# Presentation: 196455

## Bioequivalence and Baseline Correction of Endogenous SubstancesCase Study: Levothyroxine Sodium Products

**Leonard Wartofsky, M.D.**
**Division of Endocrinology**
**Chairman, Department of Medicine, Washington Hospital Center**
**Clinical Professor of Medicine, Georgetown, Howard, & George Washington Universities**
**G. Richard Granneman, Ph.D.**
**Vice President, Center of Clinical Assessment, Abbott Laboratories**
**FDA Advisory Committee for Pharmaceutical Science**
**March 13, 2003**

## Bioequivalence and Baseline Correction of Endogenous SubstancesCase Study: Levothyroxine Sodium Products

**Leonard Wartofsky, M.D.**
**Division of Endocrinology**
**Chairman, Department of Medicine, Washington Hospital Center**
**Clinical Professor of Medicine, Georgetown, Howard, & George Washington Universities**

## Critical Scientific and Clinical Conclusions:

**Current FDA recommendations to determine bioequivalence are not sufficiently sensitive to detect small differences**
**Small differences in dosage or bioavailability have significant clinical impact, both on safety and efficacy**

## T4 is Required for the Treatment of Patients with Hypothyroidism and Thyroid Cancer

**T****4**** is the synthetic version of the naturally-occurring hormone thyroxine (T****4****)**** **
**No alternative drug is an adequate substitute **
**Virtually all patients require chronic, lifetime T****4**** treatment**
**Over 13 million Americans rely on T****4**

## Thyroid Hormone is Tightly Regulated by a Complex System, via the Exquisitely Sensitive Response of TSH

**Hypothalamus**

**     ****Pituitary     **

** ****Thyroid Gland**

**T****4****   ****   T****3****  **
**         ****Liver         **

**       ****Heart         **

**       ****Liver         **

**       ****Bone         **

**        ****CNS          **

**TSH**

**T****4**

**TRH**

**Target Tissues**

**–**

## Dosage of T4 is Individualized for Safe and Effective Medical Treatment

**Physicians use TSH (thyroid stimulating hormone) to individualize the optimal T****4**** dose**
**Small changes in T****4**** dose causes significant changes in TSH levels**
**T****4**** is provided in 12 dosage strengths**
**Adjacent doses differ by as little as 9%**

## Accurate Patient Treatment Demands Controlling Both T4 and TSH Levels

**Euthyroid**
**Free-T****4****	********0.8 –  2.7 ng/dL**
**TSH****	****  0.4 – 4.0 μIU/mL**
**Mild hypothyroidism**
**Free-T****4**** is within the reference range**
**TSH is mildly elevated**
**Mild hyperthyroidism**
**Free-T****4**** is within the reference range**
**TSH <0.1 μIU/ml**

## Small Changes in T4 Dose Can Result in Abnormal TSH Levels

**Changes as small as 12.5 μg (~12.5%) would move many patients into mild hyperthyroidism or hypothyroidism**

*Carr D, et al, Clin Endocrin 1988; 28:325*

## Small Dosage Changes Can Result in Under- orOver-treatment, with Serious Clinical Outcomes

**Populations at greatest risk:**
**Elderly patients with cardiac disease**
**Pregnant women**
**Patients with thyroid cancer**

**Consequences of mild hypothyroidism**
**Elevated cholesterol levels**
**Atherosclerosis and myocardial infarction**
**Decreased intellectual function in the off-spring of women hypothyroid in early pregnancy**
**Consequences of mild hyperthyroidism**
**Atrial fibrillation and other arrhythmias**

## Bioequivalence and Baseline Correction of Endogenous SubstancesCase Study: Levothyroxine Sodium Products

**G. Richard Granneman, Ph.D.**
**Vice President, Center of Clinical Assessment, Abbott Laboratories**

## Does Bioequivalence = Therapeutic Equivalence for T4 Products?

**We fear that with current FDA criteria, this will not always be the case;**
**We expect that small differences in dosage or  bioavailability will have clinical consequences**

## Key Findings of Abbott’s Study 417

**Without baseline correction, doses differing **_**<**_**33% are BE**
**All correction methods resulted in BE failure for 25% differences in dose**
**Baseline correction methods cannot distinguish doses that differ by 12.5%**
**Additional analyses, using TSH data, show significant promise of detecting 12.5% differences**

## Study 417: Designed to Assess and Compare  Uncorrected and Baseline-Corrected BE

**Randomized 3-way, fasting, single dose, crossover**
**T****4**** doses (same pre-NDA lot of 50 μg tablets)**

**Washout = 44 and 53 days (**_**>**_** 6 half-lives of T****4****)**
**N=33 healthy male and female subjects evaluated for PK **
**Complete PK for Day–1 through Day 4 : T****3****, T****4****, TSH**** **

| Dose | Unit | %  from 600 μg |
| --- | --- | --- |
| 600 μg | 12 • 50 μg |  0 |
| 450 μg |   9 • 50 μg | –25 |
| 400 μg |   8 • 50 μg | –33 |

## Correction Methods to Account for Endogenous T4 Levels

**Correction Methods to Account for Endogenous T****4**** Levels**

*Study M02-417*

**TSH change**

## Correction Methods and / or Goal Posts Need to Change to Ensure Bioequivalence 

**Correction Methods and / or Goal Posts Need to Change to Ensure Bioequivalence **

## Simple Methods are Inadequate Because They Ignore Complex Biology

**Diurnal variation**
**p<0.001 18-hour *****vs.***** hours 0-4**
**Biologic carryover**
**Period:       p=0.0001**
**Carryover: p=0.0003**

**Mean Endogenous ****T****4**** on Day–1 By Period**

*Study M02-417*

## All pathways are controlled by T3 and TSH
T4 t1/2 : 4 days in hyper
T4 t1/2 : 9 days in  hypo
TSH changes exponentially with changes in free T4

In normals, T4 may be the only drug whose clearance increases when there is too much and decreases when there is not enough

**T****4**** t****1/2**** : 4 days in hyper**
**T****4**** t****1/2**** : 9 days in  hypo**
**TSH changes exponentially with changes in free T****4**
**In normals, T****4**** may be the only drug whose clearance increases when there is too much and decreases when there is not enough**

- Plasma

**Thyroid**

**Thyroglobulin**

- T3

- T4

- T4

- T3

- T4

- T3

**Hypothal**

**Tissues**

**TBG**

**TBG**

- T4

- T3

- T2

- rT3

**T3**
**conj**

**Pituitary**

**  ****TRH**

**TSH**

**T****3****R**

**Thyroid Homeostasis Obscures Real Differences Among Non-equivalent T****4****s in Healthy Subjects**

## TSH Adds Pharmacodynamic Perspective to T4 Results

**TSH Adds Pharmacodynamic Perspective to T****4**** Results**

**Express T4 and TSH as fold-change from pre-dose baseline**
**Invert TSH ratio**

**Large fold change in TSH for a small perturbation in T****4**
**Pronounced hysteresis**
**Discriminates doses**
**Adds biologic context**

## Biologically inconsistent
Reduces true AUC48 10-15%
Attenuates differences between nonequivalent formulations
Produces negative AUC values
2-3 day half-life estimate

Recall:  Significant error in point estimate; 90% CI did not include actual value

** ****T****4 **** (μg/dL)**

**Hours**

**Biologically inconsistent**
**Reduces true AUC****48**** 10-15%**
**Attenuates differences between nonequivalent formulations**
**Produces negative AUC values**
**2-3 day half-life estimate**
**Recall:  Significant error in point estimate; 90% CI did not include actual value**

**Horizontal Correction Ignores Thyroid Biology**

## Baseline Correction Summary

**All methods are OK for 25% differences, but not for 12.5%.   Horizontal correction is biologically inconsistent**
**Intra-subject variability of T****4**** is low**
**To detect 12.5% differences, 80-125% criteria are too broad for T****4**** BE **
**Using TSH data, alone or with T****4****, is more discriminating than T****4**** alone**

## Physicians Want to Know that Switching Products Poses No Patient Risk

**Why not conduct BE studies in subjects with no thyroid function?**
**Precedent in estrogen products**
**Multi-dose, steady-state cross-over**
**Validate with a known difference (e.g., 100 *****vs.***** 88 ****μ****g)**
** **
**Bioequivalence criteria must be tied to clinically relevant marker **
**TSH is the medically acceptable marker**
**Must define maximal TSH changes**

## Conclusions

**Small differences matter for patient safety**
**Products that differ by 12.5% cannot be distinguished using current criteria**
**We should ****engage experts in establishing BE criteria for T****4**** products (i.e., utility function analysis of risk)**
**FDA**
**Academia**
**Endocrine Societies**
**Industry**