FAQs In Clinical research

Q. We have a protocol for a global trial, which is approved by DCGI and EC. It

does not mention the total patients number and sites to be included in India. We

plan to increase the number of sites and patients. Do we need to go to EC and DCGI

office for approval or will the old approval what we received will suffice? Could you

please clarify?

The current CDSCO checklist requires data on number of sites and patients in India. The

approval is based on this data. Hence, even if the global protocol does not mention the

number of Indian sites/patients, it is essential to obtain the amendment approved by EC

and DCGI. The DCGI office recommends that such amendments should be approved by

IEC and notified or submitted for approval from DCGI office. See the relevant extract.

Those amendments which require notification to the Licensing Authority but need not

wait for permission

1. Additional investigator sites

2. Change in investigator with the consent to withdraw from the earlier investigator

3. Amended investigators brochure, amended informed consent

Those amendments which require prior permission of the Licensing Authority

1. Additional patients to be recruited

2. Major changes in protocol with respect to study design, dose and treatment options

3. Any change in inclusion or exclusion criteria

Q. Is it possible to conduct phase 4 study as a comparative study? Is it possible to

conduct phase 4 study in such small patient e.g. 400?

ICH E 8 guidelines on general considerations for clinical trials defines phase IV as

follows:

3.1.3.4 Phase IV (variety of studies: - therapeutic use)

Phase IV begins after drug approval. Therapeutic use studies go beyond the prior

demonstration of the drug's safety, efficacy and dose definition. Studies in phase IV are

all studies (other than routine surveillance) performed after drug approval and related to

the approved indication. They are studies that were not considered necessary for approval

but are often important for optimising the drug's use. They may be of any type but should

have valid scientific objectives.

Indian GCP defines phase IV as:

Studies performed after marketing of the pharmaceutical product. Trials in phase IV are

carried out on the basis of the product characteristics on which the marketing

authorization was granted and are normally in the form of post-marketing surveillance,

assessment of therapeutic value, treatment strategies used and safety profile. Phase IV

studies should use the same scientific and ethical standards as applied in pre-marketing

studies

You can conduct phase IV as a comparative study if the objectives are scientifically

justified. The sample size depends on the objectives and endpoints and has to be

statistically valid.

Q. We are conducting a multicentre, multinational BE trial on patients with a

reference drug marketed in US. Can a sponsor conduct such studies i.e. directly

phase III study in India without conducting phase I or II or without any previous

pre-clinical data?

The sponsor will have to provide the data required as per Schedule Y for permission to

conduct clinical trials.

This includes

● Drug and the therapeutic class

● Chemical and pharmaceutical information

● Animal pharmacology

● Animal toxicology

● Phase I, II, III as applicable

● Regulatory status in other countries

If the sponsor wants to conduct phase III in India, he will have to provide above pre-

clinical information and data of phase I and II to DCGI office.

Q. Can the chairperson or the designated member of an IEC review & approve

minor (patient / safety related) amendments to the protocol & ICF without the

presence of other members?

Yes if the EC has an SOP for such procedures

Indian GCP covers this under interim review.

2.4.2.7. Interim Review

The IEC should decide and record the special circumstances and the mechanism when an

interim review can be resorted to instead of waiting for the scheduled time of the

meeting. However, decisions taken should be brought to the notice of the main

committee. This can be done for the following reasons:

i ) Re-examination of a proposal already examined by the IEC;

ii) Research study of a minor nature such as examination of case records etc;

iii) An urgent proposal of national interest.

ICMR guidelines 2006 recommend as follows:

2. Expedited Review

The proposals presenting no more than minimal risk to research participants may be

subjected to expedited review. The Member- Secretary and the Chairperson of the IEC or

designated member of the Committee or Subcommittee of the IEC may do expedited

review only if the protocols involve -

1. Minor deviations from originally approved research during the period of approval

(usually of one year duration).

2. Revised proposal previously approved through full review by the IEC or continuing

review of approved proposals where there is no additional risk or activity is limited to

data analysis.

3. Research activities that involve only procedures listed in one or more of the following

categories:

a) Clinical studies of drugs and medical devices only when -

i) Research is on already approved drugs except when studying drug interaction or

conducting trial on vulnerable population or

ii) Adverse Event (AE) or unexpected Adverse Drug Reaction (ADR) of minor nature is

reported.

4. Research involving clinical materials (data, documents, records, or specimens) that

have been collected for non-research (clinical) purposes.

ICMR guidelines also permit such review in research on interventions in emergency

situation and on disaster management.

Q. What is a different between protocol deviation and violation?

Protocol Deviation: Any alteration/modification to the IRB-approved protocol. The

protocol includes the detailed protocol, protocol summary, consent form, recruitment

materials, questionnaires, and any other information relating to the research study.

Protocol Violation: Any protocol deviation that is not approved by the IRB prior to its

initiation or implementation.

● Major Violation: a violation that may impact subject safety, affect the integrity of study

data and/or affect subject's willingness to participate in the study.

● Minor Violation: a violation that does not impact subject safety, compromise the

integrity of study data and/or affect subject's willingness to participate in the study.

Q. If we want to do 4-week single dose dosing in phase I then how many weeks'

animal toxicity data is required?

As per Schedule Y, for Oral or Parenteral or Transdermal dosing of > 2-week but up to 4

weeks in Phase I, II, III, toxicity studies are required in 2 species (1 rodent and 1 non-

rodent) for 12 weeks.

Q. If a drug under BA/BE study has vomiting as an expected adverse event (AE),

can we give anti-emetic drug at before drug administration in order to prevent AE?

Yes you can give an anti-emetic prior to dosing, if 1) the anti-emetic does not affect the

BA/BE of the study drug and 2) the protocol permits this.

Q. Can the patient's relatives claim for insurance in case of the participant's death

even if the death does not have a causal relationship with the investigational

product?

A) Yes. See the relevant section of Indian GCP guidelines

2.4.7. Compensation for Accidental Injury

Research subjects who suffer physical injury as a result of their participation in the

Clinical Trial are entitled to financial or other assistance to compensate them equitably

for any temporary or permanent impairment or disability subject to confirmation from

IEC In case of death; their dependents are entitled to material compensation.

2.4.7.1. Obligation of the sponsor to pay:

The sponsor whether a pharmaceutical company, a government, or an institution, should

agree, before the research begins, to provide compensation for any serious physical or

mental injury for which subjects are entitled to compensation or agree to provide

insurance coverage for an unforeseen injury whenever possible.

Q. What are the regulatory requirements/ethics/consent requirements for global

epidemiology study in India involving telephonic survey? This study will be

conducted on household people and not on patients at hospitals.

For epidemiology studies, there are ICMR guidelines. Please see the current guideline of

2006. It is desirable to follow the usual ethical requirements for such studies e.g. EC

approval. The consent depends on the nature of survey and its impact on the participants.

You need to consult the EC re: need for consent. This applies to all surveys whether done

in hospital or in community.

Q. What are the Indian regulatory requirements for Serious Unexpected Adverse

Reactions (SUSAR) reporting?

Indian regulations do not specifically refer to SUSARs. However, as per Schedule Y any

unexpected serious adverse event (SAE) (as defined in GCP guidelines) occurring during

a clinical trial should be communicated promptly (within 14 calendar days) by the

Sponsor to the Licensing Authority and to the other Investigator(s) participating in the

study (see Appendix XI)

Investigator(s) shall report all serious and unexpected adverse events to the Sponsor

within 24 hours and to the Ethics Committee that accorded approval to the study protocol

within 7 working days of their occurrence.

Most of the companies follow international reporting timelines as per ICH.

ICH Clinical Safety Data Management:

1. Single Cases of Serious, Unexpected ADRs (SUSAR)

All adverse drug reactions (ADRs) that are both serious and unexpected are subject to

expedited reporting. This applies to reports from spontaneous sources and from any type

of clinical or epidemiological investigation, independent of design or purpose.

Reporting Time Frames

1. Fatal or Life-threatening Unexpected ADRs

Certain ADRs may be sufficiently alarming so as to require very rapid notification to

regulators in countries where the medicinal product or indication, formulation, or

population for the medicinal product are still not approved for marketing, because such

reports may lead to consideration of suspension of, or other limitations to, a clinical

investigations program. Fatal or life-threatening, unexpected ADRs occurring in clinical

investigations qualify for very rapid reporting. Regulatory agencies should be notified

(e.g., by telephone, facsimile transmission, or in writing) as soon as possible but no later

than 7 calendar days after first knowledge by the sponsor that a case qualifies, followed

by as complete a report as possible within 8 additional calendar days. This report must

include an assessment of the importance and implication of the findings, including

relevant previous experience with the same or similar medicinal products.

2. All Other Serious, Unexpected ADRs

Serious, unexpected reactions (ADRs) that are not fatal or life-threatening must be filed

as soon as possible but no later than 15 calendar days after first knowledge by the sponsor

that the case meets the minimum criteria for expedited reporting.

Q. We are doing a global clinical trial which involves an active drug and

comparator drugs. Is it necessary to provide all information pertaining to quality,

preclinical and clinical data of Drug B and Drug C to DCGI for getting approval?

Yes GCP includes all drugs - comparators and investigational in sponsor's responsibility.

See below ICH definitions and sections.

1.14 Comparator (Product)

An investigational or marketed product (i.e., active control), or placebo, used as a

reference in a clinical trial.

1.33 Investigational Product

A pharmaceutical form of an active ingredient or placebo being tested or used as a

reference in a clinical trial, including a product with a marketing authorization when used

or assembled (formulated or packaged) in a way different from the approved form, or

when used for an unapproved indication, or when used to gain further information about

an approved use.

5.13 Manufacturing, Packaging, Labelling, and Coding Investigational Product(s)

5.13.1 The sponsor should ensure that the investigational product(s) (including active

comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of

development of the product(s), is manufactured in accordance with any applicable GMP,

and is coded and labelled in a manner that protects the blinding, if applicable.

5.13.5 If significant formulation changes are made in the investigational or comparator

product(s) during the course of clinical development, the results of any additional studies

of the formulated product(s) (e.g. stability, dissolution rate, bioavailability) needed to

assess whether these changes would significantly alter the pharmacokinetic profile of the

product should be available prior to the use of the new formulation in clinical trials.

Q. What is the meaning of satellite site? If an investigator is using a satellite site,

what is the procedure for approval?

A satellite site could mean

1) Another institution where investigator has attachment or

2) Another institution which is willing to refer patient to the investigator or

3) Another investigator site willing to work under the investigator.

The procedure depends on what is the role and responsibility of the satellite site. If it is 1)

or 2) an EC approval must be taken for these sites. If it is 3) an EC and regulatory

approval must be taken.

Q. What if a patient has written wrong date in ICF? What should be done to resolve

it?

The investigator has to call the patient back and request him to write on the consent form

that

a) There was an error while writing the date and

b) The correct date should have been (actual date of consent).

The patient should sign and date this statement with the date on which he writes this

correction. This information that the patient has written wrong date should be entered in

the source data.

Q. I would like to know if the regulatory guidelines state anything regarding annual

progress report of the study after approval including the status of recruitment and a

summary of SAEs to be submitted to EC?

Please see relevant information from Indian GCP and Schedule Y.

Indian GCP 2.4.2.6. Decision Making Process

The IEC should be able to provide complete and adequate review of the research

proposals submitted to them It should meet periodically at frequent intervals to review

new proposals, evaluate annual progress of ongoing ones and assess final reports of all

research activities involving human beings through a previously scheduled agenda,

amended wherever appropriate.

Schedule Y

(ii) Ethics Committee(s) should make, at appropriate intervals, an ongoing review of the

trials for which they review the protocol(s). Such a review may be based on the periodic

study progress reports furnished by the investigators and/or monitoring and internal audit

reports furnished by the Sponsor and/or by visiting the study sites. Approval Letter

The Institutional Ethics Committee / Independent Ethics Committee expects to be

informed about the progress of the study, any SAE occurring in the course of the study,

any changes in the protocol and patient information/informed consent and asks to be

provided a copy of the final report.

Q. We have completed a BE study approved from DCGI for 28 patients. Now we

want to increase the number of subjects to 56. Do we need DCGI approval for this

amendment?

Yes you need permission of DCGI office before you can add new subjects. All

amendments need EC approval. See the recommendation from DCGI office below:

Protocol Amendments

a. Those amendments which do not require any information or permission

i) Administrative and logistic changes

ii) Minor protocol amendments and additional safety assessments in case the institutional

ethical committee has already approved these changes

b. Those amendments which require to be informed but need not wait for permission

i) Additional investigator sites

ii) Amended investigators brochure, amended informed consent

c. Those amendments which require prior permission before implementation of the

amendments.

i) Change of principal investigator

ii) Additional patients to be recruited

iii) Major changes in protocol with respect to study design, dose and treatment options

Q. As per our regulatory requirement we submit clinical trial dossier to DCGI. Do

we need to submit the same to ICMR? What is the role of ICMR?

ICMR role is advisory. DCGI office needs ICMR expert advice prior to giving approval

in certain situations e.g. Phase I trial of an Indian discovery or clinical trial in an area of

high priority e.g. AIDS, In such a situation, the sponsor has to submit a separate

application to ICMR

Q. Is it necessary to register the IRBs / IECs with ICMR or any other government

organization?

ICMR guidelines of 2006 suggest the following:

Once the legislation of ICMR guidelines occurs which is currently under active

consideration by the Ministry of Health, a Biomedical Research Authority will be set up

under the proposed Bill on Biomedical Research on Human Participants (Promotion and

Regulation) which would require that all IECs register with this Authority. It will also

evaluate and monitor functioning of the IECs, and develop mechanisms for enforcing

accountability and transparency by the institutions. The above process is not yet

completed. Hence, registration of IEC will happen after the ICMR guidelines become a

law.

Q. If we are amending the protocol, which is approved by the DCGI, do we need to

send the amended protocol to the DCGI for re-approval? The amendment does not

increase the exposure to the study drug and does not have any safety implications.

Current guidelines of DCGI office (www.cdsco.nic.in) are as follows:

Protocol Amendments

a) Those amendments which do not require any information or permission

i) Administrative and logistic changes

ii) Minor protocol amendments and additional safety assessments in case the institutional

ethical committee has already approved these changes

b) Those amendments which require to be informed but need not wait for permission

i) Additional investigator sites.

ii) Amended investigators brochure, amended informed consent.

c) Those amendments which require prior permission before implementation of the

amendments.

i) Change of principal investigator.

ii) Additional patients to be recruited.

iii) Major changes in protocol with respect to study design, dose and treatment options.

All amendments must be approved by the concerned Institutional Ethics Committee

before their implementation .Please see under which category your amendment is and act

accordingly.

Q. What is the purpose of a "Tentative Approval Letter" for a drug, when issued by

US FDA?

A )Approvable Original New Drug Applications

An approvable letter indicates that FDA is prepared to approve the application upon the

satisfaction of conditions specified in the approvable letter. Drug products which are the

subject of approvable letters may not be legally marketed until the firm has satisfied the

identified deficiencies, as well as any other requirements that may be imposed by FDA,

and has been notified in writing that the application has been approved.

Q. What are the minimum ICH GCP requirements for essential documents at site

before investigational product (IP) can be sent to the site?

A )You need Regulatory and Ethics Committee approval before sending IP to the site.

Q. What are the Indian Regulatory requirements for conducting trial of

dermato/cosmetic products?

A ) No so specific requirements are mentioned in regulations. However, the requirements

depend upon the indication for product fits into definition of cosmetic or drug as per

Drugs & Cosmetics Act. The definitions are as follows:

"Cosmetic" means any article intended to be rubbed, poured, sprinkled or sprayed on, or

introduced into, or otherwise applied to, the human body or any part thereof for

cleansing, beautifying, promoting attractiveness, or altering the appearance, and includes

any article intended for use as a component of cosmetic.

"Drug" includes

(i) All medicines for internal or external use of human beings or animals and all

substances intended to be used for or in the diagnosis, treatment, mitigation or prevention

of any disease or disorder in human beings or animals, including preparations applied on

human body for the purpose of repelling insects like mosquitoes

(ii)such substances (other than food) intended to affect the structure or any function of the

human body or intended to be used for the destruction of [vermin] or insects which cause

disease in human beings or animals, as may be specified from time to time by the Central

Government by notification in the Official Gazette

(iii) All substances intended for use as components of a drug including empty gelatin

capsules; and

(iv) Such devices intended for internal or external use in the diagnosis, treatment,

mitigation or prevention of disease or disorder in human beings or animals, as may be

specified from time to time by the Central Government

If a cosmetic product for a trial fits definition of drug, you have to follow all trial

regulations as per Schedule Y.

Q. Is it necessary that the investigator has to maintain the certificate of analysis

(COA) for both reference and test product?

A ) As per ICH-GCP, investigational product includes all products under investigation

i.e. reference and test product for all human studies. ICH guidelines, under essential

documents mention that COA should be in the sponsor's file.

Q. Would you kindly clarify on what occasion/situation we will use "file note" and

"memo to file" during a study? Can QA observations be clarified using a file note?

A )File Note is used to document

● Anything that is not self explanatory in the study or in study progress

● Any deviation from the protocol, even if it is the accepted standard of care but not a

part of the protocol.

In short, any verbal explanations that are needed to be provided by the study team

(inclusive of the site members) with respect to the study are either filed in by the study

team as "Note to File" or "File Note" or "Study Memo" or "Memo to File".

However, if QA observations concern site issues e.g. consent errors, you also need site to

document clarifications in source notes or to ask the site to call the concerned consenting

patient to document the explanation for error.

Q. Subject X is checked in for period 01 of a BA/BE study one day before the dosing

and was allotted a subject number. Immediately after check-in, he wants to

withdraw from study due to personal reasons. Can he be replaced by another

subject by giving the same number?

A ) It is not advisable to allot the same number to another subject. The reason is

essentially driven by completeness and transparency of documentation. In clinical

trials/BE studies, the subject may withdraw for several reasons e.g. adverse events. If you

give same number to another subject, there will not be any record of the subject who

withdrew.

Q. Can a dummy run be done for sending the blood sample to the central lab before

the regulatory approvals and if the sample is not from a subject participating in the

study but a random blood sample e.g. donated blood? This process is just to test if

the site does it right.

A) If one wishes to use donated blood for a dry run, you are using the sample for a

purpose for which the donor is unaware and did not consent. In such a situation, you will

need the donor's consent. Another option is to use a sample of any hospital patient who

requires a blood test for diagnosis of his/her condition using the test which will be

conducted by the lab. If this is possible, one can avoid most potential ethics issues.

Q. My question is on retention of investigational products sample in IND

application.

1. What is the quantity to be retained and for how many years?

2. Who should retain, by sponsor or at investigator site?

A) The requirements for sponsor are as follows:

This relates to batches used in trials at any phase.

ICH-GCP suggests 5.14.5 the sponsor should:

(a) Take steps to ensure that the investigational product(s) are stable over the period of

use.

(b) Maintain sufficient quantities of the investigational product(s) used in the trials to

reconfirm specifications, should this become necessary, and maintain records of batch

sample analyses and characteristics. To the extent stability permits, samples should be

retained either until the analyses of the trial data are complete or as required by the

applicable regulatory requirement(s), whichever represents the longer retention period.

Drugs and Cosmetics Rules of India recommend:

The licensee shall maintain reference samples from each batch of the drugs manufactured

by him in a quantity which is at least twice the quantity of the drug required to conduct

all the tests performed on the batch. In case of drugs bearing an expiry date on the label,

the reference samples shall be maintained for a period of three months beyond the date of

expiry or potency. In case of drugs where no date of expiry of potency is specified on the

label, the reference samples shall be maintained for a period of three years from the date

of manufacture.

Q. In one of the BA/BE study, during the course of the study a subject was suffering

from PILES for which he was operated on an outpatient basis. Will this qualify as

an SAE?

A ) As the adverse event was reported after the administration of drug, and the subject

was hospitalized this becomes an SAE. In this case the issue is how does one define

hospitalization. Although the subject was operated on an outpatient basis, you need to

find out how long was the subject in the hospital.

Common usage of "inpatient hospitalization" generally would include being treated by a

physician in a hospital for at least a 24-hour period.

However, it is desirable to consult the study protocol, as sponsors may define specific

terms in the context of the study, and provide criteria that would control whether other

events should also be reported (e.g., an unscheduled office visit that results in

administration of intravenous fluids; any emergency room visit lasting over four hours).

Q. Is it necessary for an investigator and sub-investigator in BA/BE study to have

documented training in GCP?

A ) GCP training is a must for the whole team. Relevant sections of ICH are cited below:

2.8 Each individual involved in conducting a trial should be qualified by education,

training, and experience to perform his or her respective task(s).

ICH 4.1.3 the investigator should be aware of, and should comply with, GCP and the

applicable regulatory requirements

4.2.4 The investigator should ensure that all persons assisting with the trial are adequately

informed about the protocol, the investigational product(s), and their trial-related duties

and functions.

Q. If I conduct a clinical trial for US FDA submission in India, I need to fill FDA

1572 and financial disclosure form. But my confusion is that before conducting a

clinical trial in India, do I need to fill and submit investigator undertaking to

DCGI?

A )Investigator undertaking is an Indian regulatory requirement for obtaining clinical trial

permission. . Hence, you need to submit this to obtain clinical trial permission. Besides,

as per GCP, all trials should be in compliance with protocol, GCP, SOPs and applicable

regulatory requirements. In this case, applicable requirements refer to US FDA and

Indian regulations.

Q. We have a novel device for delivery of medicines in the eye. We have entered into

an agreement with Indian investigators to supply them with the device for their use

in an investigator initiated study. The device is 510K-able in the U.S., so we can ship

the device, providing we are not violating any Indian laws. Please advise us about

laws governing import of these devices into India.

A) CDSCO has issued new guidelines in Mar 2006 for import and manufacture of

devices. We do not have separate rules for import of devices for clinical trials. As the

device is for delivery of medicines in eye, this seems to be drug-device combination.

Hence, all regulations for a drug trial will apply. I feel that you need to obtain regulatory

clearance of protocol and import licence before you ship the devices to India.

Q. Do we need EC approval for post marketing trials (for the approved as well as

unapproved indication)?

A) All clinical trials, whether pre or post marketing trials require EC approval.

Q. Do we need EC for retrospective medical record reviews?

A) It would be advisable to obtain approval of the head of your institution.

Q. Is QA certificate mandatory after completion of audit of every site? Is it

obligatory to issue QA certificate after resolution of all queries raised by Quality

Assurance or can we issue QA certificate only to be evidence that visit has been

performed by QA persons?

A ) It is not mandatory to issue the audit certificate after completion of site audit. Audit

certificate is issued when it is required by the applicable law/regulations of the country

the audit is being performed or requested by the sponsor for contracted audits. In practice,

you can issue audit certificate along with the audit report.

In India Schedule Y requires audit certificate to be appended if available to clinical trial

report. (Appendix II Structure of Clinical Trial Reports item 16 audit certificate).

Similarly ICH E3 guidelines for Clinical Trial Report require an audit certificate to be

appended, if available (appendix 16.1.8).

Q. Can a doctor (BHMS or MBBS) CRC write source notes/hospital files (of a

clinical trial patient) if he is designated to do so by the principal investigator?

A) Yes. This is allowed if the doctor is authorized by the investigator to do so. The

investigator should ensure that the designated doctor is trained in completing source

notes.

A recent FDA guidance "Guidance for Industry Protecting the Rights, Safety, and

Welfare of Study Subjects - Supervisory Responsibilities of Investigators" discusses such

issues. FDA cautions researchers on delegation of study tasks and advises that the

investigators should be very careful in delegating clinical trial responsibilities.

The investigator should ensure that any individual to whom a task is delegated is

qualified by education, training, and experience to perform the delegated task.

Appropriate delegation is primarily an issue for tasks that would be considered to be

clinical or medical in nature, such as evaluating study subjects to assess clinical response

to an investigational therapy (e.g., global assessment scales, vital signs) or providing part

of the medical care provided to subjects during the course of the study. Most

clinical/medical tasks require formal medical training and may also have licensing or

certification requirements. Clinical investigators should take such qualifications/

licensing requirements into account when considering to whom it would be appropriate to

delegate specific tasks. . The investigator is also responsible for overseeing the work of

any staff members who are not directly employed by the site, such as employees of site

management organizations.

The investigator should ensure that staff:

● Have a general familiarity with the study and the protocol

● Have a specific understanding of the details of the protocol and the investigational

product, relevant to the tasks they will be performing

● Are aware of regulatory requirements and acceptable standards for the conduct of

clinical trials, both in respect to conduct of the clinical trial and human subject protection

● Are competent to perform the tasks that they are delegated

● Are informed of any pertinent changes during the conduct of the trial and educated or

given additional training as appropriate.

Q. If any violation during the study (in house) what will be the compensations and /

after completion of the study if the subjects expire what will be the compensation?

A) Please see Indian GCP guidelines on compensation.

2.4.7 Compensation for Accidental Injury.

Research subjects who suffer physical injury as a result of their participation in the

Clinical Trial are entitled to financial or other assistance to compensate them equitably

for any temporary or permanent impairment or disability subject to confirmation from

IEC. In case of death, their dependents are entitled to material compensation.

2.4.7.1. Obligation of the sponsor to pay.

The sponsor whether a pharmaceutical company, a government, or an institution, should

agree, before the research begins, to provide compensation for any serious physical or

mental injury for which subjects are entitled to compensation or agree to provide

insurance coverage for an unforeseen injury whenever possible.

Q. In a retrospective study, if the sponsor or investigator wants to use the medical

records of the patient database of his centre, is it mandatory to obtain the ethical

committee (EC) approval and the consent of that particular patient?

A) The sponsor can not use the retrospective data directly. He has to obtain the data

through the investigator. If the patients are part of the investigator's database, he can use

them after the institutional EC have given permission.

Generally agreed upon criteria for allowing retrospective record review without patient

consent

● When record review would not pose more than minimal risks to subjects

● When research could not practicably carried out if consent were to be required

● When research will not adversely affect the rights or welfare of subjects.

Q. As per Indian regulations, when is the start date of safety reporting local and

overseas SAEs for clinical trials. Is it after regulatory and EC approval? After site

initiation visit? After first patient first visit?

A) There is no clear Indian regulation. Logically, overseas SAEs must be reported as

soon as you receive regulatory approval. The local SAEs for the trial can only be reported

after the first patient is screened.

Q. Do we need to have a sponsor's approval page in the protocol?

A ) Yes. Usually the signature page comes after the title page and contains space for all

signatures

● Investigator

● Sponsor responsible person usually medical director / head clinical research

● Sponsor's statistician (if applicable)

Q. Please let me know whether herbal products (made in India) for local application

(such as ointments, nose or eye drops, etc) are exempt from phase I trials here? Can

such products be registered by getting straight in to a phase II trial and by-passing

first in man altogether?

A) The Indian GCP guidelines recommend as follows:

For the herbal remedies and medicinal plants that are to be clinically evaluated for use in

the Allopathic System and which may later be used in allopathic hospitals, the procedures

laid down by the office of the DCG (I) for allopathic drugs should be followed.

It may not be necessary to undertake phase I studies. However, it needs to be emphasized

that since the substance to be tested is already in used in Indian Systems of Medicine or

has been described in their texts, the need for testing its toxicity in animals has been

considerably reduced. Neither would any toxicity study be needed for phase II trial unless

there are reports suggesting toxicity or when the herbal preparation is to be used for more

than 3 months. It should be necessary to undertake 4-6 weeks toxicity study in 2 species

of animals in the circumstances pointed out in the preceding sentence or when a larger

multicentric phase III trial is subsequently planned based on results of phase II study

The regulatory situation re: clinical trials of herbals is unclear as traditionally, any

company can market a herbal, if it is known / cited in any of the approved ayurvedic

texts, after obtaining a licence from state FDA. Besides, DCGI office usually does not

consider herbal drug clinical trials. Dept of Ayush is involved in opining on such issues.

Q.Can a sponsor attend IEC meet if IEC request sponsor to do so particularly to

give explanation on queries raised by IEC on preclinical data?

A) Yes. As per Indian GCP, if necessary, the applicant/investigator may be invited to

present the protocol or offer clarifications in the meeting. However, the sponsor should

not be present when IEC discusses the protocol and is voting for a decision.

Q.What to do if a site person takes informed consent before signing Signature and

delegation log?

A) If consent is taken before the authorized person signs the log, this should be

documented as a file note in site file and in source notes. The relevant signature log

should be completed with current date.

Q. What is the definition of a legally acceptable representative (LAR)?

A) As per Schedule Y, an LAR is a person who is able to give consent for or authorize an

intervention in the patient as provided by the law(s) of India). This would usually include

parents, adult children, adult siblings, and spouse.

Q. Can a daughter-in-law sign as LAR for her mother-in-law in informed consent

process?

A) If mother-in-law is literate, you do not need an LAR. If mother-in-law illiterate, she

can put her left hand thumb impression on the consent form. In this situation, you do not

need an LAR but an impartial witness. In such a situation, the daughter-in-law will sign

as an impartial witness.

Q. Do we need to take DCGI approval for conducting comparative efficacy trials on

already marketed drugs in India? Which one will be the comparator product in

such cases among different old drug brands?

A) You need to consider whether this study falls into one of the new drug categories as

per Drugs & Cosmetics Rules and whether it is truly a Phase IV post-marketing trial. The

relevant definitions are:

● Indian GCP definition

● Phase IV

Studies performed after marketing of the pharmaceutical product. Trials in phase IV are

carried out on the basis of the product characteristics on which the marketing

authorization was granted and are normally in the form of post-marketing surveillance,

assessment of therapeutic value, treatment strategies used and safety profile. Phase IV

studies should use the same scientific and ethical standards as applied in pre-marketing

studies.

After a product has been placed on the market, clinical trials designed to explore new

indications, new methods of administration or new combinations, etc. are normally

considered as trials for new pharmaceutical products.

You do not need DCGI approval if the product is not a new drug as per the definition in

Drugs & Cosmetic Act. However, you will need ethics committee approval.

The choice of comparator depends on the objectives of the study.

Q. What is Named Patient Programme in clinical trials? Do we require an

additional approval from DCGI for conducting such studies in India?

A) Named patient programme or expanded access programme covers use of an

unapproved drug outside clinical trial setting.

A patient with:

● advanced disease

● No approved treatment options

● no appropriate clinical trial options

May consider trying to get a new, unapproved drug outside of the clinical trial.

Access to a scientifically-tested drug outside of a clinical trial and prior to regulatory

approval is usually referred to as compassionate use.

Expanded Access Programme (EAP)

A pharma company in the late stages of drug development including the Phase III clinical

trial stage can offer EAP for patients who are unable to enroll in a clinical trial. The

regulatory authority generally approves these programmes if the drug has demonstrated

some effectiveness in the on-going clinical trials.

Q. What are Phase 0 studies?

A) FDA guidance document, Exploratory IND Studies, offers recommendations about

safety testing, manufacturing, and clinical approaches that can be used in very early

studies, sometimes called exploratory, or phase 0 trials.

Q. In a retrospective study, if the sponsor or investigator wants to use the medical

records of the patient database of his center, is it mandatory to obtain the ethical

committee (EC) approval and the consent of that particular patient?

A) The sponsor can not use the retrospective data directly. He has to obtain the data

through the investigator. If the patients are part of the investigator's database, he can use

them after the institutional EC have given permission. Generally agreed upon criteria for

allowing retrospective record review without patient consent

● When record review would not pose more than minimal risks to subjects

● When research could not practicably carried out if consent were to be required

● When research will not adversely affect the rights or welfare of subjects.

Q. As per Indian regulations, when is the start date of safety reporting local and

overseas SAEs for clinical trials. Is it after regulatory and EC approval? After site

initiation visit? After first patient first visit?

A) There is no clear Indian regulation. Logically, overseas SAEs must be reported as

soon as you receive regulatory approval. The local SAEs for the trial can only be reported

after the first patient is screened

Q. Do we need to have a sponsor's approval page in the protocol?

A) Yes. Usually the signature page comes after the title page and contains space for all

signatures.

● Investigator

● Sponsor Responsible Person usually Medical Director/ Head Clinical Research

● Sponsor's statistician (if applicable)

Q. Please let me know whether herbal products (made in India) for local application

(such as ointments, nose or eye drops, etc) are exempt from phase I trials here? Can

such products be registered by getting straight in to a phase II trial and by-passing

first in man altogether?

A) The Indian GCP guidelines recommend as follows: For the herbal remedies and

medicinal plants that are to be clinically evaluated for use in the Allopathic System and

which may later be used in allopathic hospitals, the procedures laid down by the office of

the DCG (I) for allopathic drugs should be followed.

It may not be necessary to undertake phase I studies. However, it needs to be emphasized

that since the substance to be tested is already in used in Indian Systems of Medicine or

has been described in their texts, the need for testing its toxicity in animals has been

considerably reduced. Neither would any toxicity study be needed for phase II trial unless

there are reports suggesting toxicity or when the herbal preparation is to be used for more

than 3 months. It should be necessary to undertake 4-6 weeks toxicity study in 2 species

of animals in the circumstances pointed out in the preceding sentence or when a larger

multicentric phase III trial is subsequently planned based on results of phase II study

The regulatory situation re: clinical trials of herbals is unclear as traditionally, any

company can market a herbal, if it is known/cited in any of the approved Ayurvedic texts,

after obtaining a license from state FDA. Besides, DCGI office usually does not consider

herbal drug clinical trials. Dept of Ayush is involved in opining on such issues.

Q. Can a sponsor attend IEC meet if IEC request sponsor to do so particularly to

give explanation on queries raised by IEC on preclinical data?

A) Yes as per Indian GCP, if necessary, the applicant/investigator may be invited to

present the protocol or offer clarifications in the meeting. However, the sponsor should

not be present when IEC discusses the protocol and is voting for a decision.

Q.What to do if a site person takes informed consent before signing signature and

delegation log?

A) If consent is taken before the authorized person signs the log, this should be

documented as a file note in Site File and in source notes. The relevant signature log

should be completed with current date.

Q. Can a QA-auditor become the member secretary of the EC for the same study?

A) We need to consider this from several angles vis-à-vis responsibilities of a member of

EC. As per GCP, the EC member will be involved in initial review, progress report

review, SAE review, notifications/amendments, final report review and decisions of

termination of a study. The question is what will be implications if QA person becomes

an EC member? How will the QA per son separate 2 roles - one as a member and another

as an auditor? An auditor's role is to audit a study usually at the conclusion of the study

and make observations on quality based on available documents and based on facts

without any bias. If the auditor is a member of the EC, s/he will get information about the

study through EC documents and will form his/her opinion about the study before the

audit. This can make him/her biased about the study. Hence, it does not appear prudent to

have QA-auditor as member secretary of the study.

Q. Can an institutional/independent ethics committee approve the protocol of a

study being planned by other organizations?

A) It can approve the study of other organizations provided 1) the committee is really

independent (not attached to any company) 2) the other organizations accept its authority

in writing to approve and oversee the conduct of trial at their center. 3) the committee's

SOPs permit this.

Q. Can an institutional/independent ethics committee located in a city approve the

protocol of a study being planned by other organizations in another city?

A) The issue is not whether they can give approval or not. The issue is) how they will

protect rights, safety & well being of subjects located in another city 2) oversee the study

in another city 3) review and monitor issues e.g. serious adverse events This is not

logistically possible for an EC of another town unless the EC chairperson / secretary are

willing to travel to the other location for regular oversight of the study.

Q. What is to be done if the site has missed to record or report some protocol

deviations to IEC and Sponsor particularly when these deviations were noted after

the end of the study?

A) As per Indian GCP IEC requires notification on the following items. The following

circumstances require the matter to be brought to the attention of IEC:many amendment

to the protocol form the originally approved protocol with proper justification; mserious

and unexpected adverse events and remedial steps taken to tackle them; many new

information that may influence the conduct of the study.

IEC does not expect information on all protocol deviations. Indian GCP requires that the

monitor should promptly inform the sponsor and the ethics committee in case any

unwarranted deviation from the protocol or any transgression of the principles embodied

in GCP is noted. If the protocol deviations are unwarranted and / or represent

transgression of the principles embodied in GCP, then you need to inform IEC

If the deviations are minor, they are covered in the monitoring report, documented in

protocol deviation form/log and described in the final study report. A copy of final study

report has to be submitted to IEC.

Q. Who is authorized to sign for ethical approval in India - the chairman or the

member secretary?

A) Either can sign usually member secretary. However, this should be as per EC SOP

Q. We want to conduct clinical trials in India, for the products that registered in

other countries, but new to Indian Market. What procedure should we follow for

this? Besides, are there any guidelines available for conducting clinical trials in

India?

A) Pl see the website www.cdsco.nic.in - official website of Drugs Controller General's

Office. The website has links to Drugs & Cosmetics Rules, amended Schedule Y and

Indian GCP. These are the regulations for conducting clinical trials in India.

Q. Can an ethics committee member become a subject in a clinical trial which is

approved by the same ethics committee? What are the possible implications? How

will an auditor / inspector view this?

A) If an Ethics Committee member becomes a trial subject on a trial that they were

involved in approving then there has been a major conflict of interest. The following

situations need to considered:

1) IEC member reviews study without any prior knowledge of the study, votes, and then

afterwards is approached by clinical research team to participate. Possibly this is OK but

thereafter it is suggested that the member should no longer be part of the IEC that reviews

that study. This will be difficult in practice, so therefore not advisable.

2) IEC member already knows about the study and is voting in order to be able to

participate. This is clearly not acceptable and made worse if there is additional financial

incentive for the study (e.g. volunteer study).

ICH GCP requires Ethics Committee members to be independent of the investigator and

the sponsor to avoid conflicts of interest.

Q. This is with respect to the constitution of ethics committee of our organization,

for which I need your valuable guidance and suggestion in understanding the

qualification of Chairperson of Ethics committee.

A) First you need to consider whether it is appropriate for your organization to form an

Ethics Committee. If yours is an academic medical / research, institute, forming an EC is

essential and justified.

Independence and competence are the two hallmarks of an IEC. If your organization is a

private enterprise - a for-profit entity -, the independence of EC would be questioned by

the auditors and regulatory inspectors.

There is no specific qualification prescribed for the chairperson in ICMR guidelines /

Schedule Y. However, usually EC selects a chairperson who has achieved success and

social recognition in life and work and who can understand the ethical issues related to

research in human beings.

Q. Is it necessary to submit protocols of all BA/BE studies to IEC at least 3 weeks

before the IEC meeting? I have learnt that as per Schedule Y it is must to submit

protocols at least 3 weeks before the meeting for review.

A) This is Indian GCP recommendation applicable to all clinical studies including

BA/BE.

Indian GCP 2.4.2.5. Submission of Application

The researcher should submit an appropriate application to the IEC in a prescribed format

along with the study protocol at least three weeks in advance.

However, the submission depends on SOP of the EC. Most ECs have a submission date

and a meeting date. If the EC submission date is shorter then 3 weeks, you can follow

their SOP for submission.

Q. In a multicentric, multinational phase III trials, Principal Investigator (PI) of one

site was changed. Does it require a site-specific amendment of protocol or general

amendment of the protocol?

A) This is a site specific amendment which requires approval of IEC of the site.

Q. What is the difference between an IRB (Institutional Review Board) and IEC

(Independent Ethics Committee)?

A)IRB is a US concept. IRB is a body which reviews both scientific and ethical aspects

of a study. In India, most institutions have 2 committees - 1 scientific committee for

scientific review and 2 ethics committee.

Q. Is it necessary to have at least one female member in an IEC?

A) One can not fix a number for female members. It all depends on the total number of

members in IEC. If the number is large e.g. 11, EC should have proportionate number of

female members.

Prepared by

Dr Nicky