EMA 发布鼻用制剂治疗等效性要求指南草案并公开征求意见
Draft guideline on the requirements for demonstrating therapeutic equivalence for nasal products
EMA 发布鼻用制剂治疗等效性要求指南草案（EMA/220888/2026），于 2026 年 10 月 8 日启动公开征求意见。草案针对含相同活性部分的鼻用制剂，按体外、药代动力学以及药效学与临床的递进方式说明治疗等效性或生物等效性的论证要求，并列出体外比较参数及接受标准。CHMP 于 2026 年 10 月 5 日通过该草案供征求意见，意见截止 2027 年 2 月 28 日。
草案把鼻用制剂治疗等效性判定分为体外、PK 与临床递进路径，并列出各体外参数及接受标准，便于对照征求意见稿定位章节。
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17 2026年10月5日
18 EMA/220888/2026
19 人用药品委员会（CHMP）
20
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22 鼻用制剂治疗等效性证明要求指南
23
24 草案
由免疫及炎症性疾病工作组（IIWP）于2026年7月达成一致的草案
由CHMP通过以供征求意见 2026年10月5日
公开征求意见开始 2026年10月8日
征求意见结束（评论截止日期） 2027年2月28日
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26
请使用此EUSurvey表单提供评论。如有任何技术问题，请联系
EUSurvey支持。
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关键词 鼻用，等效性
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29
30
官方地址 Domenico Scarlattilaan 6 ● 1083 HS Amsterdam ● The Netherlands
来访及递送地址 参见 www.ema.europa.eu/how-to-find-us
向我们提问 请访问 www.ema.europa.eu/contact 电话 +31 (0)88 781 6000 欧盟机构
© European Medicines Agency, 2026。在注明来源的前提下允许复制。
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31
32 目录
33 目录......................................................................................... 2
34 执行摘要 ..................................................................................... 3
35 1. 引言（背景） ................................................................. 3
36 2. 范围 .................................................................................................. 3
37 3. 法律依据及相关指南 .................................................... 4
38 4. 一般考虑 ....................................................................... 4
39 5. 体外比较............................................................................. 6
40 6. 药代动力学 ................................................................................ 9
41 6.1. 局部作用药物 ......................................................................... 9
42 6.1.1. 全身安全性方面的等效性 .......................................... 9
43 6.1.2. 有效性方面的等效性 ...................................................... 9
44 6.2. 全身作用药物............................................................... 10
45 7. 药效学和临床研究 .............................................. 12
46 7.1. 局部作用药物 ....................................................................... 12
47 7.2. 全身作用药物............................................................... 13
48 7.3. 局部耐受性............................................................................. 13
49 8. 儿童和青少年 .................................................................. 14
50 9. 可用性研究................................................................................ 14
51 10. 定义 ........................................................................................ 15
52 11. 缩略语表 ......................................................................... 16
53
54
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55
56 概述
57 本指南旨在作为《吸入和鼻用产品药学质量指南》（EMEA/CHMP/QWP/49313/2005 rev. 1）的补充。它阐述了
58 对含有相同活性部分（一种或多种）的经鼻给药产品证明治疗等效性（TE）的要求。
61 局部作用鼻用产品之间 TE 的证明基于逐步推进的方法，即如果满足所有体外要求（药学等效），
62 则可在体外证明 TE；否则，尽管存在某些体外差异，若能够证明等效的全身暴露（作为安全性的替代
63 指标）和等效的局部吸收/沉积（作为有效性的替代指标），则最好通过药代动力学（PK）来证明。
64 使用药效学（PD）或临床终点来证明 TE 通常较为困难，因为这些终点很少具有足够的灵敏度。
67 本指南还阐述了通过 BE 研究证明含有相同活性部分（一种或多种）的全身作用鼻用产品生物等效性（BE）的要求，
68 并描述了在何种情况下可基于体外数据豁免这些研究。
70
71 1. 引言（背景）
72 本指南的目的是详细说明证明在鼻黏膜局部作用、含有相同活性部分（一种或多种）的鼻用
73 药品之间 TE 所需的数据要求。此外，还涵盖了证明含有相同活性部分（一种或多种）的全身作用
74 鼻用药品 BE 所需的数据要求，以及生物豁免的标准。
76 本指南拟与《吸入和鼻用药品药学质量指南》（EMEA/CHMP/QWP/49313/2005 rev. 1）配合使用，
77 以涵盖与证明 TE 相关的方面。因此，就局部作用制剂而言，它是《用于哮喘和慢性阻塞性肺疾病（COPD）的
78 经口吸入产品（OIP）治疗等效性证明要求指南》（CPMP/EWP/4151/00 Rev. 2）的姊妹指南，
79 后者涵盖 OIP 产品的 TE 相关方面。就全身作用制剂而言，参考了证明 BE 的指南
80 （《生物等效性研究指南》（CPMP/EWP/QWP/1401/98 Rev 1/Corr）和 ICH M13A）。
84
85 2. 范围
86 本文件就证明含有相同活性部分（一种或多种）的鼻用制剂之间等效性的要求提供指导，
87 包括单活性物质产品和复方产品。本指南涵盖在鼻黏膜局部作用（例如赛洛唑啉、氟替卡松、
88 氮䓬斯汀）和全身作用（例如纳洛酮、去氨加压素、芬太尼、氯胺酮、佐米曲普坦）的药品。
91 本指南侧重于简化申请，但所述原则可能适用于所有其他基于与参比产品相比证明 TE 的申请，
92 例如产品线扩展、变更申报或产品开发期间。此外，在需要确认与已有文献数据的产品
93 （例如成熟使用申请）的相似性时，同样适用相同的原则。
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96
97 3. 法律依据和相关指南
98 本指南应结合指令2001/83/EC附件I的引言和一般原则第I部分和第II部分
99 以及欧盟和国际人用药品技术要求协调理事会（ICH）指南中概述的其他相关要素
100 一并阅读，尤其是以下指南：
101 • CPMP/EWP/239/95：含已知成分的局部应用、局部作用产品临床要求指南注释；
102
103 • EMEA/CHMP/QWP/49313/2005 rev. 1：吸入和鼻用产品药学质量指南；
104
105 • EMA/CHMP/QWP/BWP/259165/2019：药品与医疗器械联合使用时的质量文档指南；
106
107 • CPMP/EWP/QWP/1401/98 Rev.1/Corr**：生物等效性研究指南；
108 • ICH M13A 速释固体口服剂型生物等效性指南
109
110 4. 一般考虑
111 治疗等效性（TE）意味着受试产品与参比产品的有效性和安全性特征充分
112 可比，从而能够可靠地排除产品之间具有临床相关性的差异。该
113 表述适用于体外或体内数据采集。
114 鼻用局部作用产品之间治疗等效性的证明基于逐步
115 方法。应提供体外数据（见第5节），并满足一系列要求，
116 方可得出治疗等效性的结论。如果无法在体外证明相似性，可使用PK数据
117 支持局部作用药品的治疗等效性（见第6节）。基于PD
118 数据证明治疗等效性可能是一种选择，但不推荐，因为被认为难以确保检测灵敏度
119 （见第7节）。
120 对于含相同活性部分、具有全身作用的鼻用药品，
121 需要证明受试产品与参比产品的生物等效性，通常通过
122 开展体内BE研究来实现。然而，对于溶液剂，如果满足第5节所述
123 证明治疗等效性的标准，可以基于体外数据豁免。如果无法确认BE，
124 则不能接受使用PD或临床数据。
125
126 该概念示意图见图1。
127
128
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129 图 1 流程图——经鼻给药产品之间等效性的证明
局部 全身
作用 作用
溶液 非溶液
在体外比较受试
制剂和参比制剂
在体外比较受试
受试制剂和参比制剂是否
制剂和参比
可通过体外数据证明等效？
制剂在体外
受试制剂和参比
制剂是否可通过体外
否 数据证明等效？
开展 PK 研究 研究应涵盖作为安全性替代指标的总暴露量，以及作为 开展 BE 研究
局部暴露量（若胃肠道对吸收的贡献
是否证明 BE？
不可忽略时，在采用活性炭的 吸收的替代指标
效力的替代指标。
是否证明 TE？ 所有活性成分是否可通过
PK 数据证明等效？
是 否
否 是
重新处方或 重新处方或 是 单独（即
单独（即非 非桥接）
是
桥接）临床数据 临床数据
可能需要 需要
可使用 PD/临床桥接研究， PD/临床桥接
但由于测定灵敏度低而不推荐 研究不可用于
支持 TE
已证明等效
130
131
132
133
134
经鼻产品治疗等效性证明要求指南
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135
136 5. 体外比较
137 体外特性的表征是评价和证明受试产品与参比产品之间治疗等效性（TE）的第一步。
138 应研究下文规定的体外标准，如果
139 并非所有标准均满足，则需要进入体内研究。对于全身作用的产品，
140 仅对溶液剂可豁免体内生物等效性（BE）研究，且须满足下文所述证明 TE 的所有标准。
141
142 体外表征和比较是必不可少的，无论是否已决定开展 PK 研究，均应始终进行。
143 体外可比性试验
144 应按照研究方案中的预先规定进行和评价，方案应包括相似性
145 条件、比较方法和接受标准。体外比较的检验方法
146 应为当前最先进的方法，并证明适用于预期用途。在仅基于体外数据
147 证明 TE 的情况下，应至少检测受试产品的三个连续批次和
148 参比产品的三个批次，每批至少十个单位。如果
149 在关键质量属性（CQA）中观察到高变异性，则需要检测更多批次
150 和/或每批更多单位。为限制变异性并最大化重现性，
151 建议使用自动驱动装置检测喷雾装置相关参数。受试产品批次
152 应能代表拟上市产品及生产工艺——即
153 处于或接近生产规模的批次。或者，若生产工艺和设备
154 无变更，可使用至少为生产规模 1/10 的中试规模批次
155 用于表征和比较目的，但应提供证据证明放大不影响产品
156 质量。用于体外等效性比较的参比产品批次
157 应能代表市场上的产品，包括考虑不同货架期。
158 若体外比较仅对 TE 起支持作用，且需要开展体内研究，
159 则较小的数据集即被认为足够，例如受试产品和参比产品各三个批次、五个单位。
160 对于声称与参比药品具有 TE 的鼻用药品，所需的研究组合
161 取决于药物剂型。可能对
162 药品的有效性和安全性产生影响、因而需要进行比较的 CQA，应予以界定并
163 论证。此外，对于不被视为关键（因而无需比较）的属性，
164 也应进行讨论和论证。应考虑下文表 5.1 中规定的参数，
165 但根据具体药品特性，其他参数也可能相关而需使用。
166 如果受试产品与参比产品相比满足所有相关体外标准，则足以证明 TE。
167
168 表 5.1. 用于证明受试与参比鼻用产品之间 TE 的体外参数。
用于证明 TE 的体外参数 鼻喷雾剂 鼻滴剂
鼻用粉雾剂
证明 TE 溶液剂 混悬剂 溶液剂 混悬剂
i. 定性和定量
组成，以及 是 是 是 是 是
药品剂型 ii. 装置的操作 是 是 是 是 是
iii. 活性成分的
否 是 否 是 是
粒径分布
iv. 活性成分的其他
否 是 否 是 是
物理特性 v. 递送剂量 是 是 是 是 是
vi. 制剂的理化
是 是 是 是 是
特性 vii. 产品的液滴/颗粒
是 是 否 否 是
粒径分布
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viii. 喷雾模式和喷雾羽流
是 是 否 否 是
几何形状
ix. 液滴/颗粒中的质量
是 是 否 否 是
小于 10 µm
169
170 i. 定性和定量组成，以及药物剂型
171 受试产品应含有与参比产品相同的活性物质（即相同的盐、
172 酯、水合物或溶剂化物）。辅料宜在定性上相同，在定量上
173 相似。若存在任何定性和/或定量差异，必须充分证明
174 该差异不影响相关 CQA 和/或产品性能的任何方面，
175 包括滞留时间、吸收、安全性和局部耐受性。
176 药物剂型应相同（例如鼻喷雾剂、滴鼻剂、鼻用粉末），
177 且活性物质的分散状态相同（例如溶液、混悬液）。
178 ii. 给药装置的操作
179 受试产品和参比产品为释放所需量活性物质而进行的
180 装置操作应相似。
181 iii. 活性物质的粒度分布
182 如果活性物质为固态，粒度分布应相似。如果除
183 活性物质外，制剂中还含有其他固态物质，则应
184 采用能够区分活性物质颗粒与其他颗粒的方法。应评价 D10、D50、
185 D90 和跨度（(D90-D10)/D50）。若为正态分布曲线，
186 比较 D50 和跨度即可。如果存在聚集体/团聚体，研究还应
187 在给药后的产品上进行。为判定相似性，受试产品和参比产品
188 几何均值比的 90% 置信区间（CI）应落在
189 ±15% 的可接受标准内，假设数据呈对数正态分布（85-118%）。
190 iv. 活性物质的其他物理特性
191 如果活性物质为固态（粉末、混悬液），任何差异，例如
192 晶体结构和/或多晶型的差异，均不应影响产品的性能。如适用，
193 应比较结晶活性物质中无定形物质的百分比以及颗粒
194 表面的粗糙度。
195 v. 递送剂量
196 平均递送剂量应相似。对于溶液，递送质量可能足以
197 进行比较。关于相似性评价方法，见第 iii 点。
198 vi. 制剂的理化性质
199 根据药物剂型的不同，可能有不同的理化性质是关键且
200 需要比较的。例如，可加入黏度增强剂以延长在
201 鼻腔中的滞留时间。对于混悬液，可使用润湿剂以降低表面张力，
202 从而增强颗粒分散。评价和比较时需考虑的关键参数
203 可能包括流变学性质（例如触变性、黏度）、表面张力、pH、密度、渗透压摩尔浓度和
204 缓冲容量。应充分讨论并论证理化性质。
205 对于定量质量理化特性，受试产品和参比产品
206 几何均值比的 90% CI 应落在 ±10% 的可接受标准内，假设
207 数据呈对数正态分布（90-111%）。如果参比产品的变异性高于
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208 10%，根据参比制剂
209 的变异性，采用标度平均等效性，按照 [U, L] = exp [±k·sR] 计算，接受范围可放宽至 ±20%（80-125%），其中 U 为
210 接受范围的上限，L 为接受范围的下限，k 为监管
211 常数，设定为 1.056，sR 为参比制剂
212 参数经对数转换后数值的标准差。表 5.2 给出了使用该方法时不同变异性水平如何导致不同
213 接受限度的示例。
214 表 5.2. 取决于参比制剂变异系数（CV）的接受限度。
CV 接受范围
10.0 ±10% 90-111%
12.5 ±12.3% 87.7-114%
15.0 ±14.6% 85.4-117%
17.5 ±16.8% 83.2-120%
20.0 ±18.9% 81.1-123%
21.365 ±20% 80-125%
215
216 或者，对于与规格无关的定量质量理化特性，可提出 CQA-
217 范围（基于参比制剂的潜在分布），采用
218 市场上所有参比制剂批次均代表可接受质量的原则。对于
219 理化 CQA，使用试验分布与该
220 参比范围的重叠来证明相似性，可能比使用带有固定百分比
221 变异的均值作为接受范围更为合适。建议申请人向
222 主管当局申请科学建议，如果这是其首选方法，则寻求对其策略的认可。
223 vii. 产品的液滴/粒径分布
224 对于鼻喷雾剂，应使用非空气动力学方法（例如激光衍射）比较产品的液滴粒径分布；对于鼻用粉末，应比较产品的
225 粒径分布。D10、
226 D50、D90 和 span（(D90-D10)/D50）应分别评估，并在距激光束两个不同的、经论证的
227 距离（例如 2 至 7 cm 之间）进行测试，且至少相隔 3 cm。若为
228 正态分布曲线，比较 D50 和 span 即可。关于相似性
229 评价方法，见第 iii 点。
230 viii. 喷雾模式和羽流几何形状
231 喷雾模式和羽流几何形状描述了所喷出喷雾羽流的
232 大小和形状特征。喷雾装置的特性，如阀门、泵和驱动器，可能对
233 喷雾模式有显著影响。喷雾模式应使用单次驱动确定，通常
234 在两个距离（例如 3 至 7 cm 之间）测试，至少相隔 3 cm。对于喷雾模式测量，应评估 Dmin、Dmax、椭圆度
235 比（Dmax/Dmin）和面积。对于羽流几何形状测量，应评估羽流角度和
236 羽流宽度。羽流
237 几何形状的分析应在喷雾充分发展阶段进行，最好是在
238 喷雾仍与喷嘴尖端接触时进行。
239 对于所有参数，应进行统计评估。假设数据呈对数正态分布，受试制剂与参比制剂几何均值
240 比的 90% CI 应包含在 ±20% 的接受标准内
241 （80-125%）。
242 ix. 小于 10 µm 的液滴/颗粒质量
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243 Small droplets/particles (less than 10 µm) are more likely to be swallowed or inhaled and thereby
244 deposited in the gastrointestinal (GI) tract or the lungs rather than in the nasal cavity. Therefore, the
245 mass of active substance in droplets/particles smaller than 10 µm is considered a CQA for a nasal
246 spray/powder and should be compared. A cascade impactor, or an abbreviated impactor with a cut-off
247 plate insert for 10 µm, configured for nasal use, is recommended. For solutions, laser diffraction may
248 be used. For the test product, the mass of active substance in droplets/particles smaller than 10 µm,
249 or for solutions the fraction of droplets smaller than 10 µm, should not be more than +10% compared
250 to the reference product. The 90% CI for the geometric mean ratio of the test and reference products
251 should not be above +10% (one sided), assuming log-normal distribution of data (not larger than
252 111%).
253 6. Pharmacokinetics
254 6.1. Locally acting drugs
255 For locally acting medicinal products, if TE has not been demonstrated based on in vitro data as
256 discussed in section 5, TE may be demonstrated using in vivo PK studies as described below. See
257 Section 6.1.2 for general recommendations regarding the PK study (study design, study population,
258 test and reference products, dose or strength to be tested, sampling schedule considerations).
259
260 It may however be necessary to administer more than one dose due to low plasma concentrations and
261 analytical limitations, provided that participant-safety is adequately ensured and justified.
262
263 The same batches should be used for the efficacy and safety PK studies, whenever feasible.
264
265 6.1.1. Equivalence regarding systemic safety
266
267 i. Study design
268 In order to investigate systemic safety, the total systemic exposure for the test and reference product
269 should be compared in a PK study as outlined in Section 6.2.
270
271 ii. Primary PK parameters and acceptance criteria
272 To support safety, it is sufficient to demonstrate that the systemic exposure is not higher for the test
273 product than for the reference product, i.e., the upper limit of the 90% CI for the ratio of the test and
274 reference product for AUC(0-t) and Cmax should not exceed the upper BE acceptance limit of 125.00%.
275 For Cmax the recommendations in the Guideline on the investigation of BE regarding widening
276 acceptance criteria for Cmax based on high intra-individual variability can be followed.
277
278 iii. Additional considerations
279 Safety assessments including monitoring of adverse events should be included in the PK study. For
280 additional considerations on local tolerability, refer to section 6.3.
281
282 6.1.2. Equivalence regarding efficacy
283 i. Study design
284 In case the contribution from the GI tract to the total systemic exposure following nasal administration
285 is negligible (<5%) a PK study without charcoal blockade can be used for both efficacy and safety
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286 comparisons. A low oral absolute bioavailability per se is, however, not synonymous with a negligible
287 systemic contribution from GI absorption, since the contribution from the GI tract depends on the
288 fraction of the dose being deposited in the nose and being swallowed, respectively, as well as on the
289 fraction absorbed into the systemic circulation from each site. For investigation of efficacy, a PK study
290 with activated charcoal should thus be performed, unless it can be justified that the contribution from
291 the GI tract to the total systemic bioavailability following nasal administration is negligible (<5%).
292
293 It should be noted that the contribution from the GI tract is generally larger for nasally administered
294 locally acting products than for orally inhaled products due to larger fraction of the dose being
295 swallowed. Therefore, it is not possible to claim negligible contribution from the GI tract following nasal
296 administration based on conclusions on negligible GI tract contribution following oral inhalation.
297
298 It is acknowledged that systemic exposure in a study with activated charcoal may not fully reflect local
299 nasal availability (and nasal efficacy), e.g. since absorption could partly occur via the lung from small
300 particles/droplets. However, the site of action and main site of absorption will be the nasal mucosa and
301 similar PK exposure is expected to imply comparable behaviour of the two formulations. Since use of
302 PK is more sensitive than a clinical endpoint study to detect differences between test and reference
303 product, this approach is recommended to demonstrate TE regarding efficacy.
304
305 The charcoal blockade efficiency in terms of binding, charcoal dose and frequency of administration
306 needs to be demonstrated (e.g., by in vitro binding studies and using a method that has been shown to
307 be effective in the literature).
308
309 In case the study with activated charcoal would not demonstrate measurable absorption, a PK study
310 would not be relevant in order to conclude on TE regarding efficacy.
311 If systemic exposure is known or expected to be non-measurable, PK data would not provide relevant
312 information. In such cases, it is recommended to seek scientific advice to discuss possible alternative
313 ways to demonstrate TE.
314
315 ii. Primary PK parameters and acceptance criteria
316 TE with regard to efficacy can be concluded if the 90% CI for the ratio of the test and reference
317 products is contained within the acceptance interval of 80.00-125.00 for AUC(0-t) and Cmax in the study
318 with activated charcoal blockade. A widening of the acceptance criteria for Cmax based on high intra-
319 individual variability in line with the recommendations in the Guideline on the investigation of
320 bioequivalence, may be possible. Any deviations from these acceptance criteria must be thoroughly
321 justified and can never be accepted for results below the lower limit of the acceptance range or when
322 data on safety is generated from a study using different test and/or reference batches.
323
324 6.2. Systemically acting drugs
325 For medicinal products intended for systemic action, demonstration of BE of the test product to the
326 reference product is required, generally via the conduct of an in vivo BE study. However, for solutions,
327 a waiver based on in vitro data is possible if the criteria in section 4 are fulfilled.
328 The guidance below is mainly applied for cases where both test and reference products are nasally
329 administered formulations. The same general principles may apply also in case the reference product
330 has a different route of administration (e.g. oral or intramuscular). However, in those cases there may
331 be a need for additional data relevant for the new route of administration compared to the approved
332 route.
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333 i. Study design
334 Regarding study design considerations, primary PK parameters and acceptance criteria etc, reference
335 could, for most aspects, be made to the Guideline on the investigation of bioequivalence
336 (CPMP/EWP/QWP/1401/98 Rev 1/Corr) and ICH M13A Guideline on bioequivalence for immediate-
337 release solid oral dosage forms. However, it should be kept in mind that the latter GL is mainly
338 dedicated for drugs absorbed by the gastro-intestinal tract, while absorption is expected to occur
339 mainly at the nasal mucosa for systemically acting nasally administered drugs. Therefore, some items
340 in relation to the particularity of the oral route may not be relevant here (e.g. a potential need for both
341 a fasted and a fed study).
342 An open (bioanalytical laboratory blinded) randomized single-dose cross-over study is recommended
343 and deemed to be appropriate in most cases. However, alternative designs, such as replicate crossover,
344 parallel group or repeated-dose administration, could be accepted if justified as described in the BE
345 guidelines referred to above.
346
347 ii. Study population
348 To reduce variability, BE studies should be conducted in healthy volunteers. The outcome of the
349 investigations in healthy volunteers could be extrapolated to patients for which the drug is intended. If
350 the investigated active substance is known to have adverse effects and the pharmacological effects or
351 risks are considered unacceptable for healthy subjects, the study may instead be conducted in a
352 targeted patient population under suitable precautions and supervision. Healthy volunteers should be
353 understood here as subjects with normal general health conditions but also with no chronic or transient
354 nasal affections.
355 If the product is self-administered by subjects, it is critical that all subjects included are properly
356 trained to administer the product correctly in line with the product information and also to confirm
357 during the study that subjects administer the product correctly. Also, in case of administration by study
358 staff, correct administration should be confirmed. If administration is not correctly performed, subjects
359 should be excluded. Decision on exclusion should be made before bioanalysis.
360
361 iii. Investigational test and reference products
362 The batch of the reference product should be representative of the commercial batches available on
363 the market. How the representative batch(es) is chosen should be fully justified. Characterisation of
364 several batches of the reference product should be performed. A minimum of five batches may be
365 sufficient if suitably justified. However, if the reference product shows great variability or quality
366 changes over storage, a larger number of batches is needed. The delivered dose of the reference
367 batch(es) chosen for the in vivo study(ies) should be as close as possible to the calculated median of
368 the observed reference product batches. A deviation within ±15% is reasonable.
369 The test product should be representative of the product to be marketed. Production scale batches are
370 preferred but pilot scale batches may be used, if there are no changes in the manufacturing process
371 and if it is demonstrated that scale-up does not affect product quality.
372
373 iv. Dose or strength to be tested
374 The dose to be administered should follow the recommendations of the reference product as
375 presented in the product information.
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376 If two or more strengths are available, it may be sufficient to include only one strength in the BE
377 study. The following requirements must be met:
378 a) The different strengths of the test product are manufactured by the same manufacturing
379 process.
380 b) The different strengths of the test product have the same qualitative and similar quantitative
381 composition. For example, the lower strength is achieved by a formulation with lower
382 concentration without any changes in actuator, metering valve or pump.
383 c) For solutions, the droplet size distribution should be similar for the test product strengths. For
384 suspensions and powders, the droplet size and the particle size distribution should be similar
385 for the test product strengths. For similarity criteria, see section 5.
386
387 v. Sampling schedule considerations
388 It is critical that the sampling schedule is planned so that Cmax can be reliably estimated and that it
389 can be avoided that Cmax is observed in the first sample post-dose. The sampling schedule should
390 cover the plasma concentration - time curve long enough to provide a reliable estimate of the extent
391 of exposure, which is achieved if AUC(0-t) covers at least 80% of AUC(0-∞).
392 If justified, a suitably truncated AUC can be used instead of AUC(0-t) for drugs with long terminal
393 elimination half-life. When such an approach is claimed, the decision for sampling cutoff time should
394 be defined prospectively in the study protocol and take into account the local residence time of the
395 drug before being cleared from the nasal mucosa. It should be noted that the truncation of AUC at 72
396 hours mentioned in ICH M13A is based on GI transit time. However, in most cases, this sampling time
397 would likely be sufficient also for nasally administered products.
398
399 vi. Primary PK parameters and acceptance criteria
400 The Cmax and AUC(0-t) should be evaluated. BE can be concluded if the 90% CI for the ratio of the test
401 and reference products is contained within the acceptance interval of 80.00-125.00 for AUC(0-t) and
402 Cmax. Intraindividual variability may be an issue for drug administered by nasal route. For Cmax the
403 recommendations in the Guideline on the investigation of bioequivalence regarding widening of
404 acceptance criteria for Cmax based on high intra-individual variability can be followed.
405 For drugs where the early onset of action is clinically relevant, an additional primary PK parameter
406 such as area under the concentration vs. time curve between two specific time points (pAUC) or tmax
407 should be used to establish BE as recommended in ICH M13A.
408
409 7. Pharmacodynamic and clinical studies
410 7.1. Locally acting drugs
411 As the objective is to demonstrate TE with the reference product rather than efficacy and safety of the
412 test product, PK endpoints are considered more sensitive to detect differences between test and
413 reference product than PD or clinical endpoints. For locally acting medicinal products, if TE has not
414 been demonstrated based on in vitro data (see section 5) or in an in vivo PK study (see section 6), it is
415 generally recommended to reformulate the product.
416
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417 However, if other approaches with PD or clinical endpoints are considered, the study design must be
418 such that assay sensitivity is clearly shown at an acceptable level. Appropriate efficacy endpoints for TE
419 may include objective measures of nasal congestion/nasal airway resistance and/or inflammation,
420 depending on the drug’s mechanism of action. Subjective endpoints may be included as co-primary or
421 secondary endpoint, but use of only subjective endpoints is not acceptable. Safety assessments
422 including monitoring of adverse events should always be included in the efficacy studies regardless of
423 the design.
424
425 Regardless of the objective of the study, it is necessary to demonstrate that the sensitive part of the
426 dose/response curve for the PD/clinical parameter under investigation has been studied. To allow
427 estimating assay sensitivity, it is essential to include at least one non-zero dose level besides the dose
428 level(s) primarily investigated.
429
430 As for the PK studies (see section 6.2.2), the same batch of reference product should be used for
431 safety and efficacy PD studies, unless adequately justified, and should be representative of the product
432 on the market (see section 6.1). When feasible, it is of value to have access to PK data from the PD
433 studies.
434
435 It is recommended that the statistical analysis allows calculating relative potency. The relative potency
436 of the test product to the reference product is defined as the dose of the test product that produces the
437 same biological response as one unit of the dose of the reference product. This analysis should be
438 conducted based on the approach by Finney (1964)1 for the primary efficacy variable, unless
439 otherwise justified. The acceptance criteria for the 90% CI of the relative potency should be
440 prespecified and normally retained within 0.67 to 1.50. To support TE, it should be clearly shown that a
441 certain strength of the test product is more similar to the same strength of the reference product than
442 the closest adjacent differing higher or lower strength (anticipated to differ by a factor 2 irrespective of
443 whether there is an approved such strength or not). Any other choice of statistical approach must be
444 sensitive enough to ensure assay sensitivity at this level.
445
446 7.2. Systemically acting drugs
447 In line with the principles for generic development of oral formulations, for generic nasal products of
448 systemically acting drugs, PD or clinical data are not acceptable in case of deviation from BE. If a
449 waiver based on in vitro data, as discussed in section 5, is not applicable and BE has not been
450 demonstrated in an in vivo BE study, it is generally recommended to reformulate the product, or a full
451 stand-alone clinical data package would need to be provided to support a MAA instead of a BE
452 approach.
453
454 7.3. Local tolerability
455 Local tolerability of nasal medicinal products is an important consideration as some drugs or
456 formulations can irritate the nasal mucosa, leading to discomfort, sneezing, or nasal discharge. In
457 general, local tolerability may be ascertained by knowledge of the active substance and the choice of
458 well-established excipients.
1
Finney DJ. Statistical methods in biological assay. London: 104:1057–61. Griffin, 1964
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459 Equivalence with respect to quality (see section 5 above) provides assurance of safety and local
460 tolerability if the excipients are qualitatively the same and quantitatively similar. However, if the
461 excipients are not qualitatively the same or not quantitatively similar, impact on the local safety profile
462 should be addressed in a local tolerability study in humans or thoroughly justified based on literature,
463 including e.g., irritation, changes in nasal secretions (discharge) or breathing (congestion), and nasal
464 mucosal appearance. Consideration should also be given to particular aspects of medicinal product use
465 e.g., posology and duration of treatment.
466
467 8. Children and adolescents
468 In case of a new nasal delivery device, not previously approved for children but where the reference
469 product has a paediatric indication, data on usability needs to be provided (see section 9). The
470 characteristics of the delivery device may be such that the device is more difficult to use for a child
471 than for an adult and, therefore, the child or their caregiver is less able to use the device correctly, or
472 the child/caregiver may use the device differently from an adult. Such differences in the handling of
473 the product by a child/caregiver may result in a different risk/benefit relationship in the child compared
474 with that seen in the adult. In case it has been shown that the device can be correctly handled and
475 emptied by children/caregivers and TE/BE has been demonstrated (see sections 5 and 6 above), the
476 lowest approved age for the test product could be set at the same as the reference product without
477 further data or justification.
478
479
480 9. Usability studies
481 For medicinal products for which the medical device and/or device part and the medicinal product form
482 an integral product that is not reusable (hereafter called integral), a formal usability study (also named
483 human factor study) may be required to demonstrate safe and effective use of the integral medicinal
484 product by the intended user population as stated in the ‘Guideline on quality documentation for
485 medicinal products when used with a medical device’ (EMA/CHMP/QWP/BWP/259165/2019), section
486 5.4.
487
488 For such studies, study participants should be recruited to include a number of distinct user groups
489 including patients (adults, and where appropriate children and adolescents) and caregivers, within
490 which both reference product-naïve and experienced users should be included. A minimum of 15
491 participants should be recruited in each distinct user group. Participants selection for these studies
492 should ensure representativeness of the intended users population incorporating general population
493 trends (e.g., left handedness, elderly, patient with manual coordination difficulties, such as arthritic
494 patients). The study protocol should direct participants in simulating the use of the new nasal delivery
495 device to deliver doses as per normal use using an empty or placebo device, unless a different study
496 setting is justified. The exercise should include the unpacking of a new device from the patient pack,
497 simulated delivery of the first dose, as well as the intended storage of the device. Participants should
498 be asked to simulate the delivery of further doses to assess the user interface with the device
499 throughout its life. Areas of focus should allow ensuring that the user understands key features of the
500 device. Clear acceptance criteria should be pre-specified together with an accompanying rationale in
501 the protocol. The outcome of this summative usability study should be reported in the form of a
502 usability report that should include details such as the intended use, observed risks, and study results
503 as well as its corresponding appendices, including the study protocol.
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10. Definitions
Abridged application Application (generic, hybrid, biosimilar)
submitted under Articles 10(1), 10(3) and
10(4) of Directive 2001/83/EC
Active moiety The molecule or ion responsible for the
physiological or pharmacological action of the
drug substance
Assay sensitivity Ability of a clinical trial to distinguish an
effective treatment from a less effective
treatment or ineffective treatment.
Delivered dose The quantity of drug substance that is available
to the user, ex-device in one spray or actuation.
Dose/Single dose Amount of drug administered on a single
occasion. One dose may consist of several
actuations.
Metered dose The quantity of drug substance contained in the
delivery device metering chamber.
Reference product A product against which therapeutic
equivalence is claimed/assessed.
Relative potency The relative potency of the test product to the
reference product is defined as the dose of the
test product that produces the same biological
response as one unit of the dose of the
reference product (i.e., comparative outcomes
for different doses).
Single dose study Study involving a single administration of each
dose level under investigation.
Strength/dose Strength refers to the amount of active
substance metered or delivered in a single
actuation (e.g., 125 microgram per actuation of
a nasal spray). Dose, by contrast, refers to the
total amount of active substance administered
on one occasion. For example, one actuation in
each nostril (e.g., 2 x 125 microgram).
Therapeutic equivalence The performance of the test and reference
products is sufficiently comparable (within the
acceptance criteria outlined in this guideline) to
ensure negligible impact on efficacy or safety.
For systemically acting formulations, the term
bioequivalence is normally used, but in this
guideline, therapeutic equivalence may refer
also to systemically acting formulations.
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11. List of abbreviations
AUC Area Under the Curve
BE Bioequivalence
CI Confidence Interval
Cmax Peak concentration
D10, D50, D90 Droplet/particle diameter at which 10%, 50% or
90% are smaller
Dmin, Dmax Minimum or maximum diameter of the spray
plume area
GI Gastrointestinal
ICH International Conference on Harmonisation
PD Pharmacodynamic
PK Pharmacokinetic
TE Therapeutic equivalence
tmax Time to peak concentration
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来源：EMA Scientific Guidelines · ema.europa.eu