Key players in the biotechnology industry are leading an effort to obtain global approval processes for generic biological medicines, which experts say could provide cheaper access to costly but widely prescribed and promising treatments.

These highly complex medicines, many of which have recently or will soon come off patent, are difficult to produce and reproduce and highly expensive to purchase.

This raises questions about how patients can access these cutting-edge technologies, and whether the creation of generic versions – called biosimilars, biogenerics, or follow-on biologics — is feasible. Key issues with biosimilar creation include the question of who owns the right to use data from clinical trials, and whether it is possible to make versions of such complex products similar enough that they can be substituted for the brand-name originals.

The term biologics generally refers to protein-based medicines, as opposed to chemical based medicines, and their production involves genetic manipulation and large-scale cultures of living cells rather than chemical synthesis. This means that “biologics are inherently much more difficult to copy and to replicate than small-molecule products,” said Hans Sauer of the Biotechnology Industry Organization (BIO). Slight modifications to the production process may induce biologics to behave differently.

The Center for Biologics Evaluation and Research, part of the US Food and Drug Administration, notes that biologics are often “at the forefront of biomedical research” and “may offer the most effective means” to treat medical conditions “for which no other treatments are available.” They also cost on average twenty-two times more per daily dose than traditional chemical medications, according to a 2008 paper by Boston University economics professor Laurence Kotlikoff [pdf].

What constitutes appropriate regulation for these new technologies is still being considered, and multilateral discussion is still in its fledgling stages. Outcomes arising from select areas of the world – the recent European guidelines or the result of the current US debate – are likely to shape international policy on these issues.

Thus, debates over regulation of and access to biologics are set to become increasingly important. In the United States, this has been primarily an “industry versus industry fight, brand name versus generic,” said Sarah Rimmington of think-tank Essential Action.

However, Sauer said lines between these stakeholders are blurring, with a “pretty diverse field of industrial participants” — from classic generics companies to emerging biotechnology companies to the traditional innovator companies — interested in biosimilars.

Designing A Pathway for Biosimilars

Innovator, or brand-name, companies who stand to benefit from fewer generic versions of their inventions cast doubt on the interchangeability of biosimilars with brand-name biologics.

Sauer said that “we are convinced, and do believe, that the concept of follow-on biologics [biosimilars] is viable. We think it’s possible.” However, he said that even with more testing, it is still not possible to make identical copies of biologics as with traditional chemical drugs.

“Many more studies in patients than are required for small molecule generic drugs will be necessary for follow-on biologics because the science is just not there at this point to ensure that we can make follow-on biologics that are identical to the reference product.,” he said.

The US FDA, in its response to the House Energy and Commerce Subcommittee on Health inquiry on biosimilars [pdf], stated that “protein products are more complex [than traditional chemical drugs] and… in most cases, follow-on protein products will not be the same as the reference product in the manner that generic drugs … are the same as the listed drug.”

The response adds that the risk of potentially life-threatening immune-system responses could make switching from one product to another dangerous, and expresses concern that “patients not be exposed to an avoidable safety risk by being switched to a product not known to be interchangeable with the product they are currently receiving.”

Interchangeability and substitution is “where the value of generic competition will create substantial savings for consumers,” said Charlie Mayr, speaking on behalf of the Generics Pharmaceutical Association (GPhA). Without an approval process that allows for a designation of interchangeability, biosimilars would be essentially like a brand product, he added.

The generics industry has been a vocal proponent of a biosimilars pathway, or a way for regulatory authorities to determine if interchangeability is possible and what tests are needed to confirm it.

Currently, generics companies must perform the same clinical trials as innovator companies to market biosimilars, a much costlier process than the abbreviated submissions required for traditional chemical medicines. This, said Mayr, would not “offer consumers substantial savings” because the biosimilars company would incur all of the clinical testing costs and marketing costs that innovators do. The industry seeks market access upon patent expiry as is the case for traditional chemical drugs.

Data Exclusivity in a Legislative Void

From the initial concerns regarding science, the debate has “shifted to getting held up over details, in particular the marketing exclusivity issue has been a real hold up,” said Rimmington.

Exclusivity refers to a period following the approval of the biologic or the expiry of its patent that may prolong the patentee’s monopoly beyond the term of the patent. Marketing exclusivity prevents manufacturers from marketing biosimilars during the exclusivity period whereas data exclusivity prevents them from relying on the data generated by the innovator for an abbreviated approval submission. The terms are often used interchangeably and most often refer to data exclusivity.

Traditional chemical medicines have a data exclusivity period of four to five years in the United States. Innovator companies claim that a comparable period for US biologics would have to be 14 years, due to differences in the market, the approval process, and the medicines themselves.

Sauer said that these differences are in part due to the fact that patent protection of and the approval process for biologics are not “paired up” as well as they are for traditional chemical drugs. As a biosimilar need only be comparable, rather than identical, to the brand-name biologic, “the follow-on product could be similar enough to get abbreviated approval…but different enough to escape the patent,” Sauer added.

This means the biosimilar could be approved for market – using the shorter approval process for generic products – but remain distinct enough that its release before patent expiry of the branded medicine would not be considered infringement.

The generics industry, however, believes “that it should be significantly less than fourteen years” and that it is something that “is to be negotiated,” said Mayr.

Europe led the way in designing regulation in 2005 by issuing its “Guideline on Similar Biological Medicinal Products” [pdf], a scheme for producing biosimilars which provides ten years of data exclusivity to the innovator and requires generic companies to justify “differences between the similar biological medicinal product and the reference (innovator) medicinal product … by appropriate studies on a case-by-case basis.” The guideline notably remains silent on the issue of interchangeability.

Only a handful of other countries have an effective pathway for biosimilars, though some countries have simplified the general approval for biological products. Australia adopted the EU guideline in June 2006 and Malaysia adopted a guideline in August 2008. Canada recently published a draft guidance document and received comments on it, but has yet to introduce any guidelines or legislation. Japan is also considering regulatory options.

In a 2005 bioequivalence and bioavailability guideline [pdf], India’s Central Drugs Standard Control Organization noted that complex interchangeability issues could be resolved by the applicant “on the basis of contemporary scientific rationale,” but did not define what this entails. Brazil and China, both with potential biopharmaceutical capacity, do not have clear guidelines on how to approve biosimilars.

In the United States, several measures have been proposed recently, all of which died with the end of Congress last year. Developments in the United States on this issue may have important international ramifications because the country currently accounts for fifty-six percent of the worldwide biologics market.

Multilateral System Checks In

Biologics are attracting the attention of some intergovernmental organisations, but not drawing attention in some others. The World Health Organization (WHO) held an informal consultation to discuss the issue in April 2007. The participants “agreed that WHO should develop a global regulatory guideline for biosimilar products” and that “a WHO working group should be established to take this issue forward,” according to the meeting report [pdf].

Alison Brunier, a communications officer at the WHO, said that the long-standing Expert Committee on Biological Standardization discussed issues pertaining to biologics, namely a pathway for biosimilars, during its meeting in October 2008. Although the committee’s report is currently awaiting approval and is expected to issue shortly, she said that the committee concluded that the resolutions of a document it was reviewing needed to be strengthened and should be reviewed at its next meeting scheduled for October 2009.

In November 2007, the World Intellectual Property Organization invited a speaker to discuss biologics during as part of its Symposia on Intellectual Property and Life Sciences, but has otherwise not weighed in on the debate.

Separately, a source familiar with WIPO proceedings said that there is no obvious way to introduce the biosimilars issue politically into WIPO as “nobody’s really pushing it internationally.” However, the source noted that the creation of biosimilars might have significant international consequences as it could lead to either market access or World Trade Organization Trade-Related Aspects of Intellectual Property Rights agreement disputes depending on whether the issues are viewed from a regulatory or intellectual property perspective.

The “whole [access to medicines] debate is structured on the small molecule paradigm,” said the source, but biologics “will be the access issue of the day.” The US debate is important because “the way that it is teased out at the national level will influence the international debates… Ultimately, the issue will be decided in a few jurisdictions,” the source added.

WIPO’s disinterest in and WHO’s concern with biosimilars are generally consistent with how states handle generic medicines legislation, namely more as an access to medicines and health safety issue than an IP issue, despite strong links to the IP regime.

Some nongovernmental organisations have expressed opinions, though seldom in international fora. Rimmington noted that Essential Action has long identified biologics as an important issue, but does not “have the capacity” to participate in international debates at this point, despite their involvement in international health issues such as access to medicines and research and development.

Biologics also are being recognised as a significant concern for developing countries. Rimmington said biologics are a “really high-priced class of drugs, and they are for major killers – serious auto-immune diseases, cancer, multiple sclerosis and diabetes – and those conditions kill more people globally in developing and developed countries than even very big killers like AIDS and [tuberculosis] and malaria do.”

A recent report by the Pharmaceutical Research and Manufacturers of America (PhRMA) [pdf] found that many biotechnology medicines currently in development relate to HIV/AIDS and infectious diseases, typically associated with developing countries. However, several sources stated that developing country governments and NGOs dealing with those countries do not really have an appetite for this issue at this time.

Kiernan A. Murphy was an intern with Intellectual Property Watch in January 2009.