Abstract

In the past, all medical devices were not regulated as would have been expected from a region that is fourth in Asia after Japan, China, and South Korea. Medical devices in India were clubbed with regulations for new drugs, biologicals and vaccines. Medical devices are widely used by healthcare professionals across the globe. Keeping in view the broad objectives for ensuring protection of the health and safety of patients and healthcare professionals, CDSCO an agency of Ministry of Health & Family Welfare, Government of India has released the Medical Device Rules, 2017^c, effective from January 1, 2018 for regulating Medical Devices, including in vitro diagnostic kits.

1       Introduction

India has been a country that the west and the east were keenly looking at for a long time for the conduct of clinical trials. A sleuth of reactive responses to judiciary and civil society brought out notifications, circulars and orders resulting in the downfall of clinical trial approvals, with a peak of 500 approvals in 2010. Realisation though slow, has lead to reframing the Drugs and Cosmetics Rules leading to Medical Devices Rules, 2017 effective from January 1, 2018 for medical devices, including in vitro diagnostic kits; New Drugs and Clinical Trials Rules, 2019 effective from March 19, 2019; and draft Cosmetics Rules, 2018 issued for public opinion on November 29, 2018.

The Indian market is among the top 20 in the world by market size^a. Worldwide medtech sales forecast to reach $522 Billion by 2022 with a CAGR of 5.1% between 2016 and 2022. In vitro diagnostics is expected to remain the largest medtech segment in 2022 with annual sales of $70bn; Roche remains top player with expected sales of $12.8bn in 2022^b. 

Government regulations are tools used to achieve social, political, environmental and economic outcomes that would otherwise not be achieved within the market. Laws can often have adverse consequnences, but it is still necessary to protect consumers.

Not all biopharmaceutical companies are good corporate citizens. Many regulations, including most of those involving human health protection by way of safe drugs and medical devices, are a result of industries failing to regulate themselves. 

Pharmaceutical industries could monitor their “own adherence to legal, ethical, or safety standards, rather than have government monitor and enforce those standards.” But history is filled with examples of corporations that put social responsibility far down their priority lists, if it is on their agenda at all. Their priorities of course are profit, shareholder returns and competitive advantage. But in pursuit of those goals, some companies engage in practices that are socially irresponsible, if not dangerous.

2       Medical devices rules, 2017

In the past, medical devices were regulated under Schedule Y of the Drugs and Cosmetics Rules, 1945. Under these, 14 medical devices were notified as ‘Drugs’. These ranged from disposable hypodermic syringe and needle, perfusion sets, cardiac and drug eluting stents, catheters, intraocular lens, intravenous cannulae, bone cement, heart valve, scalp vein, orthopaedic implant, internal prosthetic replacement and in vitro diagnostic kits for human immunodefeciency virus (HIV), Hepatitis B surface antigen (HBsAg) and Hepatitis C virus (HCV). For those which required import, the medical devices had to be registered in Form 41 and imported in Form 10. Approval of new medical devices were through Form 44. The Medical Device Advisory Committee (MDAC) evaluated the clinical trial protocol and study data, published reports, literature, and package insert. Based on the recommendations of MDAC, the medical device was registered for marketing in Form 10 under rule 122A.

The Medical Devices Rules, 2017 of the Drugs and Cosmetics Act, 1940 came into force with effect from January 1, 2018. The rules are applicable for i) substances used for in vitro diagnosis and sterile surgical dressings, surgical bandages, surgical staples, surgical sutures, ligatures, blood and blood component collection bag with or without anticoagulant, ii) substances including mechanical contraceptives (condoms, intrauterine devices, tubal rings), disinfectants and insecticides; and iii) devices notified from time to time.

1.1      Medical device classification

The medical devices are classified mainly on intended purpose of the device, how invasive they are, how long they will be implanted. 

Non-invasive medical device that comes in contact with injured skin but not breached the dermis is class A, and if it is used in breached dermis or connected to an active medical device which is in class B, C, or D; it is classified as class B; or class C is if it is a blood bag or that modifies the biological or chemical composition of blood or other body liquids or other liquids intended for infusion into the body. 

Invasive (body orifice) medical devices for transient use (intended for continuous use for <60 minutes) is classified as class A, however if used on the external surface of an eyeball, oral cavity as far as the pharynx or in an ear canal up to the ear drum or in a nasal cavity it is class B. 

Reusable surgically invasive medical devices for transient use is assigned as class A. If they are not reused, then they are class B or class C if they are intended for passing ionising radiation. A transient or short term use surgically invasive medical device is assigned to class C, if it is intended for the administration of any medicinal product by means of a delivery system. A transient or short term (intended for continuous use for >60 minutes to 30 days) use surgically invasive medical device is assigned to class D, if it is intended to be used specifically in direct contact with the central nervous system or for the diagnosis, monitoring or correction of a defect of the heart or of the central circulatory system through direct contact.

Surgically invasive medical device intended for short term use shall be assigned to Class B.

An implantable medical device or a surgically invasive medical device intended for long term use is assigned to class C. A long-term use (intended for continuous use for > 30 days) medical device shall be assigned to Class B, if it is intended to be placed into any tooth. A long term use medical device shall be assigned to Class D, if it is intended to be used in direct contact with the heart, the central circulatory system or the central nervous system; is life supporting or life sustaining; is an active medical device; wholly or mainly absorbed by the body; for administration of any medicinal product; or is a breast implant.

Medical devices incorporating animal or human cells, tissues or derivatives is assigned to Class D, if it is manufactured from or incorporates cells, tissues or derivatives of cells or tissues, or any combination thereof, of animal or human origin, microbial or recombinant origin.which are or have been rendered non-viable. 

Medical devices intended to be used for contraception or the prevention of the transmission of any sexually transmitted disease is assigned to class C or D, if it is an implantable medical device or an invasive medical device intended for long term use, respectively.

1.2      In vitro diagnostic medical device classification

Classification of IVDs are governed by the intended purpose of the devices. IVDs are assigned to class A, if it is a reagent or an article which possesses any specific characteristic that is intended by its product owner to make it suitable for an in vitro diagnostic procedure related to a specific examination; an instrument intended specifically to be used for an in vitro diagnostic procedure; or  a specimen receptacle.

IVDs are assigned to class B, if it is intended to be used to obtain test results that are not for the determination of a medically-critical status; preliminary test results which require confirmation by appropriate laboratory tests; or used for the assessment of the performance of an analytical procedure or a part thereof, without a quantitative or qualitative assigned value.

IVDs are assigned to class C, if it is intended for use in detecting the presence of, or exposure to, a sexually transmitted agent; detecting the presence in cerebrospinal fluid or blood of an infectious agent with a risk of limited propagation; or an erroneous result that will cause death or severe disability to the individual or foetus; pre-natal screening of women for Rubella or Toxoplasmosis; screening for disease stages, for the selection of patients for selective therapy and management, or in the diagnosis of cancer; human genetic testing, such as the testing for cystic fibrosis or Huntington's disease; monitoring levels of medicinal products, substances or biological components, where there is a risk that an erroneous result will lead to a patient management decision resulting in an immediate life-threatening situation for the patient being tested (for example, cardiac markers, cyclosporin or prothrombin time testing); management of patients suffering from a life-threatening infectious disease such as viral load of HIV or HCV; screening for congenital disorders in the foetus such as Down’s syndrome or spina bifida; intended to be used for self-testing; used for near-patient testing in a blood gas analysis or a blood glucose determination (Anticoagulant monitoring, diabetes management, and testing for C-reactive protein and Helicobacter pylori).

IVDs are assigned to class D, if it is intended to be used for detecting the presence of, or exposure to, a transmissible agent present is in blood, blood component, blood derivative, cell, tissue or checking for suitability of organ transfusion or transplantation; or that causes a life-threatening disease with a high risk of propagation; intended to be used for blood grouping or tissue typing according to the ABO system, the, the Duffy system, the Kell system, the Kidd system, or the rhesus system.

1.3      Grouping of medical devices

If the device is intended to be used in combination with another device, the classification rules shall apply separately to each of the devices. Accessories are classified in their own right separately from the device with which they are used.

Software, which drives a device or influences the use of a device, falls automatically in the same class.

If the device is not intended to be used solely or principally in a specific part of the body, it must be considered and classified on the basis of the most critical specified use.

If several rules apply to the same device, based on the performance specified for the device by the manufacturer, the strictest rules resulting in the higher classification shall apply.

3       National accreditation body

National Accreditation Board for Certification Bodies (NABCB) under the Quality Council of India set up by the Ministry of Commerce and Industry, Government of India act as the national accreditation body for the purposes of accrediting Notified Bodies.

NAB lays down the conformity assessment activities for accreditation of Notified Bodies and standards for such accreditation; prepare norms and procedures for accreditation of Notified Body; and audit a Notified Body periodically for assessing conformance with the Medical Devices Rules.

4       Notified body

For a fee, the Notified Body accredited by the NAB audit the manufacturing sites to to verify conformance with the Quality Management System and other applicable standards as specified in the rules. For now, Intertek India, TUV Rheinland (Delhi), and TUV Sud South Asia (Mumbai) are the Notified Bodies registered for the purpose.

5       Test license to manufacture for the purpose of clinical investigation/ performance evaluation, examination, demonstration or training 

Application shall be made in Form MD-12 for the manufacture in small quantities for the purpose of clinical investigation/ performance evaluation, examination, demonstration or training. The fee for Test License is INR 500.

6       Clinical investigation of medical devices

In the past, investigations were necessary if the investigational medical device fell under the notified 14 categories. This has changed under the MDR and a new list of notified medical devices was released on November 1, 2017. The list contains 351 medical devices under 29 categories (table 1), and 247 IVDs under 21 categories (table 2).

No sponsor is allowed to conduct any clinical investigation without approval from CDSCO and institutional ethics committee. An application to conduct pilot or pivotal clinical investigation is made in Form MD-22 or MD-24 for IVD by the Sponsor/ CRO along with information specified in the Seventh Schedule of MDR and submitted online. For pivotal study, data emerging from pilot clinical investigation is required to be submitted as well. The clinical investigation should be initiated by enrolling first participant within a period of one year from the date of grant of permission, failing which prior permission from CDSCO shall be required to initiate clinical investigation.

Medical devices requiring clinical investigation but claiming substantial equivalence to a predicate device also requires CDSCO approval. Clinical investigation/ performance shall be conducted in accordance with the approved clinical investigation/ performance plan (study protocol) and CDSCO-Good Clinical Practices guidelines. All study related document templates are listed in table 4 for investigator brochure, table 5 for clinical investigation plan, table 6 for case report form, table 7 for reporting serious adverse event, table 8 for informed consent document, table 9 for investigator undertaking, and table 10 for clinical investigation report.

The sponsor as specified under rule 122DAB of the Drugs and Cosmetics Rules, 1945 should provide medical management or compensation in the event of death causally related to the investigational medical device, as in pharmaceutical research (Schedule Y).

The site and sponsor shall maintain all data, records, registers and other documents for a period of seven years after completion of clinical investigation.

In addition, the sponsor is expected to give source and quantity of samples which shall be used during evaluation, a description of the device including specification of raw material and finished product, data allowing identification of the device in question, proposed instruction for use, labels and regulatory status in other countries, in-house performance evaluation data used to establish stability, specificity, sensitivity, repeatability and reproducibility. The medical device should be tested and evaluated by Government testing laboratory that is accredited by National Accreditation Body for Testing and Calibration Laboratories (NABL).

The study should be registered with Clinical Trial Registry of India before enrolling the first participant. Annual status report of each clinical investigation/ performance as to whether it is ongoing, completed or terminated, shall be submitted to CDSCO by the sponsor.

Medical device, including IVDs which does not have predicate medical device indicated in life threatening, serious diseases or diseases of special relevance to the Indian health scenario, national emergencies, extreme urgency, epidemic and medical devices indicated for conditions, diseases for which there is no therapy, the animal data or clinical data requirements may be abbreviated, deferred or omitted, as deemed appropriate by CLA.

In respect of class A investigational medical device or IVD, data on clinical investigation/ performance may not be required, except in cases, where depending on the nature of the medical device, the CLA, for reason to be recorded in writing, considers such data necessary.

The results of clinical investigation/ performance may not be required to be submitted where the investigational medical device/ IVD is approved by the regulatory authorities of either the United Kingdom, United States of America, Australia, Canada or Japan and the said device has been marketed for at least two years in the above-mentioned country and CLA is satisfied with the data of safety, performance and pharmacovigilance of the device, and there is no evidence or theoretical possibility, on the basis of existing knowledge, of any difference in the behaviour and performance in Indian population, the applicant has given an undertaking in writing to conduct post marketing clinical investigation/ performance with the objective of safety and performance of such investigational medical device as per protocol approved by CLA.

The fee for application to conduct pilot or pivotal clinical investigation is INR 100,000 and to conduct clinical performance evaluation is INR 25,000. Per rule 51(2), no fee shall be payable by any institute, organisation, hospital-run or funded by Central or State Government for conduct of clinical investigation.

7       Import of medical devices

An authorized agent in India having license to manufacture or wholesale license for sale or distribution for sale or distribution shall make an application for grant of import license to CDSCO through online portal in Form MD-14. 

For import or manufacture of medical device which does not have predicate medical device, an application for grant of permission for such medical device after completion of its clinical investigation under Chapter VII shall be made to the CLA in Form MD-26 either by an authorized agent in case of import or the manufacturer.

An application for grant of permission to import or manufacture a new IVD may be made in Form MD-28 either by an authorised agent in case of import or the manufacturer.

The fee for import of class A medical device per site is USD 1000 and USD 50 per product; for class B per site is USD 2000 and USD 1000 per product; and for class C or D per site is USD 3000 and USD 1500 per product.

The fee for import of class A or B IVD per site is USD 1000 and USD 10 per distinct product; and for class c or D per site is USD 3000 and USD 500 per distinct product.

Fee for import license for test, evaluation, demonstration or training for each distinct medical device is USD 100.

8       Manufacturing

The application shall be made through online portal of the Ministry of Health and Family Welfare in Form MD-3 for manufacture of class A and B (obtain marketing authorization in MD-5 for class A and MD-6 for class B); class C in MD-7 and class D in MD-8 (obtain marketing authorization in MD-9 and MD-10) respectively.

For class A medical devices, the State Licensing Authority shall, after scrutiny of documents, grant a licence to manufacture within 45 from the date of application. No audit of the manufacturing site is necessary prior to grant of manufacturing licence. However, audit of such manufacturing site by the registered Notified Body is carried out within 120 days from the date on which the licence was granted by the State Licencing Authority.

Audit of the manufacturing site of class B shall be carried out within 90 days from the date of application by the registered Notified Body prior to grant of marketing authorisation.

Before grant of license to manufacture for sale or for distribution in respect of Class C or D medical device, the manufacturing site shall be inspected within a period of 60 days from the date of application by a team comprising not less than two Medical Device Officers which may include an expert, or a Notified Body personnel. 

A manufacturing license or loan licence is valid in perpetuity, subject to payment of licence retention fee before completion of the period of five years from the date of its issue, unless, it is suspended or cancelled by State/ Central Licensing Authority.

The fee (and renewal) for manufacturing of class A or B medical device per site is INR 5000 and INR 500 per product; and for class C or D per site is INR 50,000 and INR 1000 per product.

The fee for permission to import or manufacture a medical device that does not have its predicate device is INR 50,000 and IVD is INR 25,000.

9       Post-marketing

The permission holder of Form MD-27 shall inform the date of launch of medical device in the market to the CLA and shall submit Periodic Safety Update Report from the date of launch in the market and such report shall be submitted every six months for first two years followed by submission of the said report annually for the two more successive years.

10    Materiovigilance

CDSCO in collaboration with Indian Pharmacopoeia Commission has the responsibility to conduct Materiovigilance programme of India (MvPI). Indian Pharmacopoeia Commission functions as National Coordination Centre (NCC) for MvPI.

MvPI is meant to enable safety data collection in a systematic manner so that regulatory decisions and recommendations on safe use of medical devices being used in India could be based on data generated. The program is meant to monitor medical device-associated adverse events (MDAE), create awareness among healthcare professionals about the importance of MDAE reporting in India and to monitor the benefit-risk profile of medical devices. It is also meant to generate independent, evidence-based recommendations on the safety of medical devices and to communicate the findings to all key stakeholders.

11    Recall of medical device

If a manufacturer has reasons to believe that the medical device that has been imported, manufactured, sold or distributed, is likely to pose risk to the health of a user during its use and therefore may be unsafe, such manufacturer or authorised agent shall immediately initiate procedures (action taken to prevent risk to the patient) to withdraw the medical device in question from the market and patients, indicating reasons for its withdrawal and inform CLA the details thereof immediately.

12    Export of medical devices

Where a manufacturer intends to export any medical device, manufactured in India, and for that purpose, requests a certificate in the nature of free sale certificate or a certificate about quality, safety and performance in relation to that medical device as required by the authority concerned of the importing country, such person, may apply to CLA for the purpose along with a fee as specified.

13    Acknowledgement

None.

14    References

a)   Deloitte and NATHEALTH, Medical Devices-Making in India-A leap for Indian Healthcare, 2016. http://bit.ly/mpo180450

b)   https://info.evaluategroup.com/WPMT2017-SOC.html?MD=SC&SC=TW&CLP=C1

c)   Medical Devices Rules, 2017

Sudhakar Bangera is a clinical development consultant at AILEEN Clinical Research Services LLP. Latha MS, Phd, is a partner at AILEEN Clinical Research Services LLP.