vish14184
★    

India,
2016-04-20 21:22
(2898 d 12:49 ago)

Posting: # 16224
Views: 5,956
 

 Canada HVDS update [BE/BA News]

Dear All,

Health Canada published Policy on Bioequivalence Standards for Highly Variable Drug Products on 18th April 2016.

Please refer below link for your ready reference.
http://www.hc-sc.gc.ca/dhp-mps/prodpharma/activit/announce-annonce/notice-avis-be-hvdp-nb-pphv-eng.php

main points:
  1. The scaled approached defined HVDS does not apply to veterinary or biological drug products.
  2. Change in acceptance criteria based on variability:
For human pharmaceutical drugs the following comparative bioavailability standards should be met:
  1. The 90% confidence interval of the relative mean AUC of the test to reference product should be within the following limits:
    1. 80.0%–125.0%, if sWR ≤0.294 (i.e., CV ≤30.0%);
    2. [exp(–0.76sWR) × 100.0%]–[exp(0.76sWR) × 100.0%] if 0.294 <sWR ≤0.534
      (i.e., 30.0% <CV ≤57.40%);
      or,
    3. 66.7%–150.0%, if sWR >0.534 (i.e., CV >57.4%).
  2. The relative mean AUC of the test to reference product should be within 80.0% and 125.0% inclusive;
  3. The relative mean maximum concentration (Cmax) of the test to reference product should be between 80.0% and 125.0% inclusive.

With Regards,
Vishal Nakrani


Edit: THX for posting! Category changed. [Helmut]
jag009
★★★

NJ,
2016-04-20 23:22
(2898 d 10:48 ago)

@ vish14184
Posting: # 16227
Views: 4,627
 

 Canada HVDS update

Thanks!

So they allow a partial replicate as well? The Same as FDA :-|

John
Helmut
★★★
avatar
Homepage
Vienna, Austria,
2016-04-21 02:43
(2898 d 07:28 ago)

@ jag009
Posting: # 16229
Views: 4,909
 

 at best half baked

Hi John,

❝ So they allow a partial replicate as well? The Same as FDA :-|


You used the wrong emoticon. Correct: :-(
Replicate designs are generally acceptable for HC:

Replicated cross-over designs may also be used, where the formulations are tested more than once in the same subjects.


After last June’s meeting László wrote to me “One step ahead, three steps back!”

[image]Some thoughts:
  • The EMA’s upper cap at CVwR 50% (i.e., scaling ends at expanded limits of 69.84 – 143.19%) is arbitrary but at least we have some empiric evidence that it “works” since an acceptance range of 70 – 143% for Cmax (only!) was used in the EU in the 1990s. I don’t think that such an AR was ever acceptable for AUC (very rarely 75 – 133%).

  • Where does HC’s upper cap at CVwR 57.40% come from? In the June 2015 proposal it was 50%. A yellow compromise somewhere in between the EMA’s and the FDA’s “implied BE limits” of 62.11 – 161.01% to get “nice” numbers for the expanded limits of 66.7 – 150.0%?
       round(100*exp(c(-1, +1)*0.76*sqrt(log(0.574^2+1))), 1)

  • I don’t like HC’s strategy of less significant digits than other agencies use. Remember NTIDs? Everywhere else the AR is 90.00 – 111.11% but in Canada (for “critical dose drugs”) it is 90.0 – 112.0% (Eric Ormsby: “More convenient and easier to remember”).
    Same here: 100/0.667  150.0.

  • Hip hip hooray, a mixed effects model! Splendid, I like it.
    • By definition the cross-over design is a mixed effects model with fixed and random effects. […] If the mixed model approach is used, parameter constraints should be defined in the protocol. Higher order models must be analysed with the mixed model approach in order to estimate random effects properly.
    Partial replicate? You know what might happen! The EMA in their Q&A-document give the RTRT|TRTR and the partial replicate as examples but accept the RTR|TRT as well. HC: “Either RTR, TRR, RRT or TRTR, RTRT”. Nothing else. Good morning?
    At least no SAS-code is given. Hence, nothing speaks against using FA0(1). However, I still hold that the partial replicate is a lousy design.

  • I expect an inflation of the Type I Error very similar to the EMA’s ABEL in the critical region around CVwR 30%. Well done! Papers1,2 published in US-journals ignored out of principle? OK, maybe only Canadian ones count? The two Lászlós reported3 for CVwR 30% a Type I Error of 6.98% already back in 2009…

  1. Wonnemann M, Frömke C, Koch A. Inflation of the Type I Error: Investigations on Regulatory Recommendations for Bioequivalence of Highly Variable Drugs. Pharm Res. 2015;32(1):135–43. doi:10.1007/s11095-014-1450-z.
  2. Muñoz J, Alcaide D, Ocaña J. Consumer's risk in the EMA and FDA regulatory approaches for bioequivalence in highly variable drugs. Stat Med. (early view 28 Dec 2015). doi:10.1002/sim.6834.
  3. Endrényi L, Tóthfalusi L. Regulatory Conditions for the Determination of Bioequivalence of Highly Variable Drugs. J Pharm Pharmaceut Sci. 2009;12(1):138–49. [image] free resource.

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