BIOSIMILARS- THE FUTURE OF BIOLOGICAL DRUGS

A MOHAMED KASIM

INTRODUCTION:Biological agents are produced in a living system like a micro-organism, plant or an animal cell by harnessing rDNA.

The end product is a protein directed against a specific gene or another protein which is highly specific for its function and target antigen.

The introduction of biological such as erythropoietin, insulin, growth hormones and anti-cytokine therapies brought a new era in modern medicine and transformed the treatment of many chronic diseases.

The first biologic approved was humulin in 1982 by USFDA.

DEFINITIONS:BIOLOGICAL PRODUCT: Medical products are made from a variety of natural sources using biotechnology methods and other cutting edge technologies and are intended to prevent or treat diseases and medical conditions.

BIOSIMILAR(EMA): A biosimilar is biological medicinal product that contains a version of the active substance of an already authorized original biological medicinal product. It demonstrates similarity to the reference product in terms of quality characteristics, biological activity, safety and efficacy.

BIOSIMILAR(INDIA): A biological product/drug produced by genetic engineering techniques and claimed to be similar in terms of safety, efficacy, and quality to a reference biological.

GENERIC DRUG: A generic drug is same as the brand name drug in dosage, safety, strength, how it is taken, quality, performance and intended use.

BIOLOGICS AND SMALL MOLECULE DRUGS:

Active substances can be divided into small and large molecule drugs.

Small molecule drugs(SMDs) are stable, inorganic molecules with a low molecular weight, typically manufactured by chemical synthesis and can be fully characterized.

Largemolecular drugs/Biologics are 200-1000 times the size of SMD made in living organism by rDNA or by controlled gene expression methods. They are vulnerable to degradation in GI tract thus given parenterally

GENERICS AND BIOSIMILARS:

GENERICS:They have active ingredients whose chemical and therapeutic characteristics are identical to the reference products in terms of dosage, strength, route of administration, quality, safety, efficacy and intended use.

Regulatory agencies generally approve applications of generic drug manufacturers requiring only demonstration of bioequivelance to reference products in terms of pharmacokinetics parameters and bioavailability.

BIOSIMILARS:The same standards of generic drugs cannot be applied to biosimilars as there are many differences.Two independently developed biologicals maybe bioequivalent yet not pharmaceutically interchangeable in the absence of evidence gathered from clinical studies.Biosimilar cannot be made an exact replica of reference biological due to:1- Complex structure.2- Complex manufacturing process and heterogenecity.3- Characterisation.4-Effect of external conditions.

ADVANTAGES:The biggest advantage is the accessibility of effective, affordable biologics to the underserved patients suffering from chronic diseases.

VARIABILITY:The complex manufacture process of biologics can introduce minor variations in the end product that it affects its stability, safety, sfficacy and immunogenicity. A study was carried out on 16 biosimilar brands covering three different biological : recombinant C- GSF, Recombinant human C- GSF and rHuEPO.It showed a lack of comparability between biosimilars and reference products and significance difference in purity among biosimilars of C- GSF and erythropoietin.

SAFETY INCLUDING IMMUNOGENICITY:Immunogenecity is an important safety concern for biosimilars. Immune reactions may lead to inactivation of drugs and thus limiting its efficacy and affecting its safety leading to adverse effects.Factors affecting immunogenicity include:1- Product-Related factors2- Route of administration3- Patient Factors4- Eprex episode.

RECALL AND DRUG SHORTAGE:The complex manufacturing process of a biosimilar may often lead to quality concerns and batch-to-batch variation which may impact patient safety.This may result in recall of some batches of the products and result in drug shortages which can have significant disruption ins in treatment practices.

NAMING:While conventional generic names have the same INN as the reference compound, naming has become very difficult.Effects of biosimilars may differ in patients and are often delayed and therefore it is important to trace the effect of a biological in patients from safety point of view.

NAMING:While the conventional generic drug have the same INN as the reference compound naming conventions have become complex.Effects of biosimilars may differ in patients and are often delayed, therefore it is important to trace the biological effect in patient in view of safety point of view.Tracking the identity and traceability by INN in case of an undesirable effect may create an unforeseen delays.SUBSTITUTION AND INTERCHANGEABILITY:Generic SMDs are considered interchangeable and easily substituted, biosimilars cannot be considered interchangeable.Interchangeability for biological cane be considered at two levels, one between the biosimilars and the reference product and second between the two biosimilars of the same reference product.

REGULATORY OUTLOOK OF BIOSIMILARS:1- EUROPEAN MEDICAL AGENCY(EMA):EMA was the first to establish the regulatory framework for approval of biosimilars in 2005.Omnitrope(Somatropin) was the first biosimilar approved by EMA in 2006.It has issued overarching guidelines for demonstrating similarity between biosimilars and reference product, followed by guidelines on quality, non-clinical/clinical issues, with additional product specific guidelines for interferon alpha, LMWH and monoclonal antibodies.Safety assessment plan including postmarketting surveillance, pharmacovigilance and risk management plans must be included in the data package submitted for product approval.

RUGULATORY GUIDELINES BY EMA:1- Guidelines on similar biological medicinal product.2- Guidance on similar medicinal products containing recombinant human insulin.3- Guidelines on nonclinical and clinical development of similar biological medicinal products containing LMWH4- Guideline on similar biological medicinal products containing recombinant FSH.

UNITED STATES FOOD AND DRUG ADMINISTRATION(USFDA):BPCIA was passed in 2010 which created an abbreviated licensure pathway for biological products shown to be biosimilar or interchangeable with FDA.This pathway permits reliance on certain existing scientific knowledge about the safety and effectiveness of the reference product.The first biosimilar approved by FDA was Zarxio(Filgrastim-sndz) in march 2015.FDA issued three draft guidance documents in 2012 on biosimilar products addressing scientific and quality considerations and recommending a step-wise approach to demonstrate biosimilarity.As per guidelines the biosimilar manufacturers will have to conduct animal toxicology studies, pre-approval clinical trials, and potentially postmarketting safety studies.

INDIAN REGULATORY GUIDELINES FOR BIOSIMILARS:In july 2012 guidelines on similar biologics: Regulatory requirements for marketing authorization in India was introduced.It outlines an simple abridged procedure for evaluation in similar biologics.The demonstration of similarity depends upon detailed and comprehensive product characterisations, preclinical and clinical studies carried out in comparison with a reference biological.

India has a robust growth in biosimilar drugs development.Biosimilar products being marketed currently include erythropoietin, human growth hormone, recombinant human insulin, G-CSF, interferon, etanercept, infliximab, rituximab and adalimumab.Developing a biosimilar is far more expensive than manufacturing generic both in terms of time and cost.For development of a biological it is estimated that a biosimilar can cost 20-40% less than their reference product.This reduction is marginal compared to generics of SMDs where the reduction is as large as 70-80-%.

COMMON BIOSIMILARS AVAILABLE IN INDIA:Epoetin alpha recombinant erythropoietin- Anemia, cancer and CKDEtanercept- Ankylosing spondylitis, JIA, RA, Psoriais and psoriatic arthritis.Filgrastim- Recombinant G-CSF- Neutropenia, hematopoietic SCTFollitropin alpha(FSH)- female infertilityRecombinant human insulin- Diabetes mellitusRecombinant human interferon alpha- Carcinoids, Hep-B&C, hairy cell, CMLRecombinant streptokinase- Arterial occlusion, DVT, PERecombinant rTPA- Myocardial infarction.Rituximab Monoclonal Ab targeting CD20- Leukemia, Lymphoma, RATrastuzumab- RAAdalimumab- Ankylosing spondylitis.Teriparatide- Post-menopausal women with osteoporosis who are at risk for fracture

CONCLUSION:Biosimilars offers the promise of more accessible to biological products to patients suffering from chronic disease.High degree of variability among the biological products, quality issues and safety issues such as immunogenicity call for careful selection.Physicians and health care profesionals need comprehensive information on biosimilars with awareness about critical aspects of biosimilars such as safety, interchangeability, tracking and substitution.

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