biosimilars: interchangeability topics for physicians .... biosimilars... · refine these for...

Biosimilars: Interchangeability Topics for Physicians, Pharmacists and Regulators

Iqbal Ramzan PhDProfessor of Pharmaceutical SciencesSydney Pharmacy School, Faculty of Medicine and Health

Definition: What is a biologic medicine?

Active substance(s) made by or derived from a biological source, rather than a chemical source or synthesized chemically. These are either relatively small molecules such as human insulin or erythropoietin, or large and complex molecules such as monoclonal antibodies. They are typically proteins or protein containing agents produced using biotechnology (e.g. recombinant DNA techniques) and manufactured in cell culture or living organisms including humans, animals or microorganisms

Terms like “de novo biologics drugs or “bio-originators” have also been used

SINDUSFARMA, IPS/FIP and ANVISA VIII Symposium- New Frontiers

Wide variety of biologic medicines


➢ Hormones (e.g. insulin for diabetes or growth hormone [GH] for GH disorders)

➢ Monoclonal antibodies (for autoimmune diseases and cancers) and recombinant therapeutic

proteins

➢ Blood and blood components (e.g. coagulation factor concentrates for haemophilia)

➢ Immunomodulators (e.g. beta-interferon for multiple sclerosis) or BDMARDS in

rheumatology

➢ Enzymes (e.g. to remove blood clots)

➢ Vaccines (for prevention of bacterial/viral infections); novel targeted vaccines for cancer

➢Allergenics (allergen extracts, allergen patch tests and antigen skin tests)

➢ Somatic cells, gene-based and cellular therapies and tissues (forefront of innovator biologics)

Definition: What is a biosimilar (follow-on biologic)?

➢A biological product that is ‘highly’ similar to and has no clinically meaningful differences from an approved reference/innovator product

➢‘Highly’- extensively characterize structure and function of the reference and the proposed biosimilar product. Chemical identity, purity and bioactivity compared to demonstrate that the biosimilar is ‘highly’ similar to the reference product

➢Minor differences between the reference product and the proposed biosimilar product in clinically inactive components are acceptable

➢A biosimilar has no clinically meaningful difference in terms of purity, safety and potency (safety and efficacy)


Definition: What is a biobetter?


➢Biobetters are related (but not identical) to existing biologics by target of action but deliberatively improved in manufacturing attributes, disposition, efficacy and safety➢Biobetters build on the success of an existing approved biologic but

present a lower commercial risk than a new class of biologic➢Some regulatory jurisdictions define biobetters differently and

some countries do not use the term biobetters➢From a regulatory perspective, biobetters are considered as

innovator drugs (while biosimilars follow class-specific guidance)

Definitions: Interchangeability, switching & substitution


➢Interchangeability- the medical practice of changing one medicine for another to achieve the same clinical effect in a given clinical setting and in any patient, on the initiative of, or with the prescriber’s agreement. An interchangeable product is a biosimilar that produces the same clinical outcome in any given patient

➢Switching- decision by treating physician to exchange one medicine for another with the same therapeutic intent in a given patient (compare with non-medical switching, NMS, switching for economic or other reasons)

➢Substitution- dispensing one medicine instead of another equivalent/ interchangeable medicine by the pharmacist without consulting the prescriber

Pivotal differences

Biologics Small molecule drugs (SMDs)

Large/complex molecules or mixtures of these molecules

Well defined chemical structures

Product is the process - >1000 process steps Manufactured by chemical synthesis- specific agents are used in an ordered and sequential manner

Living processes that are very sensitive to minor changes in manufacturing- may alter product and its function (efficacy, safety)

Well defined chemical process or isolation -subject to lower batch-to-batch variability

Ensure product quality, purity and function by ‘stable’ or ‘consistent’ manufacturing

Finished product can be analysed to identify/quantify each individual component

Unwanted immune reactions are common (i.e., NOT rare)

Unwanted immune reactions may occur BUT are rare

Why is it difficult to develop biologics?


‘Effect of Molecular Complexity on Process Development and Analytical Data Requirements to Support Drug Marketing Applications.’Fig 1 from Konara et al (2016): Trend Biotech 34 (1): 70-83

Manufacturing & post-translational modifications (PTMs)


➢Aggregation/misfolding- most common for recombinant proteins➢Oxidation (of methionine) and sometimes of other amino acids➢Deamidation (of asparagine) and Amidation (e.g., for stem cell factors)➢Glycosylation heterogeneity- specific to the protein and expression system➢Human pathogen transmission (similarity of expression host to human cells)➢Hydroxylation (primarily proline); Sialylation and Carboxylation➢Sulphation- specific to surface exposed tyrosine residues surrounded by acidic

residuesMay profoundly affect protein therapeutics requiring

biophysical/functional assays to ensure stability, efficacy and safety

Analytical tools for characterising innovator biologics and biosimilars and identifying PTMs


➢Aggregation- SE-HPLC, analytical ultracentrifugation and ion-exchange (IEX)

chromatography, light scattering & extrinsic dye binding methods

➢Oxidation- MS, UV of peptide fragments, IEX/hydrophobic interaction (HI) chromatography

➢Deamidation (of asparagine)- IEX & IEF, peptide mapping/mass fingerprinting

➢Glycosylation heterogeneity- MS techniques following digestion

➢Others techniques- Spectroscopy (MS, Flourescence, UV-VIS, Light scattering and NMR);

Microscopy (TEM, Optical and AFM) for studying aggregates and particle size

➢MS and LC are the industry workhorses- but sensitivity or other shortcomings

➢ There is need for more specific and sensitive analytical techniques

Pharmacists need to be aware of innovations in analytical tools to characterise all biologics

Regulatory & policy frameworks


➢Does a National Medicines Policy exist? – if so key components of these➢Is there a national policy on adoption of biosimilars and regulatory and subsidy

frameworks to support this?➢Rapidly evolving evidence- how to respond in an agile but responsible (measured)

manner? (especially for cutting-edge biologics like CAR-T therapies)➢Local (hospital/area health district) policy on biosimilars or use of specific

innovator biologics?- role of Pharmacy and Therapeutics Committees➢ Specific policy for substitution of innovator biologics? (e.g. In the EU,

substitution policy is made at national not EMA level and varies between different countries). How does SUS in Brazil fit into this policy framework?

Pharmacoeconomic and pricing considerations


➢Expenditure on innovator biologics and biosimilars can be easily identified

➢Biosimilars have very different price dynamics compared to SMD generics

➢Many drivers of biosimilar pricing (e.g. tendering, launch price, supply and demand-side policies, evergreening, LDN, etc)

➢Pharmacists, especially those providing procurement advice, need to understand the complexities of biosimilar pricing

Post-marketing risk management (RM) and pharmacovigilance plans


➢Generally the risk profile of biosimilar is expected to mirror that of the innovator biologic➢But a similarity exercise may fail to detect differences in safety and

efficacy signals between innovator biologic and its biosimilar➢Most regulatory jurisdictions require pharmacovigilance plans as

part of approval➢Such plans need to be robust – of sufficient duration, longitudinal,

appropriate data capture/transfer, specifically identify product used (naming convention is important to achieve this)

Quality Use of Medicines (QUM)


➢QUM concepts firmly accepted and embedded internationally for SMDs➢Refine these for innovator biologics/biosimilars taking into account national and

international medicines policies and regulatory frameworks➢Consideration of issues for patients (and their carers and health practitioners)

regarding benefits and harms➢Pragmatic and economic considerations for hospitals and payers (governments or

other third party payers/insurers)➢Policy discussion and implementation to ensure sustainable access (across

continuum of patient care) to innovator biologics or biosimilars (need a viable Biotech Pharma Industry in line with National Medicines Policy)


Australian Government Biosimilar Uptake Drivers

Key Underlying Principles

➢Prescribers will retain choice of brand to prescribe

➢PBS will consider uptake drivers on a case-by-case basis

➢ Existing authority to prescribe reference brands will not be increased (widened)

➢Greater use of biosimilars is key to access to clinically cost effective innovator biologics

Underlying principles driven by 1) Simpler and faster approval process for prescribing

biosimilars 2) Lower cost via Price Disclosure

KEY OUTCOME SOUGHT- Encourage/Increase Prescribing of Biosimilars

Does the Brazilian SUS Promote Biosimilar Uptake?

Enhancing adoption of biosimilars: an exemplar from Australia

Knowledge areas on biosimilars for pharmacy students

Pharmaceutical /biomedical sciences Enabling pharmacy & public health practice

Fundamental biochemical and biophysical properties of proteins and large molecules including vaccines and antibodies

Therapeutic differences between biologics and SMDs

Battery of complex biophysical/functional tests

QUM and behaviour change concepts for wider adoption of biosimilars

PK/PD of proteins/large molecules (their distinct elimination pathways and mode[s] of action)

Pharmacoeconomics of biologics –biosimilars are not priced like generics

Cell biology and basic immunology and immunogenicity from proteins and antibodies

Pharmacoepidemiology and post-marketing pharmacovigilance and safety plans for innovator biologics/biosimilars

What pharmacists need to know about biosimilar interchangeability issues? # 1


✓History of innovator biologic (time on market) and preclinical/clinical rationale

✓ Class of biologic (target for mode of action)?

✓How is it manufactured, stored and transported (are PTMs likely)?

✓Method/frequency of administration- stability in supply-chain and environmentally-

challenged countries

✓Delivery device (pre-filled syringes, pens, pumps etc)- do these affect compliance?

✓Availability of biosimilar(s)?

✓Naming convention- does it enhance (or detract from) acceptance and uptake

✓ Likelihood of reduced efficacy- nocebo effect

✓Reduced efficacy- neutralisation of biosimilar or endogenous counterpart(s)

What Pharmacists need to know about biosimilar interchangeability issues? # 2


✓ Cost (Vs innovator)- Pharmacoeconomic considerations including government subsidy

✓ Key adverse effects (especially propensity for immunogenicity responses)

✓Current/prior SMD (continue or cease?)

✓ Familiarity with rapidly changing regulatory guidelines (e.g. EMA, FDA, ANVISA, TGA)

✓Anticipate likely key questions from clinical team or patient

✓Risks of immunogenicity; Definitions of adverse effects: Very Common (≥1 in 10);

Common/Frequent (≥1 in 100 & < 1 in 10); Uncommon/Infrequent (≥ 1 in 1000 & < 1 in

100); Rare (≥ 1 in 10,000 & < 1 in 1,000) and Very Rare (< 1 in 10,000) CIOMS/WHO/UMC

✓Do’s & Don’ts for patients (e.g., storage, continue or cease SMD etc)

Check-off items as discussion proceeds/evolves to minimise critical omissions

Key take-home messages


➢Science is complex and evolving at a faster rate than policy makers can embed regulatory and policy frameworks

➢Greater economic pressures for biosimilars of innovator biologics

➢ Pharmacists need to be aware of new data as they are ideally placed to have conversations with doctors and patients

➢Need more extensive training of pharmacists on innovator biologics and biosimilars; this has implications for pharmacy educators

Key points about biosimilars- Pharmacists need to understand:


➢Interchangeability principles➢Regulatory frameworks for biosimilar approvals➢Naming conventions➢Manufacture, formulation and delivery devices➢Pharmacoeconomics and cost drivers of biosimilars➢Post-marketing pharmacovigilance plans to gather real

world data➢Clinical implications (efficacy, safety) of using biosimilars

vs innovator biologics➢QUM for biosimilars to deliver optimal patient outcomes

Thank you and questions


Acknowledgments: Associate Professor Veysel Kayser; Mouhamad Reslan; Vicki Sifniotis)

Useful References

➢ Ward et al (Biosimilar Awareness Initiative)

http://www.health.gov.au/internet/main/publishing.nsf/Content/biosimilar-literature-review

➢ McKinnon et al (Biosimilarity and Interchangeability: Principles and Evidence: A Systematic Review

(BioDrugs- https://doi.org/10.1007/s40259-017-0256-z)

Future Resources

➢ Ramzan I (Editor) Biologics, Biosimilars, and Biobetters: “An Introduction for Pharmacists, Physicians

and Other Health Practitioners” Wiley: Publication date: 2020

➢ Ramzan I: Biosimilars: interchangeability issues for pharmacists. Clinical Pharmacist (invited review,

under revision, June 2019)

https://doi.org/10.1007/s40259-017-0256-z

Additional Brazilian References


❖ Scheinberg MA et al (2018). Partnership for productive development of biosimilar products: perspectives of

access to biological products in the Brazilian market. einstein (São Paulo). 16 (3): 1-6.

❖ Azevedo VF et al (2012): Potential regulatory and commercial environment for biosimilars in Latin America.

Value in Health Regional Issues 1: 228-234

❖ Bertoldi AD et al (2012): Is the Brazilian pharmaceutical policy ensuring population access to essential

medicines? Globalization and Health 8: 6-16.

❖ Fuller R (2010): Editorial: Are we prepared to prescribe biosimilars? Bras J Rheumatol 50 (3): 221-224

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