No. S 335
Medicines Act
(CHAPTER 176)
Medicines (Clinical Trials)
Regulations 2016
In exercise of the powers conferred by section 18 of the Medicines Act, the Minister for Health makes the following Regulations:
PART 2
CLINICAL TRIALS OF MEDICINAL PRODUCTS
Division 2 — Regulatory submissions for clinical trials
of medicinal products
Requirement for clinical trial certificates
7.  A person must not commence or conduct a clinical trial unless —
(a)a clinical trial certificate has or clinical trial certificates have been issued for the trial in accordance with regulation 8; and
(b)the conduct of the trial has been approved by an institutional review board.
Application for clinical trial certificates
8.—(1)  The sponsor must apply to the Authority for a clinical trial certificate for each principal investigator of the clinical trial, before the commencement of the trial.
(2)  The application for any clinical trial certificate must be made in the form and manner specified on the Authority’s website.
(3)  Where the application is for a clinical trial certificate for a clinical trial in an emergency situation, the Authority must not issue any clinical trial certificate for the trial unless a principal investigator who is conducting the trial and 2 specialists who are not conducting the trial certify in writing that —
(a)the trial needs to be conducted on potential subjects who are facing a life-threatening situation to determine the safety or efficacy of a medicinal product;
(b)available treatments or procedures are unproven or unsatisfactory;
(c)there is a reasonable prospect that participation in the trial will directly benefit the potential subjects because —
(i)the potential subjects are facing a life-threatening situation that necessitates intervention;
(ii)the appropriate non-clinical and clinical studies have been conducted, and the information derived from those studies and related evidence support the potential for the proposed use of the medicinal product to provide a direct benefit to the potential subjects; and
(iii)the risks associated with the trial are reasonable in relation to what is known about —
(A)the medical condition of the potential subjects;
(B)the risks and benefits of standard therapy, if any; and
(C)the risks and benefits of the proposed use of the medicinal product;
(d)the potential subjects are unable to consent to being subjects as a result of their medical condition;
(e)it is not feasible to obtain consent from the legal representatives of the potential subjects within the window period;
(f)there is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the trial; and
(g)the trial cannot practicably be carried out if the consents referred to in regulation 16 must be obtained.
Conditions of clinical trial certificates
9.—(1)  The Authority may issue a clinical trial certificate for a principal investigator subject to such conditions as the Authority thinks necessary and may, from time to time, by notice in writing to the sponsor —
(a)modify or remove any condition of the certificate; or
(b)attach any new condition to the certificate.
(2)  The conditions referred to in paragraph (1) may include a condition requiring the sponsor to obtain and maintain insurance to provide compensation in the event of injury or loss arising from the clinical trial on such terms as the Authority may approve.
(3)  The Authority may refuse to issue, or suspend or revoke, any clinical trial certificate.
(4)  Any person aggrieved by a refusal, suspension or revocation referred to in paragraph (3) may appeal to the Minister, whose decision is final.
Amendments and substantial amendments to clinical trial, etc.
10.—(1)  The Authority may, at any time, direct the sponsor to make an amendment (including a substantial amendment) if it appears to the Authority that the amendment is necessary to ensure —
(a)the safety or scientific validity of the clinical trial;
(b)compliance with the principles of good clinical practice in relation to the clinical trial; or
(c)compliance with the conditions of a clinical trial certificate,
and the sponsor must comply with the direction.
(2)  Subject to regulation 21, the sponsor must not make a substantial amendment, except with the approval of the Authority.
(3)  An application for approval of a substantial amendment referred to in paragraph (2) must be made by the sponsor in the form and manner specified on the Authority’s website.
(4)  The sponsor must —
(a)keep records of all amendments; and
(b)send such records, or copies of such records, to the Authority, in accordance with any request by the Authority for the same.
Notification of serious breaches and urgent safety measures
11.—(1)  The sponsor must notify the Authority in writing of any serious breach during the clinical trial of any of the following, as soon as possible and in any event not later than 7 days after becoming aware of the breach:
(a)the principles of good clinical practice;
(b)the protocol relating to the trial, as amended from time to time in accordance with regulation 10;
(c)these Regulations.
(2)  Where the relevant institutional review board of a clinical trial requires any person to report to it any serious breach during the trial of any of the following, the person must do so in accordance with the requirements of the board:
(a)the principles of good clinical practice;
(b)the protocol relating to the trial, as amended from time to time in accordance with regulation 10.
(3)  The sponsor must, as soon as possible and in any event not later than 7 days after the date any urgent safety measure referred to in regulation 21 is taken in relation to a subject of the clinical trial, give written notice to the Authority of the measure taken and the circumstances giving rise to the measure.
(4)  In this regulation, “serious breach” means a breach during a clinical trial which is likely to affect to a significant degree —
(a)the safety, or physical or mental integrity, of any subject of the trial; or
(b)the scientific value of the trial.
Notification of status of clinical trial
12.—(1)  Within 14 days after the end of each reporting period of a clinical trial, the sponsor must provide to the Authority a report on the status of the trial in the form and manner specified on the Authority’s website, which must include the following:
(a)whether the trial has commenced and, if so, the date of commencement of the trial;
(b)the number of subjects who have been enrolled at a trial site;
(c)the number of subjects who have completed the trial at a trial site;
(d)whether any audit has been conducted on the trial;
(e)whether the trial is concluded, terminated or suspended and, if so, the date of the conclusion or termination, or the date of suspension.
(2)  In addition to paragraph (1), the Authority may at any time require the sponsor to give the Authority a report on the status of a clinical trial immediately or within such other time as the Authority specifies; and the sponsor must comply with the requirement.
(3)  The sponsor must —
(a)subject to paragraph (4), notify the Authority of the conclusion of the clinical trial within 30 days after the date of such conclusion; and
(b)submit to the Authority a final report of the trial within one year after the date of such conclusion, or such longer period as the Authority may allow in any particular case.
(4)  The sponsor must notify the Authority of any suspension of the clinical trial, or its termination (if the termination takes place before the date of conclusion of the trial or the concluding event specified in the protocol for the trial), within 15 days after the date of the suspension or termination.
(5)  The notifications referred to in paragraphs (3) and (4) must be in the form and manner required by the Authority.
(6)  In this regulation, a reference to a reporting period of a clinical trial is a reference to —
(a)a period of 6 months starting on the day a clinical trial certificate for the trial is issued; and
(b)each successive period of 6 months of the trial, excluding any such period of 6 months during which the sponsor notifies the Authority of the conclusion or termination of the trial under paragraph (3) or (4), as the case may be.
Division 3 — General duties
Subdivision (1) — Good clinical practice and
conduct of clinical trials
Conduct of clinical trials: good clinical practice
13.—(1)  Every person conducting a clinical trial must do so in accordance with the principles of good clinical practice.
(2)  The sponsor must put and keep in place arrangements for the purpose of ensuring that the principles of good clinical practice are satisfied or adhered to by all persons involved in conducting the clinical trial.
Conduct of clinical trials: in accordance with clinical trial certificates
14.  Subject to regulation 21, every person conducting a clinical trial must do so in accordance with —
(a)the protocol relating to the trial; and
(b)the conditions of any clinical trial certificate for the trial,
as may be amended from time to time in accordance with regulation 10.
Place of clinical trial
15.  The sponsor and a principal investigator must ensure that the clinical trial is conducted only at such trial site as may be specified in the clinical trial certificate.
Subdivision (2) — Duties relating to consents and
provision of information
Consent of subjects, etc., in clinical trials
16.—(1)  A principal investigator must ensure that no person is used as a subject in the clinical trial except in accordance with this regulation and regulations 17 to 20, as may be applicable.
(2)  Subject to paragraph (3), before an adult can be a subject —
(a)a full and reasonable explanation of all of the matters referred to in regulation 19(1)(a) to (u), in accordance with regulation 19(3), must be given to the adult; and
(b)the adult must consent to being a subject.
(3)  Despite paragraph (2), where an investigator of the trial who is a qualified practitioner, and another qualified practitioner who is a registered medical practitioner who is not conducting the clinical trial, certify in writing that —
(a)the adult lacks capacity to consent to being a subject; and
(b)it is not likely that the adult will regain capacity within the window period,
then, the consent of the adult need not be obtained if the conditions in paragraph (4) are met.
(4)  For the purposes of paragraph (3), the conditions are all of the following:
(a)a full and reasonable explanation of all of the matters referred to in regulation 19(1)(a) to (u), in accordance with regulation 19(3), is given to the adult’s legal representative, and the adult’s legal representative —
(i)consents to the adult being a subject; and
(ii)if the legal representative is below 21 years of age, has sufficient understanding and intelligence to give the consent;
(b)it is established that there is a reasonable prospect that participation in the clinical trial will directly benefit the adult, unless —
(i)the objectives of the trial cannot be met by means of a trial in subjects who can give consent personally;
(ii)the trial is conducted in subjects having a disease or condition for which the medicinal product being tested in the trial is intended;
(iii)there is some direct benefit for the group of subjects involved in the trial;
(iv)the foreseeable risks to the subjects involved in the trial are low; and
(v)the negative impact on the wellbeing of subjects involved in the trial is minimised and low.
(5)  Subject to paragraph (6), before a minor can be a subject, a full and reasonable explanation of all of the matters referred to in regulation 19(1)(a) to (u), in accordance with regulation 19(3), must be given to the minor and the minor’s legal representative, and —
(a)the minor and the minor’s legal representative must consent to the minor being a subject; and
(b)if the legal representative is below 21 years of age, the legal representative must have sufficient understanding and intelligence to give the consent.
(6)  Despite paragraph (5), where the minor lacks capacity to give consent to being a subject, or the minor lacks sufficient understanding and intelligence to give such consent, then, the consent of the minor need not be obtained if the conditions in paragraph (7) are met.
(7)  For the purposes of paragraph (6), the conditions are all of the following:
(a)a full and reasonable explanation of all of the matters referred to in regulation 19(1)(a) to (u), in accordance with regulation 19(3), is given to the minor’s legal representative, and the minor’s legal representative —
(i)consents to the minor being a subject; and
(ii)if the legal representative is below 21 years of age, has sufficient understanding and intelligence to give the consent;
(b)it is established that there is a reasonable prospect that participation in the clinical trial will directly benefit the minor, unless —
(i)the objectives of the trial cannot be met by means of a trial in subjects who can give consent personally;
(ii)the trial is conducted in subjects having a disease or condition for which the medicinal product being tested in the trial is intended;
(iii)there is some direct benefit for the group of subjects involved in the trial;
(iv)the foreseeable risks to the subjects involved in the trial are low; and
(v)the negative impact on the wellbeing of subjects involved in the trial is minimised and low.
(8)  For the purposes of paragraphs (4)(b) and (7)(b), participation in a clinical trial does not have any reasonable prospect of direct benefit to a person unless —
(a)appropriate non-clinical and clinical studies have been conducted, and the information derived from those studies and related evidence support the potential for the proposed use of the medicinal product to provide a direct benefit to the person; and
(b)the risks associated with the trial are reasonable in relation to what is known about —
(i)the medical condition of the person;
(ii)the risks and benefits of standard therapy, if any; and
(iii)the risks and benefits of the proposed use of the medicinal product.
(9)  If a subject is an adult referred to in paragraph (3) or a minor referred to in paragraph (6), and the adult or minor subsequently regains capacity to consent to being a subject, the principal investigator must ensure that, at the earliest feasible opportunity —
(a)the adult or minor is given a full and reasonable explanation of all of the matters referred to in regulation 19(1)(a) to (u), in accordance with regulation 19(3); and
(b)the adult’s or minor’s consent to continue being a subject is obtained.
(10)  If the adult or minor referred to in paragraph (9) refuses to consent, the principal investigator must ensure that the adult or minor ceases to be a subject in the clinical trial.
Consent of subjects, etc., in clinical trials in emergency situations
17.—(1)  The consents referred to in regulation 16 need not be obtained in accordance with that regulation in order for a person to be a subject in a clinical trial in an emergency situation if all of the following are satisfied:
(a)the Authority has issued the clinical trial certificate or clinical trial certificates required for the trial, as a clinical trial in an emergency situation;
(b)the relevant institutional review board of the trial has reviewed and approved —
(i)the circumstances in which the consents referred to in regulation 16 need not be obtained for the purposes of the trial; and
(ii)the procedure to be adopted in the trial to ensure that paragraphs (3), (4), (5) and (7) are complied with;
(c)an investigator of the trial who is a specialist and one specialist who is not conducting the trial certify in writing before using the person in the trial that —
(i)the person is facing a life-threatening situation which necessitates intervention;
(ii)the person is unable to consent as a result of the person’s medical condition;
(iii)it is not feasible to obtain consent from the legal representative of the person within the window period; and
(iv)neither the person nor the legal representative of the person nor any member of the person’s family has informed any investigator of any objection to the person being a subject in the trial.
(2)  Despite paragraph (1), paragraphs (3) to (7) must be complied with.
(3)  If the consent of the person who is to be or is a subject in the clinical trial in an emergency situation cannot be obtained because of the medical condition of the person and if, at any time, the person regains capacity to give such consent, the principal investigator must ensure that, at the earliest feasible opportunity —
(a)the person is given a full and reasonable explanation of the matters referred to in regulation 19(1)(a) to (u), in accordance with regulation 19(3); and
(b)the consent of the person to be or to continue to be a subject in the trial is obtained.
(4)  If the consent of the person who is to be a subject in the clinical trial in an emergency situation cannot be obtained because of the medical condition of the person, the principal investigator must ensure that, at the earliest feasible opportunity (including during the window period) —
(a)all reasonable efforts are made to contact the legal representative of the person;
(b)the legal representative is given a full and reasonable explanation of the matters referred to in regulation 19(1)(a) to (u), in accordance with regulation 19(3); and
(c)the legal representative’s consent for the person to be or to continue to be a subject in the trial is obtained.
(5)  Without prejudice to paragraph (4), where the consent of the person who is to be a subject in the clinical trial in an emergency situation cannot be obtained because of the medical condition of the person and it is not feasible to obtain consent from the legal representative of the person within the window period, then the principal investigator must ensure that, at the earliest feasible opportunity (including during the window period) —
(a)all reasonable efforts are made to contact any member of the person’s family; and
(b)the member of the person’s family is given a full and reasonable explanation of the matters referred to in regulation 19(1)(a) to (u), in accordance with regulation 19(3).
(6)  To avoid doubt —
(a)despite (pursuant to paragraph (4)) the legal representative of the person consenting to the person being or continuing to be a subject in the clinical trial in an emergency situation, paragraph (3) continues to apply; and once the consent under paragraph (3) is obtained, paragraph (4) ceases to apply; and
(b)despite (pursuant to paragraph (5)) a member of the person’s family being contacted and not objecting to the person being or continuing to be a subject in the clinical trial in an emergency situation, paragraphs (3) and (4) continue to apply; and once the consent under paragraph (3) or (4) is obtained, paragraph (5) ceases to apply.
(7)  The principal investigator must ensure that a person is not or ceases to be a subject in the clinical trial in an emergency situation if, at any time —
(a)the person or the person’s legal representative refuses to give the consent referred to in paragraph (3) or (4), as the case may be; or
(b)where neither the consent of the person nor the consent of the legal representative of the person has been obtained, any member of the person’s family informs the principal investigator of any objection to the person being or continuing to be a subject in the trial.
(8)  In this regulation, “specialist” means a person registered as a specialist under section 22 of the Medical Registration Act (Cap. 174) in the branch of medicine under which the subject is to be treated.
General requirements as to consent
18.—(1)  Any consent required under these Regulations for a person to be a subject must be obtained by an investigator who is a qualified practitioner in accordance with this regulation.
(2)  The consent must be —
(a)in writing and in the form approved by both the Authority and the relevant institutional review board of the clinical trial; and
(b)signed and dated by the person giving the consent.
(3)  If the person giving the consent is unable to sign or date the written form referred to in paragraph (2)(a), the consent must —
(a)be signed and dated in the form and manner approved by the relevant institutional review board of the clinical trial; and
(b)be obtained in the presence of an impartial witness.
(4)  If the person giving the consent is unable to read, the written form referred to in paragraph (2)(a) must be read and explained to the person in the presence of an impartial witness.
(5)  The impartial witness referred to in paragraph (3) or (4), as the case may be, must sign and date the written form mentioned in paragraph (2)(a) to attest that —
(a)in the case of paragraph (4), the written form was accurately explained to the person giving the consent; and
(b)in any case, the person’s consent was freely given.
(6)  Any legal representative making a decision for the purposes of regulation 16 or 17, or a family member making a decision in connection with regulation 17(5), must act in the best interests of the person to be used as a subject in the clinical trial.
(7)  Section 6 of the Mental Capacity Act (Cap. 177A) applies for the purpose of determining what is in the best interests of a subject in a clinical trial.
(8)  Where consent for a person to be or to continue to be a subject is obtained in accordance with these Regulations, or is not required under these Regulations, then the consent is validly obtained or waived, as the case may be, despite any other requirement in any other written law or rule of law.
Duty to give full explanation and information
19.—(1)  The matters for which a full and reasonable explanation must be given under regulations 16 and 17 to a potential subject, a subject, a legal representative, or a family member, as the case may be, in relation to a clinical trial are all of the following:
(a)that the trial involves research;
(b)the purpose of the trial;
(c)the treatments or procedures to be administered in the trial and the probability for random assignment of each treatment or procedure;
(d)the procedures to be followed in the trial, including all invasive procedures;
(e)the responsibilities of the subject;
(f)the aspects of the trial which are experimental;
(g)the reasonably foreseeable risks or inconveniences to the subject and, where applicable, to any embryo, foetus or nursing infant;
(h)the reasonably expected benefits, including whether there is any intended clinical benefit to the subject;
(i)any alternative procedures or treatments available to the subject, and their potential benefits and risks;
(j)any compensation and treatment available to the subject in the event of injury arising from participation in the trial;
(k)the circumstances which may result in the pro-ration of payment to the subject for participating in the trial;
(l)any anticipated expenses to the subject from participating in the trial;
(m)that the subject’s participation in the trial is voluntary and that the subject’s participation in the trial may be refused, or the subject withdrawn from the trial, at any time without penalty or loss of benefits which the subject would be entitled;
(n)the persons who will be granted access to the subject’s medical records and the extent of such access, including the possibility that the Authority may inspect the records;
(o)the extent to which records identifying the subject will be kept confidential;
(p)that —
(i)any person whose consent is required under regulation 16 or 17 (including a subject who regains capacity to consent); or
(ii)the family member contacted under regulation 17(5), in circumstances where the consent of neither the subject nor the legal representative has been obtained,
will be informed in a timely manner of any information which becomes available and which may be relevant to the decision of the potential subject being, or the subject continuing to be, a subject (as the case may be);
(q)the persons to contact for further information relating to the trial and the rights of subjects in the event of injury arising from participation in the trial;
(r)any foreseeable circumstances under or reasons for which a subject’s participation may be terminated;
(s)the expected duration of the subject’s participation in the trial;
(t)the approximate number of subjects involved in the trial;
(u)any other information which the Authority may require to be given.
(2)  If any information becomes available which may be relevant to the decision for a subject to continue being a subject in the clinical trial, a full and reasonable explanation of that information must be given at the earliest feasible opportunity to —
(a)the person whose consent is required in order for the subject to continue being a subject in the trial (including a subject who regains capacity to consent); or
(b)the family member contacted under regulation 17(5), in circumstances where the consent of neither the subject nor the legal representative has been obtained,
as the case may be.
(3)  A principal investigator must ensure that the explanations referred to in paragraph (1) or (2), as the case may be, are given in accordance with that paragraph by the principal investigator, another investigator involved in the clinical trial, or a person authorised by the principal investigator.
Coercion
20.  A person must not, by coercion, intimidation, deception or misrepresentation, cause, compel or induce another person —
(a)to be, or continue to be, a subject in a clinical trial; or
(b)to give consent, or refrain from withdrawing consent, for the purposes of a clinical trial.
Subdivision (3) — Duties relating to safety
and interests of subjects
Urgent safety measures
21.  In order to protect any subject against any immediate hazard to the health or safety of the subject, the sponsor and any investigator of the clinical trial may take appropriate urgent safety measures.
Suspension or termination of clinical trial
22.—(1)  The Authority may require the suspension or termination of a clinical trial, or any part of a clinical trial, for which the Authority has issued any clinical trial certificate, or the suspension or termination of the conduct of such a trial at a particular trial site, if, or if the Authority has reasonable grounds to suspect that —
(a)any information provided in respect of any application for a clinical trial certificate for the trial is false or misleading;
(b)any sponsor, principal investigator or person assisting the principal investigator has contravened, is contravening or is likely to contravene —
(i)any condition to which any clinical trial certificate issued for the trial is subject; or
(ii)any provision of these Regulations;
(c)any ground for the conduct of the trial on the basis of scientific validity is no longer applicable or true; or
(d)the continuance of the trial will compromise the safety of any subject of the trial.
(2)  Where the Authority has suspended or terminated a clinical trial, the sponsor and a principal investigator must ensure that the suspension or termination is adhered to by all persons involved in the trial.
Subdivision (4) — Duties relating to information obtained
and reports
Record of clinical trials
23.—(1)  The sponsor and a principal investigator must keep such records of the clinical trial, in accordance with paragraph (2), as will individually and collectively —
(a)permit proper evaluations to be made of the conduct of the trial and the quality of the data produced; and
(b)demonstrate compliance by each person involved in the trial with the principles of good clinical practice and all applicable regulatory requirements.
(2)  The records mentioned in paragraph (1) must —
(a)be kept up-to-date at all times;
(b)be available at all times for inspection by the Authority or any person authorised by the Authority in that behalf; and
(c)be kept at least until the later or the latest, as the case may be, of the following:
(i)the date where there is no more pending or contemplated application under the Act for a product licence for the medicinal product being tested in the clinical trial;
(ii)the expiry of 2 years after the last approval of such application for the medicinal product to be tested in Singapore;
(iii)where the clinical trial is terminated, the expiry of 2 years after the Authority has been informed of the termination of the trial under regulation 12;
(iv)the expiry of 6 years after the conclusion of the clinical trial;
(v)the expiry of such other period as the Authority may direct in any particular case.
(3)  Without limiting the generality of paragraph (1), the principal investigator must maintain a record of every person assisting the principal investigator in the clinical trial, containing all of the following information:
(a)the person’s name;
(b)the person’s qualifications;
(c)the person’s responsibilities in the trial.
Made on 13 July 2016.
CHAN HENG KEE
Permanent Secretary,
Ministry of Health,
Singapore.
[HSA 401:04/05-000; HSA/LPPD/711:12/59-000; AG/LLRD/SL/176/2010/11 Vol. 1]