Bioequivalence and Bioavailability Forum

Hi David & VSL,

sorry for excavating an old thread.

❝ […] 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.

According to Directive 2005/28/EC (6)

Provisions for the functioning of the Ethics Committees should be established in each Member State on the basis of common detailed guidelines, in order to ensure the protection of the trial subject while at the same time allowing a harmonised application in the different Member States of the procedures to be used by Ethics Committees.

Hence, ECs are set up according to National laws. E.g., in Austria acc. to §41 of the Medicines Law (my translation):

• (2) The ethics committee must be composed in a balanced proportion of women and men and at least consist of:
  1. A physician who is entitled to pursue a self-employed profession and is not the investigator,
     
  2. A specialist physician in whose special subject the respective clinical examination falls […] and is the investigator,
     
  3. A representative of the senior service for health care and nursing,
     
  4. A lawyer,
     
  5. A pharmacist,
     
  6. A patient representative,
     
  7. A member of a representative disabled organization as well as a representative of the elderly, who is part of a senior citizens ‘organization in accordance with the Federal Senior Citizens’ Law, BGBl. I No. 84/1998,
     
  8. A person who has biometric expertise and
     
  9. Another person not covered by items 1 to 8, who is responsible for the perception of pastoral affairs or otherwise has the appropriate ethical competence.

Similar in Germany’s Medicines Law §41a(2)

[…] interdisciplinary composition of the ethics committee involving at least one lawyer, one person with scientific or professional experience in the field of ethics in medicine, one person with experience in the field of experimental planning and statistics, three physicians who have experience in clinical medicine, including a specialist in clinical pharmacology or pharmacology and toxicology, as well as a layperson.

Which are the rules for ECs in Portugal? BTW, I know some members of the Portuguese Agency whose knowledge of statistics is excellent.
It can even be that the EC is more knowledgeable than an agency. Happened to me. Joachim Röhmel (one of the pioneers of adaptive designs) is a member of the EC of Berlin. He was very happy with my first study in a Two-Stage Design. Later I learned that the Dutch MEB didn’t like (‼) it.

❝ 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 …

Wow! Do you think that’s possible?

❝ ❝ 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.

❝ … 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.

Is that reasonable? You may fall into the trap of post hoc power.¹ We know that θ₀ and CV used in designing the study are assumptions or, at best, estimates. The applicant might have used conservative values.² If the GMR turns out to be “better”, the CV and/or the dropout-rate lower than expected you will face high post hoc power. But this does not necessarily imply that the study was some kind of “forced bioequivalence”.

❝ My intent is to publish a paper with that information …

Great. But given what I wrote above, IMHO, it will not be sufficient to solely plugin the numbers. You have to dive into the protocol and report in order to get insights about what was going on.

❝ … 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.

Good! Members of an EC are in a difficult situation. There is no database giving the sample sizes of studies performed with a particular reference. I guess in many cases the assessment would require a member with a good memory. If he/she/it has seen studies of drug X with sample sizes of, say ~32 subjects and the protocol suggests 120, that should ring the alarm bells. I think it is difficult to draw the line.

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1. Hoenig JM, Heisey DM. The Abuse of Power. The Pervasive Fallacy of Power Calculations for Data Analysis. Am Stat. 2001;55(1):19–24. doi:10.1198/000313001300339897. free resource.
   
2. Not conservative but a waste of money & unethical: I know one company, which for years – when they had no clue about the CV_w – simply used s∕x reported for the reference. No crossover, total CV instead of CV_w. They called it “in order to be on the safe side”. Well, … In the meantime they opt for pilots or TSDs.