# Presentation: 282824

## What may be needed in terms of clinical studies for a follow-on protein product?Public Workshop, FDA and HHS, Sept. 14-15, 2004

***What may be needed in terms of clinical studies for a follow-on protein product?******Public Workshop, FDA and HHS, Sept. 14-15, 2004***

- Murray P. Ducharme, PharmD, FCCP, FCP
- Vice President, PK/PD, MDS Pharma Services
- And, Professeur Associé, Faculté de Pharmacie, U of Montreal

## Plan:

- Background on clinical studies needed for follow-on small molecule compounds
- Differences between small molecule compounds and protein products
- Clinical studies that may be needed for follow-on protein products

## Standard Generic submission (A/B switchable)(Follow-on small molecule product)

- When filing an ANDA, one only has to prove bioequivalence between two formulations of the same products, pending that the drug product is bioavailable first, and then distributes to its sites of activity (efficacy and toxicity)

## Submission of a “supergeneric” (non switchable)(Follow-on small molecule product)

- Known safety and efficacy: no need to “re-invent the wheel”
- Bioequivalence (CI do not need to be met necessarily)
- Need to fill the “gaps” at the agency in terms of studies that were not done as part of the NDA/NDS (e.g., PK/PD study in hepatic impaired subjects, pre-clinical studies such as a reproductive toxicology one,
- Minimal Phase-III safety assessment needed if any.

## Examples of Biologics marketed:

- Insulin
- Imiglucerase
- Glucagon
- Human Growth Hormone
- Erythropoietin
- G-CSF
- Interferon

## Important differences with large molecules (“protein products” or biologics”) vs. small ones (“drugs”)

- PK can dramatically change with a slight change in the molecule (e.g., glycosylation)
- PD may not necessarily be the same even if PK is the same because it may not be fully possible to prove that 2 products are exactly the same

*What does not change between large molecules (“protein products” or biologics”) and small ones (“drugs”)*

- Efficacy and toxicity related to concentrations of the compounds at the biophase

## Slide 7

## Two different approaches can be sought from a clinical perspective, in order to bring a follow-on formulation of a protein product on the market:

- Clinical Approach: By indication/mechanism of action, relying on extensive Phase III studies
- BE Approach: Using a PK/PD approach, by concept in-line with clinical pharmacology principles, relying on extensive Phase I studies

## Phase-I PK/PD studies:

- 1) **Clinical approach**:
- Objective: to evaluate the PK/PD of a follow-on protein product and calculate an “equivalent dosage” to the reference product
- 1) Single dose PK/PD study. Ratios of the PK and PD parameters of interest are calculated

- If T/R ratios within 80-125, then do SS study
-  with comparable dosage (if necessary)

- If T/R ratios outside 80-125, then repeat SD study
-  with an « equivalent » dosage of the test product before doing the SS study (if necessary).

- 2) SS PK/PD study (if necessary). Ratios of the PK
-  and PD parameters of interest are calculated.

## Phase-III studies: Clinical approach

- Objective: to prove than an “equivalent dosage” of the follow-on protein product behaves similarly to the reference product in a patient population
- ex: Follow-on EPO product, study influenced by Nissensson et al.(2002):
- 600 patients recruited that are on a stable regimen of Epo-alfa given s/c. 8 week baseline period to make sure hemoglobin is at 11 g/dl (9.5 -12.5 g/dl)
- Patients randomized 1:1 between continuing reference treatment or follow-on product given at the equivalent dose determined by the Phase I studies.
- Patients will receive products for 20 weeks during which their dose will be titrated (Hemoglobin at 11 g/dl, range 9.5 - 12.5 g/dl)

- Nissenson AR, et al. _Am J Kidney Dis_ 2002;40(1):110-118.

- Confirmation of equivalence must be tested. 90% CI for T/R ratio of
-  hemoglobin levels have to be between 80-125%.

- Equivalence in terms of dosage must be proven. 90% CIs for the ratio of post dose versus baseline must lie between 80-125 for both test and
- follow-on products. (n=258/group, 80% power, alpha=0.05)

## Phase-I PK/PD studies:

- 2) **BE approach:**
- .Objective: to prove that the PK and the PD of the follow-on protein product are equivalent to the reference one. Ratios and confidence intervals for PK and PD metrics must lie between 80 -125.

- 1) Single dose PK/PD study. 90% ratios and CI of the PK and PD parameters
-  of interest are calculated and have to lie between 80 and 125.

- 2) SS PK/PD study (if necessary). 90% ratios and CI of the PK and PD parameters of interest are calculated and have to lie between 80 and 125.

- If T/R ratios and CI are outside 80-125, then need to change
- approach to the clinical one or change formulation.

## Phase-III studies:

- 2) **BE approach:**
- Safety assessment of the new formulation in patients. Number of subjects needed may be ~300-500.
- A population PK/PD analysis(1) (NONMEM) using a sparse sampling regimen can be done as part of this to provide additional supportive evidence that the formulations are equivalent. This could be done, for example, in 100 patients where the PK and PD are simultaneously modeled and “formulation” is to be tested as a covariate. If significant, the 90% CI must lie between 80-125%.

## Examples of possible requirements with the Clinical Approach:

*Examples of possible requirements with the Clinical Approach:*

- (*) High labeled dose because of non-dose proportionality.
- (#) Multiple-dose BE needed because of time-dependence non-linearity

## Examples of possible requirements with the BE Approach:

*Examples of possible requirements with the BE Approach:*

- (*) High labeled dose because of non-dose proportionality.
- (#) Multiple-dose BE needed because of time-dependence non-linearity

## Acknowledgments:

- 	Paul Chamberlain (MDS PS)
- 	Ian Dews (MDS PS)
- 	Diane Potvin (MDS PS)