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As patents expire, clinical trials will be caught in the middle between copyists and original innovators.
Twenty years ago, when the research-based European pharmaceutical industry started to panic about the gathering tide of patent-expiry dates for many of its leading products, its anxieties were met in part.
Some relief came from the creation of supplementary protection certificates—the consequence of the industry's energetic campaign for patent term restoration. But even more effective relief was provided by the growing trend toward innovation through biotechnology. This led to the development of new classes of highly sophisticated products that seemed less vulnerable to generic copying than the classical chemistry-based products that the industry had depended on for half a century. Not any more.
The technological innovations that provided pioneers with new types of products are proving double-edged: generic nemesis is catching up, as the same technological innovations make it possible for competitors to exploit the same technology and produce copies—biosimilars, as biotech generics have come to be inelegantly termed.
For the first time, many patents protecting first-generation biologic innovations have come to an end in Europe, making the creation of generic versions of these medicines technically possible. Against this background, 2006 promises to be the year of the battle of the biosimilars. And the clinical trial community is likely to be caught right in the middle of it.
The European Medicines Agency in London (EMEA) has set up a working party on biosimilar medicinal products, and a glance at its work plan for the year tells its own story. It is holding four formal meetings of two days each, but the real work will be going on behind the scenes. It will be finalizing a new guideline on nonclinical and clinical issues in relation to biosimilar medicinal products containing biotechnology-derived proteins as active substance, on which consultation ended in late 2005. And it will be doing the same, and on the same timetable, for guidelines on similar biological medicinal products containing somatropin, recombinant erythropoietins, recombinant human insulin, and recombinant granulocyte-colony stimulating factor.
Concept papers are also due to appear by April 2006 on nonclinical and clinical issues for biosimilars containing recombinant á-interferons, and on immunogenicity assessment of biological/biotechnology-derived proteins, with new draft guidelines on each subject being released for formal consultation before the end of the year. And the third quarter of 2006 also promises to see a three-month consultation start on an update to EMEA's note for guidance on non-clinical and clinical issues in relation to comparability of medicinal products containing biotechnology-derived proteins as active substance. Revision is needed, says the Agency, since comparability issues are now separated from development and evaluation of similar medicinal products. The working party will round off the year with a specific training course for regulatory staff and experts on assessment of similar biological medicinal products.
EMEA had already been preparing its ground for what will be a difficult discussion. In particular, it organized a meeting in Paris at the end of 2005 with key biotech players, academics, and others with an interest. The responses to this meeting mark out clearly the terrain the battle of the biosimilars will be fought over.
EuropaBio, one of the European associations defending the pioneers, welcomed the EMEA-initiated dialogue, but issued a firm call for the EU "to settle all outstanding important issues before the first biosimilars enter the market." It says that these issues need to be discussed "in a transparent manner in order to ensure that biosimilars will be used safely and effectively, including the need for a unique name and label for a biosimilar." Clear and distinct labelling is essential to avoid confusion between the innovator product and a biosimilar, and to facilitate pharmacovigilance obligations, EuropaBio explains. And the chairman of its healthcare council, Dr. Andrea Rappagliosi of Serono, emphasized the need for "sound and science-based guidelines."
The Emerging Biopharmaceutical Enterprises (EBE)—representing Europe's smaller pharmaceutical firms with an involvement in biotechnology—also welcomed the opportunity for discussions, with similar emphasis on "an open, transparent setting." And it claimed that the ultimate goal of the emerging framework of guidelines "should be to ensure biosimilar medicines do not compromise the safety of patients."
It isn't very hard to decipher the code being employed by the pioneers in their formal statements. There is a common thread in their allusions to "balancing the state of our existing knowledge of these complex medicines with the need to increase access in a safe, legitimate manner," or to "appropriate risk management programs," "labelling that allows physicians to make informed decisions," and "appropriate pharmacovigilance and postmarketing surveillance." Basically, they don't want copy products slipping into the market through a back door—and they urge a clear and rigorous regulatory regime as the best way of stopping that from happening.
EBE decided its statement should not leave anything open to doubt. "Biosimilar medicines are not generic products, and therefore require different development, assessment, and registration approaches that are adapted to their specific nature and complexity. Unlike traditional pharmaceuticals, biologic medicines are made through a process involving living cells and have the potential to cause serious immune responses if not manufactured, tested, and monitored properly," it insisted. And now that the EU is putting a "transparent and clear regulatory pathway" in place, "companies developing biosimilar medicines have a responsibility to follow this pathway and ensure that the products concerned demonstrate the standards of quality, safety, and efficacy expected by patients and prescribers."
The companies that are pressing to get their biosimilars onto the market are—unsurprisingly—seeking to defuse all the concerns about safety and maximize their own unique selling proposition: They can give health care providers a better deal because their products are going to be cheaper.
Greg Perry, director general of the European Generic Medicines Association (EGA), announced on the fringes of the Paris meeting: "The current level of biological science and recently enacted pharmaceutical legislation in Europe mean that the next generation of affordable medicines is no longer a distant dream, but rather a soon to be realized reality." He emphasized that Europe's biosimilar companies "have the scientific expertise and the technical experience to produce safe and effective follow-on pharmaceuticals based on medicines derived from biotechnology."
Hitting where originator companies can provide little counter-argument, Perry also underlined that "Europe's health care systems are more than ready for the cost relief these new products will bring in addition to increased patient access to life enhancing treatments." EGA claims that the first wave of just six biosimilars is capable of generating savings of more than US$2 billion per year on Europe's overall medicines bill. "This amount would allow an additional 500,000 people suffering from kidney failure to receive EPO treatments, prolonging the time before they need dialysis," it argues. Similarly, EGA presented figures suggesting that biosimilars could offer savings of up to 40% on the seven biologicals in the top ten injectable medicines in Europe.
So while EGA talks about a "solid science-based agenda" too, its interpretation of solid science is ensuring "timely and efficient access to these more affordable biological products" by making them substitutable and interchangeable for originator products, and by applying "the established risk management framework pragmatically and sensibly."
The territory where these two forces will clash—with pioneers seeking to mount their final stand against losing their market to dubious copies and copyists determined to win what they see as realistic evaluation of their products—is, of course, on clinical trials hill. Tough trial requirements and evaluation will provide a discreet mechanism for keeping copies off the market. As EBE says, its members "are confident that our regulators will take care to ensure the proposed clinical trial programs for biosimilar products do not put patients at risk." By the same token, generous—or what EGA calls "pragmatic"—interpretation of what is needed to prove a copy can do as much as the originator product will allow health care providers to cut their bills.
Observant readers of this column will have noticed a reversion to the use of EMEA as the designation for the European Medicines Agency. It's not an accident—it's a tribute to a distinguished professional with a worldwide reputation in the clinical trials community.
A casual remark in this column about the discrepancy between that name and initials of the recently renamed European Medicines Agency triggered a response from no lesser figure than the agency's Advisor on Integrated Quality Management, Marijke Korteweg. I had mischievously pondered in passing ("It's the Children Again," Applied Clinical Trials, October 2005) about when the agency would adopt initials that fit its new name and stop using its old acronym EMEA, derived from its working title: European Medicines Evaluation Agency.
Marijke pointed out to me—with characteristic precision—that EMEA didn't accurately reflect the previous formal name either, which was originally the European Agency for the Evaluation of Medicinal Products. When the legal change in name to the more convenient European Medicines Agency was considered, serious investigation was conducted into changing the acronym, related to the domain names EMEA and EMA. But "the outcome was that EMEA should be kept," she told me, and pointed out with equal precision, "The actual logo, EMEA, always had that second 'e.'"
If I were to be ungracious, I might still ponder about why on earth the agency ever chose EMEA in the first place, since the acronym never reflected its real name. But I shall instead draw my lesson from Marijke's accompanying comments, which firmly relegate reflections on the Agency's name to the margins of discussion. "I believe we should focus in the first place on the quality of the deliverable and the efficiency of our processes," she insists. "Some 399 staff in 20 languages try nowadays at the EMEA to do so, and I hope they can help to make health care in Eu-rope better. If we can contribute to a world-class regulatory system, it may satisfy more than one stakeholder."
And Marijke is pushing ahead with her customary energy to help achieve just that. Plans are under discussion for an exercise in the benchmarking of medicines agencies right across Europe, based in part on the work undertaken by the EMEA in the last few years to help integrate new member states from eastern Europe into the EU's system of medicines regulation. Watch this space for further news.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.