendix A contains a flowchart demonstrating the clinical trial process required to obtain the CE Mark when clinical information is complete while Appendix B contains a flowchart demonstrating the process required when additional information is still required. Additionally, according to MHRA, a local research ethics committee approval is required prior to commencement of the clinical trials. However, without approval of MHRA, even with the ethic committee approval clinical testing may not occur (“Information for”, 2006). In condensed terms clinical trial requirements for CE mark for implantation must follow several critical steps and demonstrate suitability, compliance and safety by following the below listed format: “be performed on a basis of an appropriate plan with well-defined aims and objectives; make use of procedures appropriate to the device under examination; be performed in circumstances similar to the intended conditions of use; include sufficient devices to reflect the aims of the investigation taking into account the potential risk of the device; examine appropriate features involving safety and performance and their effects on patients so that the risk/benefit balance can be satisfactorily addressed; fully record all adverse events and report serious adverse events to the UK Competent Authority; be performed under the responsibility of a medical practitioner or a number of medical practitioners; and include the making of a final written report, signed by the medical investigator(s) responsible, which must contain a critical evaluation of all the data collected during the clinical investigation, with appropriate conclusions” (MHRA, 2002, p. 6). It is important to note that with the case of implant devices including the new cement designed, the degradation of the material needs to be fully analysed and assessed as well as its relationship to the material it will come in contact with including biological material point of contacts within the implant area and the medical device which it will attach. At a minimum this requires demonstration of toxicology in three areas: the chemical composition of the cement, any prior use of the material (in this case there would be none as it is a new material, and the biological test data obtained to determine safety of the cement. Further testing will be required to determine the amount of leaching that will be demonstrated by the use of the cement. MHDA advises that testing is required only as indicated by the toxicology and application. “National laws may prohibit unnecessary animal tests and the need for testing should always be judged in relation to the predictive value of the test and animal welfare considerations” (“Guidance on biological”, 2006, p. 7). Whether or not clinical testing is required is based on a number of different facts, but in this case as the cement in new and unique it conforms to the criteria designated by MHRA which requires the clinical testing. It should also be noted that if the cement will be undergoing testing under other bodies of competent authority in other nations. For example, if testing will be completed for application in the United States, the appropriate protocol which will be used for the Federal Drug Administration (FDA) approval must be included or stated that it is identical to the protocol for clinical testing to be used in the UK testing. Appendix C contains a listing of all documentation required for the submission of the CE Mark application. Appendix D contains a list of required documentation that does not need to be submitted with the application for CE Mark but may be required during the approval phase as determined by MHDA and should be readily available if needed. There are four levels of control for the conformity of the cement based on the health and/or safety risk demonstrated from the clinical trials. These four levels, from least restrictive (lowest risk) to most restrictive (highest risk) are: Class I, Class IIa, Class IIb, and Class III. The various flowcharts depicting the certification assessment process are contained in Appendix E. References BS EN 30993-6:1995 Biological evaluation of medical devices – Part 6: Tests for local effects after implantation.” “Conformity assessment procedures.” (2006, February). Bulletin No. 4. EC Medical Devices Directive. Medicines and Healthcare Products Regulatory Agency (MHRA). London: Crown Printing. “Information for Clinical Investigators” (2006, January). EC Medical Devices Directive. Medicines and Healthcare Products Regulatory Agency (MHRA). London: Crown Printing. “Guidance on biological safety assessment.” (2006, January). EC Medical Devices Directive. Medicines and Healthcare Products Regulatory Agency (MHRA). London: Crown Printing. “MDA Guidance on the medical devices vigilance system for CE marked joint replacement implants.” (1998). Medical Devices Agency, London: Crown Printing. “MHRA safeguarding public health.” (2002). Medicines and Healthcare Products Regulatory Agency (MHRA). EC Medical Device Directives One. London: Crown Printing. “Pre-clinical assessment guidance for assessors.” (2006, January). EC Medical Devices Directive. Medicines and Healthcare Products Regulatory Agency (MHRA). London: Crown Printing. Van de Belt, H., Neut, D., Schenk, W., Van Horn, J. R, Van der Mei, H. C. and Busscher, H. J. (2001). “Infection of orthopaedic implants and the use of antibiotic-loaded bone cements.” Acta Orthopaedic Scandinavian, 72 (6), pp. 557-571. Appendix A Flow Chart of Clinical Investigation Process for MHRA if all data complete3 Appendix B Flow Chart of Clinical Investigation Process for MHRA if all data not complete4 Appendix C Documentation Required for CE Mark Application5 Appendix D Documentation not required for CE Mark Application but must be Available as needed by MHDA6 Appendix E CE Marking Routes by Class7 Read More