Lead Author: Amit Sengupta
Additional Author: K M Gopakumar
Organization: Peoples Health Movement and Third World Network
Country: India


Drugs developed using biotechnology are different because they are produced in living cells. The molecules, which make up these drugs, are larger in size and more complex than the ‘small molecule’ drugs manufactured using the chemical synthesis method. Biotherapeutic products (BTP) are increasingly being used for treating cancer one of the prioritised non-communicable disease (NCD). However, BTPs are not accessible at affordable price. Even the non-originator BTPs is not affordable. Access to BTPs is critical for treating both communicable and non-communicable diseases. However, there are three main barriers to access to affordable BTPs viz technology, intellectual property and regulatory barriers. This submission mainly focuses on the bio-similar regulatory pathway, which makes the availability of non-originator BTP costly. Submission makes 6 proposals to facilitate availability of non-originator BTP affordable price.



The next new-frontier of disease control lies in finding remedies that can effectively cure and control cancers and several degenerative diseases. The field of biotechnology is starting to deliver entirely new forms of treatment. Drugs developed using biotechnology are different because they are produced in living cells. The molecules, which make up these drugs, are larger in size and more complex than the ‘small molecule’ drugs manufactured using the chemical synthesis method. These drugs – termed as biotherapeutic products (BTP) – have several potential advantages as they can, theoretically, be tailored to hit specific ‘targets’ in the human body. Also known as 'Biologics' these products are fast becoming the new ‘top selling’ drugs in the global market.

The fastest growing segment of the biotherapeutics market is the recombinant glycosylated proteins segment– projected to grow annually at 25% by 2018. Within this, the monoclonal antibody segmented alone, it is projected, will grow at an estimated CAGR (compounded annual growth rate) of 41.9% from 2013 to 2018

There are 8 BTPs among the top IMS list of worlds top selling 20 medicines. There are three top selling BTPs viz. arerituximab, bevacizumab and trastuzumab are classified as essential medicine by WHO. Access to BTPs is important to achieve targets mentioned in SDG 3. BTPs are increasingly being used for treating cancer one of the prioritised NCDs.

At least eight major biologic Monoclonal Antibody (MAb) drugs are already/will be off-patent products between 2013 and 2018. These include Rituxan/MabThera, Remicade, Herceptin, Humira, Avastin, Synagis, Erbitux, and Lucentis.

Unlike in the case of conventional ‘small molecule drugs’ it is never possible to produce an exact replica of the original drug. BTPs are extremely sensitive to the manufacturing process and the starting material. As the starting material is a living cell, it is impossible to have an exactly similar starting cell. Moreover very small changes in the manufacturing process can bring about changes in the final product. Thus, even in the case of the original product, there are variations in the product – between batches and even within the same batch. Thus 'bio-generics' (also called biosimilars in the literature) can never be exact replicas of the reference molecule, that is the original BTP. Though it needs to be emphasized, as we mention earlier, even for the originator BTP, differences exist in the molecule produced in different batches.

BTPs, especially monoclonal antibodies are valuable therapeutic products, whose use is currently limited by their extremely high costs. The three most targeted products for development of bio-generics are Rituximab (used to treat leukemia, lymphomas and auto immune disorders such as rheumatoid arthititis), Infliximab and Adalimumab (both used to treat a range of debilitating auto-immune disorders such as ulcerative colitis, Crohn's disease and Psoriasis). All three have high worldwide sales and are marketed for multiple indications.

However BTPs are extremely expensive and consequently not accessible to patients, especially in Low and Middle Income Countries (LMICs). For example the cost of one vial of adalimumab (for the originator product Humira from AbbVie) would cost about $ 1000 -- almost equivalent to the average annual wage in a low income country. Even though BTPs available from the non-originator companies are available, the current price differential is extremely modest, at 40-50 per cent less than the originator price.. The high prices of BTPs are increasingly taking large share of the public health budget of many countries. According to the Colombian Health Minister Alejandro Gaviria, last year biotech medicines accounted for 35 % of the pharmaceutical market in Colombia, and the sector is growing rapidly. Similarly in Brazil while BTPs account for 4% by volume of drugs distributed through its National Health System, they account for over half of the Ministry of Health's expenditure on medicines.

This submission is focusing on access to Bio-therapeutic products (hereafter BTP) at affordable price from the non-originator companies.

Statement of the Problem

Unlike in the case of generic equivalents of small molecule originator drugs, there is no effective competition in the market for BTPs even in situations where the patents of the originator molecules have expired. Contributing to this situation is the complex structures of BTPs and their dependence on relatively complex manufacturing processes involving living cells. Current analytical methods cannot fully characterize these complex molecules sufficiently to confirm structural equivalence of a biogeneric with the reference molecule (the original BTP). This complexity brings various barriers to competition in the market. These barriers are: technological, intellectual property rights and regulatory barriers.

Technological Barriers: Manufacturing of BTPs based on using recombinant DNA technology is a relatively new area as the process involved are entirely different from those used to produce drugs through the chemical synthetic route. It is important to build technological capabilities in the BTP sector in 'non-traditional' manufacturing countries. Importantly, unlike in the case of small molecule generic industry, many Multinational pharmaceutical companies (viz. Sandoz) are entering the area of bio-generic manufacture. The latter have a stake in keeping the prices of bio-generics comparatively high, and hence repeated industry led assertions that bio-generic introduction will lead to a modest drop of 40-50% in prices. This assertion is belied by recent evidence -- for example India's Zydus Cadila has recently introduced its version of adalimumab (Exemptia) leading to a 80% price reduction . Companies from South Korea, China, India, Brazil and Argentina are now active in the bio-generics segment but face entry barriers because of the chilling effect of harsh regulatory systems (as we see later) in most parts of the world

IP Barriers: BTPs are protected through patents, date exclusivity and trade secrets. BTPs are protected through product and process patents. Unlike small molecules, in the case of BTPs process patents can act as a major barrier. Even after BTPs lose patent exclusivity, trade secrets can continue to create barriers to the entry of bio-generics. Since the knowhow around BTPs is protected through trade secrets by the originator company, bio-generic manufacturers are not in a position to exactly characterise the molecule. This is unlike in the case of small molecules where, if the original molecule is known, its manufacturing process can be determined through reverse engineering. This barrier around knowhow is linked to the regulation of marketing approval of non-originator BTPs and regulatory regimes generally support the restrictions on full disclosure through the medium of trade secrets.

Regulatory Barrier: Since late 1990’s non-originator BTPs have been known by different names viz. follow-on biologics, bio-generics, bio-betters, bio-similars, etc. Generally speaking, these nomenclatures are closely linked to the regulatory pathways followed for the approval of non-originator BTPs. Regulatory pathway for the non-originator BTPs were recognised in many Asian countries since 1990s and many such products have been available in the market for decades. The regulatory pathway followed in Asian countries was different from the bio similar regulatory pathway. The bio similar pathway was initially developed by the ICH (International Conference on Harmonization) -- a closed regulatory standard setting body consisting of only drug regulators of EU, USA and Japan and the originator pharmaceutical manufacturing associations of these countries. European Guidelines build on these standards in 2005. In 2009 the WHO Expert Committee on Biological Standardisation adopted Guidelines on Evaluation of Similar Bio-Therapeutic Products. These guidelines drew heavily from the ICH guidelines.

Since then there has been a major push for the adoption of bio similar guidelines in other countries. Including in LMICs, that conform to guidelines initially developed by the ICH, largely reflective of the interests of originator companies. These guidelines require 'head to head' comparability of the non-originator product with the originator product. According to the WHO Guideline “Demonstration of similarity of a SBP (similar bio-therapeutic product i.e. non originator product) to a RBP (reference bio-therapeutic product i.e. originator product) in terms of quality is a prerequisite for the reduction of the non-clinical and clinical data set required for licensure. After each step of the comparability exercise, the decision to proceed further with the development of the SBP should be evaluated”. Further, it states: “The basis for licensing a product as a SBP depends on its demonstrated similarity to a suitable RBP in quality, non-clinical, and clinical parameters. The decision to license a product as a SBP should be based on evaluation of the whole data package for each of these parameters should be evaluated”. According to WHO Guideline “If comparability exercises and/or studies with the RBP are not performed throughout the development process as outlined in this guidance document, the final product should not be referred to as a SBP”. Thus the WHO Guidelines insist that the non-originator has to prove not only safety and efficacy but also similarity in structure with the originator product.

Such insistence is not commensurate with the science underlying BTPs. All BTPs irrespective of whether applied to originator or non-originator products are inherently variable due to the fact that they are produced from living organisms. This variability exists within batches, from batch to batch, and when production processes are improved or changed or differs between manufacturers. The variability of biopharmaceuticals is greater than that typically observed for conventional pharmaceuticals and applies to originator reference products as well as bio-generics. Even in the case of the original product, there are variations in the product – between batches and even within the same batch.

This demonstration of similarity with originator requires comparative clinical trials with the originator. According to industry sources 50% of the bio-similar development cost are as a result of the need to purchase the originator’s product. Further, the burden of proof on similarity also increases the duration of bio-generic development. Lastly, every bio-generic developer, even when a molecule is fully characterised, needs to carry out fresh clinical trials for safety and efficacy (potentially is in conflict with the Helsinki Protocol). These onerous regulatory requirements prevent significant drop in prices when bio-generics are introduced and represent the most significant barrier to affordable access to BTPs. These requirements have little scientific validity as safety and efficacy of bio-generics is what regulatory agencies need to be concerned about and not precise similarity to the originator molecule -- which anyway is virtually impossible to accomplish. Thus claims of 'similarity' of structure are arbitrary, thus placing enormous arbitrary power in the hands of regulatory agencies to reject applications for registration of new bio-generics.

Reflecting the concerns on non-availability of BTPs including bio-generics at affordable prices the World Health Assembly in 2014 adopted a resolution on BTP. This resolution stated: “to work to ensure that the introduction of new national regulations, where appropriate, does not constitute a barrier to access to quality, safe, efficacious and affordable biotherapeutic products, including similar biotherapeutic products”. The resolution further requested the Director General “to convene a WHO "Expert Committee on Biological standardization to update the 2009 guidelines, taking into account the technological advances for the characterization of biotherapeutic products and considering national regulatory needs and capacities and to report on the update to the Executive Board”. However, there is no such updating of the Guidelines on Evaluation of Similar Bio-Therapeutic Products has taken place till date. In 2015 the WHO Expert Committee on Biological Standardisation came up with a new protocol titled “Regulatory Assessment of Approved RDna derived Bio-Therapeutics” authorities states : “Products already approved under the pre-existing regulations will need to be reassessed to ensure that they meet the new requirement”. In other words national regulatory agencies should undertake a stepwise regulatory review of all biotherapeutic products already authorized for marketing, which do not meet current WHO regulatory expectations. . Thus the new guideline casts doubts on the safety of products approved through alternative regulatory pathways.

WHO's Guidelines on Evaluation of Similar Bio-Therapeutic Products was criticised for its similarity proof requirement. The current situation is summed up by two authors as follows : ““Biosimilars regulatory guidance should be reviewed in light not only of the scientific and regulatory experience gained over time, but also of the needs and interests of national health systems and pharmaceutical markets in low-resource countries . Stringent regulatory authorities such as EMA have already begun to waive requirements for comparability exercise at clinical level under appropriate circumstances. This approach is supported by academic experts who claim that non-comparative clinical trials are sufficient for regulatory purposes, and who call for pragmatic approaches focused primarily on the patients clinical outcomes and on scientific c principles, using the state-of-the-art tools” .

Further, the authors conclude that “The current WHO guidelines on similar biotherapeutic products should be reassessed based on accumulated science and experience, and in ways that foster the development and marketing of quality-assured, safe and effective biological drugs.”.
In 2014, Colombia through a Presidential Decree amended its bio-similar guidelines to enhance access to affordable BTPs. It said: “The decree will allow patients to have therapeutic alternatives of equal quality and lower price and establishes three routes for obtaining registration of bio-similars, which are: The “complete file route”: applicable to new drugs and clinical and pre-clinical tests with animals and humans should be included before approval. The “route of comparability”: applicable to drugs that are not new, but not yet sufficiently known and should include results of comparative studies between the biological drug and the bio-similar. The“short route of comparability”: applicable to known drugs with fully characterized chemical, where there is no need to repeat all experiments with animals and humans, but evidence of studies made to the drug to be produced must be provided”.
Another related issue is that originator companies often block the inter changeability of originator BTP with bio-generics. It is important that inter changeability should be permitted as is currently the case in many countries including in the EU.
This current regulatory framework is based on questionable scientific proof. As a result it prevents access to affordable BTPs’. Current regulations prevent people from enjoying their right to utilise the benefits of scientific progress and its applications (Article 15 .1 (b) of the International Covenant on Economic social and Cultural Rights). Further, it also comprises the enjoyment of Right to Health.
Against this background we propose

Proposal 1

WHO should establish a fresh panel of independent experts, free of conflict of interest, to examine the comparability requirement on the basis of latest scientific evidence and to suggest amendments to the Guidelines on Evaluation of Similar Bio-Therapeutic Products.

Proposal 2

WHO should suspend the implementation of the latest Regulatory Assessment of Approved RDna derived BioTheraupatics till the above mentioned process is over.

Proposal 3

WHO Member States should review their bio similar guidelines and the requirement to demonstrate similarity to quality, non-clinical, and clinical parameters with the originator BTP on the basis of scientific evidence.

Proposal 4

WHO Member States should make public investment to build the technological capability in developing affordable BTPs including mechanisms such as the public funding of clinical trials.

Proposal 5

All UN Member States should allow inter changeability of originator’s BTP with non-orginator BTP.

Proposal 6

Bilateral, regional and plurilateral Free Trade Agreements should not contain language that inhibits sharing of knowhow regarding BTPs, including, for example, language that provides for data exclusivity.

Bibliography and References

Note that in this submission we use the term 'biotherapeutics' for biotechnologically derived originator products and 'biogenerics' for non-originator products
http://cellculturedish.com/2015/03/10-biologics-on-best-selling-drugs-list-for-2014/ also see WHO ELM http://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf
WHA 67.21 http://apps.who.int/gb/ebwha/pdf_files/WHA67-REC1/A67_2014_REC1-en.pdf#page=25 p. 68