- On 9 May 2000 at 22:58:07, Korbtham Sathirakul (pyksk.at.mahidol.ac.th) sent the message

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Dear All

I found that there is a round off issue for CI in the recent BA/BE

guideline in August 1999. Could you please give me some suggestion? If the

upper limit of my generic products 1.2499 or lower limit is 0.7999. Then;

the conclusion should be BE or not BE. Thank you for your comments.Asst.

Prof. Dr. Korbtham Sathirakul

Mahidol University

Bangkok, Thailand - On 10 May 2000 at 14:58:51, Art Straughn (ASTRAUGHN.aaa.utmem.edu) sent the message

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The limits are 80 to 125. 79.9999999999999999999 is not 80 and 125.00000000001

is not 125. OK?

Art Straughn - On 10 May 2000 at 22:32:54, jw5886.at.cnsvax.albany.edu sent the message

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Although different people have different opinion. First of all, I think it

is a good question. Just how much attention ought we devote to the issue

of valid decimal places?. Imagine u r doing HPLC msrmnt of a chemical,

the computer spits out a zillion numbers including the decimal place,

and you

calculate the AUC, guess what u take 8 numbers regardlessly. NOw you

export it to the excel spreadsheet, guess what, it adds decimal places

just because it is from a different package. Now you give it to the

statistician, who probably uses SAS, he/she ask u, well, how much decimal

place should I use? U said, PICKACHU, how about 2. Given all the

confusion, u come up with 79.999999 and 120.000000000000001, how in the

world can you be so sure that it is not Bioequivalent? OK?!!!

Plus, r u saying if u r one cent richer than Bill Gates, then u r richer?

I guess my question is, was there a rule in taking numbers? I know

in other descipline, there is recognized convention. Please enlighten

me. - On 11 May 2000 at 15:02:20, Art Straughn (ASTRAUGHN.-at-.utmem.edu) sent the message

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The guidance did not say a value which rounds off to 80 is acceptable. It says

80. If the FDA were to accept 79.51, who is to say they should not accept

79.49. In my courses, a student whose final average is 79.95000 (Excel round

off to 80) will receive a B-, while one whose average is 79.9499999 (round off

to 79) receives a C+. Therefore, my cutoff is really 79.5 not 80. This cutoff

and round off is clearly stated in my course syllabus. The C+ student will

invariably end up in my office with a reason for changing the grade to B-. The

grade debate become much more lively when the "round off" places them closer

and closer to probation (i.e. outside the acceptable limits). I will probably

make a concession to the student. I doubt the FDA would change the grade.

Art Straughn - On 11 May 2000 at 20:56:33, David_Bourne (david.-a-.boomer.org) sent the message

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[Two replies - db]

From: harry.mager.hm.at.bayer-ag.de

To: " - *PharmPK.at.boomer.org"

Subject: Re: BA/BE draft guidance 1999

Date: Thu, 11 May 2000 09:14:01 +0200

In my understanding, it's just a "rule of thumb", in some sense comparable to

the famous 5% significance level. Of course, 4.45% would work equally well. It

goes without saying that the specified limits nether will be the correct ones,

even when neglecting covariates and interindividual variability. The interval

may be to wide for drug A and to narrow for drug B, and even the whole concept

might be disputable in some cases. Thus, as you mentioned, it seems to be a

convention maybe based on averaged experience.

Harry Mager

---

Date: Thu, 11 May 2000 07:00:53 -0700 (PDT)

From: Richard Molitor

To: PharmPK.-at-.boomer.org

Subject: Re: PharmPK Re: BA/BE draft guidance 1999

From the "real world" of clinical practice here's a thought:

Why split hairs (or fractions) about trying to meet the minimum acceptable

standard? Spend a few more dollars and make the product more like 95-105%

of the reference agent. This would be especially prudent if it's a narrow

therapeutic index agent.

Richard Molitor, R.Ph.

http://www.angelfire.com/wa/pharmacist/

---

From: Peter Gingras

To: "'PharmPK.-at-.boomer.org'"

Subject: RE: PharmPK Re: BA/BE draft guidance 1999

Date: Thu, 11 May 2000 11:22:10 -0400

The limit is 80 to 125%. Please refer to USP 23, p 3, Significant Figures and

Tolerances. While 79.999999 may not be 80, when rounded to the required

tolerance of 80 (ie not 80.000000) it complies with the requirements. USP is

very clear about the acceptability of rounding to the required tolerance.

Peter Gingras

pgingras.aaa.apotex.ca - On 14 May 2000 at 22:30:27, "Ed O'Connor" (efoconnor.aaa.snet.net) sent the message

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The precision of numbers in an assay and in any subsequent application such

as, statistical analysis and PK are generally governed and restricted by the

precision associated with the standard preparation. Reported numbers should

have the same precision (or less). Interim numbers used in calculations may

have more, but should be consistent so that reviewers, QA and the FDA get the

same results when the reported numbers are checked. This consideration is

not trivial. When calcuating CI, the same considerations must be made. - On 29 May 2000 at 13:42:15, Stanley110.at.aol.com sent the message

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This is a very interesting and challenging question. From a regulatory

perspective the answer is clear: report the answer with the same number of

decimal places as in the specification. The specification is legal, not

mathematical.

The rules of sig figs and rounding are, amazingly enough, not universally

agreed upon and not well founded mathematically. Sig fis and rounding are

only one expression of uncertainty; statistics gives us others; the latter

are more useful.

If you are interested in this subject, contact the chemistry faculty at the U

of Oregon. They have studied this and publisheed.

Stan Alekman - On 1 Jun 2000 at 13:53:54, Peter Gingras (pgingras.-at-.apotex.com) sent the message

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I believe the original question was something to the effect, "Is it acceptable

to round your calculated CI such that 79.95% is reported as 80%, and can you

claim your result meets the stated requirement of 80%?"

The answer to this question is yes, you can round if you follow the

rules of USP

General Notices, Significant Figures and Tolerances, p. 3, USP 23. It is not a

vague "rule of thumb" convention, as Harry Mager suggests, and the method for

rounding is very clearly stated.

Ed Connor's message was on the right track. Ed says that rounding is permitted

for legal reasons, which is true. But there is also a scientific reason. An

analytical result is meant to signify a true value, with a stated amount of

uncertainty, based upon known variability of the measurement process, and

conventions for required precision and accuracy. Some numbers that are

calculated are purely artefactual. They do not represent a true measurement

result, but are derived from a silicon chip. One should not make scientific

decisions based upon artefactual numbers.

I somewhat disagree with Richard Molitor's suggestion that we simply test to

tighter limits, to ensure that we comply with the real limits. To some degree

this is done during the sample size calculation. No one wants to spend all that

time and money, and then marginally fail to meet the CI requirement. However, a

perfect BE study result is one where the mean ratio result (test to reference)

is 100% with confidence limits of 80% and 125%. And the real world reality is

that it is the statisticians job, in a pharmaceutical company, to estimate the

correct sample size, not one too large or too small. By the way, spending more

money on the testing won't improve the product.

In any event, don't pay too much attention to .001, when you can barely see .1,

and keep your stick on the ice.

Peter Gingras

pgingras.-a-.apotex.ca - On 2 Jun 2000 at 10:49:57, David_Bourne (david.-at-.boomer.org) sent the message

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[Two replies - db]

Sender: PharmPK.-a-.boomer.org

Reply-To: Stanley110.-at-.aol.com

MIME-Version: 1.0

From: Stanley110.at.aol.com

Date: Fri, 2 Jun 2000 01:06:52 EDT

To: david.-a-.boomer.org

Subject: Re: PharmPK Re: BA/BE draft guidance 1999

USP under General Notices allows rounding up into compliance with a

specification for compendial tests. While releasing a product at a

specification limit is unwise for several reasons, rounding up into

compliance is acceptable practice. This has no bearing on the subject

guidance but it is interesting.

Stan Alekman

---

Alternate-recipient: prohibited

Date: Fri, 02 Jun 2000 07:56:27 -0500 (CDT)

From: Art Straughn

Subject: PharmPK Re: BA/BE draft guidance 1999

To: postmaster

MIME-version: 1.0

Posting-date: Fri, 02 Jun 2000 07:56:28 -0500 (CDT)

Importance: normal

Priority: normal

Sensitivity: Company-Confidential

A1-type: MAIL

Dear All,

A possible answer to the appropriate number of decimal places to use in

reporting the confidence interval values may be found at the end of the draft

guidance from the FDA titled "BA and BE Studies for Orally Administered Drug

Products -- General Considerations". It was issued 8/1999 and posted at their

web site 8/27/1999. This draft guidance states: "Confidence interval (CI)

values should not be rounded off; therefore, to pass a CI limit of 80-125, the

value should be at least 80.00 and not more than 125.00"

Unfortunately, this statement is ambiguous. If rounding off is not allowed,

then 79.999999999 will not pass; but if one uses the given example value of

80.00, then the USP 24/NF 19 rules for significant figures (pages 3-4)

indicates 79.99999 will pass. I think a clarification from the FDA is needed -

do you or don't you round off?

Art Straughn - On 3 Jun 2000 at 15:26:01, "Ed O'Connor" (efoconnor.-at-.snet.net) sent the message

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80.00 is written to 4 significant figures while 125.00 is written to five. The

nonsense is that these are percents and reflect a set value of 0.80

or 1.25 times

the values returned by the method itself.. The method will return

values to double

precision or however the computer is constrained to report. These

values in turn

are multiplied by the percent limits of 80 or 125. The precision

reported should

not exceed the precision of these multipliers. So how many angels do

fit on the

head of a pin? How small are the angels, how large the pin? - On 8 Jun 2000 at 19:33:36, Wei-jian Pan (weijian.pan.aaa.abbott.com) sent the message

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The following message was posted to: PharmPK

Stan (Alekman),

You recent comments that "the precision reported should not exceed the term

in the

calculation with the least precsion, according to the rules of sig figs and

rounding" is very much to the point. In fact, those who are not clear about

this basic concept should review their Analytical Chemistry 101 to refresh

their memory.

See: page 41 of Quantitative Chemical Analysis by Daniel C. Harris, 4th Ed.,

W. H. Freeman and Company, New York, 1995.

Regards!

Wei-jian

Wei-Jian Pan, Ph.D.

Dept. of Clinical Pharmacokinetics

Abbott Laboratories

Abbott Park, IL 60064-6104

847-935-5335

weijian.pan.aaa.abbott.com - On 12 Jun 2000 at 11:06:22, =?iso-8859-9?B?3WxiZXlpIEHwYWJleW/wbHU=?= (ilbeyi.aaa.tr-net.net.tr) sent the message

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This discussion about the precision of the reported results is important.

Most of the analytical instruments give three significant figures as the

value. So, any reported final result should be three sinificant figures. In

between calculations, however, should be carried out to the number of

significant figures supplied by the computer/calculator. Otherwise rounding

errors will cumulate excessively.

Instruments like scintillation counters might give six significant figures,

but these are probably not reproducible beyond the third significant figure.

Prof.Dr.Ilbeyi Agabeyoglu

Gazi Univ.Fac.Pharmacy

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