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ADMINISTRATIVE ORDER

No. ________________

SUBJECT: GUIDELINES ON THE CONDUCT OF CLINICAL INVESTIGATION OF

MEDICAL DEVICES FOR HUMAN SUBJECTS IN THE PHILIPPINES

I. RATIONALE

The Philippines, as a signatory to the ASEAN Agreement on Medical Device Directive

(AMDD), is mandated to institutionalize an appropriate system for the conduct of clinical

investigation of medical devices, taking into account the Helsinki Declaration adopted by

18th World Medical Assembly in Helsinki, Finland, in 1964 and any subsequent amendments

or revisions to this Declaration by the World Medical Association.

As the regulatory agency for medical devices in the Philippines and pursuant to the

provisions of Republic Act 9711, otherwise known as the “Food and Drug Administration

(FDA) Act of 2009”, FDA has been tasked to develop policies on the regulation of medical

devices to ensure public health and safety from the use of these products. In addition, FDA

is also given the power to conduct, supervise, monitor and audit research studies on health

and safety issues of health products undertaken by entities duly approved by the FDA.

To implement the mandate of FDA and to ensure that all measures relating to the

protection of human subjects are carried out during the conduct of clinical investigation of

medical devices, this set of guidelines is hereby issued for strict compliance of all concerned.

II. OBJECTIVES

This Order aims to establish guidelines on the conduct of clinical investigation of medical

devices for human subjects in the Philippines. Specifically, it aims to ensure that the medical

device is suitable for the population for which it is intended and to ensure the safety and

well-being of subjects participating in the clinical investigation.

III. SCOPE

This Administrative Order shall apply to Contract Research Organization, Sponsors

and/or other entities engaged in the conduct of clinical investigation of the following medical

devices in the Philippines:

1. New medical device that will be marketed in the Philippines

Republic of the Philippines

Department of Health

OFFICE OF THE SECRETARY

Building I, San Lazaro Compound , R izal Av·enue, Sta .Cruz, 1003 Mani la • Trunk Line 651-7800 • Direct Line: 7 1 1-9501

Fa x: 743-1829, 743-1786 • URL: http://www.doh.gov.ph • e-mail: osec@doh.gov.ph

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2. Medical devices with corresponding authorization (Certificate of Medical Device

Registration or Certificate of Medical Device Notification) that have new intended

purpose as determined by the product owner

This guideline shall not cover medical devices that will be studied for thesis or research

purposes and that the product owner has no intention of marketing/selling the device. It does

not apply to clinical investigation of in vitro diagnostic medical devices.

IV. DEFINITION OF TERMS

For purposes of this Order, the terms below shall be defined as follows:

A. Certificate of Clinical Investigation Approval (CCIA)- a registration document issued

by the FDA for the purpose of allowing the conduct of clinical investigation of a medical

device in the country.

B. Class A medical device – low risk medical device

C. Class B medical device – low-moderate risk medical device

D. Class C medical device – moderate-high risk medical device

E. Class D medical device – high risk medical device

F. Clinical Investigation- systematic investigation in one or more human subjects,

undertaken to assess the safety or performance of a medical device. It is synonymous

with “Clinical trial” or “clinical study”.

G. Clinical investigation plan (CIP) - document that state(s) the rationale, objectives,

design and proposed analysis, methodology, monitoring, conduct and record-keeping of

the clinical investigation

H. Conflict of Interest – a situation created when persons or entities in the public and/or

private sectors involved in conducting research, making recommendations and decisions

have personal, financial or any other interest that may influence decision-making in favor

of the medical device industry.

I. Contract research organization (CRO) - person or organization contracted by the

sponsor to perform one or more of the sponsor's clinical investigation-related duties and

functions

J. Investigator - individual member of the investigation site team designated and

supervised by the principal investigator at an investigation site to perform critical

clinical-investigation-related procedures or to make important clinical investigation-

related decisions

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K. Investigator's brochure (IB) - compilation of the current clinical and non-clinical

information on the investigational medical device(s), relevant to the clinical investigation

L. Investigational medical device - medical device being assessed for safety or

performance in a clinical investigation

M. In vitro diagnostic medical device – any reagent, reagent product, calibrator, control

material, kit, instrument, apparatus, equipment or system, whether used alone or in

combination with any other reagent, reagent product, calibrator, control material, kit,

instrument, apparatus, equipment or system, that is intended by its product owner to be

used in vitro for the examination of any specimen, including any blood or tissue donation,

derived from the human body, solely or principally for the purpose of providing

information:

1. concerning a physiological or pathological state or a congenital abnormality;

2. to determine the safety and compatibility of any blood or tissue donation with a

potential recipient thereof; or

3. to monitor therapeutic measures and includes a specimen receptacle

N. License to Operate – authorization issued by the FDA to a licensed research entity to

conduct clinical investigation of medical devices or other related activities delegated by

the sponsor

O. Medical Device – any instrument, apparatus, implement, machine, appliance, implant,

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

purpose(s) 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; preventing infection; control of conception;

disinfection of medical devices; which does not achieve its primary intended action in or

on the human body by pharmacological, immunological or metabolic means but which

may be assisted in intended function by such means.

P. Monitor – refers to a qualified person responsible for overseeing the progress of a

clinical investigation and to ensure that it is conducted, recorded, and reported in

accordance with the CIP, written procedures, PNS ISO 14155:2018 or its subsequent

amendments and other applicable rules and regulations

Q. Product owner – in relation to a medical device, means any person who:

1. supplies the medical device under his own name, or under any trade mark, design,

trade name or other name or mark owned or controlled by him; and

2. is responsible for designing, manufacturing, assembling, processing, labelling,

packaging, refurbishing or modifying the medical device, or for assigning to tit a

purpose, whether those tasks are performed by him or on his behalf.

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R. Principal investigator – qualified person responsible for conducting the clinical

investigation at an investigation site

S. Research Ethics Committee (REC) – independent body whose responsibility is to

review clinical investigations in order to protect the rights, safety and well-being of

human subjects participating in a clinical investigation.

T. Research entity – refers to sponsor, CRO or principal investigator for principal

investigator initiated research.

U. Serious adverse event- adverse event that 1. Led to death

2. Led to serious deterioration in the health of the subject, that either resulted in

a. A life-threatening illness or injury, or

b. A permanent impairment of a body structure or a body function, or

c. In-patient or prolonged hospitalization, or

d. Medical or surgical intervention to prevent life-threatening illness or injury or

permanent impairment to a body structure or a body function

3. Led to fetal distress, fetal death or a congenital abnormality or birth defect

Note: Planned hospitalization for a pre-existing condition, or a procedure required by the CIP, without

serious deterioration in health, is not considered a serious adverse event.

V. Sponsor - individual or organization taking responsibility and liability for the initiation

or implementation of a clinical investigation

V. GENERAL GUIDELINES

A. Clinical investigations on human subjects shall be carried out in accordance with PNS

ISO 14155: 2018 Clinical investigation of medical devices for human subjects – Good

clinical practice or its subsequent revision(s) and other pertinent rules and regulations.

This includes every step in the clinical investigation from first consideration of the need

and justification of the study to publication of the results.

B. The conduct of clinical investigation shall demonstrate compliance with relevant

Essential Principles (including safety, clinical performance and acceptability of

risk/benefit ratio associated with its use) as stipulated in the ASEAN AMDD and shall

only be conducted if there are no sufficient data available through other sources (such as

literature or preclinical testing).

C. The following crucial steps shall be considered in clarifying the need for pre-market

clinical investigations:

1. Identify relevant clinical Essential Principles (for example, specifics of safety,

clinical performance, acceptability of risk/benefit ratio) for the medical device and

its intended purpose(s) and use(s)

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2. Perform risk management activities to help in identifying the clinical data necessary

to control residual risks and aspects of clinical performance not completely resolved

by available information e.g. design solutions, preclinical and material/technical

evaluation, conformity with relevant standards (ISO 14791), labelling, etc.;

3. Conduct a proper clinical evaluation to demonstrate which clinical data are necessary

and can be adequately contributed to by other methods, such as literature searching,

prior clinical investigations or clinical experience, and which clinical data remain to

be delivered by clinical investigation(s). Available clinical data for comparator

medical devices shall be carefully examined for compatibility and adequacy.

D. To avoid unnecessary experimentation on human subjects, the following justifications

shall be considered for the need for clinical investigation:

1. be necessary as assessed as per sub-section V.C of this guideline;

2. be designed properly (see Annex E);

3. be ethical as approved by REC

4. follow a proper risk management procedure to avoid undue risks; and

5. be compliant with all applicable statutory and regulatory requirements

E. Trials of Class D medical devices, such as implants which may present a potential serious

risk to health, safety or welfare of the participant, shall not be conducted on healthy

volunteers. The current safety data on the medical devices shall be gathered, and the risks

posed by the device shall be considered and evaluated.

VI. SPECIFIC GUIDELINES

A. License to Operate

1. No CRO and/or sponsors shall be involved in the conduct of clinical investigation of

a medical device for purposes of product registration/notification without a License

to Operate (LTO) from the FDA. For principal investigator-initiated research, the

principal investigator shall apply for a License to Operate.

2. No clinical investigation of a foreign sponsor may be conducted in the country unless

an FDA-licensed CRO takes up the responsibility for the foreign sponsor.

3. Other FDA licensed establishments desiring to engage in clinical investigation of

medical devices for purposes of registration/notification of the product as either a

sponsor or CRO shall secure the appropriate LTO.

4. Entities engaged in the following investigation related duties and functions delegated

by a sponsor are required to secure an LTO as CRO:

a. Oversight (e.g. ensuring quality assurance and/or quality control systems are in

place to ensure clinical investigation of a medical device are conducted, data are

gathered, and subsequently reported)

b. Management of clinical investigation of medical devices

i. Development of Clinical Investigation Plan/Protocol

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ii. Selection of investigator(s) and/or site(s)

iii. Screening and recruitment of subjects

iv. Data handling (e.g. collection, analysis/evaluation, and record keeping)

5. Entities involved in the procurement/importation, storage, and/or distribution of

investigational medical device are not required to secure an LTO as CRO, unless they

are involved in other activities mentioned above. These entities shall follow other

existing licensing requirements.

6. Applicants shall submit the documentary requirements based on the checklist

specified in Annex A.

7. The LTO shall be valid for three (3) years for approved initial application and five

(5) years for approved renewal application.

8. Application for Variation

a. The licensed research entity shall apply for approval from the FDA of any change

(major variation or minor variation) in the issued LTO. The types of major and

minor variation and the documents to be submitted when applying for FDA

approval are listed in Annex B.

b. The licensed research entity applying for minor variations may continue

business operations provided that an application for such variation has already

been filed.

B. Requirements for Class B, C or D Investigational Medical Devices

1. Certificate of Clinical Investigation Approval (CCIA)

a. The licensed research entity shall apply for a CCIA with the FDA before

undertaking clinical investigation of Class B, C or D medical devices.

b. Applicants shall submit the documentary requirements listed in Annex D when

applying for a CCIA. FDA may issue appropriate issuances to specify details or

provide clarifications on the list of documentary requirements.

c. The FDA shall create a Regulatory Experts and Scientific Advisory Committee

(RESAC) who will review the documents relative to the application for CCIA.

d. Compliance to applicable international or Philippine National Standard(s) shall

be considered in the evaluation and approval of the application for CCIA.

2. REC approval. The licensed research entity shall obtain approval from a Philippine

Health Research Ethics Board (PHREB) level 3 accredited REC prior to the conduct

of the clinical investigation of Class B, C or D medical devices. The licensed research

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entity shall submit to FDA a copy of such REC approval within thirty (30) days after

receipt of the approval.

C. Requirements for Class A Investigational Medical Devices

1. The licensed research entity shall obtain only approval from a PHREB level 3

accredited REC prior to the conduct of the clinical investigation of Class A medical

devices. The licensed research entity shall present to the REC an explanation why the

device was classified as Class A.

2. The licensed research entity shall notify the FDA of the REC approved clinical study

of Class A medical device by providing a copy of the REC approval fifteen (15) days

after receipt of the approval. All other provisions of this guideline shall be complied

with when conducting a clinical investigation of Class A medical devices.

D. Requirements for Investigational Medical Device for Treatment of a Serious or

Immediately Life-Threatening Disease or Condition

The FDA shall issue a separate guideline for medical devices that are not yet approved

for marketing but that will undergo clinical investigation for a serious or immediately

life-threatening disease or condition of patients for whom no comparable or satisfactory

alternative device or other therapy is available.

E. Exemption from LTO and CCIA Requirement

The following categories of clinical investigations are exempted from securing LTO and

CCIA from FDA:

1. A medical device undergoing consumer preference testing, testing of a modification,

or testing of a combination of two or more devices in commercial distribution, if the

testing is not for the purpose of determining safety or effectiveness and does not put

the subject at risk.

2. A device intended solely for veterinary use.

3. A device shipped solely for research on or with laboratory animals and labeled in

accordance with section VI.F.3 of this guideline.

4. A custom-made medical device unless the device is being used to determine safety or

effectiveness for commercial distribution.

F. Labeling of Investigational Devices

1. An investigational device or its immediate package shall bear a label with the

following information: the name and place of business of the manufacturer, importer,

the quantity of contents, if appropriate, and the following statement: "CAUTION-

Investigational device. Exclusivey for use in a clinical investigation” The label or

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other labeling shall describe all relevant contraindications, hazards, adverse effects,

interfering substances or devices, warnings, and precautions.

2. The labeling of an investigational device shall not bear any statement that is false or

misleading in any particular and shall not represent that the device is safe or effective

for the purposes for which it is being investigated.

3. An investigational device shipped solely for research on or with laboratory animals

shall bear on its label the following statement: "CAUTION-Device for animal testing

only.”

G. Import Permit

To facilitate the release of the medical device intended for clinical research, the

applicants shall apply for an Import Permit from the FDA. Documents to be submitted

are listed in Annex C.

H. Approval of the Application for Clinical Investigation

1. FDA shall give the final decision to approve or deny an application based on the

appropriate written recommendation by the RESAC.

2. A document (CCIA) granting approval for the conduct of a clinical investigation shall

be issued by FDA to the licensed research entity.

I. Amendments to Clinical Investigation that need FDA Approval

The following amendments in the clinical investigation shall require FDA approval prior

to implementation:

1. Amendment to the CIP

a. Changes to the study objectives and study endpoints (safety and efficacy

endpoints) b. Changes to inclusion and exclusion criteria c. Changes to the study treatment, major and significant study procedures and

withdrawal criteria d. Change in Study Site and main investigator or Principal Investigator e. Any change in sponsorship, contract delegation such as change of Contract

Research Organization f. Increase or decrease in study population g. Any other amendment that will affect the safety of the subjects

2. Amendment to the subject’s informed consent form if the deviation will affect

subject’s rights, safety and well-being

3. Changes in key personnel (principal investigator)

4. In addition to Sections VI.I.1 through VI.I.3, FDA may issue a separate issuance

regarding the circumstances and/or amendments in the clinical investigation that

need FDA approval as may be deemed necessary and appropriate.

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J. Conflict of Interest

All hospitals, personnel, and parties involved in implementing clinical researches or

clinical investigation of medical devices (including consultants, contractual, project

based, trainees) shall follow/comply the with the FDA guidelines on the full disclosure

and management of conflict of interest.

K. Inspection/Audit by FDA

The FDA shall have the authority to enter any establishment for (1) inspection/audit of

compliance and/or (2) verification of submitted documents in relation to any application

for issuance of appropriate authorization. A separate guideline shall be issued by FDA

for the audit/inspection relative to clinical investigation of medical devices.

L. Termination of the Study

At any time, FDA may terminate all clinical investigation that have failed to comply with

this guideline, PNS ISO 14155: 2018 Clinical investigation of medical devices for human

subjects – Good clinical practice or its subsequent revision(s) and/or other pertinent rules

and regulations; or after careful evaluation of the incident report involving serious

adverse event, result of inspection/audit, deviation report, and information and findings

from other National Regulatory Authority and international bodies.

M. Post-Market Clinical Follow-up Studies

A separate guideline shall be issued by FDA regarding post-market clinical follow-up

studies in accordance with the ASEAN Agreement on Medical Device Directive and

other pertinent laws.

VII. PROHIBITION OF PROMOTION AND OTHER PRACTICES

A sponsor, CRO or principal investigator or any person acting for on or behalf of a sponsor,

CRO or principal investigator shall not:

A. Promote or test market an investigational device, until after FDA has approved the device

for commercial distribution.

B. Commercialize an investigational device by charging the subjects or investigators for a

device a price larger than that necessary to recover costs of manufacture, research,

development, and handling.

C. Unduly prolong an investigation. If data developed by the investigation indicate that

premarket approval cannot be justified or that the device will not comply with an

applicable performance standard or an amendment to that standard, the sponsor shall

promptly terminate the investigation.

D. Represent that an investigational device is safe or effective for the purposes for which

it is being investigated.

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VIII. RESPONSIBILITIES OF LICENSED RESEARCH ENTITY

In addition to the responsibilities of the sponsor stipulated in PNS ISO 14155: 2018 and/or

its subsequent amendments and in the National Ethical Guidelines, the sponsor shall be

responsible for the following:

A. Upload in the Philippine Health Research Registry (http://registry.healthresearch.ph) the

information related to the clinical investigation of medical devices it is conducting within

thirty (30) days after receipt of CCIA and clinical investigation for Class A medical

devices to conduct the clinical trial/investigation has been granted.

B. Prompt submission, after awareness, of adverse device event or serious adverse device

event, if any, prepared and signed by the principal investigator. The sponsor shall indicate

if the same report was received by the monitor and REC.

C. Prompt submission of deviation report if any, prepared and signed by the principal

investigator. The sponsor shall indicate if the same report was received by the monitor

and REC.

D. Notify FDA and participating investigators of any withdrawal of approval of an

investigation or part of an investigation by a reviewing REC within 5 working days after

receipt of the withdrawal of approval.

E. Notify the reviewing REC and participating investigators of any withdrawal of FDA

approval (CCIA) within 5 working days after receipt of the withdrawal of approval.

F. Prompt notification of any changes in key personnel (principal investigator – requires

FDA approval) of the on-going clinical study/investigation. The licensed research entity

shall submit to FDA, at 6-month intervals, a current list of the names and addresses of all

investigators participating in the investigation. The sponsor shall submit the first such list

6 months after FDA approval.

G. Submit to FDA progress report at least yearly.

H. Notify FDA and the REC of any request that an investigator return, repair, or otherwise

dispose of any units of a device. Such notice shall occur within 30 working days after the

request is made and shall state why the request was made.

I. Notify FDA within 30 working days of the completion or termination of the investigation

of Class B, C or D and submit a final report to FDA, REC and participating investigators

within 6 months after completion or termination. In the case of investigation of Class A

medical device, notify FDA and REC within 6 months after termination or completion.

J. Prompt submission of any information or findings on similar studies from other countries

that may have bearing on the health of the subjects.

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K. Prompt notification of any amendments to the approved CIP

L. Report pregnancy and outcome of pregnancy during the conduct of clinical investigation

of medical device (if applicable)

M. Ensure that essential clinical investigation documents are maintained in the investigation

site and sponsor files as specified in PNS ISO 14155:2018 or its subsequent

amendment/s.

IX. RESPONSIBILITIES OF THE PRINCIPAL INVESTIGATOR

The responsibilities of the principal investigator shall be those specified in PNS ISO 14155-

2018: Clinical investigation of medical devices for human subjects – Good clinical practice

or its subsequent amendment(s) and those specified in the National Ethical Guidelines for

Health and Health-Related Research.

X. RESPONSIBILITIES OF A MONITOR/QUALIFIED PERSON

A monitor/qualified person within the organization of the licensed establishment must be

identified. The qualified person must be in charge of the overall operations of the

establishment which shall include:

A. Monitoring/supervision of all operations of the establishment.

B. Observance of PNS ISO 14155:2018 and/or its subsequent amendments and other

applicable international best practices.

C. Ensuring that all clinical investigation have satisfactorily complied with the requirements

of the research ethics committee, as well as other relevant government agencies.

D. Ensuring any adverse events experienced by subjects/patients are properly handled,

documented, and reported to FDA

E. Ensuring compliance of the establishment with existing regulations.

F. The abovementioned responsibilities should be properly translated into a Standard

Operating Procedure (SOP) which shall be duly validated during post-licensing

inspection/audit by the FDA.

XI. RESPONSIBILITIES OF FDA

A. Processing of application for License to Operate, CCIA and Import Permit relative to the

conduct of clinical investigation of medical devices.

B. Coordinating with the REC on matters relevant to the conduct of the ethical review of

clinical investigation protocols

C. Receiving and acting on amendments and other changes to the clinical investigation

protocol

D. Monitoring compliance to this guideline and to mandatory requirement for participation

in the Philippines Clinical Trial Registry

E. Conduct on-site inspection/audit of clinical investigation and licensed clinical research

entity covered by this guideline.

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F. Coordination with the RECs as well as PHREB on all matters related to the applications

under review to resolve whatever issues will arise.

XII. SCHEDULE OF FEES

The applicant shall be guided by the latest FDA circular on the schedule of fees.

XIII. TRANSITORY PROVISION

Upon effectivity of this Order, all sponsors, CROs and principal investigator for investigator

initiated research and all other establishments/research institutions within the scope of this

Order shall be given six (6) months from the date of publication of this Order in leading

newspaper to comply with the provisions of this guideline.

XIV. SEPARABILITY CLAUSE

If any of the provisions of this Administrative Order is found by a court of competent

jurisdiction to be void or unenforceable, in whole or in part, such provision shall be deemed

deleted from this Administrative Order but the remaining provisions thereof not affected

shall remain in full force and in effect.

XV. REPEALING CLAUSE

Sections V.6 and VII.C of DOH Administrative Order No. 2018-0002, other existing

administrative orders, circular, memoranda and other issuances inconsistent with this

Administrative Order are hereby repealed or amended accordingly.

XVI. EFFECTIVITY

This Administrative Order shall take effect after fifteen (15) days following the completion

of its publication in a newspaper of general circulation and filing with the University of the

Philippines - Office of the National Administrative Register (UP-ONAR).

FRANCISCO T. DUQUE III, MD, MSc

Secretary of Health

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ANNEX A

DOCUMENTARY REQUIREMENTS

A. LICENSE TO OPERATE (LTO) INITIAL APPLICATION

1. Proof of business name registration (not applicable for principal investigator initiated

research)

For single proprietorship – Certificate of Business Registration issued by the

Department of Trade and Industry

For corporation, partnership and other juridical person – Certificate of Registration

issued by the Securities and Exchange Commission (SEC) and Articles of

Incorporation

For government-owned or controlled corporation/university – the law highlighting

the provision creating the establishment/university

2. For principal investigator initiated research, authority from the president of the research

institution where the clinical investigation will be conducted

3. Credentials of monitor/qualified person

The Certificate of Attendance to basic and advanced GCP courses or any equivalent

courses/training for medical devices of the identified qualified person must be

submitted

4. Risk management plan (contains details on how to identify, characterize, prevent or

minimize risk relating to the clinical investigation project they engage with)

B. RENEWAL LTO APPLICATION

Copy of Certifications issued as a result of LTO Variation (if applicable)

C. REISSUANCE OF LOST OR DESTROYED LTO

1. Letter of request

2. Affidavit of loss or destruction

D. VOLUNTARY CANCELLATION OF LTO

Letter of request

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ANNEX B

DOCUMENTARY REQUIREMENTS FOR VARIATION APPLICATION FOR

SPONSORS AND CONTRACT RESEARCH ORGANIZATION

A. MAJOR VARIATIONS (Requires inspection prior to approval of variation)

1. Change of Ownership

a. Proof of business name registration reflecting the name of new owner

b. Deed of sale or transfer of rights of ownership

c. Updated delegation of authority (where applicable)

2. Transfer of Location

Proof of business name registration reflecting the new address

3. Change of key person

Updated delegation of authority

B. MINOR VARIATIONS – PRIOR APPROVAL

1. Additional activity (refers to an additional activity engaged by the CRO (e.g. oversight

with additional development of protocol and/or design activity) or change from the

initially approved activity (e.g. data handling to oversight)

Contract agreement to prove activity

2. Expansion of establishment (refers to the expansion made which is adjacent to the

existing location of the establishment or inclusion of additional floors where the building

is occupied)

Letter of request

3. Change of Business Name (no transfer of location or change of ownership)

Proof of business name registration reflecting the new name of the establishment

4. Zonal Change in Address (refers to change of the name/number of the street/building

without physical transfer of the establishment)

Document issued by the local municipality as proof of zonal change

5. Change of Delegated Sponsor Activities (refers to addition or deletion of any delegated

sponsor-clinical activities)

a. Updated delegation of authority

b. Contract agreement to prove activity/termination of contract or conformance letter

(where applicable)

C. MINOR VARIATION – NOTIFICATION

Change of Monitor/Qualified Person (there is a change in the initially identified qualified

person with no change of delegated sponsor activity)

Credentials of qualified person

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ANNEX C

DOCUMENTARY REQUIREMENTS FOR APPLICATION FOR IMPORT PERMIT

FOR MEDICAL DEVICE INTENDED FOR CLINICAL INVESTIGATION

1. Application Form

2. Letter addressed to the Director of CDRRHR stating that the medical device will be used

solely for research and is not intended for sale. The letter should contain the following

information:

a. Complete list of devices indicating the quantity, brand and the complete name of the

manufacturer of the product

b. Declaration that the organization shall be the sole entity responsible for the medical

devices and that the FDA will not be held liable for any safety issue concerning the

product

3. Packing list

4. Proof of payment

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ANNEX D

DOCUMENTARY REQUIREMENTS FOR APPLICATION FOR CLINICAL

INVESTIGATION APPROVAL FOR CLASS B, C AND D MEDICAL DEVICES

1. Duly accomplished application form

2. A complete report of prior investigations of the device

3. A description of the methods, facilities, and controls used for the manufacture,

processing, packing, storage, and, where appropriate, installation of the device 4. An example of the agreement to be signed by the investigators and a list of the names

and addresses of all investigators. The agreement shall include:

a. The investigator’s curriculum vitae.

b. Where applicable, a statement of the investigator's relevant experience, including

the dates, location, extent, and type of experience.

c. If the investigator was involved in an investigation or other research that was

terminated, an explanation of the circumstances that led to termination

d. A statement of the investigator's commitment to:

i. Conduct the investigation in accordance with the agreement, the investigational

plan, this guideline and other pertinent laws and regulations and conditions of

approval imposed by the reviewing REC or FDA;

ii. Supervise all testing of the device involving human subjects; and

iii. Ensure that the requirements for obtaining informed consent are met.

e. Disclosure of conflict of interest

5. Certification that all investigators have signed the agreement, that the list of

investigators includes all investigators participating in the study, and that new

investigators will sign the agreement before being added to the study. 6. A list of the names, addresses, and chairpersons of all RECs that have or will be asked

to review the investigation.

7. The name and address of any institution other than those identified in item 6 at which

a part of the investigation may be conducted. 8. Investigator’s brochure

9. Clinical investigation plan

10. Sample of labelling attached to investigational device

11. Insurance certificates

12. Copies of all informed consent forms and all related information materials to be

provided to subjects including translations

13. Any other relevant information that the FDA may request for review of application

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ANNEX E

GENERAL PRINCIPLES OF CLINICAL INVESTIGATION DESIGN

The design of the clinical investigation, including the study objectives and statistical

considerations, should provide the clinical data necessary to address the residual risks,

including aspects of clinical performance. Some factors that may influence the extent of

data requirements include, but are not limited to, the following:

1. Type of medical device and/or regulatory experience;

2. Novel technology/relevant previous experience;

3. Clinical applications/indications;

4. Nature of exposure to the medical device, e.g.: surface contact, implantation,

ingestion;

5. Risks inherent in the use of the medical device, e.g.: risk associated with the

procedure;

6. Performance claims made in the medical device labelling (including instructions for

use) and/or promotional materials;

7. Component materials;

8. Disease process (including severity) and patient population being treated;

9. Demographic, geographic and cultural considerations (e.g.: age, race, gender, etc.);

10. Potential impact of medical device failure;

11. Period of exposure to the medical device;

12. Expected lifetime of the medical device; and

13. Availability of alternative treatments and current standards of care and ethical

considerations