The sponsor is responsible for selecting the investigator(s).

Before entering an agreement with an investigator and an institution to conduct a trial, the sponsor should provide the investigator(s) and the institution(s) with the protocol and an up-to-date Investigator's Brochure, and should provide sufficient time for the investigator to review the protocol and the information provided.

The sponsor should obtain the investigator's and the institution's agreement:
1.to conduct the trial in compliance with this Regulations and the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval by the Ethics Committee;
2.to comply with procedures for data recording and reporting;
3.to permit monitoring, auditing and inspection;
4.to retain the essential documents that the investigator and the institution should file within the time period sponsor specified.
The sponsor, the investigator and the institution should sign the protocol, or an alternative document, to confirm this agreement.

A sponsor may transfer any or all of the sponsor's trial-related duties and functions to a CRO.
The ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor.
The delegation referred to in the preceding paragraph should be made in writing.
Within the scope of the transferred duties and obligations referred to paragraph 1, CRO shall apply mutatis mutandis to the relevant provisions of the sponsor in this Regulations.

The sponsor may consider establishing an independent data-monitoring committee (IDMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals.
The IDMC can recommend to the sponsor whether to continue, modify, or stop a trial.
The IDMC should have written operating procedures and maintain written records of all its meetings.

The sponsor should designate appropriately qualified medical personnel who will be readily available to advise on trial related medical questions or problems. If necessary, outside consultant(s) may be appointed for this purpose.

Prior to initiating a trial, the sponsor should define, establish, and allocate all trial-related duties and functions.

The sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator and the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.

When the investigator, the institution or any trial staff fails to comply with the protocol or this Regulations, the sponsor should adopt immediate measures to ensure the compliance.
While the investigator or the institution does not adopt the measures referred to in the preceding paragraph, the sponsor should take action in accordance with Article 116.

The sponsor is responsible for implementing and maintaining quality assurance and quality control systems with written SOPs to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, this Regulations, and the applicable regulatory requirement(s).

The sponsor is responsible for securing agreement from all involved parties to ensure direct access to all trial related sites, source data/ documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by the Competent Authority.

Agreements, made by the sponsor with the investigator, the institution and any other parties involved with the clinical trial, should be in writing, as part of the protocol or in a separate agreement.

The sponsor should utilize appropriately qualified individual to design the protocol, produce case report forms (CRFs), plan the analysis, and prepare interim and final clinical trial reports.

Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been processed correctly.

The sponsor should utilize appropriately qualified individuals to be responsible for the following work:
1.to supervise the overall conduct of the trial,
2.to handle the data and to verify the data,
3.to conduct the statistical analyses, and to prepare the trial reports.
4.to perform operations related to conducting the trial.

When using electronic trial data handling or remote electronic trial data systems, the sponsor should:
1. Based on the risk assessment, ensure that the electronic data processing system(s) conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistent intended performance (i.e. validation).
2.Follow and maintain SOPs for using these systems.
3.Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data; the system shall maintain an audit trail, data trail, edit trail separately.
4.Maintain a security system that prevents unauthorized access to the system or data.
5.Maintain a list of the individuals who are authorized to make data changes.
6.Maintain adequate backup of the data.
7.Safeguard the blinding.
8.Ensure the data integrity in the case of any change in the computer system.

If data are transformed during processing, it should always be possible to compare the original data and observations with the processed data.

The sponsor should use an unambiguous subject identification code that allows identification of all the data reported for each subject.

The sponsor, or other owners of the data, shall retain all of the sponsor-specific essential documents pertaining to the trial for at least 2 years after approval of the marketing application of the investigational product(s) in Taiwan. However, these documents shall be retained for a longer period if required by other applicable regulatory requirements.

If the sponsor discontinues the clinical development of an investigational product, the sponsor should notify all the trial investigators, institutions and the Competent Authority.
Under the preceding circumstance, the sponsor shall maintain all sponsor-specific essential documents for at least 2 years after formal discontinuation. However, these documents shall be retained for a longer period if required by other applicable regulatory requirements.

Any transfer of ownership of the data shall be reported to the Competent Authority.

The sponsor should inform the investigator(s) and the institution(s) in writing of the need for record retention. When the trial related records are no longer needed, the sponsor should notify the investigator(s) and the institution(s) in writing.

When planning trials, the sponsor should ensure that sufficient safety and efficacy data from nonclinical studies and/or clinical trials are available to support human exposure by the route, at the dosages, for the duration, and in the trial population to be studied.

The sponsor should update the Investigator's Brochure as significant new information becomes available.

The characters of the investigational product(s), including active comparator(s) and placebo should be appropriate to the stage of development of the product(s).The manufacturing, handling and storage of the investigational product(s) shall comply with the GMP. The labeling and codes should protect the blinding design.

The sponsor should determine, for the investigational product(s), acceptable storage temperatures, storage conditions, storage times, reconstitution fluids and procedures, and devices for product infusion, and should inform monitors, investigators, pharmacists, storage managers and any other involved parties.

The investigational product(s) should be packaged to prevent contamination and unacceptable deterioration during transport and storage.

In blinded trials, the coding system for the investigational product(s) should include a mechanism that permits rapid identification of the product(s) in case of a medical emergency, but does not permit undetectable breaks of the blinding.

If significant formulation changes are made in the investigational or comparator product(s) during the course of clinical development, studies about whether the new formulated product(s) significantly alter the stability, dissolution rate, bioavailability and other pharmacokinetic profile of the product(s) should be completed prior to the use of the new formulation in clinical trials.

The sponsor should not supply an investigator and an institution with the investigational product(s) before the trial is approved.

The sponsor should ensure that written procedures include:
1.The instructions that the investigator and the institution should follow for the handling and storage of investigational product(s).
2.Procedures about handling, storage, dispensing, retrieval of unused product from subjects, and return of unused investigational product(s) to the sponsor.

In the aspect of the handling of investigational product(s), the sponsor should:
1.Ensure timely delivery of investigational product(s) to the investigator(s).
2.Maintain records that document shipment, receipt, disposition, return, and destruction of the investigational product(s).
3.Follow and maintain a system for retrieving investigational products and documenting this retrieval.
4.Follow and maintain a system for the disposition of unused investigational product(s) and for the documentation of this disposition.
5.Ensure that the investigational product(s) are stable over the period of use.
6.Maintain sufficient quantities of the investigational product(s) used in the trials to reconfirm specifications if necessary.
7.Maintain records of batch sample analyses and characteristics.
For samples referred to in item 6 and item 7 for extending storage 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.

The sponsor is responsible for the ongoing safety evaluation of the investigational product(s).

The sponsor shall take into account the risk over subjects’ protection and data integrity when establishing a monitoring plan, in order to ensure that the trial is conducted under appropriate monitoring.
The sponsor may choose on-site monitoring, system remote monitoring, or both.
Where the system remote monitoring referred to in the preceding paragraph is adopted, the same shall be implemented only upon a reasonable assessment to verify the adequacy thereof.
The contents of the plan referred to in Paragraph 1 cover the monitoring strategies, the monitoring responsibilities, the monitoring methods and reasons for adoption of the plan, as well as key data and processes to be monitored.

The purposes of trial monitoring are to verify that:
1.The rights and well-being of human subjects are protected.
2.The reported trial data are accurate, complete, and verifiable from source documents.
3.The conduct of the trial is in compliance with the currently approved protocol/amendment(s), with this Regulations, and with the applicable regulatory requirement(s).

Selection and qualifications of monitors should comply with:
1.Monitors should be appointed by the sponsor.
2.Monitors should be appropriately trained, and should have the scientific and clinical knowledge needed to monitor the trial adequately.
3.A monitor’s qualifications should be documented.
4.Monitors should be thoroughly familiar with the investigational product(s), the protocol, informed consent form and any other written information to be provided to subjects, the sponsor’s SOPs, this Regulations, and the applicable regulatory requirement(s).

The sponsor should determine the appropriate scope and nature of monitoring. The determination of the scope and nature of monitoring should be based on considerations such as the objective, purpose, design, complexity, blinding, scale, and endpoints of the trial.
On-site monitoring should be conducted before, during, and after the trial. However, the sponsor may increase some monitoring procedures such as investigators’ training or meetings.
Statistically controlled sampling can be an acceptable method for monitor(s) to select the data to be verified.

The monitor(s) should carry out the following activities in accordance with the sponsor’s requirements to ensure that the trial is conducted and documented properly:
1.Acting as the main line of communication between the sponsor and the investigator.
2.Verifying that the investigator has adequate qualifications and resources and remain adequate throughout the trial period.
3.Verifying trial staff and the facilities, including laboratories, equipment, are adequate, safely and properly to conduct the trial and remain adequate throughout the trial period.
4.Verifying, for the investigational product(s):
(1)That storage times and conditions are complies with the requirement(s), and that supplies are sufficient throughout the trial.
(2)That the investigational product(s) are supplied only to subjects who are eligible to receive it and at the protocol specified dose(s).
(3)That subjects are provided with necessary instruction on properly using, handling, storing, and returning the investigational product(s).
(4)That the receipt, use, and return of the investigational product(s) at the trial sites are controlled and documented adequately.
(5)That the disposition of unused investigational product(s) at the trial sites complies with applicable regulatory requirement(s) and is in accordance with the sponsor.
5.Verifying that the investigator follows the approved protocol and amendment(s).
6.Verifying that informed consent was obtained before each subject's participation in the trial.
7.Ensuring that the investigator receives the current Investigator's Brochure, all documents, and all trial supplies needed to conduct the trial properly.
8.Ensuring that the investigator and the investigator's trial staff are adequately informed about the trial details.
9.Verifying that the investigator and the investigator's trial staff are performing the specified trial functions, in accordance with the protocol and any other written agreement between the sponsor and the investigator and the institution, and have not delegated these functions to unauthorized individuals.
10.Verifying that the investigator is enrolling only eligible subjects.
11.Reporting the subject recruitment rate.
12.Verifying that source data, documents and other trial records are accurate, complete, and maintained.
13.Verifying that the investigator provides all the required reports, notifications, applications, and submissions, and that these documents are accurate, complete, timely, legible, dated, and identify the trial.
14.Checking the accuracy and completeness of the CRF entries, source documents, files and other trial-related records against each other. The monitor specifically should verify that:
(1)The data required by the protocol are reported accurately on the CRFs and are consistent with the source documents.
(2)Any dose or therapy modifications are well documented for each of the trial subjects.
(3)Adverse events, concomitant medications and intercurrent illnesses are reported in accordance with the protocol on the CRFs.
(4)Visits that the subjects fail to make, tests that are not conducted, and examinations that are not performed are clearly reported as such on the CRFs.
(5)All dropout subjects from the trial are reported and explained on the CRFs.
15.Informing the investigator of any CRF entry error, omission, or illegibility. The monitor should ensure that appropriate corrections, additions, or deletions are made, dated, explained, and initialled by the investigator or by a member of the investigator's trial staff who is authorized to initial CRF changes for the investigator. This authorization should be documented and filed.
16.Checking all adverse events (AEs) are appropriately reported within the time periods required by Article 106.
17.Determining whether the investigator is maintaining the essential documents of the trial.
18.Communicating deviations from the protocol, SOPs, this Regulations, and the applicable regulatory requirements to the investigator and taking appropriate action designed to prevent recurrence of the detected deviations.

The monitor(s) should follow the sponsor’s established written SOPs as well as those procedures that are specified by the sponsor for monitoring a specific trial.

The monitoring report should comply with the following requirements:
1.The monitor should submit a written report to the sponsor after each trial-site visit or trial-related communication.
2.Reports should include the date, site, name of the monitor, and name of the investigator or other individual(s) contacted.
3.Reports should include a summary of what the monitor reviewed and the monitor's statements concerning the significant findings/facts, deviations and deficiencies, conclusions, actions taken or to be taken and actions recommended to secure compliance.
4.The sponsor should designate representatives to record, review and follow-up of the monitoring report.

A sponsor's audit should be independent of and separate from routine monitoring or quality control functions. The purpose of auditing is to evaluate trial conduct and compliance with the protocol, SOPs, this Regulations, and the applicable regulatory requirements.

Selection and qualification of auditors should comply with:
1.The sponsor should appoint individuals, who are independent of the clinical trials and data capture systems, to conduct audits.
2.The sponsor should ensure that the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented.

The auditing procedures should comply with:
1.The auditing procedures is conducted in accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports.
2.The sponsor's audit plan and procedures for a trial audit should be guided by the importance of the trial, the number of subjects in the trial, the type and complexity of the trial, the level of risks to the trial subjects, and any identified problem(s).
3.The observations and findings of the auditor(s) should be documented in writing.
4.To preserve the independence and value of the audit function, the Competent Authority should not routinely request the audit reports, except when evidence of serious non-compliance with this Regulations exists, or in the course of legal proceedings, the Competent Authority may seek access to an audit report on a case by case basis.
5.The sponsor should provide an audit certificate.