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Back to the forum  Query: 2017-06-27 02:11 CEST (UTC+2h)
 
VSL
Junior

India,
2017-06-05 20:34

Posting: # 17444
Views: 683
 

 General BE topics [Design Issues]

Dear all,
Could you please give your views on the following topics?
  1. Half-life: Is half life independent of formulation effect? I mean, IR vs. MR products of the same substance. I am asking as protocol design depends a lot on it.
  2. High variable drug substance vs. High variable drug products, Is there is any demarcation for protocol design aspects?
  3. If there are two strengths, say, tablet, 10 and 20 mg and 20 mg is RLD. The company wishes to market only 10 mg strength but 10 mg is not RLD. What should be RLD in BE study? Is comparison of 10mg x2 tablets (test) vs. 20mg RLD right?
  4. What is the minimum sample size for parallel group BE study?
  5. For endogenous substances, how many and for how much time duration (-48 hours etc.) baseline samples should be collected?
  6. Why passing ratio is high for BE studies (especially pivotal studies) conducted in India compared to foreign countries? Is there any geographical/ethnic/staff expertise/deliberate effect?
  7. For some therapeutic class drugs BE study, I have not seen any PD effect. Example, For Antihypertensive drugs, no change in BP in vital recordings even at/around Cmax. Please explain.

Thanks and Regards,
VSL
ElMaestro
Hero

Denmark,
2017-06-06 00:20

@ VSL
Posting: # 17445
Views: 597
 

 General BE topics

Hello VSL,


» 1 Half-life: Is half life independent of formulation effect? I mean, IR vs. MR products of the same substance. I am asking as protocol design depends a lot on it.

Half-life can refer to the intrinsic half-life, or to the apparent half-life (what you observe in practice, given the formulation etc). The latter is what guides it.

» 2. High variable drug substance vs. High variable drug products, Is there is any demarcation for protocol design aspects?

No. Observed CV is what matters.

» 3. If there are two strengths, say, tablet, 10 and 20 mg and 20 mg is RLD. The company wishes to market only 10 mg strength but 10 mg is not RLD. What should be RLD in BE study? Is comparison of 10mg x2 tablets (test) vs. 20mg RLD right?

2x10mg, probably, but you should contact OGD.

» 4. What is the minimum sample size for parallel group BE study?

Wrong question. You will most likely not show BE in any parallel study at the minimum sample size. If you try, it might be unethical.

» 5. For endogenous substances, how many and for how much time duration (-48 hours etc.) baseline samples should be collected?

There is no rule if it isn't mentioned in the product-specific guidance.

» 6 Why passing ratio is high for BE studies (especially pivotal studies) conducted in India compared to foreign countries? Is there any geographical/ethnic/staff expertise/deliberate effect?

Wow, this one is toxic. :-D:-D:-D
Perhaps companies are powering their studies higher e.g. 90% rather than 80% when conducting them in India??
VSL, sometimes failure is not an option and sometimes shortcuts are taken to cut down effort/cost or to stay within agreed timelines. Google Semler, GVK Bio, MTR... I am sure you know the issues already.
Anyways, I never saw official passing statistics for India compared to other places. Can you show a reference?

» 7. For some therapeutic class drugs BE study, I have not seen any PD effect. Example, For Antihypertensive drugs, no change in BP in vital recordings even at/around Cmax. Please explain.

Some modern antihypertensives often have little effect in healthy volunteers. They are very, very safe. E.g. Telmisartan, Perindopril etc. But be aware you have nothing to compare with in BE trials since both arms are active and no placebo recording is available. If there is an effect you won't see it. Comparing BP at baseline to BP at Tmax is not particularly informative.

Have a good day.

I could be wrong, but…


Best regards,
ElMaestro

- since June 2017 having an affair with the bootstrap.
Helmut
Hero
Homepage
Vienna, Austria,
2017-06-06 14:24

@ VSL
Posting: # 17452
Views: 536
 

 General BE topics

Hi VSL,

I agree with all of what ElMaestro wrote. Hence, only some more remarks.

» 1. Half-life: Is half life independent of formulation effect? I mean, IR vs. MR products of the same substance.

Without IV data and after a PO dose we can only assume that the apparent half-life = the intrinsic half-life (elimination). This assumption is reasonable for IR products (ka > ke). When you slow down the absorption process you will reach ka = ke or “flip-flop PK”. If you go further (ka < ke) the apparent half-life (now the slowest phase) is no more the intrinsic half-life but absorption. That’s why the EMA (in contrary to IR) for MR products additionally to AUC0–t requires AUC0–∞ and does not allow using a truncated AUC.

» 2. High variable drug substance vs. High variable drug products, Is there is any demarcation for protocol design aspects?

No, but you have to know the drug and your formulation. If the high variability is a property of the drug (HVD) you can design the study as usual (but taking the high CV into account and possibly opt for reference-scaling). If you have to deal with a HVDP it depends. F.i., gastric resistant formulations exhibit a wide range of tmax-values (due to variability in tlag caused by the interplay of the formulation with gastric transit). In such a case you should increase the number of samples in order to “catch” Cmax.

» 5. For endogenous substances, how many and for how much time duration (-48 hours etc.) baseline samples should be collected?

As ElMaestro wrote: No rule rulez. There is a wide range of options.
  • Best case:
    If you know that the baseline is stable it might be sufficient to collect just three samples within one hour before the administration and subtract the mean (I prefer the median) from the profile.
  • Worst case:
    Circadian rhythm and levels of the endogenous compound depend on food. Have a run-in period where you standardize food. Sample an entire “blank” profile before administration and subtract concentrations at corresponding time points.

» 6. Why passing ratio is high for BE studies (especially pivotal studies) …

I have heard that pilot studies never fail. The CROs want to perform the pivotal ones as well.

» … conducted in India compared to foreign countries? Is there any geographical/ethnic/staff expertise/deliberate effect?

Fabricated data, plain fraud, etc. Sorry to say.
One of my clients (her boss’ decision) started to perform studies in India (before mainly in Canada, Central, and Eastern Europe). The company always powered studies to 90%. Since the sample size estimation is based on assumptions and with 90% power one can expect that 10% will fail by pure chance – and that was essentially what she observed in the past. In two years none (!) of the studies performed in India failed. Every study was monitored. No obvious explanation. She was concerned and called me up. Given the number of studies the chance that none failed (Fisher’s exact test) was not significant but scratching the limit.

Absence of evidence is not evidence of absence.    Carl Sagan


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Helmut Schütz 
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VSL
Junior

India,
2017-06-06 19:34

@ Helmut
Posting: # 17455
Views: 507
 

 General BE topics

Dear ElMaestro and Helmut,

Thank you very much for the explanation.

One more question, why regulatory agencies are allowing studies with deliberate high power? I mean, it is forced BE, unethical and violation of Declaration of Helsinki (Human exposure without scientific rationale). There has to be the scientific tradeoff in setting alfa and beta values while calculating sample size rather mere assumption. I have seen post analysis power more than 90% in many studies. If you ask biostatisticians, they say, we don't know, it comes, no justification is required as the study has passed.

Thank you again.
DavidManteigas
Regular

Portugal,
2017-06-12 12:35

@ VSL
Posting: # 17487
Views: 351
 

 General BE topics

Hi VSL,

In my opinion, from my knowledge of the portuguese regulators, there is a lack of members with statistical expertise to properly assess the adequacy of the sample size, or any other question regarding statistical methods, either in Ethics Committees or the regulator.

In my plans for 2018, I will attempt to meet with the portuguese regulator so they can gave me access to their approved studies in bioequivalence in the last years so I can quantify the degree of overpowering of bioequivalence studies when compared to the observed CV and the predicted/guessed/magically obtained predicted CV. My intent is to publish a paper with that information and to sensitize regulators and ethics committees to this issue, which mixes both the sample size calculation and the adequacy of the study design in light of the available information.
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