This guidance represents the Ministry of Food and Drug
Safety's (MFDS's) current thinking on the topic to consider in
Phase I Clinical Trial for healthy subjects. It does not create
or confer any rights for or on any person and does not
operate to bind MFDS or the public.
※ Guidance represents the Ministry of Food and Drug Safety’s
opinion on specific topics publically (Code for Guidance Control
published from the Ministry of Food and Drug Safety (MFDS
published rulings))
※
Please, contact Ministry of Food and Drug Safety, Pharmaceutical Safety
Bureau, Clinical Trials Management Division, if you have any concern or
question on this guidance.
Phone: 043-719-1863
Fax : 043-719-1850
Contents
I. Purpose
···············································································································
1
II. Requirements ····································································································· 1
III. Scope ·················································································································· 2
IV. Sponsor ·············································································································· 2
1. Site & PI selection ··························································································· 2
2. Contracts ············································································································ 3
3. Audit ··················································································································· 3
V. Clinical Trial Site ···························································································· 4
1. Institutional Review Board ············································································ 4
2. Recruitment of Study Subjects ····································································· 4
3. Informed Consent ·························································································· 5
4. Standby Subject ································································································ 6
5. Personnel ············································································································ 7
6. Volunteer/Subjects care ·················································································· 8
7. Confidentiality ··································································································· 9
8. Clinical Trial Implementation and Records ·············································· 9
9. Adverse Events ······························································································· 10
10. Internal Quality Assurance ········································································ 11
Ⅵ
. References ······································································································· 11
Revision History ··································································································· 12
Guidance on Phase I Clinical Trial in Healthy Subjects
I. Purpose
In Phase I Clinical trials, new drugs or new combined formulations
are applied first-in-(mostly healthy) human, so it is important to
minimize the potential risks for study subjects. In pahse I clinical trial,
many study subjects are recruited and subject to hopsitalization/visit
· drug administration · blood sample collection for a short period. Thus,
Clinical trial site should have appropriate facility and personnels for
this purpose.
The「Regulation for Drug Safety」[Attachment 4] Good Clinical Practice
(GCP) is applied to Phase I Clinical Trials, but it is mainly written for
patient-oriented clinical trials. This guidance is for Phase I clinical
trials for healthy subject, and the purpose of this guidance is to
protect the study subjects’s safety and human right. It is expected for
Sponsors and Clinical Trial Sites to conduct Phase I clinical trial in
healthy human subjects after consulting the compliance details in this
guidance.
Ⅱ
. Requirements
Clinical trial Sponsor and Clinical trial Site should follow the GCP
and this guidance is a modified form of the GCP for Phase I clinical
trials specifically for healthy human subjects.
Ⅲ
. Scope
This guidance is applied to the Phase I clinical trial for healthy
subjects. Ⅳ. Sponsor section describes the selection of PI and Clinical
Trial Site for Phase I clinical trial, Contracts, Monitoring and The range
of audit. V. Clinical Trial Site describes IRB, Recruiting of study subjects,
Consent, Subject management procedure, Appropriate personnel/staff for
clinical trial, Conduct, Records, Adverse Events collection, and so on.
Ⅳ
. Sponsor
1. Site & PI selection
A. The selection of optimal clinical site and PI is one of the most
important factors to protect study subjects’ safety during the
clinical trial. Thus, sponsor has to evaluate PI’s clinical trial
experience, specialty and so on. Because many personnels/staffs in
clinical trial has to attend the trial for a short period in pahse I
clinical trial, their qualification and education/training should be
evaluated. In particular, if a protocol (Clinical trial application or
Investigational New Drug) written in english is approved, foreign
language ability should be evaluated.
B. If a clinical trial is overlapped with another clinical trial, Sponsor
has to confirm the availability of enough number of clinical trial
staffs, the recording procedure of drug administration, collection of
blood sample and adverse events and select clinical trial site and
PI after evaluating factors which may affect the quality of clinical
trial.
C. Therefore, Sponsor has to develop internal procedure to evaluate
factors described in “Ⅴ. Clinical Trial Site” and perform the
Feasibility check in advance. The sponsor has to evaluate and
record the optimal PI and clinical trial site.
2. Contract
A. Sponsor and the head of Clinical Trial Site have to agree on a
written Contract before the initiation of clinical trial. The contract
has to include the financial affairs of clinical trial, the delegation
and assignment of duties and the responsibility of the head of
clinical trial site and sponsor
B. If sponsor use CRO for the whole or a part of clinical trial, the
sponsor has to evaluate and select CRO based on the Sponsor’s
internal standard in advance. Sponsor has to make a written
contract which includes a detailed list of tasks for the CRO to do.
C. It is not appropriate for the CRO to make a subcontract with
another CRO for a part of tasks which the sponsor requested.
3. Audit
A. Sponsor has to audit the practice of phase I clinical trial whether
it is performed as described in the protocol, sponsor’s and clinical
trial site’s SOP and related law as is in phase II and III clinical
trial. This audit is separated from Monitoring or Quality Assurance.
B. Therefore, sponsor has to make SOP for auditor’s selection and
qualification and audit procedure. The sponsor has to audit
thoroughly as described in the procedure and consider the factors
which are specific for phase I clinical trial.
Ⅴ
. Clinical Trial Site
1. Institutional Review Board(IRB)
A. IRB has to be indepenent and composed of at least 5 members
who have experience and quality enough for review and evaluation
in ethical, scientific and medical aspects. The qualifiction and list of
IRB members has to be described in SOP.
B. Non-scientific or non-affiliated member has to review thorougly the
ethical aspect of the consent of healthy study subject,
appropriateness of financial compensation and recruiment procedure
of healthy study subject and recorded a meeting log in detail.
C. Clinical Trial Site may review the written consent of clinial trial
for healthy study subjects in lay person’s view and has to establish
the procedure for non-scientific or non-affiliated member who can
represent the human right of study subject. A persone with experience
as non government organization, caregiver, social worker or relevant
specialist in society, law or ethics (lawyer, religious person, bioethics
expert and so on) cab be considered as a candidate.
2. Recruitment of Study Subject
A. IRB has to review the procedure and method of recruitment
(public notice, media and so on) before initiating clinical trial.
B. The expression to emphasize financial compensation (eg: the
amount of money and so on) should not be used in the public
notice to recruit healthy subject for clinical trial.
C. IRB prepares SOP to review the appropriateness of media for
recruitment as well as the contents of public notice for recuritment.
IRB reviews according to the SOP and records in evaluataion form
or meeting log about the review in detail
D. If PI intends to use online meia for recruitment, it is
recommended to use homepage of the hospital. In particular, it is
not recommended to use other online media such as personal blog,
internet cafe, SNS and so on because an edited or modified
version of the notice or a part of the notice may be provided to
an unspecified population.
E. It is prohibited for the healthy subject in Phase I clinical trial to
participate in another clinical trial within 3 months as is the case of
bioequivalence clinical trial. If the volunteer database of study
subject is operated to prevent the inappropriate participation of
healthy study subjects, clinical trial site should have SOP for
management department, training of the recruitment staff and
management method and so on and comply with the law on the
use of personal information of study subjects when it manages
study subjects and their personal information.
F. If pre-trial screening for study subjects is necessary, the proper
procedure such as the scope of pre-trial screening, informed
consent and so on, has to be prepared. If necessary, it is
recommended to be included in the protocol.
3. Informed Consent
A. In principle, study subjects should be individually informed and
given sufficient time and opportunity to make a voluntary decision
on the participation in the study (including the Q&A session).
B. The informed consent process for a small group (explanation and
questions) is acceptable when it is considered more efficient for
better understanding. The desirable number of study subjects in a
small group is 5〜10. It is prohibited for PI or staff to force study
subjects’s participation or to give inappropriate explanation which
may affect study subject’s decision. In particular, for a study
subject who participates Phase I clinical trial for the first time, it is
recommended to give an explanation and to get a consent
individually.
C. If the informed consent process for a small group of study
subjects takes place, the checklist to confirm the study subjects'
understanding should be prepared. Records can be made to
confirm the starting time of explanation and the time of obtaining
the consent. Even if the informed consent process is taken place
for a large group of study subject, Q&A session and obtaining the
consent have to be proceeded individually.
4. Standby Subject
A. Standby Subject should be thoroughly managed when the
hospitalization begins at the previous day of study drug
administration, by pro-actively implementing the facts to the
protocol and consent.
B. Especially, the phrases explaining that study subjects may be
assigned to the standby group and that the compensation scheme
for the standby subjects in the consent. The validity and
management plan for standby subjects should be carefully reviewed
by IRB review process.
C. PI or staff(physician) should get consents from standby subjects
after sufficient explanation, and manage them in a same way as
for the study subject hospitalization process.
5. Personnel
A. PI or delegated staff(physician) should be qualified by education,
training, and experience to assume responsibility for the proper
conduct of the Phase I Clinical Trial as per the study site's SOPs.
B. During the clinical trial period, no less than one physician (PI or
delegated investigator) should be assigned to be fully responsible for
the management of study subjects regarding the processes such as
hospitalization·drug administration·blood collection and so on.
C. Since the Phase I Clinical Trial generally involves many subjects'
simultaneous hospitalization to participate in the study, Chief of the
study site should give restriction on the number of clinical trials
that a PI can manage at the same time the secure the subjects'
safety and the quality of clinical trial.
D. The PI is required to consider the risks associated with clinical trial
such as the number of subjects and the study drug, then to assign
proper number of staff, especially appropriate number of nurses as
per "Medical Law". IRB should review if the proper number of staff
is secured for the clinical trial.
E. It is recommended to adjust
rather than to hospitalize
considering the other clincial
resources such as facility and
schedules of subject hospitalization
all planned subjects at a time,
trials at the same period, available
personnel.
F. If the approved protocol is written in English, PI should prepare and
secure staff with foreign language skill by proper evaluation.
6. Volunteer/Subjects care
A. Chief of the study site should prepare a detail process in the SOP
to periodically check the adverse events occurred in hospitalized
study subjects.
B. In Phase I Clinical Trial, hospitalization/outpatient visit, drug
administration and blood collection for large number of study
subjects are proceeded simultaneously. Therefore, PI should
carefully watch and manage study subjects' safety matters such as
the schedule of hospitalization/outpatient visit, adverse events
collection at the time of drug administration and blood collection.
(Monitoring of subjects) When PI him(her)self is difficult to
accomplish the duties, he(she) should delegate the duties to a staff
(physician) so that the duties can be taken care of.
C. When study subjects are hospitalized, PI and/or delegated
staff(physician) should work and at night for thorough
management of study subjects, and prepare the night time subject
care records. SOP or manual for study subject management, such
as night time management and emergency coping strategy, should
be prepared and periodically educated.
D. Chief of study site should prepare and implement the coping
strategy for potential emergency situation occurred at the time of
subject hospitalization/outpatient visit. Mock training for PI, and
staff (physician and nurse) should be periodically operated.
E. PI or delegated staff (physician) should be resident to watch and
record the adverse events at the time of drug administration and
blood collection of stud subjects. When an emergency situation like
an adverse event arises to the subject, they should be able to
interact with the hospital resuscitation team and manage the
situation. The relevant investigators like physician and nurse, should
receive the periodic life saving (resuscitation) training.
7. Confidentiality
A. All records on the personal information of study subject should be
treated according to the relevant laws and regulations so that the
secrecy can be guaranteed.
B. In addition, the personal information of study subject (residence id
number, phone number, e-mail, address and so on) should not be
recorded when the trial related worksheet and the prescription for
study drug are documented. The name of subject may be recorded
if necessary. Study subject should be managed using the screening
id or randomly assigned number. Study site should establish its
internal detail management strategy for personal information of
study subject.
8. Conducting clinical trial and Recording
A. The chief of study site should arrange the SOPs or Manual for
operating Phase I Clinical Trial with procedures of details, and the
System for education and confirmation of corresponding substance.
B. Study site is required to register the study subjects according to
the site's outpaitent/hospitalization procedures, to manage them by
the Medical Law, and in principle, to make clinical trial related
records by subjects on the eletronic medical record system.
C. However, it is possible to use different forms from (Electronic)
Medical Record if sponsor and study site agree to have specific
forms to be used by PI or delegated physician in the study
through "Source document agreement", considering that the study
population for the Phase I Clinical Trial is only healthy subjects.
D. PI may delegate trial-related tudies to staff with proper document
(Delegation Log), and the relevant document should be written in
which the person in charge of writing, review/confirmation by the
duty is identifiable.
E. PI is required to make accurate records of times and actions
during the procedures of Phase I Clinical Trial. Especially, timing
of the procedures for the drug administration and blood collection
is very important. Therefore, real time records for drug
administration and blood collection should be recorded to confirm
that those procedures are appropriately executed as planned.
F. PI or delegated investigator (Physician) should record in detail as
relevant documents regarding obtaining informed consent, subject
screening examination, evaluation of subject inclusion-exclusion
criteria, identification/evaluation of adverse events, and history of
concomitant medication.
9. Management of Adverse Events
A. PI or delegated investigator (Physician) should record in detail for
the subjects' safety such as the presence of adverse events, medical
evaluation, and medical treatment (Recording of adverse events).
B. For all cases of adverse events occurred to the study subjects, the
medical (clinical) evaluation and decision should be made and
documented by PI or delegated investigator (physician). If an
adverse event is found by other staff than physician, it should be
immediately reported to the physician in charge. Then, the
physician should make a medical decision for the event and record
with no delay. Additional medical examination by interview,
physical examination, or relevant tests should be performed when
necessary, followed by full documentation of the evaluation and
actions taken.
10. Internal Quality Assurance
For the site with many operating Phase I Clinical Trials, it is
desirable to establish proper team or unit for securing internal
quality assurance, and run internal quality assurance process as per
the proper SOPs.
VI. References
1) Annex V to Guidance for the conduct of Good Clinical Practice
inspections-Phase I Units, 2008
2) ICH, E6. Good clinical practice. London, UK: International Conference
on Harmonisation. 1996.
3) Phase 1 Accreditation Guidance, MHRA 2013
4) Phase 1 Accreditation Scheme Requirements version 2, MHRA 2013
5) ANEEX V To procedure for conducting GCP inspections requested by
the EMEA: Phase 1 units, EMEA 2008
6) Guideline on strategies to indentify and mitigate risks for first-in-human
clinical trials with investigational medicinal products
Revision History
Guidance on Phase I Clinical Trials in Healthy Subjects
No
Version
Approval
Date
Description
1
B1-2015-2-010
2015.9.22
established
Guidance on Phase I Clinical Trials
in Heathy Subjects
Date
of September 2015
publication
Publisher
Director, Pharmaceutical Safety Bureau
Kuansung Kim
Editor
in Myungjung Kim
Chief
Editors
Clinical Trials Management Division
Myungjung Kim Taekyun Nam, Jongsook Park,
Sunyoung Kim, Kyoungsoo Park, Seunghoon Han
Division
Ministry of Food and Drug Safety
Pharmaceutical Safety Bureau
Clinical Trials Management Division