# Presentation: 816221

## Use of TSH for Bioequivalence

- Robert Lionberger, PhD
- Office of Generic Drugs

## Role of Bioequivalence

- In vivo confirmation of expected equivalent product performance
- same dose
- high solubility, rapid dissolution, and permeability limited absorption
- similarity of products to solution formulations

## Possible Bioequivalence Methods (21 CFR 320.24)

- In order of preference:
- In vivo measurement of active moiety or moieties in biologic fluid
- In vivo pharmacodynamic comparison
- In vivo limited clinical comparison
- In vitro comparison
- Any other approach deemed appropriate
- Why this order?

## Study Design

- Patients or Healthy Subjects
- Single Dose or Steady State

|  | Single Dose | Steady State |
| --- | --- | --- |
| Patients | No | Possible |
| Healthy | Possible | No |

## Two Choices

- Steady State Study in Patients
- Seems very similar to actual clinical use of the product
- Single Dose Study in Healthy Subjects
- What FDA recommends to sponsors to demonstrate bioequivalence

## Steady State Study

- Imagine a patient comes in for checkup
- measure TSH levels
- no change in dose
- comes back in six weeks
- measure TSH levels again
- Will the measured TSH level be the same?

## Steady State Study

- Will the new TSH level be the same or different from old level even if the product and dose are the same?

## Possible Sources of Variability in TSH

- Time of day
- Compliance
- Disease progression
- Lifestyle changes/Diet changes
- Seasonal variation
- How you store the product (Loss of potency)
- How old the batch is

## Time of Day

- Data from Abbott Study M02-417

## Change in Product Potency

- Study Duration

## Sources of Variation

- Subjects experiencing sleep withdrawal had significant increases in average TSH levels.
- J. Behrends, K. Prank, E. Dogu, and G. Brabant, *Central nervous system control of thyrotropin secretionduring sleep and wakefulness*, Horm Res 49(3-4), 173, 1998
- Two studies in hypothyroid patients reported TSH values that were 50% to 100% higher in January when compared to summer values
- N. Konno and K. Morikawa, *Seasonal variation of serum thyrotropin concentration and thyrotropin response to thyrotropin-releasing hormone in patients with primary hypothyroidism on constant replacement dosage of thyroxine*, J Clin Endocrinol Metab 54(6), 1118 (Jun 1982).
- N. Hamada, M. Ohno, H. Morii, N. Jaeduk, J. Yamakawa, M. Inaba, S. Ikeda, and M. Wada, *Is it necessary to adjust the replacement dose of thyroid hormone to the season in patients with hypothyroidism*, Metabolism 33(3), 215 (Mar 1984).

## Sources of Variation

- One study of healthy volunteers reported a 30% decrease in TSH levels in the spring
- M. Simoni, A. Velardo, V. Montanini, M. Faustini Fustini.,S. Seghedoni, and P. Marrama, *Circannual rhythm of plasma thyrotropin in middle-aged and old euthyroid subjects*, Horm Res 33(5), 184 (1990).
- Another study reported no seasonal effect in euthyroid young male subjects, but observed a clear effect in elderly women.
- H. L. Reed, *Circannual changes in thyroid hormone physiology: the role of cold environmental temperatures*, Arctic Med Res 54 Suppl 2, 9 (1995).

## TSH Levels in Titrated Patients

- L. H. Fish, H. L. Schwartz, J. Cavanaugh, M. W. Stees, J. P. Bantle, and J. H. Oppenheimer, *Replacement dose, metabolism, and bioavailability of levothyroxine in the treatment of hypothyroidism. Role of triiodothyronine in pituitary feedback in humans*, N Engl J Med 316(13), 764 (Mar 1987).

## Implications of Variability

- Variation hides true differences in products
- Hard to use clinical outcomes to detect small differences in formulation performance

## Goal

- Patients want to know when they switch that the outcome will be the same as if they did not switch
- Bioequivalence of TSH levels in steady state does not appear to be achievable even when patients are not switched to a generic version

## Best Way to Reach Goal

- Contributions to variability
- drug product, sleep, time of day, compliance, disease progression, diet, etc.
- All are common to generic or reference product except drug product
- Single dose study in healthy subjects is the best way to confirm drug product performance

## T4 Concentration Reflects Formulation Performance

- Data from Abbott Study M02-417

## Possible Bioequivalence Methods (21 CFR 320.24)

- In order of preference:
- In vivo measurement of active moiety or moieties in biologic fluid
- In vivo pharmacodynamic comparison
- In vivo limited clinical comparison
- In vitro comparison
- Any other approach deemed appropriate
- Now we understand the preference and the critical roles of variability and sensitivity in selecting appropriate bioequivalent methods