Prof. Borut trukelj, PhDBiologics and biosimilars - why the principles of generics do not apply?ISPOR Macedonia, April 24-27, 2014

Brief CVCurrent position: professor , Pharmaceutical biotechnology, University of Ljubljana, Faculty of Pharmacy

Visiting professor: Duquesne University, Pittsburgh, USA

Former expert: EMA , Biotech Working Party (BWP) ; 2003-2012European Pharmacopoeia, Biologicals; 1996-2012

Disclosure:occasionally lecturer sponsored by Janssen, Pfizer, Abbot, Abbvie

What are biological medicines?Biotechnology by WHO: Any technological application that uses biological systems, living organisms or derivatives thereof, to make or modify products and processes for specific use.Biologic medicine or biological is a large (protein) molecule tipically derived from living cells and used in the treatment, diagnosis or prevention of disease. They are:

Proteins (glycoproteins)Fusion proteinsMonoclonal antibodies (recombinant or hybridoma tech Abs)DNA vaccinesGene products

Biologicals at a glanceFirst drugs: 1982 (recombinant human growth hormone, recombinant insulins)

More than 220 products, marketed worldwide

App. 250 products are in development

Since year 2002, first patents of biologicals expired

Biological medicines are made in living organisms: process directs the product!Process:Gene information, cloningVector selectionHost selection (bacteria, yeast, mammal cells)Expression conditionsPurificationFormulation

ADALIMUMAB

PRODUCTION, PURIFICATION AND CHARACTERIZATION OF BIOLOGICALS- Toolbox of complex processesA) Production and purification (production by living host cells, removal of product-related, host-related and process-related impurities)

B) Characterizaton (3-D structure, glycosylation sites, isoform profile) and physico-chemical properties (UV, CD, IR, NMR, HPLC, peptide mapping, sugar mapping, SDS-PAGE, IEF, X-ray, mass spectrometry)

C) Stability (oxidation, truncated forms, hydrolisis, dimerization, aggregation)D) Immunogenicity (nature of the protein, impurities, formulation, route of administration, dose and regime)

ProductionPurificationFormulationHandlingBiological activityQualitySafetyEfficacy

SAFETY: commitment or nihgtmare?EFFICACY versus SAFETY in 1890:

SAFETY OF BIOLOGICALS TODAY:EFFICACY versus SAFETY in 2000:

EXUBERA, PRCA cases

IMMUNOGENICITYCOMPARISON ON SAFETY:SCE (e.g.=paracetamol): side effects in term of purity, toxicityBIOLOGICAL : new safety profile: IMMUNOGENICITY!

Althoug biologicals closely resembles the natural counterpart protein, some immunogenicity may occur as:

- generalized immune effects

- neutralization of exogenous protein

- neutralzsation of endogenous protein (serious adverse event)

Factors that might trigger immunogenic reaction:- sequence variation- glycosylation- host cells- contaminants and process-related impurities- formulation-handling and storage

The occurence and clinical consequence of immunogenicity in humans remains unpredictable

The immunogenicity profile of biologicals and biosimilars can only come from laborous clinical trials and robust post-marketing programs

In 2012, EMA launced a guideline related to mAbs immunogenicity risk: Companies requesting mAbs registrations should develop Risk Management Plan to guarantee not only risk identification and characterization, but also risk minimizing, monitoring and mitigation startegies for post-marketing surveillance

Immunogenicity of monoclonal antibodies

Immunogenicity is not predictable, but might be minimised:

Small chemical entities

innovative generic

BIOLOGICALS

innovative biosimilar generic

Based on the above data, REGULATORY AUTHORITIES (EMA, FDA) recognised that the market approval process to generic drugs can not be applied to biosimilars!Due to complex structure, production and characterisation is is very unlikely that a biosimilar is identical to the original biologic medicine!

From AMGEN brochure on biosimilars:

The approach established for generic medicines is not suitable for development, evaluation and licencing of similar biotherapeutic products (SBPs) since biotherapeutics consist of relatively large and complex proteins that are difficult to characterize*

*WHO Expert Committee on Biological Standardization Guidelines on Evaluation of Similar Biotherapeutic Products; October 2009

The FDA 2012 biosimilar guidance provides a list of factors that assessor should consider when assesing the similarity:

Expression system

Manufacturing process

Physicochemical properties

Functional activities

Receptor binidng and immunochemical properties

Impurities

Characterization of the reference product and reference standards

Characterization of the finished drug product

Stability

The overal costs of developing biosimilars:

According to SANDOZ, the cost of developing a generic SCE is around 2-3 million Eur, whereas biosimilars have been estimated to cost around 100-250 million Eur:

complex process + clinical studies!

Assesment of similarity: MA comparison

Pharmacovigilance and traceabilityAt the time of marketing authorization, manufacturers of biologicals and biosimilars must guarantee that they have an appropriate pharmacovigilance system in place, including services of a qualified person responsible for monitoring pharamcovigilance and the necessary means for notification to regulatory authorities of adverse reastions that may occur in any country where the product is marketed. It should include:

Pre and post-authorization comparative testing

Regular tests to ensure that the manufacturing processes are the same, as biosimilariry and immunogenicity are dependent on this

Risk management in case of adverse drug reactions

An adequate system is required to guarantee specific biological or biosimilar identification (INN?) (traceability)

Substitution and intercangeabilityMost generics are considered to be structurally identical and therapeutically equivalent=interchangeable with their reference products

Contrary, biosimilars are similar to their reference products, they are not structurally or clinically identical, therefore automatic substitution from biologicals to biosimilars and vice versa (!) is not recommended (delayed side effects- traceability)Substitution means that:

The patient may potentially receive a different brand every time their medicine is dispensed!

Substitution and intercangeability, contSubstitution of biosimilars and their related biological products can be problematic due to:

A lack ot traceability in the case of adverse event

Confusion in tracking the cause of delayed adverse event. Biologicals are complex proteins that my initiate immunogenic adverse reactions that may occur several months after treatment. With substitution and switching, a patient may receive several different products prior to immunogenic reactions are detected.

Regulatory view of substitution and interchangeability

U.S.-FDAEurope- EMAWHOThe FDA can designate a biosimilar as an interchangeable biologic when the following criteria are met:The biologic product is biosimilar to the reference biologic product andIt can be expected to produce the same clinical results as the reference product in any given patientFor a biological product that is administered more than once to a patient, the risk in terms of safety or diminished efficacy of switching between the biosimilar and the reference product is not greater than the risk of using the reference product without such alternation or switch.Decisions on substitution are made at national level:UK and Belgium recommend prescribing by brand nameSpain, Germany and France prohibit automatic substitutionIreland, Poland, Slovenia and Portugal: no clear positionThe WHO does not define standards on interchangeability for biologic medicines. It should be defined by the national authorities

ConclusionsModern biologicals are produced by recombinant DNA technology and are composed of large molecules

Their characterization is complex and their structre depends on the process, therefore no identical biogenerics can exist.

Immunogenicity is one of the most specific and severe adverse effects that might occur in treatment with biologicals and biosimilars

Detailed pharmacovigilance and traceability plans shoud be prepared for eash biological and biosimilar. Traceability by using solely INN is not a satisfactory criterium!

From the safety point of view automatic interchangeability is not recommended for biologicals and biosimilars

6. As the biosimilar market expands and biosimilars become more complex, it is necessary to clarify the prescribing regulations