In principle, the reviewer will honor the decisions and suggestions of IRB. The information on the key items for review can be found in the "Checklist of Informed Consent Form (ICF) Assessment and Template Texts of Injury Compensation" on the CDE website. The reference for the Informed Consent Form (ICF) related to pharmacogenomic studies can be found in the "Reference Guide for the Informed Consent Form (ICF) of Pharmacogenomic Studies" announced on October 13, 2005 (The Executive Yuan, the Department of Health Order Wei-Shu-Yao-Tzu.No. 0940338555).

The review consideration for additional "pharmacokinetic study" is safety, which mainly involves the evaluation of the effect of the volume and timetable of blood collection on subjects' health. If the additional PG study is optional, it is important to obtain a separate consent from the subject and explain the scope of the PG study. The scope of study must be clear and can be expanded. Sometimes clinical trials will have extension studies for those subjects who have completed the main trial to continue the study. Because subjects enroll in a main study at different times, in reality the sponsor shall determine whether to conduct an extension study before the first subject completes the trial and therefore the extension study will be initiated before the main study ends. Usually a decision has to be made under a condition that long-term safety data is insufficient and thus, when reviewing such extension studies, it is important to pay attention to the known safety data of the drug and make reasonable estimation of the study risk and ensure the termination criteria are reasonable and adequate periodic risk evaluation mechanism is established, for example, Data Safety Monitoring Board

Selection of the efficacy endpoint must be consistent with the trial objective. Evaluation of the appropriateness of efficacy endpoint shall depend on the trial objective and the stage of development. If the trial is the pivotal study, the efficacy endpoint shall mainly be clinical outcomes (e.g. the survival rate of subjects, the degree of improvement in physiological functions, or the main symptoms of a disease), but in the absence of appropriate clinical endpoints, a theoretically acceptable surrogate endpoint can be selected (for example: tumor response rate, laboratory data, or biomarkers).If this trial is an exploratory phase II clinical trial, a surrogate endpoint may be selected. However, whether the surrogate endpoint is appropriate needs to be carefully evaluated with the thinking from the perspective of pathophysiology and based on clinical data.

First, evaluate what drugs are prohibited for concomitant use, in particular, those drugs that are prohibited due to safety concern. For example, If concomitant medication may lead to serious drug interactions (e.g. the effect of the special metabolic enzyme CYP3A4), special measures need to be prepared to protect the subject's safety. Second, pay attention to those concomitant drugs that may affect efficacy assessment. For example, similar pharmacological mechanisms or drug that cause similar efficacy shall be prohibited to prevent interfering with interpretation of the efficacy of the study drug. Meanwhile, the medical rights of subjects also need to be considered. If conflicts are found, the priority is to protect the medical rights of subjects. In addition, pre-medication may be given to reduce adverse reactions for certain drugs. For example, anti-histamine and corticosteroid, and it is necessary to evaluate the necessity of pre-medication.

Evaluation of the appropriateness of administration method and dose selection is based on scientific theories. If the trial is a phase III clinical trial, the results of the dose-response trial or pre-clinical trial may be referenced. If the study drug is at the early development stage, the appropriateness of administration method and dose selection may be inferred from the results of toxicological or pharmacokinetic studies. The doses used and treatment duration reported in the completed trials will be carefully considered for evaluation of the risk of this trial and possible treatment effect. whether the adverse reaction is dose-related will also be evaluated. Some study designs may have the regulations on dose adjustments (escalation or reduction) according to the adverse reactions or in order to achieve the pre-determined efficacy. The rationality of the relevant regulations will be evaluated. The rationality of treatment period, observation period, and time points of visits will be evaluated as well.

1. Treatment period: Whether the length of treatment period is reasonable will be determined based on the character of the study drug and the main objective of the trial (efficacy or adverse reactions)
2. Observation period: Observation period is usually planned for the purpose of collecting safety data, but sometimes it is planned for the purpose of observation of efficacy. For example, in antibiotics studies, subjects need to be observed for an extended period of time after the end of treatment for test of cure. the rationality of the length of the observation period will be judged by the purpose.
3. Time points of visits: The frequency of visits shall take into account the feasibility of implementation. For example, whether the patients can cooperate and whether the number of times of visits is sufficient to monitor a specific drug adverse reaction. In addition, whether the observation items specified for the time points of visits are sufficient to protect the safety of subjects will also be evaluated.

The focus of evaluation of the inclusion and exclusion criteria is safety considerations. Subjects at risk shall be carefully defined.

1. Clinical trials usually will have the minimum requirements for the basic organ function and health status of subjects, for example, the requirements on liver, kidney, heart,or lung function, Eastern Cooperative Oncology Group (ECOG) score, and Karnofsky Performance Scale (KPS). The rationality of the specified minimum requirements will be considered based on the trial risk. For example, if the test drugis known to affect liver function, the minimal requirement for liver function shall be defined in the inclusion or exclusion criteriaAs for the protection measures for high-risk groups, the priority is to consider risk control. If the risk of participation in the trial cannot be controlled , the subjectsat risk should be excluded.
2. When evaluating the inclusion and exclusion criteria, the feasibility of the trial and the representation of the selected subjects will both be considered.

The points to consider regarding safety issues in clinical trials are to define the risk group and further evaluate whether the trial risk has been controlled adequately.

1. For temporary physical discomfort that does not need to be aggressively treated, it is required to verify whether such condition meets the requirements of the inform consent because this situation belongs to tolerability issues. Besides existing human experience, evaluation of the risk of a study drug will also take into account the results of animal toxicological effects on target organs and class effects of drugs with similar mechanism.
2. For safety issues that require active medical treatment, it is necessary to understand whether there is a feasible method of control (e.g. increase the examination items and frequencies) in current clinical practice. If no adequate method of control is available or there is a doubt that the control method implemented according to the study design may be insufficient, considering whether to include the risk in the exclusion criteria is required in order to eliminate the risk group. In other words, the procedures of safety assessment shall first determine the high-risk group and evaluate whether the protection measures are appropriate, whereas protection measures shall aim to adequately control the risks and exclusion shall only be considered as a last resort.

The composition of botanical drugs is more complex. Therefore, if there is information about prior human experience and safety data is sufficient, specific pharmacokinetics/pharmacodynamics studies are not required If the active constituent(s) (or toxic constituent(s), index constituent(s) or main chemical constituent(s)) of a botanical drug has/have been confirmed, bioavailability shall also be evaluated in the future clinical trials and therefore pharmacokinetic studies may be conducted along with the animal toxicity studies to understand the pharmacokinetic characteristics of the active constituent(s).For botanical drugs with confirmed active constituent(s), evaluation of the drug-drug interactions in the future clinical trials is required. Some pre-evaluations are suggested: assess the potential for concomitant use with other drugs in clinical practice, search for clinical reports on inhibition or induction of metabolic enzymes in vivo caused by interactions, review the literature related to metabolic enzymes in vivo, etc. See the decision tree in Appendix I: Guidelines for Registration of Botanical New Drugs for assessing whether the studies of in vitro interactions need to be conducted for the product. Though the results of in vitro interaction study of botanical drugs cannot accurately reflect the in vivo situation, conducting said study is still encouraged and completion of the assessment during non-clinical stage may also be considered.

It is recommended to conduct the pharmacokinetic study (a non-GLP laboratory is acceptable) independently or concurrently with animal toxicity studies prior to the FIH clinical trial to understand the pharmacokinetic information (e.g. degree of absorption and linear pharmacokinetic characteristics, etc.) of the candidate compound in animals, so as to facilitate extrapolation of the results to the dose and time points of blood collection in human clinical trials in the future. Biological specimens of animals and humans can be used for in vitro studies for assessing the enzymes that are likely to participate in the process of metabolism, the extent of metabolism, and protein binding rate, etc. and for preliminary determination of the similarities of the pharmacokinetic characteristics of the candidate compound in animals and humans. When conducting in vitro studies, it is recommended to use higher concentrations of the candidate compound so as to cover clinical administration and dose used in future human clinical trials. Please refer to "Clinical Trial Protocol-Guidance on Technical Documents" for details.

The CMC data of active controls or concomitant drugs that needs to be submitted is in accordance with the following regulations based on the regulatory status of the drug:

1. If the drugs for active control/concomitant use have been approved for marketing in Taiwan and are made by the same manufacturer, the license number shall be provided and CMC data is not required.
2. If the drugs for active control/concomitant use have not yet been approved for marketing in Taiwan and have not been used in approved clinical trials in Taiwan, the data of drug substance and finished product shall be submitted in accordance with the provisions of the "Clinical Trial Protocol-Guidance on Technical Documents". If the drug has been marketed in one of the A10 countries (please refer to the “Regulations for Registration of Medicinal Products”), the Certificate of Pharmaceutical Product (CPP), the name and address of the manufacturer, compositions, and test reports of the drug shall be submitted.