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

1. Bioequivalence and Baseline Correction of Endogenous SubstancesCase 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

2. Bioequivalence and Baseline Correction of Endogenous SubstancesCase 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

3. 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

4. T4 is Required for the Treatment of Patients with Hypothyroidism and Thyroid Cancer • T4 is the synthetic version of the naturally-occurring hormone thyroxine (T4) • No alternative drug is an adequate substitute • Virtually all patients require chronic, lifetime T4 treatment Over 13 million Americans rely on T4

5. T3 T3 – T4 T3 R Thyroid Hormone is Tightly Regulated by a Complex System, via the Exquisitely Sensitive Response of TSH TRH Hypothalamus – Pituitary TSH Target Tissues Heart Thyroid Gland Liver T4 Bone T4è T3 Liver CNS

6. Dosage of T4 is Individualized for Safe and Effective Medical Treatment • Physicians use TSH (thyroid stimulating hormone) to individualize the optimal T4 dose • Small changes in T4 dose causes significant changes in TSH levels • T4 is provided in 12 dosage strengths • Adjacent doses differ by as little as 9%

7. Accurate Patient Treatment Demands Controlling Both T4 and TSH Levels • Euthyroid • Free-T40.8 – 2.7 ng/dL • TSH 0.4 – 4.0 µIU/mL • Mild hypothyroidism • Free-T4 is within the reference range • TSH is mildly elevated • Mild hyperthyroidism • Free-T4 is within the reference range • TSH <0.1 µIU/ml

8. 10 8 6 TSH (µIU/mL) Upper limit of normal 4 2 Lower limit of normal 1 0.2 -50 -25 OptimumT4(µg) +25 +50 +75 N=21 25 50 75 88 100 112 125 137 150 175 200 300 µg 12% 12% 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

9. 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 Small Dosage Changes Can Result in Under- orOver-treatment, with Serious Clinical Outcomes

10. Bioequivalence and Baseline Correction of Endogenous SubstancesCase Study: Levothyroxine Sodium Products G. Richard Granneman, Ph.D. Vice President, Center of Clinical Assessment, Abbott Laboratories

11. 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

12. 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

13. Randomized 3-way, fasting, single dose, crossover T4 doses (same pre-NDA lot of 50 µg tablets) Washout = 44 and 53 days (> 6 half-lives of T4) N=33 healthy male and female subjects evaluated for PK Complete PK for Day–1 through Day 4 : T3, T4, TSH Study 417: Designed to Assess and Compare Uncorrected and Baseline-Corrected BE

14. Correction Method No correction Horizontal 7-day half-life Day-1 baseline TSH-dependent half-life Correction Methods to Account for Endogenous T4 Levels TSH change Study M02-417

15. 25% Diff 12.5% Difference Method D TSH48 TSH + t1/2 Day -1 7-day t1/2 Horizontal Uncorr. 1.125 in CI Signif vs. 1.0 Fail Fail Correction Methods and / or Goal Posts Need to Change to Ensure Bioequivalence

16. 9 P 1 P 2 P 3 8 T4 Concentration (µg/dL) 7 6 0 0 6 12 18 24 Time (hours) 8 am 2 pm 8 pm 2 am 8 am Hour of the Day Simple Methods are Inadequate Because They Ignore Complex Biology Mean Endogenous T4 on Day–1 By Period • Diurnal variation • p<0.001 18-hour vs. hours 0-4 • Biologic carryover • Period: p=0.0001 • Carryover: p=0.0003 Study M02-417

17. Thyroid Homeostasis Obscures Real Differences Among Non-equivalent T4s in Healthy Subjects Thyroid • 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 Thyroglobulin T4 T3 Tissues Plasma T4 T3 T4 T3 T3R TBG TBG T2 T3 conj rT3 T4 T3 Hypothal Pituitary TRH TSH

18. Express T4 and TSH as fold-change from pre-dose baseline Invert TSH ratio Large fold change in TSH for a small perturbation in T4 Pronounced hysteresis Discriminates doses Adds biologic context T4 600 T4 450 T4 400 5.0 TSH 600 TSH 450 TSH 400 4.5 4.0 3.5 1/TSH or T4 ratio 3.0 2.5 2.0 1.5 1.0 0 24 48 72 96 Hours TSH Adds Pharmacodynamic Perspective to T4 Results

19. 16 14 12 Total T4 10 8 6 Endogenous T4 4 2 0 -24 0 24 48 72 96 Horizontal Correction Ignores Thyroid Biology • 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 T4 (µg/dL) Hours

20. Baseline Correction Summary • All methods are OK for 25% differences, but not for 12.5%. Horizontal correction is biologically inconsistent • Intra-subject variability of T4 is low • To detect 12.5% differences, 80-125% criteria are too broad for T4 BE • Using TSH data, alone or with T4, is more discriminating than T4 alone

21. 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 µg) • Bioequivalence criteria must be tied to clinically relevant marker • TSH is the medically acceptable marker • Must define maximal TSH changes

22. 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 T4 products (i.e., utility function analysis of risk) • FDA • Academia • Endocrine Societies • Industry