Bioequivalence and Bioavailability Forum

Study costs: Replicate vs. 2×2×2 [Regulatives / Guidelines]

posted by Helmut  – Vienna, Austria, 2017-03-20 14:12 (2593 d 01:53 ago) – Posting: # 17169
Views: 23,718

Hi ElMaestro & John,

❝ ❝ My concensus still would be to proceed with RSABE approach since the it is a mixed approach which allows both RSABE(if Ref SD<0.294) and ABE analysis(if Ref SD>0.294)

❝ That's valid, but if you are not really sure if you are just "borderline" then the additional overhead associated with the replicated design may not be worth it. You find an intra-CV_R of 31%, and you scale the limits a wee bit etc. But the price you paid for this moderate scaling option could be much higher than you'd be paying for a conventional 222BE trial with a few extra volunteers.

I lean towards John’s idea. Say you estimated the 31% from a previous 2×2×2 study in 40 subjects and assume that CV_wR=CV_wT=CV_w. The 95% CI of the CV is 25.1–40.6%. Hence, in the best case (high CV_wR) the FDA’s implied BE-limits would be 70.58–141.69%. That’s rather substantial.

❝ Would be interesting to discuss an objective function here

Some ideas: The number of treatments in a 2×2×4 study is roughly the same as in a 2×2×2 study – if we don’t plan for reference-scaling (which I likely would do in a borderline case).

• Equal costs
  • Design & logistics,
    
  • Ethics committee,
    
  • Medical writing,
    
  • Consumables (clinics, bioanalytics),
    
  • Sample shipment if applicable,
    
  • Biostatistics.
• Lower costs
  • Screenings & post-study exams,
    
  • Subjects’ remuneration (though higher for the individuals due to more samples, extended hospitalization).
    
• Higher costs
  • Clinics,
    
  • Analytics (not necessarily: Roughly the same number of samples but might take longer if a batch size exceeds a working day).

I would not be worried about the higher chance of dropouts in the replicate study. The impact on power is low (unless the drug is nasty and dropouts are caused by AEs).
Calculation of costs is complicated (fixed & variable costs, blahblah). In my CRO we had a spreadsheet with 100 rows… Had a quick look (19 samples / period, last sampling 16 hours; 2×2×2 in 42 subjects vs. 2×2×4 in 22). The replicate design would be ~4% cheaper. If you hope for RSABE (for CV_wR 31% 18 subjects instead of 22 for ABE) the reduction in costs would be ~12%.

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


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Complete thread:

• Highly Variable Drug BE Justification jag009 2017-03-20 04:42 [Regulatives / Guidelines] 
  • Highly Variable Drug BE Justification ElMaestro 2017-03-20 06:55
    • Study costs: Replicate vs. 2×2×2Helmut 2017-03-20 13:12
      • Study costs: Replicate seems to be cheaper VStus 2017-03-21 12:49
        • Study costs: Replicate seems to be cheaper Dr_Dan 2017-03-21 13:06
          • Study costs: Replicate seems to be cheaper Helmut 2017-03-21 14:50
            • expected power d_labes 2017-03-21 15:16
            • Doesn't hurt! VStus 2017-03-23 14:24
      • Study costs: Replicate vs. 2×2×2 mahmoud-teaima 2017-03-23 08:17
      • Study costs: Replicate vs. 2×2×2 M.tareq 2017-05-07 21:21
        • Replicate vs. 2×2×2 (ethics?) Helmut 2017-05-08 14:21
          • Replicate vs. 2×2×2 (ethics?) nobody 2017-05-08 14:52
            • Applicability of reference-scaling Helmut 2017-05-10 14:10
          • Replicate vs. 2×2×2 M.tareq 2017-05-14 23:04
            • Replicate vs. 2×2×2 Helmut 2017-05-15 19:07
              • Replicate vs. 2×2×2 M.tareq 2017-05-15 21:02
              • Regulators view of HVD drugs DavidManteigas 2017-05-16 12:41
                • Regulators view of HVD drugs Helmut 2017-05-16 15:01
                • What's the problem? ElMaestro 2017-05-17 03:30
                  • What's the problem? nobody 2017-05-17 07:48
                    • What's the problem? nobody 2017-05-17 09:31
                      • What's the problem? DavidManteigas 2017-05-17 11:25
                        • What's the problem? ElMaestro 2017-05-17 12:07
                          • What's the problem? kumarnaidu 2017-07-11 14:43
                            • What's the problem? ElMaestro 2017-07-11 14:56