Bioequivalence and Bioavailability Forum • Between study variability common for HVDs

Between study variability common for HVDs [Regulatives / Guidelines]

posted by Helmut – Vienna, Austria, 2010-08-04 21:45 (5155 d 00:07 ago) – Posting: # 5717
Views: 16,603

Dear ElMaestro, Dan and all!

❝ […] did you receive a deficiency question from module 3 regarding the product's release specifications? After all, this is where the inter-batch variability comes into the picture.

Not necessarily. Dan stated in his post that the drug is highly variable. It’s a common property of HVDs that not only the variance is high, but also the location of the T/R-ratio may vary across studies. If would suggest to have a look at papers by the “Two Lászlós” for further explanations. Remember that the restriction of the point estimate of [0.8-1.25] was introduced by the FDA after long discussions for political reasons [sic!]^* – and copypasted by the EMA. Such a restriction is questionable and not statistically justified. The pivotal studies demonstrated BE, but I would build an argument based on the natural property of the underlying distribution.

The concept of batch-to-batch in vivo BE is only of historical interest. It was discussed at the BioInternational 1994 in Munich and was dropped. Same participants even asked the heretic question whether a product would be still bioequivalent to itself at the end of the shelf-life (don’t ask me how we would store the reference batch for the final BE study: in liquid N₂?).

BTW, I agree with D. Labes’ observations about ref. 1, which was employed in studies 1 & 3.

To quote Leslie Benet’s presentation (FDA/CDER, Pharmaceutical Science Advisory Committee (ACPS) Meeting, October 06, 2006) on the point estimate restriction:

There is no scientific basis or rationale for the point
estimate recommendations
There is no belief that addition of the point estimate
criteria will improve the safety of approved generic
drugs
The point estimate recommendations are only
“political” to give greater assurance to clinicians and
patients who are not familiar (don’t understand) the
statistics of highly variable drugs

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

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes

Complete thread:

inter-batch variability? Dr_Dan 2010-08-04 10:29 [Regulatives / Guidelines]
- inter-batch variability? Pavidus 2010-08-04 11:57
- inter-batch variability? d_labes 2010-08-04 13:58
- inter-batch variability? ElMaestro 2010-08-04 17:09
  - Between study variability common for HVDsHelmut 2010-08-04 19:45
    - Between study variability common for HVDs ElMaestro 2010-08-04 21:01
      - Representative batches? Helmut 2010-08-04 23:42
        
        Representative batches? ElMaestro 2010-08-05 08:40
        
        Representative batches? Helmut 2010-08-05 12:30
        
        Representative batches? Dr_Dan 2010-08-05 08:58
        
        Representative batches? Helmut 2010-08-05 12:45
        
        Confidence intervals vs. point estimators Dr_Dan 2010-08-06 09:55
        
        Confidence intervals vs. point estimators ElMaestro 2010-08-06 12:34
        
        Confidence intervals vs. point estimates Helmut 2010-08-06 13:20
        Confidence intervals vs. point estimators Dr_Dan 2010-08-06 14:44
        
        Confidence intervals vs. point estimators ElMaestro 2010-08-06 15:01
        
        meta analysis? martin 2010-08-06 17:25
        
        meta analysis? ElMaestro 2010-08-06 17:57
        
        meta analysis? Helmut 2010-08-06 18:31
        
        meta analysis? Ohlbe 2010-08-06 23:21
        
        No chance against RMS? Dr_Dan 2010-08-10 12:27
        
        No chance against RMS? ElMaestro 2010-08-10 16:26
  - Batch-to-Batch Pharmacokinetic Variability kumarnaidu 2016-07-20 07:16
    - tlast (Common) Helmut 2016-07-20 10:48
      - tlast (Common) nobody 2019-02-21 15:20
        
        tlast (Common) ElMaestro 2019-02-21 16:32
        
        tlast (Common) nobody 2019-02-21 17:02
        
        tlast (Common) ElMaestro 2019-02-21 18:02
        
        tlast (Common) nobody 2019-02-21 18:17