Contents
Part 1: Introduction
Part 2: Phases of Clinical Trials of Investigational New Drugs
Part 3: Investigational New Drugs Requirements
Part 1: Introduction
Definition of an Investigational Product 试验药物的定义
ICH GCP defines an investigational product as,
“A pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial” (ICH GCP 1.33).
ICH GCP将试验药物定义为：，
“在临床试验中测试或用作参考的活性成分或安慰剂的药物形式”（ICH GCP 1.33）
This may include a marketed product that is being used in a different form than the one it was approved for, or a marketed product being used for an unapproved or new indication.
这可能包括以不同于批准的形式使用的上市产品，或用于未批准或新适应症的上市产品。
Definition of an Investigational New Drug 研究新药的定义
The Code of Federal Regulations (CFR) defines an investigational new drug as: "...a new drug or biological drug that is used in a clinical investigation."
联邦法规（CFR）将试验新药定义为： “……用于临床研究的新药或生物药物。”
In the U.S. Food and Drug Administration (FDA) regulations, an investigational new drug is any substance (such as a drug, vaccine or other biological product) for which FDA approval is being sought.
在美国食品和药物管理局（FDA）法规中，研究新药是指寻求FDA批准的任何物质（如药物、疫苗或其他生物制品）。
A drug may be considered “new” even if it has been in use for years if a change is proposed in its use, formulation, route of administration, use in patient population where risk would be increased, or packaging. For example, years ago the FDA approved a drug to treat high blood pressure. The manufacturer of the drug now wants to test it as a treatment for anxiety in adults. This new use of the drug would be considered investigational.
如果建议改变药物的使用、配方、给药途径、在风险增加的患者群体中的使用或包装，即使药物已使用多年，也可能被认为是“新的”。例如，几年前FDA批准了一种治疗高血压的药物。该药物的制造商现在想测试它作为成人焦虑症的治疗方法。这种药物的新用途将被视为是研究性的。
In a study protocol and other documents, an investigational new drug may be referred to as the “study drug,” “experimental product,” “experimental drug,” “new intervention,” or similar term. Investigational new drugs are regulated under CFR Title 21 Part 312 (21 CFR 312).
在研究方案和其他文件中，实验性新药可以被称为“研究药物”、“实验产品”、“实验药物”、“新干预措施”或类似的术语。实验性新药受CFR Title 21 Part 312 (21cfr 312)的监管。
Labeling of an Investigational New Drug 试验新药的标签
The labeling of an investigational new drug:
Ⅰ、Must include the following statement: “Caution: New Drug — Limited by Federal (or United States) law to investigational use.”
Ⅱ、Must not be false or misleading and should not imply that the drug is safe or effective for the investigational purpose.
试验新药的标签：
1、必须包括以下声明：“警告：新药-受联邦（或美国）法律限制用于研究用途。”
2、不得为虚假或误导，且不得暗示该药物在研究目的上是安全或有效的。
Control of an Investigational New Drug 研究新药的控制
An investigational new drug may be given to participants only under supervision by the principal investigator or by a sub-investigator. (Usually, the person supervising the administration of an investigational new drug is a physician.) The investigator cannot supply the investigational new drug to any person who is not authorized to receive it.
研究新药只能在主要研究者或副研究者的监督下给予参与者。（通常，监督研究新药管理的人员是医生。）研究人员不能向未经授权接受试验新药的任何人提供试验新药。
Research that involves the use of controlled substances must comply with U.S. Drug Enforcement Administration regulations (21 CFR 1300-end). When studying an investigational new drug that is considered a controlled substance, the investigator must take adequate precautions to prevent theft or diversion of the drug into illegal channels of distribution. Such precautions include storing the investigational new drug "in a securely locked, substantially constructed cabinet or other securely locked, substantially constructed enclosure, access to which is limited."
涉及使用受管制药物的研究必须符合美国药物管制局的规定(21 CFR 1300-end)。当研究一种被认为是管制物质的实验性新药时，研究人员必须采取充分的预防措施，以防止盗窃或将药物转移到非法分销渠道。这些预防措施包括将研究用的新药储存在“一个安全锁住、结构牢固的柜子或其他安全锁住、结构牢固的外壳中，进入该外壳是受限制的。”
Promotion of and Charging for Investigational New Drugs 研究性新药的推广和收费
Neither an investigator nor a sponsor may promote (that is, endorse or advertise) an investigational new drug as safe or effective for the investigational purpose. In addition:
研究者或赞助商不得为研究目的宣传(即，认可或宣传)一种实验性新药为安全或有效。此外:
Ⅰ、An investigational new drug cannot be distributed commercially or in a test market.
Ⅱ、An investigation cannot be prolonged “after finding that the results of the investigation appear to establish sufficient data to support a marketing application.” In other words, if there is good evidence that the investigational new drug is safe and effective, the study should be stopped and no other participants enrolled.
Ⅲ、Charging for an investigational new drug in a clinical trial is not permitted without approval from the FDA unless the drug is being provided for treatment use.
1、研究新药不能在商业或试验市场上销售。
2、在发现调查结果似乎建立了支持营销申请的足够数据后，调查不能延长换句话说，如果有充分证据表明试验新药是安全有效的，则应停止该研究，且不得招募其他参与者。
3、未经FDA批准，不允许在临床试验中对研究新药收费，除非该药物用于治疗用途。
Part 2: Phases of Clinical Trials of Investigational New Drugs 研究新药临床试验的阶段
Clinical trials of an investigational new drug are generally conducted in four phases, Phase 1 to Phase 4. Phase 0, or “exploratory” trials, also exist as small clinical trials (sometimes only a few participants) that involve dosing at a sub-therapeutic level. Phase 0 trials are not as prevalent as Phases 1-4. Each phase is designed to find out different information. Although the phases of a trial are usually conducted sequentially (one after another), they sometimes overlap.
研究新药的临床试验通常分四个阶段进行，第一阶段至第四阶段。0期或“探索性”试验也作为小型临床试验（有时只有少数参与者）存在，涉及亚治疗水平的剂量。与第一阶段相比，第四阶段试验并不普遍。每个阶段都是为了找出不同的信息。虽然试验的各个阶段通常是按顺序（一个接一个）进行的，但有时会重叠。
Individuals may be eligible for studies in different phases, depending on their age, general condition, the type and stage of their disease, and previous therapy, if any.
个人可能有资格参加不同阶段的研究，这取决于他们的年龄、一般情况、疾病的类型和阶段以及以前的治疗（如果有）。
PHASE 1 Trials
Phase 1 trials are the first studies of an investigational new drug in humans. They are usually conducted in healthy volunteers. In some cases, Phase 1 trials may be conducted in individuals who have the disease the drug is intended to treat. Phase I trials generally involve between 20 and 80 participants.
第一阶段试验是首次在人类身上研究一种试验性新药。他们通常在健康志愿者中进行。在某些情况下，可能会对患有该药物拟治疗疾病的个人进行Ⅰ期试验。第一阶段试验通常涉及20至80名参与者。
Phase 1 trials are designed to:
Ⅰ、Make a preliminary determination of the drug's safety in humans.
Ⅱ、Identify some of the side effects associated with the drug's use.
Ⅲ、Begin to define a safe therapeutic (healing) dose range.
第一阶段试验旨在：
1、初步确定该药物在人体内的安全性。
2、确定与药物使用相关的一些副作用。
3、开始定义安全的治疗（愈合）剂量范围。
PHASE 2 Trials
Phase 2 trials are usually conducted in individuals who have the disease the drug is intended to treat or are at high risk for developing the disease. Phase 2 trials are larger than Phase 1 trials but still relatively small, usually involving no more than several hundred participants.
第二阶段试验通常在患有该药物拟治疗的疾病或处于疾病高风险的个体中进行。第二阶段试验比第一阶段试验大，但仍然相对较小，通常不超过几百名参与者。
Phase 2 trials are designed to:
Ⅰ、Begin to evaluate the drug's effectiveness in treating or preventing the disease or condition of interest.
Ⅱ、Determine the optimal dosing of the drug.
Ⅲ、Determine the common short-term side effects and risks associated with the drug.
第二阶段试验旨在：
1、开始评估药物在治疗或预防感兴趣的疾病或状况方面的有效性。
2、确定药物的最佳剂量。
3、确定与药物相关的常见短期副作用和风险。
PHASE 3 Trials
Phase 3 trials are conducted after preliminary evidence from Phase 1 and 2 trials suggests that the investigational new drug is safe and effective. They usually include between several hundred and several thousand participants.
第三阶段试验是在第一阶段和第二阶段试验的初步证据表明研究新药是安全有效的之后进行的。他们通常包括几百到几千名参与者。
Phase 3 trials are designed to:
Ⅰ、Gather additional information about the drug's safety and effectiveness to evaluate whether its benefits outweigh its risks.
Ⅱ、Compare it to other commonly used treatments for the same condition (if available) or compared to a placebo. These studies can be performed in a blinded manner.
Ⅲ、Evaluate interactions with other treatments that may be used at the same time as the investigational new drug.
Ⅳ、Provide adequate information to determine the indication for which the drug will be labeled if it is approved for marketing as well as any limitations on the drug's use that should be stated in the labeling. For example, if there were insufficient information to show that a drug can safely be given to children, the labeling would restrict the drug's use to adults.
第Ⅲ阶段试验旨在：
1、收集有关药物安全性和有效性的额外信息，以评估其益处是否大于风险。
2、将其与相同条件下的其他常用治疗方法（如有）或安慰剂进行比较。这些研究可以盲法进行。
3、评估可能与试验新药同时使用的其他治疗的相互作用。
4、提供足够的信息，以确定批准上市的药物将被贴标签的适应症，以及标签中应说明的药物使用限制。例如，如果没有足够的信息表明一种药物可以安全地给儿童服用，那么标签将限制成年人使用该药物。
PHASE 4 Trials
Phase 4 trials are conducted after the drug or treatment has been approved for marketing. They are designed to:
Ⅰ、Continue testing the drug or treatment to collect additional short-term safety information.
Ⅱ、Collect information about the effect of the drug or treatment in various populations.
Ⅲ、Collect information about side effects associated with long-term use of the drug.
第四阶段试验在药物或治疗被批准上市后进行。其目的是：
1、继续测试药物或治疗，以收集额外的短期安全信息。
2、收集药物或治疗对不同人群的影响信息。
3、收集与长期使用药物相关的副作用信息。
Part 3: Investigational New Drugs Requirements 研究性新药要求
The Investigational New Drug Application 研究性新药应用
A sponsor who wishes to conduct a clinical trial that involves an investigational new drug must submit an Investigational New Drug application (IND) to the FDA. In IND studies, the IND holder is considered to be the sponsor.
发起人希望进行涉及临床试验新药的临床试验，必须向FDA提交临床试验新药申请(IND)。在IND研究中，IND持有人被认为是发起人。
Information that must be provided in an IND IND中必须提供的信息
Information that must be provided in an IND includes the following:
IND中必须提供的信息包括：
Ⅰ、The identity and contact information of the sponsor and the phase (or phases) of the trial.
Ⅱ、A commitment that an IRB will be responsible for initial and continuing review of the trial.
Ⅲ、The name of the drug, a list of its active ingredients, and its dosage and route of administration.
Ⅳ、The objectives and planned duration of the proposed clinical trial(s).
Ⅴ、A brief description of the plan for investigating the drug, including:
i、The reasoning behind the drug or the study,
ii、The indication(s) to be studied,
iii、The kinds of clinical trials to be conducted in the first year after the IND submission,
iv、The estimated number of patients who will be given the drug in the clinical trial(s), and
v、Any serious risks that are anticipated on the basis of animal studies or previous human studies of this drug or related drugs.
Ⅵ、For most trials, a copy of the investigator's brochure.
Ⅶ、A protocol for each planned study. (See related material summarized from The Research Protocol module.)
Ⅷ、The identities and qualifications of all investigators. (As demonstrated in a Curriculum Vitae and Form FDA 1572. Click here for instructions on completing Form FDA 1572.)
Ⅸ、The criteria for patient selection and exclusion and an estimate of the number of patients to be studied.
Ⅹ、A summary of previous experience with the drug in both animal and human studies, including (if relevant):
i、Previous INDs,
ii、Experience with the drug in other countries,
iii、Known safety issues, chemistry and manufacturing information, and
iv、Dependence and abuse potential.
1、主办方的身份和联系方式以及试验阶段。
2、IRB将负责试验的初始和持续审查的承诺。
3、药物名称、有效成分清单、剂量和给药途径。
4、拟定临床试验的目标和计划持续时间。
5、药品调查计划的简要说明，包括：
（1）药物或研究背后的原因，
（2）要研究的适应症;
（3）IND提交后第一年进行的临床试验种类;
（4）预计将在临床试验中使用该药物的患者人数，以及
（5）根据本药物或相关药物的动物研究或先前的人体研究，预期存在的任何严重风险。
6、对于大多数试验，一份调查员的小册子。
7、每个计划研究的方案。(参见研究协议模块总结的相关材料。)
8、所有调查人员的身份和资格。(如履历和FDA 1572表格所示。点击此处查看填写FDA 1572表格的说明。)
9、患者选择和排除的标准和估计的患者数量的研究。
10、该药物在动物和人类研究中的经验总结，包括(如相关):
（1） 以前的IND，
（2）在其他国家使用该药物的经验，
（3）已知安全问题、化学和制造信息，以及
（4）依赖和滥用的可能性。
When an IND Goes Into Effect 当IND生效时
An IND is considered safe to proceed 30 calendar days after the FDA receives it unless:
Ⅰ、The FDA notifies the sponsor that the investigation described in the IND is subject to a clinical hold, or
Ⅱ、The sponsor receives written permission from the FDA to begin the study before 30 days have elapsed.
在FDA收到IND后的30个日历日内，IND被认为是安全的，除非：
Ⅰ、FDA通知申办方IND中描述的调查将被临床搁置，或
Ⅱ、申办方收到FDA的书面许可，在30天内开始研究。
At the sponsor's request, the FDA will provide advice on specific matters relating to an IND. Meetings between a sponsor and the FDA are frequently useful, and the FDA encourages such meetings to the extent that FDA resources permit.
应赞助商的要求，FDA将就与IND相关的具体事项提供建议。赞助商和FDA之间的会议通常是有用的，FDA鼓励在FDA资源允许的范围内举行此类会议。
IND Exemptions for Studies of Lawfully Marketed Drugs IND对合法销售药物研究的豁免
Studies of lawfully marketed drugs are exempt from the IND regulations if they meet all five of the criteria listed in 21 CFR 312.2(b)(1). The first four of these criteria are straightforward and need no special comment.
如果合法上市药物的研究符合21 CFR 312.2（b）（1）中列出的所有五项标准，则可免于遵守IND法规。这些标准中的前四个很简单，无需特别评论。
Ⅰ、study is not intended to support approval of a new indication or a significant change in the product's labeling.
Ⅱ、The study is not intended to support a significant change in the product's advertising.
Ⅲ、The study is conducted in compliance with Institutional Review Board (IRB) and informed consent regulations.
Ⅳ、The study will not be used to promote non-approved indications.
1、本研究不支持批准新的适应症或产品标签的重大变更。
2、本研究无意支持产品广告的重大变化。
3、本研究按照机构审查委员会（IRB）和知情同意条例进行。
4、本研究不会用于推广未经批准的适应症。
The final criterion, however, requires interpretation.
然而，最终标准需要解释。
The investigation does not involve a route of administration, dosage level, use in a patient population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug.
调查不涉及给药途径、剂量水平、患者群体中的使用，或显著增加与药物使用相关的风险（或降低风险可接受性）的其他因素。
It is the investigator's responsibility to determine whether an IND is necessary for a study that involves a marketed drug. A critical question in determining whether such a study is exempt from IND regulation is whether the study “significantly increases the risk” associated with use of the drug.
研究者有责任确定IND对于涉及上市药物的研究是否必要。确定此类研究是否免于IND监管的一个关键问题是，该研究是否“显著增加”与药物使用相关的风险。
If an investigator is quite sure that a drug study does not require an IND, he or she can simply not submit an IND application. If the investigator is doubtful about whether an IND is required, or wishes to have proof of the IND-exempt status of a study, the IND application can be submitted with an exemption from IND guidelines requested, and FDA staff will review the application to determine whether the study is exempt. The review is limited to critical safety concerns (dose, schedule, route, and patient population). If, after this limited review, the FDA determines that a study is exempt from the requirement for an IND, it performs no further review of the application. The FDA sends a letter to the sponsor giving notice of the exemption. Prior to submission of the application, the sponsor can also set up a pre-IND meeting with the FDA in order to discuss any questions or concerns.
如果研究人员非常确定药物研究不需要IND，他或她可以不提交IND申请。如果研究人员怀疑是否需要IND，或希望获得研究的IND豁免状态的证明，则可以提交IND申请，并要求豁免IND指南，FDA工作人员将审查申请以确定研究是否豁免。审查仅限于关键安全问题（剂量、时间表、路线和患者群体）。如果在本次有限审查后，FDA确定某项研究不受IND要求的约束，则不会对该申请进行进一步审查。食品和药物管理局向申办方发送了一封信，通知其豁免。在提交申请之前，申办人还可以与FDA召开IND前会议，以讨论任何问题或担忧。
IND Protocol Amendments IND协议修正案
The sponsor of an IND must submit a protocol amendment to the FDA:
Ⅰ、To describe any change in a Phase 1 protocol that significantly affects the safety of participants; or
Ⅱ、To describe any change in a Phase 2 or Phase 3 protocol that significantly affects the safety of participants, the scope of the investigation, or the scientific quality of the study.
IND的发起人必须向FDA提交一份方案修正案：
Ⅰ、描述第一阶段方案中显著影响参与者安全的任何变化；或
Ⅱ、描述第2阶段或第3阶段方案中显著影响参与者安全性、调查范围或研究科学质量的任何变化。
The following are examples of changes that would require the submission of a protocol amendment to the FDA:
Ⅰ、An increase in drug dosage or in the duration of participants' exposure to the drug.
Ⅱ、A significant change in the study design, such as the addition or elimination of a control group.
Ⅲ、The addition of a new test or procedure to improve monitoring for, or to reduce the risk of, an adverse event, or the dropping of a test intended to monitor safety.
Ⅳ、The protocol amendment can be implemented at study sites after the amended protocol has been submitted to and approved by the reviewing IRB, and submitted to the FDA..
以下是需要向FDA提交方案修正案的变更示例：
1、增加药物剂量或在参与者接触药物的时间内。
2、研究设计的重大改变，如增加或消除对照组。
3、增加新的检测或程序，以改善对不良事件的监测或降低风险，或放弃旨在监测安全的检测。
4、在修改后的方案提交给审查IRB并获得批准，并提交给FDA后，可在研究地点实施。
A protocol change that is intended to eliminate an apparent immediate hazard to participants may be implemented immediately, provided that:
Ⅰ、The FDA is subsequently notified of the change by a protocol amendment, and
Ⅱ、The reviewing IRB is also notified of the change in accordance with the IRB's rules.
可立即实施旨在消除对参与者造成明显直接危害的方案变更，前提是：
1、FDA随后通过方案修订通知变更，以及
2、根据IRB的规则，审查IRB也会收到变更通知。
IND Safety Reports IND安全报告
Sponsors must promptly review and investigate all information they receive relevant to the safety of an investigational new drug that is received from any source, foreign or domestic, including information derived from:
发起人必须立即审查和调查从任何来源（国外或国内）收到的与试验新药安全性相关的所有信息，包括来自以下方面的信息：
Ⅰ、Clinical or epidemiological studies,
Ⅱ、Animal studies,
Ⅲ、Commercial marketing experience,
Ⅳ、Reports in the scientific literature,
Ⅴ、Unpublished scientific papers, and
Ⅵ、Reports from foreign regulatory authorities.
1、临床或流行病学研究，
2、动物研究，
3、商业营销经验，
4、科学文献报道，
5、未发表的科学论文
6、来自外国监管机构的报告。
The sponsor must notify the FDA of any unexpected fatal or life-threatening experience associated with the use of the drug as soon as possible but not later than 7 calendar days after the sponsor's initial receipt of the information. Sponsors must provide written notification to the FDA and to all investigators participating in a trial within 15 calendar days of any adverse event that is:
申办方必须尽快通知FDA与药物使用相关的任何意外的致命或危及生命的经历，但不得晚于申办方最初收到信息后的7个日历天。赞助商必须在出现任何不良事件的15个日历日内向FDA和所有参与试验的研究者提供书面通知，即：
Ⅰ、Both serious and unexpected, and
Ⅱ、Reasonably likely to have been caused by the investigational new drug.
1、严重和意外，以及
2、合理可能是由试验新药引起的。
Subsequent, appropriate follow-up information must also be submitted, as it becomes available.
随后，还必须提交适当的后续信息，因为这些信息是可用的。
The sponsor must also provide written notification of any finding from tests in laboratory animals that suggests a significant risk for human participants. The written notification must be provided as soon as possible and no later than 15 calendar days after the sponsor receives the information.
赞助人还必须提供书面通知，说明在实验室动物试验中发现的对人类参与者有重大风险的任何发现。书面通知必须尽快提供，且不得迟于赞助商收到信息后15个日历日。
IND Information Amendments and Annual Reports IND信息修订和年度报告
A sponsor must file an information amendment to report essential information about the IND that is not within the scope of a protocol amendment, IND safety report, or annual report. The following are examples of information that requires the filing of an information amendment:
Ⅰ、New information about technical features of the drug, such as its toxicology or chemistry.
Ⅱ、Discontinuation of a clinical investigation.
赞助商必须提交信息修正案，以报告不在方案修正案、IND安全报告或年度报告范围内的有关IND的基本信息。以下是需要提交信息修正案的信息示例：
1、关于药物技术特征的新信息，如毒理学或化学。
2、临床研究的中止。
Within 60 days of the first anniversary of the date the IND went into effect, and every subsequent year, a sponsor must submit a brief report of the progress of the investigation. This annual report must include:
Ⅰ、A brief summary of the status of each study in progress or completed.
Ⅱ、A summary of the most frequent and most serious adverse experiences.
Ⅲ、A summary of all IND safety reports submitted.
Ⅳ、A list of participants who died during participation in the investigation, with the cause of death for each participant.
Ⅴ、A list of participants who dropped out as a result of any adverse experience, whether or not the adverse experience is thought to be related to the investigational new drug.
Ⅵ、A summary of the general investigational plan for the upcoming year.
Ⅶ、An updated Investigator's Brochure, if available.
Ⅷ、A summary of any foreign market developments.
Ⅸ、A summary of any outstanding business with the FDA regarding the IND (i.e. a response to an FDA request for information).
自IND生效之日起一周年后的60天内，以及随后的每一年，申办人必须提交一份调查进展的简要报告。该年度报告必须包括：
1、每项正在进行或已完成的研究状态的简要总结。
2、最常见和最严重的不良经历总结。
3、提交的所有IND安全报告的摘要。
4、参与调查期间死亡的参与者名单，每个参与者的死因。
5、因任何不良经历而退出的参与者名单，无论不良经历是否被认为与试验新药有关。
6、下一年度总体调查计划概要。
7、更新的研究人员手册（如有）。
8、任何国外市场发展的总结。
9、与美国食品和药物管理局有关IND的任何未决业务的摘要（即对美国食品和药物管理局信息请求的回复）。
