# Presentation: 844375

## Limitations of Current Bioequivalence Standards James V. Hennessey M.D.Joint Public Meeting onEquivalence of Levothyroxine Sodium Products Monday, May 23, 2005Washington, DC Co-Sponsored by the Food and Drug Administration and the American Thyroid Association, The Endocrine Society, and the American Association of Clinical Endocrinologists

## Bioequivalence Definition

- Bioequivalence is defined in § 320.1 as:
- the **absence of** a significant **difference** in the rate and extent to which the active ingredient or active moiety in pharmaceutical equivalents... becomes _**available**_** **_**at**_ the _**site of**_ drug _**action**_ when administered in the same molar dose* under similar conditions in an appropriately designed study.
- * product content no **>** 5% difference

**Guidance for Industry: BA and BE studies for orally administered drug products. **
**	****	****       ****USD HHS FDA CDER July 2002**

## Model of Oral Dosage Form Endogenous Drug Performance

- Therapeutic
- Effect

- Dosage
- Form

- Gut Wall

- Drug in
- Solution

- Blood

- Site of
- Activity

**Pharmacokinetic Measurement**

**Dosage Form Performance**

**Clinical/PD Measurement**

- ln Dose

- Dose

- Body
- Production

- Feedback

**Modified from **
**D Conner 13 Mar 03 **http://www.fda.gov/ohrms/dockets/ac/03/slides/3926S2_06_Conner.ppt

**TSH**

## L-Thyroxine has a Narrow Therapeutic Ratio

- Evidence that the drug products exhibit a narrow therapeutic ratio:
- Less that a 2-fold difference in the minimum toxic concentrations and minimum effective concentrations in the blood
- Safe and effective use of the drug products requires dosage titration and patient monitoring

**Code of Federal Regulations, Title 21, Vol. 5, Subchapter D, Part 320**
**www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=320&show...**

## T4 Replacement Dosage: TRH stimulated TSH vs. FT4/FT3 and Clinical assessment

- 21 (2 M) patients with 1° Hypothyroidism
- Studied Q 6 weeks on series of L-T4 doses
- Assessments: L-T4 @ breakfast, eval. 1330-1630
- Compliance by pill counts
- Clinical: Weight, pulse, Billewicz, General well being
- Biochemical: Basal TSH, FT4, FT3, TSH 20” p TRH
- Normal TRH induced TSH response: 4.7-25 mU/l
- Dose modification by 25 or 50 mcg

**Carr D, et al. *****Clin Endocrinol*****. 1988;28:325-333.**** **

## Limitations of Bioequivalence TestingImpact of Small Dose Changes

**1**

**0**

**8**

**6**

**4**

**2**

**0.2**

- .

**1**

**-**

**50**

**-25**

**+**

**2**

**5**

**+50**

**TSH**

**mU/L**

**T****4**** (********g/day) Dose**

**+75**

**Normal TSH range**

**Above-normal TSH**

**Below-normal TSH**

**Optimum**

- Carr D, et al. *Clin Endocrinol*. 1988;28:325-333.

- Limitations of Bioequivalence TestingImpact of Small Dose Changes

## Small changes in thyroxine dose result in changes in clinical assessment: (optimal ave. 108 mcg/day):

25 mcg less than optimal dose (< 0.25 fold)
7/9 patients (89%) were classified hypothyroid

25 mcg more than optimal dose (< 0.25 fold)
11/20 patients (55%) were classified thyrotoxic

- 25 mcg less than optimal dose (**<** 0.25 fold)
- 7/9 patients (89%) were classified hypothyroid
- 25 mcg more than optimal dose (**<** 0.25 fold)
- 11/20 patients (55%) were classified thyrotoxic

**Impact of Small Thyroxine Dose Changes**

**Carr D, et al. *****Clin Endocrinol*****. 1988;28:325-333.**** **

## FDA Approved L-T4 Doses

**These are changes that clinicians make deliberately every day!**

**Difference of <25%**

## Purpose of BE

- To demonstrate therapeutic equivalence (TE)
- To assure that bioequivalent products can be substituted for each other without concern for adjustment in drug dose or the need for any follow up therapeutic monitoring.
- The most efficient method of assuring TE is to assure that the formulations perform in an equivalent manner.

**D Conner 13 Mar 03 **http://www.fda.gov/ohrms/dockets/ac/03/slides/3926S2_06_Conner.ppt

## Methods: Document BA and BE IN ORDER OF FDA PREFERENCE

**Pharmacokinetic (PK) studies**
- Rests on an understanding that **measuring** the **active ingredient** at the **site of action** is **not possible** and some relationship exists between the efficacy/safety and concentration of active moiety in the systemic circulation.
**PK** measurements are a **bioassay **assessing release of drug substance from the drug product into the systemic circulation

**Guidance for Industry: BA and BE studies for orally administered drug products. USD HHS FDA CDER July 2002**

## Model of Oral Dosage Form Endogenous Drug Performance

- Therapeutic
- Effect

- Dosage
- Form

- Gut Wall

- Drug in
- Solution

- Blood

- Site of
- Activity

**Pharmacokinetic Measurement**

**Dosage Form Performance**

- Dose

- Body
- Production

- Feedback

- D Conner 13 Mar 03 http://www.fda.gov/ohrms/dockets/ac/03/slides/3926S2_06_Conner.ppt

## Clinical Questions

- Are limits of acceptability simply too wide?
- 90% CI within an 80-125% acceptance range
- Should allow the detection of  a 20% difference in bioavailability with confidence
- Is a difference of up to 20% too great for precise LT-4 dosing?
- How do the original and updated PK methods perform in detecting known differences in BA?

## Limitations of Bioequivalence TestingHuman Study Design 

- 36 healthy volunteers (18M,18F)
- Fasting, open-label, randomized, 3-period, crossover; 42 to 54 days between periods
- Same branded LT4 lot used for all regimens:
- Regimen A: 600 mcg (12 x 50 g)
- Regimen B: 450 mcg (9 x 50 g)
- Regimen C: 400 mcg (8 x 50 g)

- Blakesley V, et al.  *Thyroid. *2004;14:189-199.

## Limitations of Bioequivalence TestingHuman Study Results

- Blakesley V, et al.  *Thyroid. *2004;14:189-199.

**Relative Bioavailability**

**Pharmacokinetic****Parameter**

**Regimens**

**.6**

**.8**

**1.0**

**1.25**

**1.4**

**1.2**

**1.3**

**.8**

**1.25**

**Range of Bioequivalence**

- -33%

- -25%

- -12.5%

- Limitations of Bioequivalence TestingHuman Study Results

## Limitations of Bioequivalence TestingHuman Study Results

- Limitations of Bioequivalence TestingHuman Study Results

**Relative Bioavailability**

**Pharmacokinetic****Parameter**

**Regimens**

**.6**

**.8**

**1.0**

**1.25**

**1.4**

**1.2**

**1.3**

**.8**

**1.25**

**Range of Bioequivalence**

- -33%

- -25%

- -12.5%

## Clinical Questions

- What difference will corrected PK detect?
_**>**_ 3.5%? (Nightingale, JAMA, 258:9, 1987, Henney, JAMA, 282:21 1999)
- 9%? (FDA 97-N-0314 [Apr 26, 2001] confidential appendix)
- 13%?
_**<**_ 20%?
- What difference in BA is acceptable for BE?

## Purpose: SNDA to compare bioavailability of Sandoz levothyroxine to Synthroid® & Levoxyl®
Design:  Open-label, randomized, single-dose, 2-way crossover study in 24 healthy adult volunteers
600 g dose administered under fasting conditions
35-day washout period
Parameters analyzed: AUC0-24, AUC0-48, AUC0-72, Cmax, adjusted for baseline 

- Design:  Open-label, randomized, single-dose, 2-way crossover study in 24 healthy adult volunteers
- 600 g dose administered under fasting conditions
- 35-day washout period
- Parameters analyzed: AUC0-24, AUC0-48, AUC0-72, Cmax, adjusted for baseline

- http://www.fda.gov/ohrms/dockets/dailys/04/oct04/100504/03p-0387-let00005-vol5.pdf  Accessed 2/14/05

- Limitations of Bioequivalence TestingRegulatory Experience

## Limitations of Bioequivalence TestingRegulatory Experience

**AUC****0-48**

**.6**

**.8**

**1.0**

**1.25**

**1.4**

**Sandoz LT****4**** vs. Synthroid****®**

**Sandoz LT****4**** vs. Levoxyl****®**

**.8**

**1.25**

**Range of Bioequivalence**

- Limitations of Bioequivalence TestingRegulatory Experience

- http://www.fda.gov/ohrms/dockets/dailys/04/oct04/100504/03p-0387-let00005-vol5.pdf  Accessed 2/14/05

## Limitations of Bioequivalence TestingRegulatory Experience

**AUC 0-48 Hours (% Ref)**

**97.7**

**112.5**

**100**

**100**

- Ratios (Ref LT4 / Sandoz LT4) of least-squares ANOVAAll 90% CI (80-125)

- Predicted difference     -2.3%                       +12.5%

- http://www.fda.gov/ohrms/dockets/dailys/04/oct04/100504/03p-0387-let00005-vol5.pdf  Accessed 2/14/05

- Limitations of Bioequivalence TestingRegulatory Experience

## Limitations of Bioequivalence TestingRegulatory Experience

**AUC 0-48 Hours (% Ref)**

**109**

**112.5**

**100**

**100**

- Ratios (Synthroid / Generic LT4) of least-squares ANOVAAll 90% CI (80-125)

- Predicted difference:   +12.5%	        +9%	    +3%

- Limitations of Bioequivalence TestingRegulatory Experience

**100**

**103**

*** ****= 90 CI**
**beyond 9%**
**difference**

- *

- *

- *

- Http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm 17 May 2005

## Limitations of Bioequivalence TestingRegulatory Experience

**AUC 0-48 Hours (% Ref)**

**97.7**

**102**

**100**

**100**

- Ratios (Levoxyl / Generic LT4) of least-squares ANOVAAll 90% CI (80-125)

- Predicted difference:  -2.3%                +2%		  +2.7%

- Limitations of Bioequivalence TestingRegulatory Experience

**100**

**102.7**

*** ****= 90 CI**
**beyond 9%**
**difference**

- *

- Http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm 17 May 2005

## Conclusions

- Clinical community and FDA have advanced precision in clinical monitoring and delivery of high quality thyroid hormone products for therapy.
- Each step of standardization has moved us closer to our goal of achieving consistent, precise LT4 preparations to enhance patient care outcomes.
- PK assessment of thyroxine appears to fall short of assuring the interchangeability of products necessary for consistent precise dosing.