# Presentation: 662083

## Highly Variable DrugsFDA Case Studies

- Barbara M. Davit, Ph.D.
- Deputy Director, Division of Bioequivalence
- Office of Generic Drugs
- Advisory Committee for Pharmaceutical Sciences
- April 14, 2004

## Overview

- Is high variability a significant issue in BE studies of ANDA submissions?
- From evaluating case studies of BE submissions, can we learn some of the reasons for high variability?

## Statistics on BE Submissions: Objectives

- Identify the scope of the problem
- What percentage of our submissions are for “highly variable drugs”?
- How many subjects are enrolled in studies of highly variable drugs?
- How narrow or wide are the 90% CIs of T/R ratios for AUC and Cmax?

## Statistics on BE Submissions: Methods

- Collected summary BE statistical data on all in vivo studies submitted and reviewed in DBE in 2003
- Used Root Mean Square Error as estimate of intrasubject variability
- Defined highly variable = RMSE _>_ 0.3
- Surveyed only solid oral dosage forms
_***All studies passed 90% CI criteria***_

## DBE Submissions with In Vivo Studies

| Description |  | No. of studies | % of total |
| --- | --- | --- | --- |
| Total BE studies |  | 212 | 100.0 |
| RMSE > 0.3
(“high intrasubject variability”) | AUC or Cmax | 33 | 15.5 |
|  | Cmax only | 28 | 13.5 |
|  | AUC only | 0 | 0.0 |
|  | AUC and Cmax | 5 | 2.5 |

## Observed frequency of RMSE values, Cmax

## Observed frequency of RMSE values, AUC0-t

## Drug products and food effects in 33 HV studies

| Description | # of ANDAs | % of total |
| --- | --- | --- |
| PK parameters highly variable (RMSE > 0.3) | 24 | 100% |
| PK parameters HV in both fed, fasted studies | 9 | 37.5% |
| PK parameters HV in only fed study | 8 | 33.3% |
| PK parameters HV in only fasted study | 7 | 29.2% |

## Highly variable Cmax in fed but not fasting study

| RMSE Values; Study Design = Two-Way Crossover |  |  |  |  |
| --- | --- | --- | --- | --- |
| Type of Drug | Fasting Study |  | Fed Study |  |
|  | Cmax | N | Cmax | N |
| Platelet-reducing agent | 0.20 | 27 | 0.31 | 32 |
| ACE inhibitor 1 * | 0.26 | 52 | 0.34 | 18 |
| Anti-parkinsonian | 0.28 | 51 | 0.30 | 49 |
| Immunosuppressant | 0.12 | 37 | 0.33 | 24 |
| Cholinergic agonist | 0.23 | 32 | 0.31 | 28 |

- * Prodrug parent compound

## Highly variable Cmax in fasting but not fed study

| RMSE Data; Study Design = 2-Way Crossover |  |  |  |  |
| --- | --- | --- | --- | --- |
| Type of Drug | Fasting Study |  | Fed Study |  |
|  | Cmax | N | Cmax | N |
| ACE Inhibitor 2 * | 0.38 | 33 | 0.24 | 34 |
| ACE Inhibitor 3 ** | 0.31 | 34 | 0.28 | 33 |

- * Prodrug parent

- ** Active metabolite of prodrug

## Highly variable Cmax in both fed & fasted studies

| RMSE Values; Study Design = Two-Way Crossover |  |  |  |  |
| --- | --- | --- | --- | --- |
| Type of Drug | Fasting Study |  | Fed Study |  |
|  | Cmax | N | Cmax | N |
| HMG-CoA Reductase In. | 0.34 | 43 | 0.41 | 23 |
| ACE Inhibitor 4 * | 0.30 | 46 | 0.34 | 18 |
| Opioid Analgesic | 0.30 | 35 | 0.32 | 23 |
| Antispasmodic | 0.38 | 45 | 0.34 | 29 |
| ACE Inhibitor 5 * | 0.32 | 47 | 0.32 | 23 |
| ACE Inhibitor 6 * | 0.31 | 57 | 0.31 | 24 |

- * Prodrug Parent Compound

## Both AUC, Cmax highly variable

| RSME Values; Study Design = Two-Way Crossover |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- |
| Type of Drug | Fasting Study |  |  | Fed Study |  |  |
|  | AUCt | Cmax | N | AUCt | Cmax | N |
| Antibiotic 2 | 0.11 | 0.12 | 26 | 0.37 | 0.33 | 26 |
| Antipsychotic | 0.34 | 0.38 | 62 | 0.30 | 0.34 | 24 |
| Antispasmodic | 0.30 | 0.38 | 45 | 0.25 | 0.34 | 29 |
| Antidiabetic | 0.38 | 0.55 | 36 | 0.22 | 0.24 | 39 |

## Test and Reference Product Variability

| Intrasubject Variability 
in Replicate Design BE Studies |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- |
| Drug | No. of Subs | Test |  | Reference |  |
|  |  | AUC | Cmax | AUC | Cmax |
| A | 33 | 0.27 | 0.37 | 0.22 | 0.32 |
| B | 77 | 0.30 | 0.35 | 0.28 | 0.38 |

## PK variability can vary with drug product

| Two-way crossover studies; same RLDs, different manufacturers |  |  |  |  |  |  |  |
| --- | --- | --- | --- | --- | --- | --- | --- |
| Drug (Dosage form) | Mfr. | Fasted Study |  |  | Fed Study |  |  |
|  |  | AUC | Cmax | N | AUC | Cmax | N |
| C
(ER tablet) | 1 | 0.18 | 0.11 | 33 | 0.21 | 0.24 | 35 |
|  | 2 | 0.31 | 0.38 | 45 | 0.25 | 0.34 | 29 |
| D
(IR tablet) | 1 | 0.16 | 0.25 | 32 | 0.13 | 0.20 | 31 |
|  | 2 | 0.38 | 0.55 | 36 | 0.22 | 0.24 | 39 |

## Number of study subjects and variability in Cmax

## Width of Cmax 90% CI versus number of subjects

## Highly variable AUC, 90% Confidence Intervals

- 1.00

- Fed, RMSE=0.34

- Fed, RMSE=0.37

- Fasted, RMSE=0.38

- Fasted, RMSE=0.30

- Fasted, RMSE=0.30

- Fasted, RMSE=0.30

- 0.75

- 1.25

- 1.16; 1.00 – 1.34

- 0.90; 0.76 – 1.07

- PE; 90% CI

- 0.95; 0.82 – 1.11

- 1.01; 0.90 – 1.12

- 1.07; 0.97 – 1.18

- 0.93; 0.89 – 0.98

- N

- 24

- 26

- 36

- 45

- 62

- 77

## Conclusions

- In 2003, 15.5% of all BE studies submitted were for drugs that met the “highly variable” criteria
- Cmax more variable than AUC
- In general, higher PK variability occurred in fed BE studies
- Replicate design studies showed comparable PK variability for T and R

## Conclusions

- In two cases, variability was associated with formulation or other factors in conducting the BE studies
- In general, the width of the 90% CI became narrower as N increased
- Of 212 passing BE studies, only 14 enrolled _>_ 50 subjects
- Of 33 passing BE studies of HV drugs, only 5 enrolled _>_ 50 subjects

## Acknowledgements

- Mei-Ling Chen
- Dale Conner
- Sam Haidar
- Qian Li
- Devvrat Patel
- Don Schiurmann