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Germany takes the lead on regulating therapeutic allergy vaccines

This article was originally published in Scrip

Executive Summary

All companies using a "loophole" in German law to sell allergy vaccination products, including injectables, on an unregulated named patient basis should have submitted a marketing authorisation application to the regulator by 1 December should they wish to continue to sell them there.

Some of the largest producers of these products in Europe are: Danish-firm ALK (some 1,500 employees and Euro260 million in revenues), French-firm Stallergenes (Euro190 million), German firm Allergo-Pharmo (part of Merck KGaA; Euro90 million), and midsize ones such as Holland's Hal (Euro45 million), Spain's Leti (Euro40 million) and UK-based Allergy Therapeutics (Euro50 million), which has submitted 10 marketing authorisation applications in Germany to meet the deadline and aims to be "one of the top three global allergy immunotherapy companies" (see box 1 for a snapshot of this firm).

Germany is the number one market in Europe for these sorts of products, which can contain a mix of allergens, including grass and tree pollens, mostly because the state reimburses them, followed by France. It is also the country that has the most developed regulation for these products which are mostly sold on a named patient basis in Europe (see box 2 for a snapshot of the EU market).

"The product is prescribed, it is produced by the manufacturer [but] there is no evidence for its efficacy and no demand to generate safety data [...] We wanted to regulate the market and to stop the abuse of a paragraph in the national drug law," Professor Stefan Vieths, head of the allergology division at Germany's Paul Ehrlich Institut (PEI), the German regulator for vaccines and biomedicines, told Scrip.

He added: "We find it necessary to stop this bypassing of this requirement for marketing authorisations, so took the initiative to regulate the use of these products. In effect, we are leading this process, but it is not perfectly co-ordinated in Europe."

The change comes about as a result of a regulation – translated as "Regulation of Therapy Allergens" – that Germany passed in November 2008, to regulate a market that has had a inconsistent approach, where some allergy vaccination products have a marketing authorisation while many are available on a named patient basis because of an exemption allowing doctors to prescribe these products on such basis.

The regulation will apply to "common" therapeutic allergen therapeutic products, specifically those containing grass or flowering trees (birch, alder, hazel) pollen, house dust mite and bee and wasp venom. "Any product containing these allergens/pollen need to be authorised now," declares Professor Vieths.

In Germany alone, more than 50% of the market are named patient based products. There are some 250 products that have German marketing authorisations, as well, but their evidence of efficacy was "based on the state of scientific knowledge at the time that they worked", says Professor Vieths. Some products were authorised in the 1980s and 1990s, but clinical trial standards are different now with the advent of the GCP Directive.

At the time of the public consultation for the regulation, there was some objection from companies that the it would bring in high costs, as they would need to perform clinical trials to show efficacy and safety. The PEI expects Phase III trials to contain at least 200 to 300 patients.

Dr Tom Holdich, R&D director for Allergy Therapeutics (pictured), a UK based firm that produces therapeutic allergy vaccines for the German market, told Scrip that it expects the regulation will mean higher costs for firms, but that it was converging with firm's own strategy that these are "value-added innovative products". "It is changing the landscape in Germany... so moving away from a mix match products to licensed products."

Long timeline: 2017 first approval?

As part of the regulation, the first stage required that from November 2008 to May 2009 all manufacturers needed to notify the PEI of any products they planned to submit a marketing authorisation application (and for those products they did not plan on doing so). Then by 1 December 2010, companies had to submit the applications based on the notifications. Firms who have filed applications can continue to sell the products on a named patient basis until the PEI starts the review process.

The PEI has a set timeframe for companies to answer questions on "deficiencies" in their dossiers: for non-clinical deficiencies, companies are given up to one year to supply the data to the PEI; for clinical deficiencies, where clinical data is required, they are allowed up to seven years to submit the data.

So approvals could in theory not be seen until 2017/2018. "Until they have reviewed the dossiers it is difficult to know what will happen with the approval timeline," says Dr Holdich. "It could be two or three years after 2017 before the first approval."

Professor Vieths agrees: "Maybe we will not see a product on the market until 2018, under the new system." However, the institute is wasting no time in dealing with quality issues with these products. "We have been doing experimental batch release to measure the potency of these products from 2009. To see whether an allergen is in the product? Some batches have not been released because they did not meet the standards. Sometimes the dose of the allergen was too low."

Another key benefit of having these products regulated is that they must face same pharmacovigilance monitoring as other regulated medicines, ie, adverse drug reaction reports, as named patient based products do not need to have ADR reporting.

Box 1: Snapshot of immunotherapy firm Allergy Therapeutics

Allergy Therapeutics saw its revenues rise by 8% to £40.8 million (for the year ended 30 June 2010), and gross profit rose by 22% to £29.6 million. Profit after tax increased to £0.6 million (there was a loss of £11.8 million for previous period). 70% of its business comes from the German market. Like many of these immunotherapy companies it is a SME, employing some 350 people, mainly at its manufacturing headquarters in Worthing, Sussex, UK, with a second office in Munich, Germany.

It has submitted 10 marketing authorisation applications to Germany's biologics regulator, the Paul Ehrlich Institut, to meet the 1 December deadline.

Its leading product is Pollinex Quattro, which makes up some 50% of its sales, and is a short four-injection immunotherapy course, containing an allergen as an "allergoid", meaning the allergen has been modified to be safer. The allergoid is bound to amino acid tyrosine to act as "depot" so there is a better immune response (the firm prefers to use tyrosine over aluminium hydroxide). An adujuvant – monophosphorolipid A (MPL) - is also included to stimulate the immune response and "direct it". "It redirects the immune response from a T helper 2 cell response, which is the abnormal response seen in patients with an allergy, to a T helper 1 cell response," says Dr Holdich.

Six of the 10 MAAs are for Pollinex Quattro, containing the following pollens: trees, grass, birch tree, grass plus tree, grass plus birch, grass plus mugwort (a weed that is common in Germany). Three of the 10 MAAs relate to its Oralvac Compact sublingual product, which will contain house dust mite, grass pollen and tree pollen.

The final MAA is for Tyrosin TU, which will contain house dust mite, as a subcutaneous injection.


Box 2: Snapshot of the EU market

There are no centrally approved allergy vaccine products in the EU, but there is a handful, "about three products in five years" that have been approved via the mutual recognition procedure, according to Professor Vieths. There include ALK's tablet-based vaccine for grass pollen allergy, Grazax.

Germany is leading the way in immunotherapy as it is the largest market for allergy vaccines, and because the Paul Ehrlich Institut is the leading body to regulate these products in Europe, according to Dr Holdich. "There is no legislation in Europe like this [Germany's]," he says.

Italy and Spain are "thinking about it", while there has not been any "significant" activity in the UK, especially since the mid-1980s' when the UK's Committee on Safety of Medicine put restrictions on the use of allergy vaccines, which "nearly killed off business in the UK", he adds.

France is the second largest allergy vaccine market in Europe. It has a registration/permit system to sell these product: "The system is half-way there," says Dr Holdich. Professor Vieths describes the French market as "more of less a named patient basis", although products are quality controlled.

The US market is still a very rudimentary system, says Dr Holdich.



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