Medical Devices: A Regulatory Overview

Abstract

The knowledge and compliance with regulatory requirement is a key to success in development and marketing of medical devices. High quality and well-designed medical devices are necessary to provide safe and effective clinical care for patients as well as to ensure the health and safety of professional and lay device users.  The present article over review the regulations in different countries for assuring safety and efficacy of medical devices. 

Introduction

The term medical devices cover a vast range of equipment; from simple tongue depressors to haemodialysis machines.¹ Medical devices are now a pervasive part of modern medical care. In many cases, these medical devices are associated with quality of care. In other cases, devices can be associated with many problems. The approach to quality of devices has depended largely on regulation.² Like any regulatory system, the medical device regulation system has the potential to negatively affect the market it controls.³ The Global Harmonization Task Force has proposed the following harmonized definition for medical devices:

“Medical device” means any instrument, apparatus, implement, machine, appliance, implant, in vitro reagent or calibrator, software, material or other similar or related article, intended by the manufacturer to be used, alone or in combination, for human beings for one or more of the specific purposes of: diagnosis, prevention, monitoring, treatment or alleviation of disease; diagnosis, monitoring, treatment, alleviation of or compensation for an injury; investigation, replacement, modification, or support of the anatomy or of a physiological process; supporting or sustaining life; control of conception; disinfection of medical devices; providing information for medical purposes by means of in vitro examination.¹

In the normal course of biomedical applications, medical devices can be in direct or indirect contact with the patient. The potential hazards of the device to the patient depend upon the conditions and duration of contact with it. Manufacturers are obliged to establish the safety of their products before they are marketed. Thus, preclinical assessments of the toxic potentials of medical devices are typically undertaken, to determine any possible hazards, which may be associated with their use.⁴ The regulatory aspects of medical devices differ from country to country. Because of the potential health and safety risks intrinsic to medical technology, medical device firms have faced strict regulatory measures in the United States, the European Union (EU), andJapan over several decades. These three markets classify all medical devices according to risk, and require approval of riskier devices before they can be marketed.  In the United States, medical devices are regulated by the Center for Devices and Radiological Health (CDRH) of the FDA and devices are classified according to their perceived risk using a 3-tiered system (class I, II, or III).⁵ In Japan, pharmaceutical and medical device agency (PMDA) of Ministry of device and radiological health responsible for regulation of medical devices classify medical devices into four classes (class I, II, III, IV).⁶ In both countries, the government retains final authority for approval of medical devices. In contrast, in European Union Medical device directive (MDD) classifies medical devices into four classes (I, IIa, IIb and III). The pre-market review and approval in the EU is principally conducted by independent third-party testing laboratories [Notified bodies (NBs)] accredited by Member State Health Ministries to review and approve medical devices for the EU market.⁷ Although both CDRH and PMDA use third parties for the preliminary assessment of low- and medium-risk devices, they retain final authority over device approval process. In the present article, an attempt is made to overview the regulatory aspects of medical devices.

Classification Of Medical Devices

It is not feasible economically nor justifiable in practice to subject all medical devices to the most rigorous conformity assessment procedures available. A graduated system of control is more appropriate. In such a system, the level of control corresponds to the level of potential hazard inherent in the type of device concerned. A medical device classification system is therefore needed, in order to channel medical devices into the proper conformity assessment route.

Medical devices are divided into different categories. The classification identifies the level of regulatory control that is necessary to assure the safety and effectiveness of a medical device.

In US, according to 1976 Medical device amendment Act, medical devices are classified mainly into three classes, on basis of risk-based system. The main classes are – class I, class II, class III and In Vitro Diagnostic Devices (IVD), the classification for these devices found under 21 CFR 862, 21 CFR 864 and 21 CFR 866.^5,8 The different classes of Medical Device with example are tabulated in Table 1.

In European Union, medical devices are classified according to their intended use. In European Union, there are 18 rules for classification of medical devices. These rules are applied to help a manufacturer determine whether the device is Class I (low risk), Class II (medium risk), or Class IIb or III (high risk).

The 18 rules are combination of following criteria:⁶

• Duration that the device is in contact with patient
• Whether it is invasive or non-invasive
• Degree of invasiveness
• Anatomy affected by the device
• Active and non-active
• Special situations (e.g. devices incorporating a medicinal substance, contact lens solution).

Classification of medical devices in EU is tabulated in Table 2. 

InJapan medical devices according to Pharmaceutical affair Law (PAL) are classified into four categories. A new system of classification, separate the medical devices into three classes, which based on the device classification of the global harmonization task force and basically depend on risk based system.^6,10 The new classification system has been tabulated in Table 3.

Regulation Aspects Of Medical Devices

Medical devices are regulated by different regulatory structures and different guidelines are followed in different countries to determine the safety and efficacy of medical devices.

The Food and Drug Administration (FDA) is responsible for protecting the public health by assuring the safety and effectiveness of a variety of medical products, including medical devices. CDRH of the FDA is responsible for premarket and postmarket regulation of medical devices.¹¹ The FDA/CDRH mandate is to promote and protect the public health by making safe and effective medical devices available in a timely manner.⁵ There are several types of marketing applications that a medical device manufacturer may submit to CDRH.¹²

Medical device manufacturers must submit PMAs for novel devices, also referred to as Class III devices. These devices tend to be higher risk or raise new types of safety and effectiveness questions that must be answered before approval for marketing. Data in a PMA application must demonstrate a “reasonable assurance” of safety and effectiveness. Manufacturers submit 510(k)s for devices similar to those already on the market. Data in a 510(k) submission must demonstrate that the new device is substantially equivalent in safety and effectiveness to a Class II device already on the market. Based on the incremental nature of device development, the majority of device applications cleared under the 510(k) program are based on non-clinical testing with no clinical data. Although the majority of PMA applications do contain clinical data, study designs are not prescribed by regulations.¹⁰ The types of marketing application are compiled in Table 4.

In EU, the marketing of medical devices regulated by directives, describing the essential (safety) requirements that products have to fulfill to obtain marketing clearance. In the EU, the need to tighten up the regulations covering the sale of medical devices was addressed by three medical device directives, which were intended to ensure the safety and performance of medical devices in the EU.

1. Active Implantable Medical Devices Directive – 90/385/EEC 4        

The first directive to be implemented which covers all powered implantable medical        devices.

2. Medical Device Directive – 93/42/EEC 5  

This directive enforced from June 1998 regulates most medical devices, for example    bandages, condoms and diagnostic X-ray Machines.

3. The In-Vitro Diagnostic Medical Devices Directive – 98/79/EC

This directive regulates products used to examine substances derived from the human body.⁷

Though there are many similarities in the regulatory process in the United States and countries within the European Union, there are important differences that impact the time and cost associated with the introduction of a new medical device. This is exemplified on basis of: Use of notified bodies, criteria for approval, and local site.¹³

The European Union system relies heavily on NBs, which are independent commercial organizations to implement regulatory control over medical devices. NBs have the ability to issue the [Confirmatory European (CE) mark], the official marking required for certain medical devices. NBs are designated, monitored, and audited by the relevant member states via the national competent authorities. Many functions performed by the FDA/CDRH within the United States are performed by NBs, including medical device certification, device type designation, assessment and verification of quality systems, and review of design dossiers for high-risk devices.  Currently, there are more than 50 active NBs within Europe. A company is free to choose any NBs designated to cover the particular class of device under review. After approval, post-market surveillance functions are the responsibility of the member state via the competent authority. NBs typically function in a closed manner, providing little visibility on criteria required for approval. This dynamic allows for a high degree of variation as well as competition among NBs. As a result, NBs are perceived by industry to be less bureaucratic organizations that can respond more quickly and efficiently than the FDA. These potential benefits may be offset by a system that is intrinsically more fragmented and highly variable and has resulted in the approval and continued marketing of devices, e.g., abdominal aorta stent grafts in Europe that failed efficacy trials in the United States.

Criteria for approval of high-risk devices are different in the EU. To receive approval to market a class III high-risk (and some class II) device in theUnited States, the manufacturer must demonstrate the device to be reasonably safe and effective, which typically requires a prospective, randomized controlled clinical trial. To receive approval to market a device in the EU, the manufacturer must demonstrate that the device is safe and that it performs in a manner consistent with the manufacturer’s intended use this difference has a profound impact on the size and scope of the clinical studies for regulatory approval. This significant difference is illustrated by examining the introduction of distal protection systems.^7,13

In Japan the evaluation of the safety and effectiveness of medical devices is performed by two centers under the control of Ministry of health and labor welfare (MHLW): Pharmaceuticals and Medical Devices Evaluation Center (PMDEC) and Japan Association for the Advancement of Medical Equipment (JAAME). PMDEC reviews manufacturing and import approval applications for drugs, cosmetics and medical devices and is responsible for evaluating all approval applications and clinical trial applications for new and improved medical devices. JAAME performs equivalence reviews of all generic, or me-too, medical device The Japanese regulatory environment for medical devices has changed significantly since the enactment of the Pharmaceutical Affairs Law (PAL). In Japan, a consolidated organization, the Pharmaceutical and Medical Devices Agency (PMDA), will be the cornerstone ofJapan’s medical product regulation.¹²

Currently, the medical device approval process depends on the type of medical device being submitted. There are different standard with regard to different classes, which are as follows-

CLASS-I – devices are renamed as general medical device and require marketing license from the prefecture government. They do not need marketing approval and their sale is not regulated.

CLASS-II- devices are renamed as controlled medical device and require third party certification. MHLW is establishing standard for accrediting third parties. MHLW will also regularly audit all third party organization. These marketing approval holders apply directly to third party certification body for marketing authorization. The third party determines whether the medical device confirms to the standards published by MHLW.

CLASS-III & IV – devices are designated highly controlled medical devices. These products are highly regulated and require marketing approval by MHLW.^6,10 Approval requirement for different classes are described in Table 5.

Medical devices firms have faced strict regulatory measures in the United States, the EU andJapan for several decades for ensuring safety and efficacy of medical devices. These three regions share somewhat of similarities beside of difference regarding classification and regulation of medical devices. The Comparison of theU.S., EU, and Japanese regulatory systems are shown in Table 6.

Conclusion

The demonstration of safety and efficacy for a new medical device is a long, arduous, and expensive developmental process. The regulation regarding confirmation of safety and efficacy of medical devices is differing from country to country. There is a need to establish a uniform format for different countries to certify that the medical device being exported complies with their domestic regulatory requirements. This certification process will greatly help importing countries to control medical devices, enhancing patient safety and increasing access to safe, effective and clinically beneficial medical technologies around the world.  The Global Harmonization Task Force is one of initiative towards this path.  However, there is further need of enhancing this global harmonisation.

References

1.Medical device regulation: global overview and guiding principle (Accessed on January, 5, 2008 at : http://www.who.int )

2.John J, Smith MD. Regulation of medical devices in radiology: current standards     and future opportunities. Radiology 2001, 218, 329-335.

3.Monsein LH. Primer on medical device regulation.Part I. history and background. Radiology. 1997, 205, 1-9.  

4.Alternative to animal testing of medical devices (Accessed on  January, 23, 2008 at a ltweb.jhsph.edu/publications/ECVAM/ecvam7.htm)

5.US Food and Drug Administration web site (Accessed May, 28, 2007 at http://www.fda.gov )

6.Medical device regulation update : China &Japan ( Accessed on October, 10, 2007 at www. devicelink.com/mddi/archive/06/10/005. html )

7.Canadian medical device industry (Accessed on January, 10, 2008 at http://www.ic.gc.ca/medimage-6k)

8.Center for device and radiological health (Accessed on December, 23, 2007 at  www. fda .gov/cdrh/index.html )

9.Guidelines to classification of medical devices (Accessed on December, 25, 2007 at http://europa.eu.int/comm/enterprise/medical_device/meddev/index.htm )

10.Japan’s new regulatory system (Accessed on November, 15, 2007 at http://www.devicelink.com/mddi/archive/04/10/015.html ) 

11. Goldstein LB. Regulatory device approval for stroke: fair and balance. Stroke 2007, 38, 1737. 

12. Felten RP, Ogden NRP, Peña C, Provost MC, Schlosser MJ, Witten CM. The Food and Drug Administration medical device review process: clearance of a clot retriever for use in ischemic stroke. Stroke 2005, 36,  404–406.

13. Kaplan AV, Baim DS, Smith JJ. Medical device development: from prototype to regulatory approval. Circulation 2004, 109, 3068–3072.      

14. George WW. The progress of global harmonization & mutual recognition effort for medical device. Food Drug Law J 1997, 52, 309-312.

15. Feigal DW, Gardner SN, McClellan M. Ensuring safe and effective medical devices. N Engl J Med 2003, 348, 191– 192.

16. Smith JJ, Shyjan AM. Defining "least burdensome means" under the Food and Drug Administration Modernization Act of 1997. Food Drug Law J 2000, 55, 435-447.  

17. Medical devices; exemption from pre-market notification requirements; class I devices; technical amendment. Final rule; technical amendment. Fed Regist. 2001, 66, 38786-38819.

Table 1. Classification of medical devices inU.S.

Table 2. European medical devices classification

Table 3. New classification system of medical devices inJapan

Table 4. Different types of marketing application inU.S.

*- demonstrate intended use, performance data, labeling, sterilization and packaging as well as compliance with special control and substantial equivalence to a predicate device.

**- must show reasonable assurance of safety and efficacy and where safety outweigh the probable risk, include clinical data.

Table 5.  Medical devices regulation inJapan based upon classification.

Table 6. Comparative regulatory aspects

About Authors:

Ruchika Swami, Jitender Singh, Deepak Kaushik, and Harish Dureja

Ms.Ruchika Swami is pursuing Masters Degree in Pharmaceutics (Drug regulatory Affairs) fromM. D. University, Rohtak. Her area of work includes World Wide Regulatory Environment on Medical Devices.

Deepak Kaushik earned his Bachelor in Pharmacy from M.D. University , India, and his Masters  in Industrial Pharmacy from S.G.S.I.T.S., Indore (India). His research areas include Formulation Development of Tablet Dosage Forms and Dissolution Enhancement of Poorly Soluble Drugs. He has published his work on development of melt-in-mouth tablets in national and international journals. He is currently working as a Lecturer in the Department of Pharmaceutical Sciences,Maharshi Dayanand University, Rohtak.

Jitender Singh studied Pharmacy at University of Rajasthan (India) and obtained Masters Degree in Pharmaceutical Chemistry from Punjabi University (India), DCA from I.IC.E. Delhi and A.I.C. from Institution of Chemist Kolkata. His research areas include Hetrocyclic Systems; He has got more than 06 publications to his credit. He is currently working as Asstt. Professor at Department of Pharmaceutical Chemistry, in Lord Shiva College of Pharmacy, Sirsa-1250555 (Haryana). He is also pursuing Ph.D. programme atGuru Jambheshwar University, Hisar.

Dr.Harish Dureja  studied Bachelor in Pharmacy at C. C. S. University (India), Masters Degree in Pharmaceutics from Punjabi University (India) and Ph. D. in Pharmaceutical Sciences from M. D. University, Rohtak (India). His research areas include in-silico ADME Modelling, Chemical Computation, Transdermal Drug Delivery Systems and Pharmaceutical Process Development. He has got more than 50 publications to his credit in various National and International Journals of repute. He is currently working as Lecturer at Department of Pharmaceutical Sciences,Maharshi Dayanand University, Rohtak.