Bioequivalence and Bioavailability Forum

Simulations highly recommended [Two-Stage / GS Designs]

posted by Helmut  – Vienna, Austria, 2024-01-05 13:40 (373 d 14:37 ago) – Posting: # 23820
Views: 7,005

Hi Achievwin,

❝ I am thinking of using two stage approach for a parallel BE study (in patients) is there an accepted procedure for sample size calculations? at stage 1 and stage 2?

In general I recommend to perform the first stage in a sample size which gives you reasonably high power to pass already. The second stage is then only a kind of ‘safety net’ if you fail in the first.

❝ Any instances where FDA accepted a two stage design methodology for calculating samples size for stage 2 after reviewing stage 1 results?

It was outlined in a presentation »Uses of Adaptive Design Approach for Generic Bioequivalence Study Submitted in FDA« by Xiaojian Jiang (Deputy Director Division of Bioequivalence II, Office of Bioequivalence, Office of Generic Drugs) at the 5^th GBHI (Amsterdam. 28 Sep 2022).

The relevant points:

• FDA will accept appropriately designed BE studies that are scientifically justified
  
  • Published literature in peer-reviewed journals in which the applicant’s proposed approach is validated
    
  • Simulation results meeting desired criteria (e.g., the Type I error probability of the proposed approach is controlled at the nominal level of 0.05 for a BE test
• The decision to use or not use adaptive design is at the applicant’s discretion
  
• Applicants are encouraged to interact with the agency early to discuss their proposed adaptve designs
  
• 14 ANDAs submitted to the FDA using two-stage adaptive design approach January 1996 to December 2020
  • Adaptive design has been used for both cross-over study and parallel study
    
  • Majority of the studies (10 ANDAs) were found acceptable

(my emphases)
If you give me your current email address, I will send you the presentation.

Practically for parallel designs simulations are mandatory because:

1. The number of subjects in the T- and R-groups (in both stages) will be different due to dropouts.
   
2. Variances likely will be different; hence the Welch-Satterthwaite test instead if the common t-test (which is liberal in these cases) has to be used.
   
3. Fine for the FDA because no specific statistical model is specified by the agency.

Simulations can be performed in the -package Power2Stage, function power.tsd.p().
Start with a reasonably narrow grid of n₁ / CV₁ combinations to find a – preliminary – adjusted α which controls the Type I Error. Repeat with some scenarios based on the worst case expected dropout rate (same for T and R, all under T – none under R and vice versa), different CVs (CV_T < CV_R, CV_T > CV_R). If the Type I Error is still controlled in all scenarios, fine. If not (likely), adjust more.

One of mine. α_adj 0.0274, validated for n₁ 124–250, homoscedastic CV 50% (our best guess), heteroscedastic (variance ratios 1:4 to 4:1). Maximum empirical Type I Error 0.04987:

32 pages report with justification, methods, all results, scripts to reproduce them. Not accepted by the EMA because “we don’t like (‼) simulations”…

—
Dif-tor heh smusma 🖖🏼 Довге життя Україна! 
Helmut Schütz


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Complete thread:

• Parallel Group Adaptive Designs Alex 2023-12-22 10:08 [Two-Stage / GS Designs] 
  • Strong Type I Error control + CI: Not yet… Helmut 2023-12-22 12:01
    • Strong Type I Error control + CI: Not yet… Alex 2024-01-08 16:22
      • Strong Type I Error control + CI: Not yet… Helmut 2024-01-09 09:48
    • Strong Type I Error control + CI: Not yet… roman_max 2024-04-04 15:18
      • Parallel design: Only simulation-based methods so far Helmut 2024-04-04 20:16
        • Parallel design: Only simulation-based methods so far roman_max 2024-04-15 21:46
  • Parallel Group Adaptive Designs Achievwin 2024-01-05 11:53
    • Simulations highly recommendedHelmut 2024-01-05 12:40
      • Simulations highly recommended Achievwin 2024-01-08 16:55
        • Simulations mandatory Helmut 2024-01-09 09:31
          • Simulations mandatory Achievwin 2024-01-09 21:11
            • Reviews are confidential Helmut 2024-01-09 22:10
              • Reviews are confidential Achievwin 2024-01-19 15:11
                • Not accepted and for a reason… Helmut 2024-04-04 20:22
                  • Quod licet Iovi mittyri 2024-04-05 20:33
                    • Non licet bovi Helmut 2024-04-05 21:50
                      • Non licet bovi mittyri 2024-04-05 22:21
                        • Quod licet bove? Helmut 2024-04-06 07:21