IND Application Procedures: Exemptions from IND Requirements
IND申请程序-免除IND要求
-
如果符合第312.2(b)节中的所有豁免标准，则上市药物的临床研究可免于IND要求。
-
FDA规定使用已批准药品的（其他未批准版本）的生物利用度或生物等效性(BA/BE)研究无需提交IND（21 CFR 320.31(b)和(d)。
-
FDA的法规（21 CFR 361.1）描述了放射性药物（含有不稳定同位素的药物）如被公认为对这些用途是安全和有效的，可以在豁免IND的情况下用于某些研究。
-
FDA并不反对在豁免IND的情况下进行冷同位素的研究。
FDA经常收到来自学术界（如临床研究者、IRB）和制药业的咨询，询问各种类型的临床研究是否应提交IND。咨询内容涉及第312部分中有关IND要求的一系列问题，例如，包括。
-
使用已上市药物的临床调查 -
生物等效性/生物利用度研究 -
使用放射性标记或冷同位素的研究 -
使用膳食补充剂或食品的研究 -
使用内源性化合物的研究 -
使用改性生物体的致病机制研究 -
在挑战模型中使用野生型生物体的研究 -
不具有商业目的的研究
Before submitting an IND application, investigators should refer to the Guidance for Clinical Investigators, Sponsors, and IRBs: Investigational New Drug Applications (INDs)— Determining Whether Human Research Studies Can Be Conducted Without an IND (PDF - 210KB) to determine whether their clinical investigations may be conducted without submitting an IND application.
The three most commonly occurring scenarios when clinical investigations may be exempted from the IND application requirements refer to certain limited situations of clinical investigations with approved marketed drugs, bioavailability or bioequivalence studies, or clinical investigations involving radioactive drugs considered safe for certain research uses. For each of these and few other scenarios, the specific criteria for exemption (PDF - 210KB) must be met.
Sponsors who are uncertain if their proposed investigation meets the criteria for IND exemption may seek advice from the FDA Review Division responsible for the relevant therapeutic area of the proposed trial. In some cases FDA staff may be able to provide this advice through informal communications (e.g., phone conversation, e-mail). In other cases FDA staff may request that the sponsor submit a summary of their proposed investigation in writing for FDA review before providing advice.
In certain cases, FDA staff may advise the sponsor to submit a full IND application for the proposed investigation for FDA review. If during that review FDA concludes the IND application meets the criteria for exemption, the sponsor will be so notified.
For additional explanation of safety reporting expectations for bioavailability and bioequivalence studies exempted from the IND application requirements refer to Guidance for Industry: Safety Reporting Requirements for INDs and BA/BE Studies (PDF - 227KB).
在提交IND申请之前，研究者应参考《临床研究者、申请人/赞助商和IRB指南》。新药研究申请（IND）--以确定临床试验是否可以在不提交IND申请（豁免）的情况下进行。
临床试验可豁免于提交IND申请的三种最常见的情况是指与已批准上市的药物进行的临床试验、生物利用度或生物等效性研究或涉及被认为对某些研究用途安全的放射性药物的临床研究的某些有限情况。对于上述每种情况和其他少数情况，必须满足特定的豁免标准（PDF - 210KB）。
申请人如果不确定拟议临床试验是否符合IND豁免的标准，可以向负责拟议试验的相关治疗领域的FDA审查部门寻求建议。在某些情况下，FDA工作人员可能会通过非正式沟通（例如，电话交谈、电子邮件）提供这种建议。在其他情况下，FDA工作人员可能会要求申请人在提供建议之前，以书面形式提交其拟议临床试验的摘要供FDA审查。
在某些情况下，FDA工作人员可能会建议申请人为拟议的临床试验提交一份完整的IND申请供FDA审查。如果在审查过程中，FDA认为IND申请符合豁免标准，将通知申请人。
关于豁免IND申请要求的生物利用度和生物等效性研究的安全报告预期的额外解释，请参考《工业指南》。IND和BA/BE研究的安全报告要求（PDF - 227KB）（https://www.fda.gov/media/79394/download）。
IV. CLINICAL INVESTIGATIONS THAT ARE EXEMPT FROM THE IND REQUIREMENTS BY REGULATION
按规定免于起诉要求的临床研究
FDA regulations describe two categories of clinical investigations that are exempt from the IND requirements in part 312, provided the criteria for exemption are met (see 21 CFR 312.2(b) and 320.31(b)). The two categories of clinical investigations and the applicable criteria are described in the following subsections. Ordinarily, clinical investigations of drugs that do not meet these criteria must be conducted under an IND as required in part 312.
FDA法规描述了两类临床研究，只要符合豁免标准，就可以免除312部分的IND要求（见21 CFR 312.2(b)和320.31(b)）。这两类临床研究和适用的标准将在下面的小节中描述。通常情况下，不符合这些标准的药物的临床研究必须按照312部分的要求，根据IND要求进行申请。
A. Certain Research Involving Marketed Drug Products
涉及已上市药物产品的某些研究
Whether an IND is needed to conduct a clinical investigation of a marketed drug primarily depends on the intent of the investigation and the degree of risk associated with the use of the drug in the investigation. A clinical investigation of a marketed drug is exempt from the IND requirements if all of the criteria for an exemption in § 312.2(b) are met:
-
The drug product is lawfully marketed in the United States.
-
The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication and there is no intent to use it to support any other significant change in the labeling of the drug.
-
In the case of a prescription drug, the investigation is not intended to support a significant change in the advertising for the drug.
-
The investigation does not involve a route of administration, dose, patient population, or other factor that significantly increases the risk (or decreases the acceptability of the risk) associated with the use of the drug product (21 CFR 312.2(b)(1)(iii)).
-
The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
-
The investigation is conducted in compliance with the requirements of § 312.7 (i.e., the investigation is not intended to promote or commercialize the drug product).
对上市药物进行临床研究是否需要IND，主要取决于研究的意图和研究中使用该药物的风险程度。如果符合第312.2(b)节中的所有豁免标准，则上市药物的临床研究可免于IND要求。
-
该药物产品在美国合法上市。
-
该研究不打算作为支持新适应症的良好控制研究报告给FDA，也不打算用它来支持该药物标签的任何其他重大变化。
-
如果是处方药，研究的目的不是为了支持药物广告的重大变化。
-
研究不涉及给药途径、剂量、患者人群或其他明显增加与使用该药物产品有关的风险（或降低风险的可接受性）的因素（21 CFR 312.2(b)(1)(iii)）。
-
研究的进行符合IRB的审查要求（21 CFR第56部分）和知情同意的要求（21 CFR第50部分）。
-
研究是按照312.7节的要求进行的（即研究的目的不是为了推广药物产品或使其商业化）。
The potential sponsor or sponsor-investigator of a planned clinical investigation using a marketed drug is responsible for determining whether the investigation meets the criteria for an exemption.9 If there is uncertainty about whether the exemption criteria are met, the potential sponsor or sponsor-investigator can seek advice from FDA on the applicability of the IND regulations (§ 312.2(e)).
Three of the criteria for exemption listed previously merit further discussion.
-
What is meant by a drug product that is lawfully marketed in the United States?
Given the range of possible modifications to a marketed dosage form, FDA cannot provide comprehensive guidance on the degree of risk presented by all such modifications. If sponsors or sponsor-investigators have concerns about whether changes to a lawfully marketed dosage form increase risk to an extent that an IND would be required, they should consult FDA (see section VIII). If a sponsor or sponsor-investigator consults FDA, they should provide FDA with a listing of chemistry, manufacturing, and controls (CMC) variations from the marketed version of the drug product, if CMC information for the marketed product is available to them, and any other pertinent information that would assist FDA in responding to an inquiry.
如果对是否符合豁免标准没有把握，潜在的申请人或发起人调查员可以就IND法规的适用性寻求FDA的建议（312.2(e)节）。
前面列出的豁免标准中有三项值得进一步讨论。
01.在美国合法销售的药物产品是什么意思？
将IND豁免标准纳入IND法规的最终规则的序言中明确指出，豁免条款的目的不是要求在临床研究中只使用药物产品的上市版本，以豁免IND要求。其目的是为修改药物产品的上市版本以用于临床研究提供一定的自由度。在答复要求FDA澄清申请人在多大程度上可以改变已上市的药品或使用条件而仍可免于遵守IND规定的意见时，FDA表示：
因此，申请人或申请人研究者可以对合法上市的剂型进行低风险的修改，例如，盲测研究。
在对已上市的剂型进行修改时，申请人和申请人调查员应根据剂型的类型和复杂性考虑修改产生的潜在风险影响。例如，对固体口服剂型进行小的改动，如改变上市剂型的颜色、刻痕或胶囊大小以达到致盲的目的，只要不涉及重大的生产或配方变化，一般都是低风险。同样，使用胶囊对已上市的剂型进行过度封装，只要胶囊符合适当的标准，一般来说也是低风险的。对更复杂的口服剂型、注射剂和其他非口服剂型的改变可能会带来更大的风险。对环境条件非常敏感的产品（如蛋白产品）也有较大的风险，因为配方、剂型、生产或初级包装的改变可能会改变这些产品的药代动力学、免疫原性或其他特性。
鉴于对已上市剂型的可能修改范围，FDA无法对所有此类修改带来的风险程度提供全面指导。如果申请人或申请人研究者对合法上市的剂型的改变是否会增加风险，以至于需要进行IND，他们应该咨询FDA（见第八节）。如果申请人或申请人研究者咨询FDA，如果可以得到上市产品的CMC信息，应向FDA提供一份与药品上市版本不同的化学、制造和控制（CMC）的清单，以及任何其他有助于FDA回应询问的相关信息。
• Is the risk associated with the product significantly increased (or the acceptability of the risk significantly decreased)?
Historically, assessing whether a particular use of a drug in a clinical investigation significantly increases the risk or decreases the acceptability of the risk, compared to its approved use or uses, has been the most difficult issue in determining whether an IND is needed for a clinical investigation of a marketed drug (21 CFR 312.2(b)(1)(iii)). This provision has been particularly difficult in the oncology setting where many of the therapies have significant toxicity; for that reason, FDA has issued guidance to help clinical investigators studying cancer treatments determine whether the risk associated with the use of the drug in a planned clinical investigation is significantly increased or the acceptability of the risk is significantly decreased.11 FDA’s cancer treatment guidance is also a useful reference for clinical studies of marketed drugs in other therapeutic areas, particularly for studies in other serious and life-threatening conditions, as the risk-benefit scenarios are at least somewhat relevant to non-oncologic settings. Investigators should carefully consider the risk implications of any conditions of use in the study that deviate from the conditions of use described in the drug’s labeling, with particular attention to the following:
- Route of Administration: A change in the route of administration can introduce a significant new risk. For example, there could be a significant increase in risk if a marketed drug for oral administration is converted to a dosage form that is to be administered by injection or intravenous, intrathecal, or inhalation route. These other routes of administration introduce concerns with increased local concentrations, sterility, pyrogenicity, hypersensitivity (e.g., airway reactivity), variations in metabolism, and other issues not present with oral administration that can significantly increase the risk, or decrease the acceptability of the risk, associated with use of the drug.
- Dose: Increases in dose, frequency, or duration of administration, compared to labeled dosing regimens, can significantly increase the risk in a study using a marketed drug. It is also possible that a decrease in dose could significantly increase risk. For example, administering a sub-therapeutic dose of an antiviral drug to study subjects could induce resistance in the subjects, thus rendering a subsequent therapeutic dose of the drug ineffective in treating the virus. The significance of changes in dose (in particular, increases in dose) can vary across therapeutic areas. For example, the cancer treatment guidance provides some latitude for conducting studies of high-dose cancer treatments without an IND because oncologists are generally familiar with the implications of high-dose regimens. In other clinical settings, use of higher doses than are recommended in labeling may be much more likely to significantly increase the risk or decrease the acceptability of the risk.
- Patient Population: The acceptability of known and unknown risks can vary across different treatment populations (see § 312.2(b)(1)(iii)). The population chosen for study could be at increased risk compared to the approved use population for a variety of reasons, such as increased age, different disease or stage of disease, concomitant illness, decreased renal or hepatic function, or concomitant therapy. For example, a drug with significant toxicity can be approved for use in a population with a life-threatening or severely debilitating disease because the risk of toxicity is acceptable in that population. Use of that drug in a clinical investigation in a population that is not so ill (e.g., to evaluate the drug for prevention of disease or symptomatic relief), however, would present a different risk-benefit situation in which the known risks might not be acceptable. When use of the drug in a specific patient population decreases the acceptability of the known risks, the study would have to be conducted under an IND as required under 21 CFR part 312.
• Does the sponsor intend to (1) report to FDA the investigation as a well-controlled study in support of a new indication, (2) use it to support any other significant change in the labeling of the drug, or (3) use it to support a significant change in the advertising (for prescription drugs only) for the drug?
Generally, it seems reasonable to infer that any well-controlled trial of a marketed drug (e.g., a study of a new indication) sponsored by the manufacturer of the drug would be intended to be used to influence labeling or promotion in some significant way and would have to be conducted under an IND. On the other hand, similar studies of marketed drugs conducted by an entity that does not have an independent ability to change a drug’s labeling – e.g., a study conducted by a sponsor-investigator in an academic setting or Government agency sponsor – would not generally be intended to be submitted to FDA to support a new indication or to otherwise influence the drug’s labeling or promotion. However, data from such studies may subsequently be submitted to FDA for that purpose and, therefore, FDA has an interest in helping to ensure that these studies are designed to yield data adequate to support a labeling change. A sponsor who would like to obtain FDA advice on study design can submit an IND for FDA review.
02该产品有关风险是否明显增加/风险可接受性是否明显降低？低）？
从历史上看，评估药物在临床研究中的特定用途与其的批准用途相比，是否明显增加了风险或降低了风险的可接受性，是确定是否需要对上市药物进行临床研究的最困难的问题（21 CFR 312.2(b)(1)(iii)）。这一规定在肿瘤学领域尤其困难，因为许多疗法都有明显的毒性；为此，FDA发布了指导意见，帮助研究癌症治疗的临床研究者确定在计划的临床研究中使用该药物的风险是否明显增加，或风险的可接受性是否明显降低。FDA的癌症治疗指导意见对其他治疗领域的上市药物的临床研究也是一个有用的参考，特别是对其他严重和威胁生命的疾病的研究，因为风险-效益情况至少与非肿瘤学环境有一定的关系。研究人员应仔细考虑研究中任何偏离药物标签中描述的使用条件的风险影响，特别注意以下几点。
- 给药途径。给药途径的改变会带来新的重大风险。例如，如果一种口服的上市药物被转换为通过注射或静脉注射、鞘内注射或吸入途径给药的剂型，风险可能会显著增加。这些其他给药途径会带来局部浓度增加、无菌性、热原性、超敏性（如气道反应性）、代谢变化以及其他口服给药不存在的问题，这些问题会大大增加使用该药物的风险，或降低风险的可接受性。
- 剂量：与标示的给药方案相比，增加给药剂量、频率或持续时间，可显著增加使用上市药物研究的风险。减少剂量也有可能大大增加风险。例如，对受试者使用低于治疗剂量的抗病毒药物可能会诱发受试者的抗药性，从而使随后的治疗剂量的药物不能有效地治疗病毒。剂量变化（特别是剂量增加）的意义在不同的治疗领域可能有所不同。例如，癌症治疗指南为在没有IND的情况下进行高剂量癌症治疗研究提供了一定的余地，因为肿瘤学家一般都熟悉高剂量治疗方案的意义。在其他临床环境中，使用比标签中推荐的更高的剂量，可能会大大增加风险或降低风险的可接受性。
- 患者人群。不同的治疗人群对已知和未知风险的接受程度可能不同（见§312.2(b)(1)(iii)）。由于各种原因，如年龄增加、疾病或疾病阶段不同、合并疾病、肾脏或肝脏功能下降或合并治疗等，选择研究的人群与批准使用的人群相比，风险可能增加。例如，一种具有明显毒性的药物可以被批准用于患有危及生命或严重衰弱疾病的人群，因为该人群的毒性风险是可以接受的。然而，在临床调查中，如果将该药物用于病情不严重的人群（例如，评估该药物用于预防疾病或缓解症状），则会出现不同的风险-效益情况，其中已知的风险可能无法接受。当在特定的病人群体中使用该药物会降低已知风险的可接受性时，该研究必须按照《联邦法典》第21章第312部分的要求，根据IND进行。
一般来说，似乎可以合理地推断，任何由药品制造商赞助的上市药品的良好控制试验（如对新适应症的研究）都将被用于以某种重要方式影响标签或促销，并且必须根据IND进行。另一方面，由没有独立能力改变药物标签的实体进行的已上市药物的类似研究--例如，由学术环境中的申办方研究者或政府机构赞助者进行的研究--一般不会被提交给FDA以支持新适应症或影响药物的标签或推广。然而，这些研究的数据随后可能因此目的会提交给FDA，因此，FDA出于兴趣帮助确保这些研究的设计能够产生足够的数据来支持标签的改变。想获得FDA关于临床研究设计的建议，申请人可以提交一份IND供FDA审查。
B. Bioavailability or Bioequivalence Studies in Humans
FDA regulations describe criteria under which bioavailability or bioequivalence (BA/BE) studies using unapproved versions of approved drug products can be conducted without submission of an IND (21 CFR 320.31(b) and (d)). Although these regulations are intended to facilitate development of generic drugs, a planned BA/BE study need not be intended for that purpose to be exempt from the IND regulations. A BA/BE study in humans does not require an IND if all of the following conditions are met:
-
The drug product does not contain a new chemical entity (21 CFR 314.108), is not radioactively labeled, and is not cytotoxic.
-
The dose (single dose or total daily dose) does not exceed the dose specified in the labeling of the approved version of the drug product.
-
The investigation is conducted in compliance with the requirements for review by an IRB (21 CFR part 56) and with the requirements for informed consent (21 CFR part 50).
-
The sponsor meets the requirements for retention of test article samples (21 CFR 320.31(d)(1)) and safety reporting (21 CFR 320.31(d)(3)).
B. 人体的生物利用度或生物等效性研究
美国食品和药物管理局(FDA)规定使用已批准药品的未批准版本的生物利用度或生物等效性(BA/BE)研究无需提交IND（21 CFR 320.31(b)和(d)。尽管这些规定旨在促进仿制药的开发，但计划中的BA/BE研究不一定是为了该目的而被豁免于IND规定。如果满足以下所有条件，人体的BA/BE研究就不需要IND：
-
药品不包含新的化学实体（21 CFR 314.108），没有放射性标签，也没有细胞毒性。
-
剂量（单剂量或每日总剂量）不超过该药物产品批准版本的标签中规定的剂量。
-
研究符合IRB的审查要求（21 CFR第56部分）和知情同意的要求（21 CFR第50部分）。
-
申请人符合保留试验品样品（21 CFR 320.31(d)(1)）和安全报告（21 CFR 320.31(d)(3)）的要求。
A. Radioactive Isotopes（放射性药物）
FDA regulations (21 CFR 361.1) describe conditions under which radioactive drugs (drugs containing unstable isotopes) can be used for certain research without an IND because they are generally recognized as safe and effective for those uses. These regulations apply to radioactive versions of both approved and unapproved drugs...
FDA的法规（21 CFR 361.1）描述了放射性药物（含有不稳定同位素的药物）如被公认为对这些用途是安全和有效的，可以在豁免IND的情况下用于某些研究。这些规定适用于已批准和未批准的药物的放射性版本...
B. Cold Isotopes（“冷区”同位素）
Cold isotopes (isotopes that lack radioactivity) have been increasingly used for the same research purposes as radioactive isotopes—to obtain basic information about drug metabolism or about human physiology, pathophysiology, or biochemistry. When used for these basic research purposes, cold (or stable) isotopes ordinarily present fewer safety concerns than radioactive isotopes. Unlike radioactive isotopes, however, there is no specific regulation analogous to 21 CFR 361.1 that addresses cold isotopes of approved drugs and unapproved drugs when used for these basic research purposes. However, FDA believes there is no need to have more stringent requirements for studies that use cold isotopes than for those that use radioactive isotopes, and historically, FDA has not objected to studies using cold isotopes being conducted without an IND. In exercising its enforcement discretion, FDA does not intend to object to clinical investigations using cold isotopes of unapproved drugs being conducted without an IND, provided the following conditions are met (the conditions are based on the criteria for studies using radiolabeled drugs...
冷同位素（缺乏放射性的同位素）已被越来越多地用于与放射性同位素相同的研究目的--获得关于药物代谢或关于人类生理学、病理生理学或生物化学的基本信息。当用于这些基本研究目的时，冷（或稳定）同位素通常比放射性同位素的安全问题要少。然而，与放射性同位素不同的是，没有类似于21 CFR 361.1的具体规定来处理用于这些基本研究目的的已批准药物和未批准药物的冷同位素。然而，FDA认为没有必要对使用冷同位素的研究提出比使用放射性同位素的研究更严格的要求，而且从历史上看，FDA并不反对使用冷同位素的研究在豁免IND的情况下进行。在行使其执法裁量权时，FDA不打算反对在没有IND的情况下使用未经批准的药物的冷同位素进行临床研究，但必须满足以下条件（这些条件是基于使用放射性标记药物的研究标准...
（暂未查到国内关于冷同位素的解释，此翻译/解释有待提高）
总结：申请人应根据相关指南确定是否可以在豁免IND的情况下进行临床研究，具体可参见如上描述的情况，如确实无法确定时，也可以咨询FDA.
