AIPPI Congress Report 3: Biosimilars - into the great unknown?

The AmeriKat successfully keeping
herself awake yesterday morning

After an ungodly early morning breakfast meeting yesterday morning, the AmeriKat dragged her paws to the second session of yesterday's Pharma Day sessions on the hot topic of "Biosimilar pharmaceutical products".  The session was promised to explore the latest developments in the area, including key definitional issues and the currently contentious issue of naming biosimilars.  Although there was an unusual lack of AIPPI audience participation, the panel did not fail to deliver.

Masahisa Yamaguchi (Chugai Pharmaceutical Co, Japan) provided a very concise and helpful summary of the biosimilars landscape.  Masahisa explained that unlike small molecule drugs, it is impossible to produce exact copies of reference biological drugs.  As such, the regulatory pathway to approval of such drugs is crucial.  However, the global regulatory position is mixed.  In Japan there is only one single guideline published in 2009 in relation to all types of biosimilars.  In the US there are four draft guidelines including the latest one, published in 2014, entitled Clinical Pharmacology Data to support Demonstration of Biosimilarity to a reference Product.  However, these are all draft guidelines.  In Europe, a general guideline has been published entitled "Similar biological medicinal products".  There are also product specific guidelines in Europe making Europe's regulatory landscape a little bit more user-friendly.

Masahisa explained that the major feature that these three systems have in common are the requirements of post-marketing surveillance studies and risk management plans.  The big difference between the three systems is that in naming.  In Japan a different non-proprietary and brand name is required to be distinguishable from the reference drug.  In Europe the biosimilar adopts the same non-proprietary name as its reference product.  In Australia they use a different non-proprietary name.  In Japan, there is a three-part naming process.  The divergence in approach has led the World Health Organization to develop its own recommendations - the use of the same non-proprietary name as the reference product plus a unique suffix.  Generally, innovators argue that a different non-proprietary name should be required, while generics oppose such an argument.  The main point in dispute, Masahisa explained, really turned on what is better for prescribers and patients.  In his view, both arguments have merit, but for now the only certainty was that the different regulatory authorities had different opinions on the issue.

AIPPI's Pharma 2 lineup for yesterday morning

Although there are many biosimilar products on the market in Europe, Masahisa explained that the US market is less developed.  In Japan, there are currently four biosimilar products on the market.  This generally low market impact could be attributable to the cost of developing biosimilars which are more expensive than small molecule generics.  A developer will need financial power behind them to develop biosimilars.  Masahisa also explained that the general price reduction of biosimilars in Europe is around 10-35%, of that of the reference product. The penetration rate in Europe is 10-30%.  In Japan, he considered that the market penetration is less than 5%.  This relatively slow and low market penetration rates may have to do with the fact that, besides expensive, biosimilar substitution is not allowed in Japan and Europe, resulting in a longer regulatory approval pathway.

Looking to the future, Masahisa explained that the projected total sales of biologics to 2020 shows rapid growth.  One of the most important and strong areas of growth is the monoclonal antibody field.  This will be the next target for biosimilars, he concluded, but it requires significant investment.

Agnes Klein (Health Canada) was next up to explain the regulatory framework for drugs and biologics in Canada under the Food and Drugs Act.  Following a technical sprint through the Canadian regime for biosimilar approval, Agnes described some key pointers for framing the studies that Canada Health look at when examining biosimilar applications.  Such factors included the preference of equivalence trial data over non-inferiority trial data, studies that are conducted using clinically relevant endpoints to detect potential differences (which could be different from the innovator's original study) and for pivotal trials, duration, route of administration and dosage ranges should be similar.  On the final point, Agnes stated that it was very unlikely that extrapolation of a different route or dosage would be permissible if there was no sufficient pharmacokinetic or pharmacodynamic data to support such extrapolation.

Health Canada says "no"
to automatic biosimilar
substitution

A significant issue with biosimilars, Agnes explained, was that of immunogenicity.  Most biologics introduce some level of anti-drug antibodies and these antibodies may have an undesirable clinical effect on pharmacokinetics and pharmacodynamics, efficacy or safety.  From a safety perspective, these antibodies can cause allergic or anaphylactic reactions, reduction to efficacy, reduction of autoimmunity and/or neutralization of an endogenous counterpart.  Unwanted immunogenicity is currently difficult to predict from analytical and non-clinical data in terms of incidence, characterization, clinical consequences and significance.  Risk based immunogenicity evaluation strategy and the filing of post-marketing risk management plans are therefore required just like any small molecule generic drug.  Agnes explained that Canada is moving towards a life-cycle management regime for all drugs, which is especially important for biosimilars as they are finding that increasingly biosimilars have common trans-properties.

Agnes concluded by explaining that Canada Health does not support automatic substitution of a biosimilar for a reference drug, but that biosimilars "are safe and effective as guidelines are sufficiently robust to ensure safety and efficacy.

Prior to introducing the final panelist for the morning, the moderator Mary Padbury (Ashurst, Australia) cited a comment made by to provide some context for the current slow growth rate of biosimilars in the global market.  Jimenez stated that although there will not be a big difference in the rate of growth of biosimilars for the next 2-3 years, there will be an inflection point in 2016-2019 when it is anticipated there will be big biosimilar launches. By 2020, we are likely to see a big impact in the biosimilar market.

Is the Hospira v Genentech case just
the first of many biosimilar cases
to come before the English Court?

The final speaker, Dominic Adair (Bristows, UK) brought the audience back to the present market conditions of low market penetration.  This has been evidenced in the UK by very few cases involving biosimilars having been heard by the High Court.  Currently there are 17 biosimilars approved by the European Medicines Authority - two of which are for monoclonal antibodies both for infliximab.  But, against this background there has not been much biosimilar patent litigation save for one case decided earlier in the year - Hospira v Genentech (see IPKat post here) - where Hospira was clearing the path in respect of two patents covering Genetech's Herceptin cancer drug.  Although the uptake in biosimilar litigation has been slow, Dominic predicted that as we begin approaching the biologic patent cliff with basic biosimilar patents expiring, there will likely be an increase in litigation activity.  In the meantime, echoing Masahisa's comments, it is likely that a reason for the generally quiet biosimilar litigation landscape could be attributable to there not being enough approvals to create litigation, a longer regulatory process to obtain marketing authorizations for biosimilars and strategic moves by biosimilar manufacturers to wait until the expiry of the basic patent.  On this final point, Dominic explained that when he investigated this issue he found that when the two EMA approvals for infliximab were granted in 2013, it was reported that Hospira and Celltrion would only enter markets that did not have patent protection for Remicade.  Eastern Europe was therefore the target for that biosimilar market launch.

Without any litigation in this space, it is difficult to predict whether the courts will react similarly to issues raised in biosimilar litigation as they do to those raised in standard  small molecule litigation.  A significant issue that Dominic raised related to the granting of interim and permanent injunctions.  In the classic case the test for an interim injunction under American Cyanamid asks whether there is a serious question to be tried, whether damages would be an adequate remedy and where the balance of convenience lies.  The launch of generics pre-patent expiry is a substantial threat to innovators given the dramatic price spiral following the first launch (see commentary in SmithKline Beecham v Apotex). The normal course of conduct is that the first generic prepares for launch, ends up challenging the patent(s), litigation ensues and depending on the outcome all the other generics with market approval pile in.  The price of the innovator product reduces dramatically and its market share can reduce significantly.  In such circumstances irreparable harm is straightforward as the price will never recover and it is therefore relatively easy to obtain an interim injunction from the English court.

What does the future of biosimilar
litigation hold?  Do we have
some idea or is it into
the great unknown?

However, the biosimilar situation is different.  There are less approvals for biosimilars, so it is arguable with only one or two biosimilars on the market innovators are not going to see the price spiral that they experience with small molecule generic launches.  On present market conditions, a biosimilar launch will see the innovator likely operating in a duopoly.  Further, given that many biologics are delivered with specific delivery devices, like Humira, and other patient care programs there may be reluctance by patients and doctors to change to a biosimilar.  Again, this could result in a less dramatic price and market share reduction.  Dominic questioned whether in these circumstances the court will be as ready to grant in injunction.  His view is that it could be more difficult, but this has to still be weighted against the difficulty in calculating damages in an assessment after trial.

So what is the take-home point from this session?  With a current diverse regulatory landscape and small market penetration, we are still few years off from reaching the precipice of the next big frontier in patent litigation.  It probably won't be until the AIPPI Congress in Cancun, Mexico in 2018 when we really start seeing how the regulators and courts will react to this current great unknown.