Bioequivalence and Bioavailability Forum

Beware of Add-on Studies! [Study Assessment]

posted by Helmut – Vienna, Austria, 2013-05-27 15:51 (4776 d 20:39 ago) – Posting: # 10663
Views: 17,268

Dear Xipei,

shit happens. You can’t simply add subjects to a failed study since the patients’s risk will not be maintained at ≤5%. Translating statistics into simple words: You have already “consumed” the entire 5% in the first study and nothing is “left” for the add-on.

Some remarks for the future:

Always plan for the PK metric with the higher CV (in most cases C_max). It doesn’t make sense to plan for BE of AUC (CV 41%) since you will fail with C_max (CV 65%). With your CVs you would need 70 subjects for AUC but 154 for C_max. If you run the study in 70 subjects, power to show BE for C_max would be only 38%! Try power.TOST(CV=0.65, n=70).
Allow for a safety margin. The CV is only an estimate carrying some degree of uncertainty (depending on the sample size). You can get an upper confidence limit of the CV from PowerTOST (df for a 2×2 cross-over = n-2). With your CV of C_max:
CVCL(CV=0.65, df=21) lower CL upper CL 0.000000 0.9452972 ← nightmare!
If you want to perform a Two-Stage method in the next study, you have to prespecify this intention in the protocol and state the framework you want to follow.
With one exception¹ all Two-Stage methods^2–4 are using a fixed T/R-ratio (0.95 or 0.90) – not the ratio observed in stage 1. Note that Karalis & Macheras limit the total sample size with 150 subjects. It will be a close shave even if you find exactly the same results like in the failed study. Try sampleN.TOST(alpha=0.0294, theta0=1.02, CV=0.65). If either the ratio or the CV is only 1% worse you will fail in stage 1 (since n_total >150).
In sample size re-estimation for stage 2 always use the adjusted α (e.g., 0.0294 for Potvin’s methods).
PowerTOST gives the total sample size – not sample sizes per sequence. See help(sampleN.TOST).
IMHO with such high CVs Two-Stage designs do not make any sense. Have a look at Potvin’s Table II for a CV of 100%: With already 60 subjects in the first stage you always will have to proceed to the second stage. Average total sample size is 359 (95% CI: 258–474). Crazy.
Talk to your agency whether reference-scaling is acceptable. If yes, ask which method they would accept (FDA’s or EMA’s). You would need a replicate design (preferably a full replicate: RTR|TRT or RTRT|TRTR). For the required sample sizes see sampleN.RSABE (FDA) and sampleN.scABEL (EMA).
Learn from the failed study. Did you sample frequently enough in order to “catch” C_max in all subjects? This is a very important aspect especially for delayed release formulations.

Maybe you find these presentions useful: Two-Stage Designs, Reference-Scaled ABE. Good luck.

Karalis V, Macheras P. An Insight into the Properties of a Two-Stage Design in Bioequivalence Studies. Pharm Res. 2013;30(7):1824–35. doi 10.1007/s11095-013-1026-3
Potvin D et al. Sequential design approaches for bioequivalence studies with crossover designs. Pharm Stat. 2008;7(4):245–62. doi 10.1002/pst.294
Montague TH et al. Additional results for ‘Sequential design approaches for bio-equivalence studies with crossover designs’. Pharm Stat. 2011;11(1):8–13. doi 10.1002/pst.483
Fuglsang A. Sequential Bioequivalence Trial Designs with Increased Power and Controlled Type I Error Rates. AAPS J. 2013;15(3):659–61. doi 10.1208/s12248-013-9475-5

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Helmut Schütz

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Complete thread:

Add more subjects after a failed BE study of a HVD wxp 2013-05-27 10:34
- bad luck Dr_Dan 2013-05-27 12:28
  - bad luck wxp 2013-05-27 14:19
- Beware of Add-on Studies!Helmut 2013-05-27 13:51
  - Beware of Add-on Studies! Shuanghe 2013-05-27 15:59
    - Oh wow! Helmut 2013-05-27 16:21
      - The same criterion of Cmax in China now wxp 2013-05-28 06:10
        
        SFDA ⇒ CFDA Helmut 2013-05-28 13:02
        
        Helmut, updated Chinese BE guideline here Shuanghe 2013-06-14 11:05
        
        BE in Chinese Pharmacopoeia Helmut 2013-06-14 14:22
        
        BE in Chinese Pharmacopoeia Shuanghe 2013-06-14 14:56
        
        BE in Chinese Pharmacopoeia Helmut 2013-06-14 16:11
  - Add more subjects after a failed BE study of a HVD wxp 2013-05-28 05:13
    - Still many subjects… Helmut 2013-05-28 12:56

Beware of Add-on Studies! [Study As­sess­ment]

Complete thread:

Beware of Add-on Studies! [Study Assessment]