The biosimilar market will soon be booming as over $80 billion worth of drugs go off patent in the next seven years – Amit Munshi, CEO, Epirus Biopharmaceuticals, Inc

A ‘biosimilar’ is a biological product that is highly similar to an existing approved biological product (notwithstanding minor differences in clinically inactive components), which has no clinically meaningful differences from the approved biological product in terms of safety, purity or potency.

To succeed, developers of biosimilars must be able to demonstrate to the regulatory authorities a high degree of structural and functional similarity between their product and the approved originator product. They must further convince the authorities that the biosimilar manufacturing process is well understood, controlled and robust. Another challenge for biosimilar developers is to manufacture their product at a lower cost than the originators.

Figure 1. Evolution of biosimilars

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Global market trends

Biologics are an important component of the pharmaceutical industry and have grown exponentially in the last decade. In recent years the pharmaceutical industry has placed greater emphasis on developing biopharmaceutical-based drugs (biologics).

Figure 1 charts the market evolution of biosimilars from 2010 to 2020.

Growth potential in India

By 2020, patents on several biological products with global sales of more than $67 billion will expire. The patent expiration dates for some of the best-selling biologics are set out in Tables 2 to 4.

Biosimilars approved in India

According to GaBI Online, in 2000 the first biosimilar was approved and marketed in India for a hepatitis B vaccine. In recent years more than 50 biopharmaceutical products have been approved for marketing in India, with more than half of them being biosimilars.

Table 5 lists some of the biosimilars that have been approved in India.

In addition, Biocon reported in its April 2014 investor report that it is working on biosimilar versions of Bevacizumab (Avastin), Adalimumab (Humira), Etanercept (Enbrel), Peg-filgrastim (Neulasta), rhinsulin, Glargine, Lispro and Aspart.

Table 1. Key players

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Leagal position

In response to the growth of the biosimilars market in India, the Guidelines on Similar Biologics: Regulatory Requirements for Marketing Authorisation in India were issued in 2012. They lay down specific standards for the development and evaluation of similar biologics.Legal position

The guidelines define a ‘biosimilar’ as a biological product produced through genetic engineering techniques which is similar in terms of safety, efficacy and quality to a reference biologic that has been granted marketing authorisation in India by the Drug Controller General of India (DCGI) on the basis of a complete dossier and that has a history of safe use in India.

Where the reference biologic is not authorised in India, biosimilars will be considered on a case-by-case basis if the reference biologic has been granted marketing approval in a jurisdiction with a well-established regulatory system (eg, the United States or Europe) and has been widely use for at least four years.

All applications for manufacturing and marketing authorisation of biosimilars in India must be evaluated on the basis of the standards set forth in the guidelines.

The demonstration of similarity depends on detailed and comprehensive product characterisation and pre-clinical and clinical studies carried out in comparison with the reference biologic.

Table 6 sets out the stages of the approval process for biosimilars.

Five different protocols for the approval of biosimilars are set out in the guidelines. They involve obtaining approvals and permissions from different agencies in India. These protocols are as follows:

  • Protocol I – indigenous product development, manufacture and marketing of pharmaceutical products derived from live modified organisms (LMOs), where the end product is not an LMO;
  • Protocol II – indigenous product development, manufacture and marketing of pharmaceutical products where the end product is not an LMO;
  • Protocol III – import and marketing of pharmaceutical products in finished formulations where the end product is an LMO;
  • Protocol IV – import and marketing of pharmaceutical products in bulk for making finished formulations where the end product is an LMO; and
  • Protocol V – import and marketing of pharmaceutical products derived from LMOs in bulk and/or finished formulations where the end product is not an LMO.

Table 2. Humanised antibodies

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Recent case

In Roche Products (India) Private Limited v Drugs Controller General of India (Delhi High Court; CS (OS) 355/2014), Roche filed suit on the following grounds:Recent case

  • Non-adherence to the guidelines – the first defendant, the DCGI, had failed to evaluate the applications for manufacturing and marketing authorisation submitted by defendants Biocon and Mylan for their biosimilars on the basis of the standards set forth in the guidelines; and
  • Misrepresentation of drugs as biosimilars and passing off – the second and third defendants, Biocon and Mylan, misrepresented the nature of their drugs as biosimilar versions of Roche’s Herceptin. Accordingly, Roche also made out a case of passing off to restrain Biocon and Mylan from misrepresenting their drugs as being of the same quality and class as Herceptin.

Table 3. Non-humanised antibodies

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Table 4. Non-antibody molecules

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In an order issued on February 5 2014 the Delhi High Court restrained Biocon and Mylan from relying on or otherwise referring to Herceptin, Herclon or Biceltis or any data relating to Trastuzumab, marketed as Herceptin, Herclon or Biceltis, including data relating to its manufacturing process, safety, efficacy or sales, in any press releases, public announcements or promotional or other materials for their own drugs (CANMAb and Hertraz), and from claiming any similarity with Herceptin, Herclon or Biceltis.

In an order issued on February 14 2014 the court observed that as Biocon had already obtained approval for the package insert in question, it could continue using that package insert until the date of the next hearing (February 28 2014); otherwise, the interim order granted on February 5 2014 remained in force.

On February 28 2014 the court rejected Biocon and Mylan’s request to withdraw its order of February 5 2014 and held that it would remain effective under the orders of the court. It also made clear that until the court ordered otherwise, none of the parties could make statements in the media as to the safety or undesirability of the other’s product.

Accordingly, while Biocon and Mylan have been restrained from making such representations, no injunction as such has been granted against the manufacturing and marketing authorisation issued by DCGI in favour of Biocon. The case is pending before the Delhi High Court.

Table 5. Biosimilars approved in India

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Strategic considerations

The emergence of competing biosimilars represents a commercial threat to originators. Price competition threatens profits and the ability of originators to recoup the significant investments that they make in R&D. Lower returns diminish their ability to take risks and assume the financial burden of developing next-generation biologics. Therefore, both originators and biosimilar manufacturers should address business competition, assure the commercial security of their investments and enable them to deliver products of the highest quality. These goals cannot be achieved without a robust IP strategy, key elements of which are addressed below.Strategic considerations

Table 6. Approval process for biosimilars

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Patents

A biosimilar may be sufficiently similar to qualify as a biosimilar under the guidelines, but not squarely covered by a patent claim of the originator product. Originators should thus aim to draft valid claims that secure broad protection for their biologics. To do so, they should consider seeking protection not only for the biologic itself, but also for the target molecule(s) of the biologic, methods of use and methods of production, if possible.

Originators should also consider how their biologics might be modified and consider obtaining patent protection for those modifications, as well as for any improvements to their biologics as per the available law.

On the other hand, biosimilar manufacturers should be aware of the intellectual property that may be involved in protecting the originator product and work out how to avoid it. They should take particular care regarding the admissions they make as to what is and is not equivalent when submitting an application under the guidelines, as such admissions may be useful evidence for an originator that institutes an action against them.

Biosimilar manufacturers should also seek patent protection for their biosimilars under the prevailing Indian law. Given the complexities in this area, biosimilar manufacturers should conduct the necessary investigations and analysis well before any application for manufacturing or marketing authorisation is filed. The steps to be taken include:

  • identifying all relevant patents;
  • determining the expiration dates;
  • identifying the patentees and licensees, if any; and
  • based on the investigation and analysis, developing detailed infringement, validity and enforceability positions.

Both originators and biosimilar manufacturers should fully understand their own patent portfolios and those of their competitors, and review them regularly.

Sophisticated legal counsel, active portfolio diligence and time sensitivity are all necessary to be adequately prepared for future IP disputes.

Trade secrets

Trade secrets are an important form of intellectual property. While patents afford protection for the duration of their term, trade secrets can protect commercially valuable information indefinitely. Trade secrets are usually used to protect manufacturing processes for biologics. These processes include many elements that could be protected as trade secrets, including precise cell growth conditions, analytical processes, purification processes and even characteristics of the cells that produce the drug. Clearly, the details of these processes constitute commercially valuable information that gives the owner a clear advantage. Accordingly, when devising an IP strategy, the importance of trade secrets should not be overlooked.

Trademarks

Trademarks remain an important tool through which originators can enforce their IP rights against biosimilar manufacturers. Biosimilar manufacturers should take care in labelling their biosimilar products so as to avoid suits for infringement or passing off.

Labelling requirements

Genentech’s vice president, US regulatory affairs, Michelle Rohrer, has observed that unique names “avoid unintended substitution, minimise risk of medication errors, allow for essential elements of pharmacovigilance such as traceability and follow-up of adverse drug reactions, as well as facilitate prescriber-patient decision making”.

While the Guidelines on Similar Biologics are silent on the labelling of biosimilars in India, the Drugs and Cosmetics Act, 1940 currently seems to regulate the field. However, this might not be the best legislation to govern biosimilars, insofar as they cannot be treated on a par with generics, which the Indian government appears to have understood.

As labelling is crucial to the safe and effective use of medicinal products, and essential to the content of subsequent promotional material, it is important to adhere to labelling standards which ensure that healthcare providers have the necessary information to make informed decisions regarding the use of these products. Otherwise, the manufacturer risks exposure to litigation based on IP rights violations, as well as the public interest at large.

Biosimilars should be comprehensively labelled, specifying any deviations from the originator product and including unique safety and efficacy data which will assist physicians and pharmacists in making an informed decision. Transparent labelling is important to ensure that physicians and patients have readily available product-specific information about biosimilars, as is the case for originator products. Transparent labelling allows physicians to make informed decisions when selecting the most appropriate medicinal product for their patients. Accordingly, the label should combine information on both the reference product and its biosimilar(s)

It is also important to consider how biosimilars should be identified and labelled to ensure accurate tracking and tracing.

Conclusion

A lot needs to be considered in this complex and important field, and India has a long way to go – especially in relation to the legal framework. There is a need for specific legislation governing biosimilars, with stringent regulatory guidelines and effective cooperation between originators and biosimilar manufacturers, to help improve healthcare standards. Moreover, there has been little litigation in the field thus far and the relevant issues are thus yet to be tested in court.

Sanjay Kumar

Arpita Sawhney

This article first appeared in IAM magazine. For further information please visit www.iam-magazine.com.