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Back to the forum  Query: 2017-12-13 08:29 CET (UTC+1h)
 
BRB
Junior

Canada,
2017-07-20 15:44

Posting: # 17581
Views: 1,924
 

 CFDA and reference scaling [Regulatives / Guidelines]

Hello all,

To anyone's knowledge does the CFDA allow for FDA or EMA reference scaling? I tried looking into the current Chinese regulatory documents:

http://www.sfda.gov.cn/WS01/CL1751/147583.html

but I could not find anything which mentions it, particularly in Annex 3 which seems to focus on the PK and stats analysis.

If anyone can provide some guidance, it would be appreciated.
Thank you!
BRB
Helmut
Hero
Homepage
Vienna, Austria,
2017-07-20 22:09

@ BRB
Posting: # 17584
Views: 1,699
 

 CFDA and reference scaling

Hi BRB,

see this post (by a native speaker). :smoke:

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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BRB
Junior

Canada,
2017-07-20 22:33

@ Helmut
Posting: # 17585
Views: 1,703
 

 CFDA and reference scaling

Thank you Helmut. Finding information about the CFDA requirements is quite a challenge. It makes finding information about ANVISA requirements seem like a walk in the park :)


Do you, or does anyone know where I could find more details about reference scaling for the CFDA? Is it similar to EMA scaling as mentioned in the quoted post? Is there anything in the public domain available that can verify this, or am I asking too much???


Thanks again!
BRB
Shuanghe
Regular

Spain,
2017-07-21 18:09

@ BRB
Posting: # 17588
Views: 1,613
 

 CFDA and reference scaling

Hi,
» Finding information about the CFDA requirements is quite a challenge. It makes finding information about ANVISA requirements seem like a walk in the park :)

I'm a native speaker and it's difficult for me to find useful information as well. So I guess it's not the issue of the language. :-D

» Do you, or does anyone know where I could find more details about reference scaling for the CFDA? Is it similar to EMA scaling as mentioned in the quoted post? Is there anything in the public domain available that can verify this, or am I asking too much???

Not in public domain but I do have a copy of the appendix 9011 from Chinese Pharmacopeia 2015 that was mentioned in my post. I've sent it to Helmut so if he has some spare time to upload it to guidance collection then you'll have it. I'm not sure if this is the verification you referred to.

There's not much new information about BE since the reform from CFDA is quite recent. They do have some training material (given by CFDA staff) which is free to download (rar file), all in Chinese obviously. Both FDA and EMA method was mentioned but they didn't say which one they prefer.

Helmut,

By the way, I thought about sending the guideline to you by forum's private message but I couldn't find a way to attach any document so I use email instead. Is it so by design or my IT skill need to be improved? ;-)

All the best,
Shuanghe
Helmut
Hero
Homepage
Vienna, Austria,
2017-07-21 18:25

@ Shuanghe
Posting: # 17589
Views: 1,608
 

 OT: Uplading / attaching files

Hi Shuanghe,

» By the way, I thought about sending the guideline to you by forum's private message but I couldn't find a way to attach any document so I use email instead. Is it so by design or my IT skill need to be improved?

Your skils are fine. By design (see there). The forum is under constant attack by bad bots. I block about 25/day (80,000 since Nov 2012). Would need a major rewrite of the forum’s scripts to allow attachments an/or uploading binary files. Sorry.

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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Helmut
Hero
Homepage
Vienna, Austria,
2017-07-21 19:23

@ BRB
Posting: # 17590
Views: 1,610
 

 CFDA: seemingly like the EMA

Hi BRB,

» […] It makes finding information about ANVISA requirements seem like a walk in the park :)

I have given up to find sumfink useful at ANVISA’s site. Some of my Portugues frined told me that the site is terrible. :-(

» Do you, or does anyone know where I could find more details about reference scaling for the CFDA?

THX to Shuanghe: Appendix 9011. Appetizers (original and Google translate):

9011 药物制剂人体生物利用度和生物等效性试验指导原则中国药典2015
1.9 生物等效性评价
[…] 髙度变异性药品的接受范围可能在某些情况下放宽。
1.11 高变异性药物或药品
高变异性药品是指药动学参数个体内变异大于30%的药品。如果申请者怀疑一个药品的吸收速度或程度可能是髙变异的,则可以进行一项重复交叉设计的试验。
对于那些高变异性药品,如果认为差异较大对于临床的影响不大,基于临床的充分理由,则可以放宽接受范围。在这种情况下, 的接受范围可以最宽为69.84%〜143.19%.为了放宽接受范围,生物等效性试验必须是一项重复设计,来证明对于试验的参比化合物受试者内变异>30%。
申请者应说明理由,计算的受试者内变异是可靠估计,而不是逸出值的结果。要求放宽区间必须在试验计划中 预先规定。
根据受试者内变异放宽接受限的可能性不适用于AUC,它的接受限保持在80.00%〜125.00%,不管变异如何。
在重复试验设计中,采用三周期或四周期交叉方案都是可以接受的。

9011 Pharmaceutical preparations Human BA and BE test guidelines – Chinese Pharmacopoeia 2015
1.9 Bioequivalence evaluation
[…] the range of acceptance of highly variable drugs may be relaxed in some cases.
1.11 Highly variable drugs or drug products
High variability drugs refers to pharmacokinetic parameters with an within-subject variability of more than 30%. If the applicant suspects that the rate of absorption or extent of a drug may be highly variable, a repeat crossover design may be performed.
For those high variability drugs, if the difference is considered to have little effect on the clinical [outcome], based on clinical justification, you can relax the acceptance range. In this case, the acceptance range can be as broad as 69.84% ~ 143.19%. To relax the acceptance range, the bioequivalence test must be a replicate design to demonstrate that the [variability of the] reference drug in the study [is] >30%.
Applicants should state the reason that the calculated variance within the subject is a reliable estimate, rather than the result of an outlier. The request for relaxation must be specified in the study protocol.
According to the possibility of variability in the subject, the acceptance limit is not applicable to AUC, and its acceptance is maintained at 80.00% ~ 125.00%, regardless of variation.
In a repeat trial design, it is acceptable to use a three- or four-period crossover design.


In short, that’s the EMA’s approach:
  • Intention to use reference-scaling stated in the protocol.
  • Justification that widening the acceptance range is clinically not relevant.
  • Cmax only.
  • Leveling off at 69.84–143.19% (upper cap).
  • Outlier check.
The GMR-restriction of 80.00–125.00% (mandatory in all other jurisdictions) is not mentioned. Forgotten?

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
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Shuanghe
Regular

Spain,
2017-07-24 18:47

@ Helmut
Posting: # 17601
Views: 1,501
 

 CFDA: seemingly like the EMA

Hi all,

» The GMR-restriction of 80.00–125.00% (mandatory in all other jurisdictions) is not mentioned. Forgotten?

I think they would prefer the word "implied" since most of the contents are just copied from EMA's guideline. :-D

All the best,
Shuanghe
yicaoting
Regular

NanKing, China,
2017-08-22 16:49

@ BRB
Posting: # 17731
Views: 1,191
 

 CFDA and reference scaling

» To anyone's knowledge does the CFDA allow for FDA or EMA reference scaling? I tried looking into the current Chinese regulatory documents:

Hi BRB
I work in China. On this issue, from my experience with CFDA, they like to adopt US FDA's RSABE guiandence.

We have submit such dossier using US FDA's method to CFDA.


Edit: Full quote removed. Please delete everything from the text of the original poster which is not necessary in understanding your answer; see also this post #5! [Helmut]
Helmut
Hero
Homepage
Vienna, Austria,
2017-08-22 16:59

@ yicaoting
Posting: # 17732
Views: 1,193
 

 CFDA and reference scaling

Hi Zhang Yong,

» On this issue, from my experience with CFDA, they like to adopt US FDA's RSABE guiandence.
»
» We have submit such dossier using US FDA's method to CFDA.

That’s interesting given Shuanghe’s post above and followings – which point towards the EMA’s method. Strange.

[image]Regards,
Helmut Schütz 
[image]

The quality of responses received is directly proportional to the quality of the question asked. ☼
Science Quotes
Shuanghe
Regular

Spain,
2017-08-29 13:12

@ Helmut
Posting: # 17750
Views: 1,041
 

 CFDA and reference scaling

Hi Helmut,

» That’s interesting given Shuanghe’s post above and followings – which point towards the EMA’s method. Strange.

As I mentioned in previous post, initially it seems that CFDA adopted EMA's method by their guideline in 2015 as an appendix of the Chinese Pharmacopeia; however, the newer guideline was published in 2016 and it's basically a copy of FDA's guidance. That's one of the reasons I said that "FDA beats EMA in China". The confusion/uncertainty comes from the fact that, unfortunately, RSABE was only mentioned in 2015 guideline but not in 2016 guideline. Though it's not clear from guideline perspective, in practice, I had a feeling that Zhang Yong might be right about CFDA's preference of FDA method though no one can be sure unless they submitted such method and the dossier was approved.

Hi Zhang Yong,

From the context I understood that you only submitted dossier to CFDA. What's their opinion? The dossier is approved or are you still waiting for the possible "deficient letter" (or whatever name they call it in china)?

For BRB, I think that if you really want to be sure that the correct method is used, it might be worthwhile to contact CFDA.

All the best,
Shuanghe
yicaoting
Regular

NanKing, China,
2017-08-29 18:51

@ Shuanghe
Posting: # 17752
Views: 1,033
 

 CFDA and reference scaling

» From the context I understood that you only submitted dossier to CFDA. What's their opinion? The dossier is approved or are you still waiting for the possible "deficient letter" (or whatever name they call it in china)

Hi Shuanghe
Yes, our submission is under review now. But we believe that CFDA will like to accept FDA's method. The drug product is listed on FDA's Drug Product Specific BE Recommendation List. As far as we know, (I am working in a big Pharma in China)CFDA is putting more and more emphasis on learning the list. The reviewer usually gives us suggestion and requirement according to FDA's BE recommendations, especially those drugs are clearly listed and those with more special properties such as HVDs and NTIDs. As you know, a lot of reviewers (such as He Ruyi serves as CSO for CFDA now)come back to CFDA from FDA these years, this definitely will has some influenceon the CFDA's attitude to many issues
in drug application review.
BTW, are you working in China now?
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