CLINICAL TRIALS OF MEDICAL DEVICES

CLINICAL TRIALS OF
MEDICAL DEVICES
DR DWAIPAYAN SARATHI CHAKRABORTY
PGT,DEPT. OF PHARMACOLOGY
IPGME&R,KOLKATA

OVERVIEW
 INTRODUCTION
 DEFINITION
 CLASSIFICATION
 GLOBAL AND INDIAN MARKET
 SALIENT FEATURES OF DEVELOPMENT
 PHASES OF MEDICAL DEVICE CLINICAL TRIAL
 TYPES OF INVESTIGATIONAL DEVICE STUDIES
 DIFFERENCES WITH DRUG TRIAL
 GLOBAL PERSPECTIVE
 INDIAN PERSPECTIVE
 CONCLUSION
MEDICAL DEVICE TRIALDSCIPGME&R KOLKATA
2

INTRODUCTION
 Medical devices play a critical role in the lives and health of millions
of people worldwide.
 Starting from deep brain stimulation implant for Parkinson’s disease
to knee replacing implants for osteoarthritis, these remarkable
products lead to increased longevity and improved quality of life.
 From everyday household product items (e.g. thermometer) to
complex implants, responsibility lies on regulators to ensure safety
and efficacy.
 Medical device regulation is complex in part because of the wide
variety of items that are categorized as medical devices
3

DEFINITION
 As per (21 U.S.C. 321(h)) U.S Food & Drug Administration:
 Medical device:
‘is an instrument, apparatus, implement, machine, contrivance, implant,
in vitro reagent, or other similar or related article, including any
component, part, or accessory, which is:
• recognized in the official National Formulary, or the US
Pharmacopeia, or any supplement to them,
• intended for use in the diagnosis of disease or other conditions, or in
the cure, mitigation, treatment, or prevention of disease, in man or
other animals, or
• intended to affect the structure or any function of the body of man or
other animals, and
which does not achieve its primary intended purposes through chemical
action within or on the body of man or other animals and which is not
dependent upon being metabolized for the achievement of its primary
intended purposes
4

As per Medical Device Rules, 2017 implemented by Ministry
Of Health and Family Welfare (Government of India)
Medical Devices means---
1) Specific devices intended for internal or external use in the
diagnosis, treatment, mitigation or prevention of disease or
disorder in human beings or animals which are notified by
the Government from the time to time under act.
2) Specific substances intended to affect the structure or any
function of the human body which are notified by the
Government. At present, the substances notified are
mechanical contraceptives (eg Condoms, IUDs,tubal rings)
and disinfectants.
3) Substances used for in vitro diagnosis.
5

CLASSIFICATION
 In accordance with the Federal Food, Drug, and Cosmetic
Act, FDA places all medical devices into one of three
regulatory classes.
 Classification is based on the level of control necessary to
ensure safety and effectiveness of the device.
NB- Devices in all three classes are subject to general controls
which require, in part, that companies:
(1) register their establishments and list the medical devices
they market with FDA;
(2) manufacture their devices in accordance with Good
Manufacturing Practices; and
(3) label their devices in accordance with labelling
regulations.[eg QUALITY SYSTEM REGULATION (QSR)
compliance] https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm127067.pdf
6

CLASS I DEVICES
 Class I devices are subject only to general controls.
 Typically present the lowest potential for harm and
are simpler in designs.
 Most are exempted from 510(k) PREMARKET
NOTIFICATION
 In some cases exempted from QSR compliance
 Clinical studies are not generally required for
marketing clearance.
 Examples are---Elastic bandage, examination gloves ,
hand held surgical instruments.
7

CLASS II DEVICES
 General controls are insufficient to provide
reasonable assurance of safety and
effectiveness.
 Carry moderate risk to patients.
 Special controls ( e.g. special labelling
requirements, mandatory performance
standards, post marketing surveillance) are
available to mitigate risk .
 Most of them require PREMARKET
NOTIFICATION via 510(k) process
 Examples are:-Powered wheelchairs, infusion
pump, surgical drapes.
8

CLASS III DEVICES
 Carry potential risk of illness or injury
 Clinical study required to demonstrate safety and
effectiveness prior to marketing approval.
 Most require PRE MARKET APPROVAL unless
marketed prior to 1976.
 To be used in supporting human life or for a use
which is of substantial importance in preventing
impairment of human health.
 Examples are:--Artificial heart valves,silicone gel
fiiled breast implants,implanted cerebellar
stimulator,coronary stents.
9

INDIAN CONTEXT CLASSIFICATION
 In INDIA, as per Medical Device Rules 2017, medical devices are
classified based on the level of risk involved in their use.
 They are classified as—
 CLASS A :-LOW RISK (Thermometer, tongue depressor)
 CLASS B:-LOW-MODERATE RISK(Suction equipment, hypodermic
needle)
CLASS C:-MODERATE-HIGH RISK( Ventillator,bone fixation plate)
CLASS D:-HIGH RISK(Heart valves,AICD)
http://www.mohfw.nic.in/showfile.php?lid=4168
10

GLOBAL MARKET OF MEDICAL DEVICE
 It is one of the biggest
industries in healthcare, driven
by innovation and new
technologies.
 Unprecedented growth in in
last decade.
 The US medical device
industry is the global leader
with sales of around $136
billion – approx. 45% of the
global market, according to the
US Government Accountability
Office (or GAO) 2014 statistics
http://marketrealist.com/2015/11/must-read-overview-medical-device-industry
11

INDIAN SCENARIO
 Medical device
market in India is one
of the top 20 in the
world & is the fourth
largest in Asia after
Japan, China and
South Korea.
 The market is growing
steadily. It was valued
at US $3.5 billion in
2015 and could
expand to approx.US
$4.8 billion by 2019.
http://www.skpgroup.com/data/resource/skp_the_medical_device_industry_in_india_.pdf
12

SALIENT FEATURES OF MEDICAL
DEVICE DEVELOPMENT
 In medical device development instead of Investigational
New Drug (IND) application, it is called INVESTIGATIONAL
DEVICE EXEMPTION (IDE)application.
 Similarly the equivalent of New Drug Application (NDA) is
PRE-MARKETING APPROVAL( PMA) application.
13

PREMARKET NOTIFICATION 510(K)
 It is submitted to FDA to demonstrate that the device to be marketed is
at least as safe and effective, that is substantially equivalent ,to a
legally marketed device.
 The 510(K) application to the FDA is required at least 90 days before
marketing.
 The submitter may market the device immediately after 510(K)
clearance is granted.
 Following four categories of parties must submit a 510(K) to FDA:
1) Domestic manufacturer introducing a device to the US market
2) Specification developers introducing a device to the US market
3) Repackers/relabellers introducing a device to the US market.
4) Foreign manufacturer/exporter or US representative of foreign
manufacturer/exporters introducing a device to the US market.
https://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/premarketsubmissions/premarketnotification510k/
14

INVESTIGATIONAL DEVICE EXEMPTION(IDE)
 The term “EXEMPTION” in this case means exempt from
laws prohibiting unapproved products to move in interstate
commerce.
 It allows the investigational device to be used in a clinical
study in order to collect safety and efficacy data.
 An IDE requires local INSTITUTIONAL REVIEW BOARD(IRB)
approval, Informed Consent from all patients, labeling of
the device for investigational use only and rigorous
monitoring of the study.
 An approved IDE permits a device to be shipped lawfully for
the purpose of conducting investigations of the device
without complying with other requirements of Food Drug &
Cosmetic Act that would apply to devices in commercial
distribution.https://www.fda.gov/medicaldevices/deviceregulationandguidance/howtomarketyourdevice/investigationaldeviceexemptionide
15

PRE-MARKETING APPROVAL (PMA)
 FDA process of scientific & regulatory review to evaluate the safety and
efficacy of Class III medical devices.
 Approval is granted only if the FDA determines new device has sufficient
scientific evidence to be safe & effective for its intended use.
 When PMA is received by FDA it has 45 days to make sure that application
is administratively complete. If not, application is returned, if complete
then it is formally filed by FDA.
 FDA regulation provide 180 days to review the PMA & determine whether
an advisory committee meeting is necessary or not.
 In reality the review time is normally longer.
 A PMA must contain following informations:--Device description including
significant physical & performance characteristics, indication for use,
description of the patient population & disease or condition that the
device will diagnose,treat,prevent,cure or mitigate, proposed
labelling,description of manufacturing process,summaries of clinical &
nonclinical data supporting the application & conclusion drawn from
studies.
16

PHASES OF MEDICAL DEVICE CLINICAL TRIAL
There are two main stages /phases---
1) PILOT (FEASIBILITY) STUDY & 2) PIVOTAL(CONFIRMATORY)
STUDY
PILOT STUDY
 First done in humans, intended to acquire specific essential information
about a device, before going to pivotal study.
 Exploratory in nature
 Use small number of patients (10-30)
 Meant to give insight into the performance & safety, but can’t provide
definitive support to specific mechanism or therapeutic claims.
 Objectives include assessing feasibility (e.g. preliminary device
performance),exploring eligibility criteria and their practical
application for pivotal randomized controlled investigation,
ascertaining potential harm(preliminary safety evaluations),validating a
method for determining an outcome measure and evaluating the
logistics of pivotal trial performance
17

2) PIVOTAL STUDY–
Definitive, confirmatory study.
Conducted in a larger number of patients (100-300) to
gather evidence for safety & efficacy
For medical device which doesn’t have a predicate medical
device but approved outside INDIA, pivotal studies need to
be carried.
 Prior to conducting a pivotal clinical investigation in Indian
subjects, Central Drugs Standard Control Organization
(CDSCO) may require pilot study data generated in Indian
population to assess whether the pilot data is in
confirmatory to the data already generated outside the
country
18

Post Marketing Clinical Investigation
may not be considered necessary at the time of device approval
but may be required by CDSCO for optimizing the intended use
of medical device.
It includes additional drug-device interaction, safety studies,
investigation designed to support use under the approved
condition(eg mortality/morbidity studies etc)
19

TYPES OF INVESTIGATIONAL DEVICE STUDIES
FDA defines 3 types of Investigational Device Studies—
A] SIGNIFICANT RISK(SR)
B] NONSIGNIFICANT RISK(NSR)
C] EXEMPT
https://www.fda.gov/downloads/regulatoryinformation/guidances/ucm127067.pdf
20

SIGNIFICANT RISK(SR) DEVICE STUDIES
 SR means an investigational device that is—
1. Intended as an implant & presents a potential risk to health, safety or
welfare of a subject.
2. Is reported to be for use in supporting or sustaining human life.
3. Is for a use of substantial importance in diagnosing, curing, mitigating or
treating disease or otherwise preventing impairment of human health.
 Sponsors of SR device studies are required to get an approved IDE from FDA
before starting their study.
 If FDA disapproved an IDE, FDA’s letter will describe the reasons for
disapproval.
 In accordance with the regulations at Part 812, the study may not start
until both FDA & IRB have given their approval.
21

NON-SIGNIFICANT RISK (NSR) DEVICE STUDIES
 Investigational device that doesn’t meet the definition of a significant risk
device.
 If an IRB finds that an investigational medical device poses a NSR ,the
sponsor doesn’t need to submit an IDE to FDA before starting the study.
 If the IRB determines that the proposed study is a NSR study, the IRB may
proceed to review the study under 21 CFR 56.109 & 21 CFR 56.111
 FDA considers a NSR device study to have an approved IDE after IRB
approval & when sponsors meet the abbreviated requirements.
 If however FDA hasn’t made the risk determination or the IRB disagrees
with the NSR determination or the IRB disagrees with the NSR
determination made by sponsor, then the IRB must notify the investigator
and, where appropriate the sponsor, that the study involves a SR device.
 If a sponsor or an IRB needs help in making the SR/NSR determination it
may ask for a written determination from FDA.
22

EXEMPT STUDIES
 Sponsors and investigators of certain studies are exempt from the
requirements of 21 CFR PART 812.
 Examples are consumer preference testing, testing of a device
modification, or testing of two or more devices in commercial
distribution if the testing doesn’t collect safety or effectiveness data, or
put subjects at risk.
 Studies of an already cleared medical device in which the device is used
or investigated in accordance with the indications in the cleared
labelling are exempt from PART 812.
 In addition diagnostic device studies are exempt from the requirements
of 21 CFR PART 812 under certain circumstances.
 The study is exempt as long as the sponsor complies with the
requirements at 21 CFR 809.10(C) for labelling.
23

DIFFERENCES WITH DRUG TRIAL
POINTS DRUG TRIAL DEVICE TRIAL
HEALTHY SUBJECT RECRUITEMENT New drugs are studied carefully in
phases starting with introduction to
a small number of healthy subjects
For medical devices specially those
that are required as surgical implants
,it’s not possible to insert the device
into healthy subjects
TOTAL NUMBER OF SUBJECTS NEEDED
TO SHOW SAFETY AND EFFICACY
Thousands Only one or two hundreads
USE OF PLACEBO For many drug trial the control is
placebo
In medical device studies it is often
unethical to use a placebo and for
many devices it would be impossible
RANDOMIZATION & BLINDING Easier to perform Difficult
Standard follow up tools to determine
the efficacy
ECG, BP,HR,biochemical parameters
etc
Imaging could be an option for
functioning assesment
NECESSITY Required in every cases; minute
change to the compostion of a drug
may result in unexpected effects
Not always required and whether or
not done will be conducted depend
upon risk assessment.
http://cdn2.hubspot.net/hub/149400/file-646377456-pdf/docs/mc-n-med-dev-trials-compare-with-drug-trials.pdf
24

WORLDWIDE MEDICAL DEVICE TRIAL
26

COMPARISON BETWEEN US & EU IN MEDICAL DEVICE REGULATION
27

REGULATORY ISSUES IN OTHER MAJOR COUNTRIES
https://www.jyoungpharm.org/sites/default/files/10.5530jyp.2016.1.3.pdf
28

INDIAN PERSPECTIVE
29

 In 2006, Medical Devices Regulation Bill was
introduced, to strengthen laws for medical devices
in India.
 However, the Bill is yet to be approved by the
Parliament, and actions related to medical devices
are governed by the Drugs and Cosmetics Act, 1940
and Rules, 1945.
 In August, 2013, Drugs and Cosmetics (Amendment)
Bill, 2013 was introduced, which included a
separate chapter for regulatory measures for
import, manufacture, sale, distribution and export
of medical devices in India.
30

MEDICAL DEVICE TRIALDSCIPGME&R KOLKATA 31
 In 2014, World Health Assembly (WHA) adopted
resolution regarding regulatory system strengthening for
medical products.
 A working document was developed by the Global
Harmonization Task Force (GHTF) Study Group and its
successor, the International Medical Device Regulators
Forum (IMDRF), and served as a guidance document that
can be enacted by member national regulatory
authorities or others.
 On 17th October, 2016, the Ministry of Health and Family
Welfare (MoH&FW) drafted a separate Medical Devices
Rules, 2016. After consultation with the Drugs Technical
Advisory Board, it finally notified the Medical Devices
Rules, 2017 on 31st January 2017, which is to be
enforced by January 1, 2018.

32

REQUIREMENTS FOR CONDUCTING CLINICAL
TRIALS OF MEDICAL DEVICE IN INDIA
 CDSCO in the year 2010 formulated few specific guidelines
 They are----
1) All informations/reports/data should be in ENGLISH only.
2) It is expected that the information submitted in the form of
hard copy shall also be submitted in the form of soft copy.
3) Application for conducting clinical trials for medical device in
INDIA should include following documents/informations-----
 COVERING LETTER—Indicating precise intent of the application ,name and
address of manufacturer as well as applicant,name of device along with a list
of documents carrying relevant informations.It should be signed by Authorized
Signatory clearly reflecting name and designation of authorized signatory.
 DULLY FILLED APPLICATION---In form 44 as prescribed in Drugs and Cosmetic
Act and Rules there under, signed & stamped by authorized signatory.
Contd…
33

 Requisite fees– As per provision of above mentioned Act in Form TR6 challan
issued by BANK OF BARODA at notified branch.
 Declaration of Responsibility---Declaration from the sponsor required to be
submitted in original on Sponsor’s letter-head stating the extent of delegation of
responsibilities to the Primary Investigator.
 Protocol--Information to be submitted in Protocol enclosed at Annexure IV
 Global Regulatory status of device– Particularly in 5 Global Harmonization Task
Force (GHTF) Countries ie USA,Australia, Japan, Canada & European Union.
 Investigator’s Undertakings– As enclosed at ANNEXURE VII
 Ethics Committee approval letter– Enclosed at Annexure VIII
 Case Report Form(CRF) ----Format for CRF should be submitted
 Patient Record Form---Format for Patient Record Form to be submitted.
 Relevant Published Literature---For the subject device/predicate device(s) should
be submitted
 Investigator Brochure
 Suspected Unexpected Serious Adverse Reaction( SUSAR)---From other
participating countries if any reported, should be submitted
 Any other specific relevant information with respect to subject device.
34

MEDICAL DEVICE RULE 2016
 Published in Part II Section 3,Subsection (i) of the Gazette of INDIA
 Important regulatory norms implemented in the field of medical device
clinical trials are----
1) No person or sponsor shall conduct any clinical
investigation in respect of investigational medical device in human participants
except in accordance with these rules and in accordance with the permission
granted by the central licensing authority.
2) An application for grant of permission to conduct
clinical investigation for investigational medical device shall be made to the
Central Licensing Authority in FORM 20 by a sponsor and shall be accompanied
with information specified in SEVENTH schedule.
 An application for grant of permission to conduct Pilot clinical investigation
or First in Human Study on an investigational device in India shall be made as
referred to in sub-rule Accompanied with fees as specified in the Second
schedule along with the information as specified in the Seventh Schedule.
 A Pivotal clinical investigation on an investigational device shall be made on
the basis of data emerging from pilot clinical investigation, as referred to in
sub-rule Accompanied with fees as specified in the Second schedule along
with the information as specified in the Seventh Schedule.
35

MEDICAL DEVICE RULES 2017
On 31st January 2017, Ministry of Health and Family Welfare ( Government
of India) notified “Medical Device Rules 2017” in a press meet.
The new Rules have been formed in conformity with GHTF
framework and confirm to best International practices.
Separate provisions for regulation of Clinical Investigational
device (ie new device) have also been made at par with International
practices and like clinical trials, these will be regulated by CDSCO. Conduct
of clinical investigations will, while following the international practices,
be conducted in a manner that ensures realization of the twin objectives of
patient safety & welfare and discovery of new medical devices.
Separate provisions for medical management & compensation
for the subjects of the trials have been introduced to achieve patient
safety. The rules have been provided for compensation of up to INR 800,000
for people affected by an adverse trial.
36

TheMoHFW initiated“Materiovigilance Programme
of India (MvPI)” vide approval dated 10/02/2015 in
an effort to ensure safety of medical devices.
MvPI has been launched by DCG (I) on 6th July
2015 at Indian Pharmacopoeia Commission (IPC)
Ghaziabad.
WHAT TO REPORT---
Any dysfunction or any change of the
characteristics and/or performance of a device,
any inadequacy in the labeling or instructions,
which might lead to death or serious relapse in the
state of health of a patient, a user or a third party.
Any technical or medical reason related to the
characteristics or performance of a device.
Cases where there was a risk of a serious incident
but avoided due to the attention and action of the
relevant people.
Contd….

http://ipc.nic.in/writereaddata/mainlinkFile/File572.pdf
38
WHERE TO REPORT—
Duly filled Medical Device Adverse Event Reporting Form can be send to Sree
Chitra Tirunal Institute of Medical Science and Technology (SCTIMST),National
Collaboration Centre-Materiovigilance Programme of India, Biomedical Technology
Wing, Poojappura, Thiruvananthapuram 695012,Kerala,India.
Or
Directly email the duly filled form to mvpi@sctimst.ac.in.
Or
Call on Toll free Helpline no. 1800 180 3024 to report Adverse event.
WHO CAN REPORT—Under MvPI- clinician, biomedical engineers, clinical
engineers, hospital technology manager, pharmacists, nurses, technicians can report
medical device adverse events.
WHY TO REPORT--Medical devices have been associated with several adverse
effects and at times fatal harmful effects to the patients. As a stakeholder it is a
responsibility to report adverse events associated with use of Medical Devices and
safeguard the health of public.

MEDICAL DEVICE ADVERSE EVENT
REPORTING FORM

CONCLUSION
 The medical device industry is inevitably growing and
becoming more important day by day.
 It’s clinical research is very essential in assessing safety and
effectiveness of numerous medical device in the market or
in the development process.
 The regulation of medical devices around the world is very
diverse.
 There has been an upsurge in the number, diversity, and
intricacy of medical devices in last two decades.
 Most countries are trying to harmonize the regulatory
guidelines for medical devices through their participation in
GHTF.
 Harmonized regulation of medical device will lead to the
availability of quality product.
40

LOOKING FORWARD TO………
41

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CLINICAL TRIALS OF MEDICAL DEVICES

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