Erythropoietin is a hot candidate biogenerics companies (picture courtesy Flamel Technologies)
The pioneers of the biotech industry get a last chance to defend their products against imitators at a meeting in Paris today and tomorrow (8 - 9 December). The European Medicines Agency (EMEA) has called the meeting as the final stage in a five-year consultation process to establish rules for the development and approval of generic versions of protein drugs that are coming off patent.
Biopharmaceuticals with global sales of more than $10 billion per annum will come off patent by 2007, opening the way to generics. But the original inventors - or innovators - are fighting to the last to maintain dominance, claiming that the nature and sophistication of their products means they are impossible to copy.
The long road to a legal framework
The step towards establishing a new legal basis for evaluating and approving biosimilars in Europe was laid down just over four years ago on 6 November 2001. This was subsequently amended in June 2003. Further developments came in March 2004, and all member states were due to have the various directives in force by the end October 2005.
Alongside the legal process EMEA has issued a series of general guidelines covering quality and safety issues, and specific guidelines for four products – erythropoietin, granulocyte-colony stimulating factor, insulin and human growth hormone.
EMEA's aim is to synthesise all the written submissions it has received on the guidelines, along with comments from the Paris meeting, and produce final guidelines in the first half of 2006.
That should put Europe in the lead over the US, where despite pressure from biogeneric manufacturers, the FDA is yet to publish a long-promised white paper on the issue. But pressure will intensify next year when new Medicare legislation comes into force under which the federal government will pick up the bill for all drugs for those over 65 years old.
Registration
To register a chemical generic the manufacturer has only to demonstrate it has the same active ingredient and is bioequivalent (that is, works in the same way in the body), and present it in the same dosage forms as the branded product. This requires small trials on healthy volunteers, but generics manufacturers are spared the huge length of time, and the expense, of conducting any other preclinical or clinical trials.
Companies with biopharmaceuticals reaching the end of their patent protection argue it is impossible to prove equivalence of a biogeneric in the same way, and that patient safety dictates that generics manufacturers should be required to conduct a series of clinical trials on patients.
EMEA concedes exact copies are impossible - and has made this explicit by ditching the term biogeneric in favour of biosimilar.
European advantage
But Europe would have much to gain in allowing biosimilars onto the market. According to the Generic Pharmaceutical Association, a US body promoting the interests of generics manufacturers, the average cost of one day’s supply of a biopharmaceutical drug is $45, while a chemical drug costs an average of $1.66 per day. Generic medicines cost up to 80 percent less than their branded counterparts, and while 53 percent of all drugs dispensed in the US are generics, they account for less than 12 percent of total spending on prescription drugs.
Biopharmaceuticals are inherently more expensive to manufacture than small molecule chemicals, making rock bottom pricing an impossibility. But the high prices mean a cost reduction of 10 or 20 percent would translate into significant cost savings for those paying the bills. And with more and more protein drugs coming through the development pipeline, many for conditions that currently go untreated, they are poised to take a larger and larger slice of the total healthcare budget.
In the face of political pressure to bring down prices, and scientific advances that make it possible to more fully characterise protein drugs, EMEA is determined to formulate a legal basis for evaluating and approving biosimilars by a shorter pathway. (See sidebar)
In doing this the agency is breaking new ground, says Julian Hitchcock, Senior Solicitor at the law firm Mills and Reeve. "Until the end of October [2005] EU legislation did not even provide a way to get approval; there is still no rule about the minimum level of similarity. Furthermore, the EMEA guidelines under discussion in Paris don’t have legal force."
Hitchcock believes the guidelines are deliberately vague, giving regulators room to deviate from them on a case-by-case basis.
Vagueness
But this vagueness annoys innovator companies such as Amgen, which says the guidelines leave many questions unanswered. This includes the vexed issue of how equivalence of a biogeneric can be demonstrated without referring to the innovator’s data. The company questions also if the safety requirements are stringent enough, and if the risk/benefit test has been passed.
Not only that, the issue of naming biosimilars, and when and whether they can be substituted for the original product is not even raised, notes Thomas Bols, Amgen’s Director of Government Affairs in Europe.
"There should be guidance about what biosimilars are called," said Bols. "Since they are similar, but not identical to the original product, they should not have the same International Non-proprietary Name (INN), as is the case for chemical generics. If you accept they are different, they should have different INNs, because without different names it will be impossible to conduct pharmacovigilance," said Bols.
Another unanswered question is whether biosimilars - acknowledged to be different - can be substituted for the original product. Some European countries allow pharmacists to dispense generics even if the prescribing physician names the original drug. "We think that should not be done with biosimilars, because they are not identical, so there is a risk of immunogenicity [triggering an immune response]," said Bols.
Amgen also questions some requirements for registering specific products. For example, the guidelines for erythropoietin (EPO) say there should be a 12-month study in 300 patients to see whether it triggers an immune response. GeneMedix, a UK company that is developing biogeneric EPO, agrees this is reasonable. But Bols said EMEA should say exactly what risk assessment it carried out to arrive at this figure. "In the past we have done 1,000 patient studies when we have made manufacturing changes."
Once a chemical generic is allowed on the market it can be prescribed for all the same indications as the innovator drug. Amgen argues that this principle should not apply to biosimilars because the mode of action can differ from one disease to another.
Expiring patents
While the US patents still have five years to run, the European patents on Epogen, Amgen’s EPO product expired at the end of 2004. In effect the lack of a regulatory process for approving biosimilar versions has given the company an extension to its market exclusivity, but twenty or so generic versions of EPO are in development, and products are on the market in countries including India and China.
The multiplicity of versions in development could kill the market for biogeneric EPO before it gets going, believes Stephen Charles, vice president of business development and licensing at Nektar, a drug development company. "Several generic EPO development programmes are under way at a high development cost for each one, and many will hit the market at the same time. Price competition will kill the attractiveness of this business."
Lining up behind Amgen is the US BioIndustry Association, the trade body representing biotech companies in the US, and its counterpart EuropaBio, which represents 1,500 companies across Europe. In its submission to EMEA, EuropaBio says, "Biosimilars are complex molecules, they are not generics and necessitate appropriate preclinical and clinical testing before being delivered to patients. There should be no relaxation of the approval standards for biosimilar medicines."
Blazing the trail for biosimilars is Sandoz, which has filed for approval of Omnitrope, its biogeneric human growth hormone in both Europe and the US. Despite finding nothing wrong with the data in the respective applications, both EMEA and the FDA have refused approval on the grounds that they don’t have the power to do so, leaving Omnitrope stuck in a regulatory no-man’s-land on both sides of the Atlantic.
While it agrees that biologicals are more complicated than chemical generics, Sandoz claims the technology has advanced to the point where it is possible to characterise protein molecules and show equivalence. The company says approval is being refused on policy issues and has filed legal cases in both jurisdictions.
'Be prudent, not brave'
However, innovators argue that improvements in analytical techniques should make the industry more aware of the possibility of differences. "We are getting down to the level where you are talking about one amino acid substituting for another," said Paola Ricci, Head of Pharmaceutical Affairs at the Swiss biotech company Serona. "In other words the more you see, the more you should get prudent, not brave."
Other biosimilars that have been filed in Europe are human growth hormone and interferon alpha, both produced by BioPartners.
All of which gives but a flavour of the vested interests to be aired as the protagonists meet up in Paris. It also shows how much is at stake: creating an open market in biosimilar drugs is being held up as a measure of Europe's ability to free itself from red tape and encourage innovation.
Whatever the objections, EMEA appears to believe its long-winded approach is about to bear fruit. "This is the final stage of public consultation before the guidelines are finalised in the first half of 2006," said an EMEA spokeswoman. "We do not expect it will lead to substantial alterations, but maybe some fine tuning."
"There is no question that EMEA will put safety first," said Hitchcock. "But have no doubt it wants to foster a free market in biosimilars."
Receive our Policy Bulletin each Tuesday & Thursday and news about bridging Europe’s east-west innovation gap twice a month in The Widening. 
