Dr Naghma Hashmi
☆

Pakistan,
2016-03-18 11:34
(1857 d 19:23 ago)

Posting: # 16116
Views: 8,999

## Bioequivalence study of Sofosbuvir [Regulatives / Guidelines]

Hi

Can anyone guide me for the bio-equivalence study of Sofosbuvir? should it be conducted as per WHO Guidance Document 25 March 2015, Notes on the design of bioequivalence study: Sofosbuvir

I have few queries regarding this document
1. Bioequivalence will be plan in fed state or fasting?
My recommendation is of fasting as according to
Effect of Food (Prescribing information)
Relative to fasting conditions, the administration of a single dose of SOVALDI with a standardized high fat meal did not substantially affect the sofosbuvir Cmax or AUC0-inf. The exposure of GS-331007 was not altered in the presence of a high-fat meal. Therefore, SOVALDI can be administered without regard to food.

2. should the sofosbuvir metabolite also analyzed?
3. What will be the minimum sample size?

Thanks

Dr. Hashmi
Technical Coordinator
Helmut
★★★

Vienna, Austria,
2016-03-18 13:23
(1857 d 17:35 ago)

@ Dr Naghma Hashmi
Posting: # 16117
Views: 8,101

## Which “target regulation”?

Hi Naghma,

without information about the country/regulation you are aiming at, it is difficult to answer. The primary purpose of the WHO’s guidelines is to support regulatory agencies of countries which don’t have their own ones so far – not applicants. Hence, the WHO’s GLs are often ambiguous (listing different approaches to select from). Until you find out which path “your” regulator will follow, picking out something from the WHO’s GLs is risky. The GL you are referring to is a good example.

» 1. Bioequivalence will be plan in fed state or fasting?

See what is stated in the section “Pharmacokinetics of Sofosbuvir” about the food effect, especially

[…] administration is recommended with food in the Summary of Product Characteristics approved by the EMA, although it can be taken irrespective of meals according to the Product Labelling approved by the FDA.

(my emphases)
You were quoting the (August 2015) label of the FDA’s RLD. Since for IR products the fasting state is considered more sensitive to detect differences between formulations – and the reference product could be administered regardless the pranial state – you would be right. However, the FDA’s product-specific guidance (June 2015) recommends two studies (fasting, fed).*
If your “target regulation” follows the WHO’s product-specific GL or the EMA’s general BE-GL (administration according to the SmPC), only one study in fed state.*

» 2. should the sofosbuvir metabolite also analyzed?

No (acc. to WHO, FDA, EMA).

» 3. What will be the minimum sample size?

Depends on which minimum power is acceptable for you. Many GLs recommend 80 – 90%.
The WHO’s GL states that Cmax might be highly variable (CVwR 54%) in fed state. If your target regulation accepts reference-scaling (widening of the acceptance range) you could follow the EMA’s approach given in the BE-GL (Average Bioequivalence with Expanding Limits, ABEL). If not, the common acceptance range of 80 – 125% for ABE is applicable. For HVD(P)s a T/R-ratio of not “better” than 0.90 should be assumed (regardless whether you intent to design the study for evaluation by ABE or ABEL). If you plan for 80% power this translates into the following sample sizes:

  design     ABE  ABEL ────────────────────── RT|TR        230   NA  RTRT|TRTR    116   28  RTR|TRT      172   44  RRT|RTR|TRR  174   42 

If your regulation accepts the FDA’s Reference-scaled Average Bioequivalence (RSABE) that would mean:

   design     RSABE ────────────────── RTRT|TRTR     22   RTR|TRT       34   RRT|RTR|TRR   30  

Note that AUC is not highly variable (CVwR 10%) and you have to evaluate it for ABE. In some cases the FDA’s mixed effects model fails to converge in the partial replicate design (RRT|RTR|TRR) – you have done the study, but the software cannot give you a result. Therefore, avoid this design.

• BTW, this makes an interesting story. Obviously the originator showed in one study lacking food effects (which lead to the FDA’s label) and in another one a 1.8fold increase in AUC (which lead to the EMA’s SmPC). Strange, politely speaking. The FDA seems to be aware of that, since asking in the product-specific guidance for two studies. If the FDA trusts in the study which lead to approval why are they asking for a fed study as well? If they have other information (which contradicts the approved label) why they don’t ask the originator for the data? Given the low variability of AUC no statistics is needed to see a significant food effect with a PE of ~180%. Regulators are a strange bunch of people sometimes.
According to the Australian PAR the originator performed two food effect studies:

The findings of both were in agreement; compared with the fasted state, food, specifically a high-fat meal, resulted in a slower rate of absorption of SOF [Sofosbuvir] (high-fat meal vs. fasted; prolonged Tmax: 1.5 vs. 0.5 hrs) with no substantial alteration in the extent of absorption (high-fat meal vs. fasted; mean AUCinf increased 67–91%). […] The equivalence criterion for a lack of food effect was not met; however, Cmax decrease was not considered clinically significant. Moreover, whilst SOF dosing in Phase 2 and 3 clinical studies was recommended without regard to food, in reality, SOF when co-administered with RBV [Ribavirin] in Phase III studies, was dosed with food, as required in the RBV prescribing information.

(bold in the original)
Fascinating that an increase of AUC by ~80% was judged Down Under to be not substantial

Dif-tor heh smusma 🖖
Helmut Schütz

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

Pakistan,
2016-03-19 09:59
(1856 d 20:58 ago)

@ Helmut
Posting: # 16118
Views: 7,666

## Bioequivalence study of Sofosbuvir

Hi

Thanks for a comprehensive reply, We are focusing WHO regulations and as per WHO there is another approach for highly variable drug (HVD) i.e. sequential design approach

Some regulatory agencies (Canada [2], Japan [3], and the World Health Organization (WHO) [4]) permit ‘add-on’ designs. With these designs, if the failure to declare the two formulations bioequivalent appears to be due to insufficient power, it is permissible to add additional subjects and pool results of the additional subjects with the original trial. For example, the WHO and Japanese guidelines allow an add-on study provided the additional sample size is at least 50% of that of the original study. Potvin D, Diliberti CE, Hauck WW, Parr AF, Schuirmann DJ, and RASmith: Sequential design approaches for bioequivalence studies with crossover designs; Pharmaceut Statist 7/4, 245–62 (2008)

Reference WHO

If the bioequivalence study was performed with the appropriate number of subjects but bioequivalence cannot be demonstrated because of a larger than expected random variation or a relative difference, an add-on subject study can be performed using not less than half the number of subjects in the initial study, provided this eventuality was anticipated and provided for in the study protocol. Combining data is acceptable only in the case that the same protocol was used and preparations from the same batches were used. Add-on designs must be carried out strictly according to the study protocol and SOPs, and must be given appropriate statistical treatment

my query: Which one will be the most appropriate approach for BE of Sofosbuvir?

1. Sequential Design Approach (initially conducted on 24 subjects and if bioequivalence cannot be demonstrated than an add-on subject will be done as per guideline)

OR

2. Reference Scaled Average Bioequivalence (RSABE), a full replicate 2 × 4 cross-over design Which can be conducted on minimum of 22 subjects?

Thanks

Dr. Hashmi
Technical Coordinator
Helmut
★★★

Vienna, Austria,
2016-03-19 17:03
(1856 d 13:55 ago)

@ Dr Naghma Hashmi
Posting: # 16120
Views: 7,930

## No “WHO regulation”!

Hi Naghma,

» Thanks for a comprehensive reply,

You are welcome.

» We are focusing WHO regulations …

Did you bother reading my entire post? There are nothing like WHO “regulations”. It might well be that you pick something out of the WHO’s GLs and at the end of the day the agency of your country will not accept it.

» … and as per WHO there is another approach for highly variable drug (HVD) i.e. sequential design approach
» Some regulatory agencies (Canada, Japan, and the World Health Organization (WHO)) permit ‘add-on’ designs.

If the bioequivalence study was performed with the appropriate number of subjects but bioequivalence cannot be demonstrated because of a larger than expected random variation or a relative difference, an add-on subject study can be performed using not less than half the number of subjects in the initial study, provided this eventuality was anticipated and provided for in the study protocol. […] Add-on designs must be carried out strictly according to the study protocol and SOPs, and must be given appropriate statistical treatment.

Which translates into:
• The CVwR of Cmax given in the SOF-GL is based on numerous studies and hence, can be considered reliable. An “appropriate number of subjects” means the sample size which as expected will result in sufficient power (i.e., ≥80%). As stated in my previous post a 2×2 crossover (ABE) would require 230 subjects.
• “Appropriate statistical treatment” is the crucial point. You must not (‼) evaluate the study with a nominal α of 0.05 (i.e., the conventional 90% CI) and afterwards add more subjects and pool the data. The consumer’s risk will not be preserved (= inflation of the Type I Error of more than 50%). This was shown for the regulations of Japan1,2 and for the ones of Argentina, Korea, and Mexico.2 Canada2 had a similar approach but it is not acceptable any more. In these add-on designs (second group ½, ¾, or equal to the first group) Bonferroni’s 0.025 (95% CI) would preserve the consumer risk. Note that the sizes of the first and second groups are fixed and have to be given already in the protocol. Since the evaluation will be done based on 95% CIs it would increase the sample size of the first group (n1) to 292 subjects. Say you stated that the second group will be ½n1. Even if you miss BE by a very small margin, you would have to perform the second part full throttle in yet another 146.
That’s something nobody likes. Better approaches are a “classical” group sequential design (fixed total sample size and one interim analysis) or adaptive two-stage sequential designs (fixed stage 1 group size with sample size re-estimation in the interim).
Now for the bad news: All this stuff so far has only be explored for 2×2 crossovers and parallel designs for conventional ABE (no replicate designs for RSABE or ABEL; see this thread). In your case the sample sizes would be a nightmare.
Note that add-on designs were dropped in the WHO’s working draft (2014) and two-stage designs suggested instead. Similar in the current (2015) version.* Although a paper was published3 for an expected T/R-ratio of 0.90 and high variability, it does not cover such extreme sample sizes. If one wants to walk that stony path, simulations have to be performed to demonstrate that the chosen adjusted α preserves the patient’s risk.

» my query: Which one will be the most appropriate approach for BE of Sofosbuvir?
»
» 1. Sequential Design Approach (initially conducted on 24 subjects and if bioequivalence cannot be demonstrated than an add-on subject will be done as per guideline)

Forget it. See above. BTW, 24 subjects would not be “appropriate” anyway. n1 292 in the obsolete add-on (α 0.025) and ~120 in the two stage design (α 0.028). If you start a TSD in a too small sample size, you will be penalized (high expected average total sample size E[N]). Likely you will have to proceed to the second stage since the power to show BE already in the first stage is low:

 n1  E[N]  in stage 2  power1  24  282     99.6%      0.4%  48  262     89.2%     10.8%  72  228     72.8%     27.2%  96  215     62.7%     37.3% 120  211     54.8%     45.2% 144  212     47.9%     52.1% 168  217     41.6%     58.4% 192  226     35.9%     64.1% 216  238     30.6%     69.3% 240  252     25.3%     73.7%

» OR
»
» 2. Reference Scaled Average Bioequivalence (RSABE), a full replicate 2 × 4 cross-over design Which can be conducted on minimum of 22 subjects?

How shall I know? Although I’m a gifted tassologist and fortune teller, my crystal ball is in the laundry. Otherwise it easily could whisper in my ear what your regulators will accept.
You should ask them, not me.

Scientifically only RSABE (n = 22) or ABEL (n = 28) makes sense.

References:
1. Wonnemann M, Frömke C, Koch A. Inflation of the Type I Error: Investigations on Regulatory Recommendations for Bioequivalence of Highly Variable Drugs. Pharm Res. 2015;32(1):135–43. doi:10.1007/s11095-014-1450-z
2. Schütz H. Two-stage designs in bioequivalence trials. Eur J Clin Pharmacol. 2015;71(3):271-81. doi:10.1007/s00228-015-1806-2
3. Montague TH, Potvin D, DiLiberti CE, Hauck WW, Parr AF, Schuirmann DJ. Additional results for ‘Sequential design approaches for bioequivalence studies with crossover designs’. Pharm Stat. 2012;11(1):8–13. doi:10.1002/pst.483

• Don’t estimate the sample size of the second stage based on the point estimate of the first stage as stated in the GL. That’s nonsense. Use only the CV. Why? See Ref. 2.

Dif-tor heh smusma 🖖
Helmut Schütz

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

Pakistan,
2016-03-22 03:51
(1854 d 03:07 ago)

@ Helmut
Posting: # 16125
Views: 7,423

## No “WHO regulation”!

Hi

By "WHO regulations" mean that our regulatory body follow WHO guidelines, sorry for the inappropriate statement which was mistranslated.

Secondly, objective is to get honorable forum member's scientific comments over the issue (not to adopt crystal ball theory) in order to get a reasonable sample size so that regulatory body could be justified on scientific ground.

Anyhow thanks for sharing of knowledge.

Dr. Hashmi

Edit: Post moved and subject line changed. [Helmut]
Helmut
★★★

Vienna, Austria,
2016-03-22 13:06
(1853 d 17:52 ago)

@ Dr Naghma Hashmi
Posting: # 16128
Views: 7,351

## Science ≠ truth ∧ regulations ≠ science

Hi Naghma,

» By "WHO regulations" mean that our regulatory body follow WHO guidelines, sorry for the inappropriate statement which was mistranslated.

Your regulatory body (Pakistan’s?) cannot “literally follow” the WHO guidelines. The WHO’s GLs in many cases offer the respective agency a series of approaches followed by other regulations to select from. You can only guess what they might prefer (or even worse: solely accept). Therefore, ask them. I’m certain they will not bite.

When it comes to the question of fasting/fed of Sofosbuvir I would say that the design primarily depends on what the label/SmPC of the orginator’s formulation approved according to your jurisdiction*1 states. Secondly, if it’s similar to the US RLD’s in regard to intake with food, still the FDA’s product-specific guidance should be taken into account. Hence:
• If like the European SmPC: One study fed.
• If like the US RLD’s label: Two studies (fasting/fed).

» Secondly, objective is to get honorable forum member's scientific comments over the issue (not to adopt crystal ball theory) in order to get a reasonable sample size so that regulatory body could be justified on scientific ground.

I wrote already that in my opinion reference-scaling for Cmax is the most reasonable approach. The WHO’s SOF-guidance starts with conventional (unscaled) ABE:
• The 90% confidence interval of the relative mean Cmax of the test to reference product should be within 80–125%.
If (!) your regulators insist in ABE1, you would need hundreds of subjects.
However, in the next paragraph of the GL the EMA’s ABEL is mentioned as an alternative (please note the tentative wording: “might be acceptable”). If (!) your regulators accept this approach1, sample sizes for desired levels of power would be:

  design     80% 85% 90% ──────────────────────── RTRT|TRTR    28  34  38  RTR|TRT      44  50  60  RRT|RTR|TRR  42  48  57 

Study costs are closely related to the number of administrations/biosamples. Considering the 80% power variant we have 28×4=112 administrations in the 4-period full replicate, 44×3=132 in the 3-period full replicate, and 42×3=126 in the partial replicate. Hence, the 4-period full replicate is the winner. If you are not limited by the sampling volume (check with the bioanalyst) that’s the way to go. You might expect a higher dropout-rate in the 4-period replicate than in the two others but the impact on power is limited.
Please read the applicable section of the EMA’s BE-GL. You have to justify in the protocol that widening the acceptance range of Cmax will not impose a risk on the patients (safety, efficacy) and that a high CVwR observed in the study is a reliable estimate (not caused by “outliers”). That’s different to the FDA’s RSABE, where such conditions are not required.

A final note:
In the forum we are discussing both scientific and regulatory approaches – which are not necessarily identical. Even if a seemingly unambiguous2 GL exists, it is still open to interpretation. To give an example:
• The EMA’s GL is applicable in 31 countries (28 EU members states + Norway, Iceland, Lichtenstein).
Two-Stage Designs are acceptable according to the GL.
• Study protocol submitted and approved in “Reference Member State” A (GL & science).
• Study performed and its design (!), the method of evaluation, and outcome not accepted by “Concerned Member State” B (interpretation).
Too bad. Deficiency letters of the second degree. Couple of months lost.

───────────
1. I don’t have the slightest idea.
2. If your regulators follow “all-encompassing” GLs – like the WHO’s – it would be extremely risky to either select something you prefer (even if scientifically just) or presume what they might accept. Talk to them!
We have six members in the forum. Until someone of them post their experiences with your agency about acceptance of ABEL you will be fishing in troubled waters.

Dif-tor heh smusma 🖖
Helmut Schütz

The quality of responses received is directly proportional to the quality of the question asked. 🚮
Science Quotes
nobody
nothing

2016-04-27 07:15
(1817 d 23:43 ago)

@ Helmut
Posting: # 16245
Views: 6,030

## Which “target regulation”?

» Fascinating that an increase of AUC by ~80% was judged Down Under to be not substantial

It's originator, stupid! Things are somewhat different in the non-generic world.

Kindest regards, nobody