# Presentation: 049388

## FDA PUBLIC WORKSHOP – SCIENTIFIC CONSIDERATIONS RELATED TO DEVELOPING FOLLOW-ON PROTEIN PRODUCTSSEPTEMBER 2004

- John Greenwood, Director of Regulatory Affairs, GeneMedix plc
- Chairman of the Biotechnology Working Group,
- European Generic Medicines Association [EGA]

## INTRODUCTION

- I am the Director of regulatory affairs at GeneMedix plc a UK
- registered company involved in the manufacture of what in the
- European Union are now being referred to as ‘Similar Biological
- Medicinal products.’
- During my time with the company and due to my involvement within
- the European Generics Medicines Association and direct discussions
- with the EMEA and the CHMP, I have gained experience in the
- development of two of these products for subsequent registration in
- Europe and today will be addressing the considerations for an
- abbreviated pre-clinical and/or clinical development programme
- Based on the outcome of *in-vitro *physicochemical and *in-vivo*
*Biological *Comparability testing.

## Data Requirements - Introduction

- Provided that physicochemical *in-vitro * and *in-vivo *biological potency
- are shown to be comparable with the innovator protein, there should
- be no concerns with reference to efficacy.  In many cases, the
- physicochemical structure of the molecule dictates its potency so that
- any non-structural conformity may well affect this parameter.
- However, as the Product is manufactured, tested and formulated using
- different cell lines, manufacturing methods, analytical testing methods
- and excipients, the prime concern of any regulatory agency will be its
- safety.  For this reason, in Europe, the requirement for additional
- studies over and above the characterisation are considered on a
- case-by-case based on the Complexity of the molecule and its
- therapeutic use during discussions between the company and the
- CHMP.

## Data Considerations – Complexity of the Molecule

- The final data package will be based on the complexity of the molecule and the ability to fully characterise that molecule:
- 	Short chain              longer chain           long chain          monoclonal antibody
- 	 peptides +TT/DT     non-glycosylated       glycosylated
- 	(Insulin)                  (GM-CSF)                 (EPO)
- Characterisation of the molecule must be by the most up-to-date methodology to
- Determine the full structure; primary, secondary, quaternary and tertiary plus
- any possible post-translational modifications and impurities either from product or
- process:
- The further to the right, the more likely pre-clinical/clinical data will be required
- and the extent of that data may increase from no pre-clinical/clinical requirements
- to possible pre-clinical toxicology/safety studies and clinical studies in patients.
- However, in all instances it should not be the intent to duplicate the pre-clinical
- and clinical studies required for registration of the innovator product.

## Techniques for physicochemical comparability testing

**Technique****	****	****	****	****Demonstrates**
- Circular dichroism			Secondary & Quaternary structure
- NMR				Primary & Secondary structure + size
- HPLC size exclusion			Size, secondary/quaternary structure/purity
- Ion exchange chromatography		Charge/primary structure/purity
- Reverse phase Chromatography	Primary/secondary/quaternary structure/purity
- Reduced electrophoresis		Size/primary structure/purity
- Non-reduced electrophoresis		Primary/secondary/quaternary structure/purity
- Isoelectric focusing			Charge/primary structure/potency
- Binding immuno-blotting		Size/ Primary/secondary/quaternary structure
- Mass spectroscopy			Size/primary structure/purity
- Receptor binding			Primary/secondary/quaternary structure
- Bioassay				Primary/secondary/quaternary structure/potency

## Data Considerations – Pre-clinical 

- In general, it is not believed that pre-clinical studies provide any data of scientific value.  However, if deemed a regulatory requirement, clinical usage of the product should be considered.
- In these cases there seems no scientific rationale for exposing animals to large doses (e.g. 100 times the human dose equivalent) as the safety of these molecules has already been proven.  In addition, due to their clinical usage, the possibility of large or even small overdoses is negated by the presentations. It would also seem inappropriate to include two or more animal species in the studies especially the use of higher order animals such as dogs and monkeys, unless there were a specific reason for doing so due to the pharmacodynamic action of the molecule.

## 

If clinical studies are deemed necessary (case-by-case), the extent of the studies should be based on clinical usage

	For example, 

Small, short-term studies for rescue therapy products
Longer-term studies for life-time usage products

- If clinical studies are deemed necessary (case-by-case), the extent of the studies should be based on clinical usage
- 	For example,
- Small, short-term studies for rescue therapy products
- Longer-term studies for life-time usage products

- Data Considerations – Clinical Usage

## The Patient Population being Treated
It should be taken into consideration the status of the 
patient to be treated in the different indications for any one
product.  If the mode of action is well understood
and considered to be the same for all indications, there should
be no requirement for clinical studies for each separate
indication. 
The route of administration
This must be considered in both pK and pD studies in animals 
and in the clinical setting.  If products have different routes of
administration for different indications or stages of treatment,
additional studies may be conducted in animal and/or humans
to demonstrate comparability.

- It should be taken into consideration the status of the
- patient to be treated in the different indications for any one
- product.  If the mode of action is well understood
- and considered to be the same for all indications, there should
- be no requirement for clinical studies for each separate
- indication.
**The route of administration**
- This must be considered in both pK and pD studies in animals
- and in the clinical setting.  If products have different routes of
- administration for different indications or stages of treatment,
- additional studies may be conducted in animal and/or humans
- to demonstrate comparability.

- Data Considerations –Patient Population/Route of Administration

## If clinical studies are indicated they should be designed on a purely 
Statistical bases not on round figures.  The ability to reduce the
numbers of patients exposed to the follow-on product is paramount
as in some instances, the patient numbers available will be limited
and even when available, may not agree to a change in their
treatment to a previously untested product. Patient numbers should
be based on the known mode of action of the molecule, the ease of
end-point measurement and the degree of difference to be allowed 
between the innovator and follow-on product in a comparative
clinical study.

- Statistical bases not on round figures.  The ability to reduce the
- numbers of patients exposed to the follow-on product is paramount
- as in some instances, the patient numbers available will be limited
- and even when available, may not agree to a change in their
- treatment to a previously untested product. Patient numbers should
- be based on the known mode of action of the molecule, the ease of
- end-point measurement and the degree of difference to be allowed
- between the innovator and follow-on product in a comparative
- clinical study.

- Data Considerations - Clinical

## Regulatory Advice

- It is essential that a company wishing to develop a
- follow-on protein consult with the agency at an early
- stage in their development programme to determine
- if and what studies will be required to demonstrate
- comparability (physicochemical and biological)
- and if further studies such as pre-clinical safety,
- toxicology and immunogenicity are required, the
- extent of those studies.