The Waterfront Partnership

Medicinal Products

Generic Medicinal Products and Their Biological Counterparts

  (This article appeared in the October 2006 issue of "Pharmaceutical Law Insight" (Volume 2 Number 9)

 

On 30 October 2005 the UK implemented Directive 2004/27 amending Directive 2001/83.  A year on, this article will distinguish between generic medicinal products and their biological counterparts, set out the commercial backdrop against which the market has emerged and highlight the major differences between the old and the new regime for marketing approval.  It will also investigate how and indeed, whether the new approach is working as desired.

 

Biological Medicines

At its very simplest a biological medicine is

"a product, the active substance of which is a biological substance... that is produced by or extracted from a biological source and that needs for its characterisation and the determination of its quality a combination of physico-chemical-biological testing, together with the production process and its control" 

Biological 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.  Indeed, the highly publicised unpredicted complications which arose as part of the Clinical Studies of Tegenero's TGN 1412 may highlight the possible difficulties faced with utilising biological medicines.

Biological medicines have very complex structures relative to traditional pharmaceutical products and are usually much larger molecules. As a consequence biological medicines are intrinsically heterogeneous and whilst they may look static, their dynamic movement forms an essential part of their functionality; resulting in fragile molecules which are closely dependent on both their starting materials and the processes, including purification processes, used to make them.

Generics and Bio-Generics/Biosimilars

Prior to Directive 2004/27 being implemented, the main routes for gaining market authorisation for a generic medicinal product were either to submit a full dossier of clinical and non-clinical data or to make use of the so-called abridged procedure provided the applicant could demonstrate that its product was essentially similar to a product which had previously received marketing authorisation and was on the market in the European Union.

There was considerable debate and difficulty over the meaning of the phrase essentially similar, which was ultimately interpreted by the European Court of Justice in the Generics (UK) case (C368/96) and incorporated in to the amending legislation.

Accordingly, it is now settled law that a generic medicinal product is:

"a medicinal product which has the same qualitative and quantitative composition in active substances and the same pharmaceutical form as the reference medicinal product and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies..."

Due to the inherent nature of biological medicines, it is very unlikely that any biologic will achieve the threshold necessary to qualify as a generic medicinal product. Complications also arise from the stipulation of a ‘reference medicinal product', in particular because traditional methods are unhelpful in characterising biologics. For example, standard analytical techniques do not give information on isoforms, the degree of heterogeneity or the number of active sites.

Further, since any generic manufacturer is unlikely to have access to the innovators starting materials or manufacturing process, one school of thought successfully promoted by the innovator camp is that any bio-generic can not therefore be a true generic; hence the language at Article 10(4) of the amended Directive which talks about a biological medicinal product being similar to a reference biological product and the commonly used phrase "biosimilar"

Article 10(4) of amended Directive addresses the requirements to obtain marketing authorisation for biosimilars using the abridged procedure.  This states that

"where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular differences relating to raw materials or differences in manufacturing processes of the biological medical product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided [in accordance with the Annex to the Directive]".

Further, on 1 June of this year guidelines issued by the CHMP (the Committee on Medicinal Products for Human Use) were brought into force which specifically relate to similar biological medicinal products; in particular quality and clinical and non-clinical issues (see www.emea.europe.eu/index/index1.htm).

So, finally it appears that the way is being eased for generic companies to obtain marketing approval for biosimilars. This is not, some would say, before time, especially in the light of the current and expected market demand for biosimilars.

Commercial context

The generic pharmaceuticals market has been and remains fiercely competitive.  The consequence of which is that once pharmaceutical compounds come off patent, generic versions gain market authorisation rapidly and fierce competition drives the prices of the drugs down leaving the margin for profit very narrow. 

The market for biologics has grown significantly over recent years. In 2005 biologics (composed of both therapeutic proteins and monoclonal antibodies) accounted for just 15% of global pharmaceutical sales. It is anticipated that this will grow to 22% by 2010. A new Datamonitor report forecasts that the value of the biologics market will reach $106 billion by 2010, amounting to a 70% increase on 2005. In addition, it has been estimated that more than $10 billion of biologic sales are scheduled to go off patent by the end of 2006 in a variety of key indications which include pyschotropic, cardiovascular, and digestive system disorders. 

In contrast with the generic pharmaceutical market, the specialist knowledge and resource required for the development of biologics means there are significantly less industry players within this market sector.  Consequently, it is anticipated that there will be only a handful of each ‘biosimilar' product available to the market allowing the potential profit margin to be substantial.

Safety and Efficacy

There is great market potential for biosimilar products.  However, the difficulties to be faced in overcoming the safety and efficacy tests are still high.  Article 10(4) of the amended Directive makes provision for biosimilars to gain marketing approval using the abridged procedure and to utilise the benefit of specific guidelines.  However in practice the sooner any potential applicant contacts the EMEA to discuss with them a strategy for overcoming safety and efficacy barriers, the more improved their chances of obtaining approval and the swifter the process will be.

The Importance of Biosimilars for the Patients

Generic companies will not make biosimilars unless they are profitable but it is also a priority to ensure that the benefits of biosimilars are communicated to patients and that any myths regarding safety and efficacy are dispelled.  The International Alliance of Patients Organization ("IAPO") is in the process of finalising a briefing paper on biosimilars. This was due for publication mid 2006 but appears to be running slightly behind schedule. 

The IAPO gave a presentation at the European Health Management Association (EHMA) Annual Conference in Berlin in June 2004. This presentation contained some of the information it is anticipated will be contained within the briefing paper.   The presentation stated that the paper will aim to highlight the differences between biological medicines and traditional pharmaceutical products, the risks and benefits of biosimilars and the patient and ethical considerations of such products. 

As difficult as the concept of ‘similarity' is to reconcile within a legal, scientific and regulatory framework it is even more difficult to communicate to the patient to whom a product offered and described as simply ‘similar' could create confusion and be distressing.  The IAPO therefore appears to be striving to give patients a balanced and informed view of biosimilars but is also highlighting the importance of regulatory transparency, good patient information and patient-health professional decision making in assessing treatment options. 

What are the implications for the industry? 

The amended Directive provides an improved route by which marketing authorisation may be obtained for biosimilars, in addition to the standard route for approval of a medicinal chemical or biological entity which requires the performance of a full programme of clinical trials. The improved route provides that an applicant seeking approval of a biosimilar must conduct appropriate pre-clinical tests or clinical trials together with further supplementary data, as specified in guidelines issued by the EMEA (where such guidelines exist) which may allow some circumnavigating of the full clinical trials which might otherwise be undertaken.

There remains a query with regarding whether a potential third route exists for approval of biosimilars under Article 10a of the Amended Directive.   Article 10a provides that tests and trial results shall be replaced by appropriate scientific literature if an applicant can:

"demonstrate that the active substances of a medicinal product has been in well-established medicinal use within the Community for at least ten years, with recognised efficacy and an acceptable level of safety"

Sandoz GmbH first sought approval for it's Omnitrope product under this provision (formerly 10(a)(ii)).  However, whilst it was given a positive opinion by the EMEA's CHMP the Commission objected to the marketing authorisation being given.  It is unclear whether the Commission would object to all marketing authorisations for biosimilars if an entity sought to utilise the Article 10a procedure of the Amended Directive however, it appears likely that this would be the case.

Although it is established that the abridged procedure is for generic medicinal products and not ‘generic biologic medicinal products' (or biosimilars) the amended Directive does specifically acknowledge the desire and requirement for biosimilar products and legislates accordingly.  This is a significant step toward the future development of biosimilars products, and one which puts the European biosimilar market streets ahead of the equivalent US market for ‘follow-on biologics' where there is currently no legal framework in place.

The Annex to the amended Directive provides a significant amount of guidance on what steps an entity must undertake in order to obtain marketing approval, which is supplemented (as previously mentioned) by guidelines relating to similar biological medicinal products. Further, the EMEA has, together with industry, drafted and finalised four further sets of product-specific guidelines which give more detailed requirements for biosimilars in a designated biologic group.  Guidelines currently exist for Erythropoietin, Insulin, Somatropin, Granulocyte-colony stimulating factor.  There is a further guideline relating to Interferons which has not yet been finalised but is awaited with interest.

Where an entity wishes to seek authorisation for a biosimilar within a biologic group which does not yet have the benefit of an issued guidance note then the EMEA is emphatic that the approach is to contact it as early as possible so that the parties can work together to prepare a new guidance note.  Such guidance note which will then be used for other parties seeking authorisation within that group. It is the EMEA's intention that such working arrangement is very much a partnership for the benefit of the furtherance of biosimilars..  Inevitably, pioneers in bringing biosimilars to market are likely to bear the heaviest regulatory burden.

It may go without saying but it should be remembered that where clinical trials are needed to be undertaken in the authorisation process for a biosimilar product they will still have to be conducted in accordance with the Clinical Trials Regulations 2004 which set out very clearly the requirements of good clinical practice, manufacture and pharmacovigilance. 

Approvals 

Despite the fact that the amended Directive has been in force for a year there have so far only been two approvals granted, both of which have been granted under the International Nonproprietary Name ("INN"). These are for Omnitrope (Sandoz GmbH) which has comparable quality, safety and efficacy profiles to Genotrope; and Valtropin (BioPartners GmbH) which has comparable quality, safety and efficacy profiles to Humatrope.

A third approval was eagerly awaited recently by BioPartners, again, for its Interferon Alpha, Alpheon^® which is biosimilar to Roche's Roferon^®-A.  However, on 28 June 2006 it received a negative opinion from the CHMP. BioPartners confirmed that ruling was based on questions which concerned characterization, manufacture and control and biosimilarity that have not yet been resolved to the extent the CHMP believes necessary for a biosimilar.  Importantly for patients the objections related to an apparent increase in return of the disease after use of the biosimilar compared with the reference product.  This example further highlights the differences between a product seeking to approval as a biosimilar as opposed to an identical active pharmaceutical ingredient seeking approval as a generic medicinal product and the major importance of manufacture, control, safety and efficacy in biosimilars.

Other Issues facing biosimilars

There also remains some controversy with regard to the naming of biosimilars.  Currently the EMEA are using the same INN as the reference product which is how generic medicinal products are named.  However, there is an argument that since the biosimilar products are similar, but not identical to, the reference product they should not have the identical INN.  The main concern expressed relates to the issue of pharmacovigilance.  However, the European Generics Medicines Association (the "EGA") expressed its opinion that the purpose of the approval process is for a biosimilar to be authorised and thereafter interchangeable with the appropriate reference product in which case use of the INN is appropriate.  It seems that this may be well be an obstacle being used by the innovator companies to slow down biosimilar competition in the market.

Industry Mood

There is increasing interest in the market for biosimilar medicinal products.  BioPartners GmbH, whilst understandably disappointed with the negative response given to Alpheon^® by the EMEA, has maintained a very positive position and states:

"it is looking forward to evaluating the EMEA report and with the issues clarified, anticipates being in an even better position for resubmission". 

Additionally, GeneMedix appears to be on track with its development programme for Erythropoietin targeting a market where the innovator products amount to approximately US$10bn per year.  According to its website (www.genemedix.com) it is also developing Interferon-alpha and Granulocyte-colony stimulating factor products. It remains to be seen whether these will be submitted for approval as biosimilar products in due course.

Conclusion

In 2005 the global generic pharmaceutical market was worth $45bn, a growth of 14% on the previous year.  The emerging biosimilars market has a long way to go before it can rival the pharmaceutical market but there is clearly enormous potential and scope for it to do so.  What goes against the relatively small number of players currently in the biosimilars market and those about to join it is the fact that biosimilars are expensive to develop requiring high R&D costs and with the risk of financial exposure due to the likelihood that market penetration will be slow.   The complicated nature of biosimilar products means that information surrounding them will have to be delivered to specialists and as such biosimilar companies will face high marketing costs.  Added to that is the fact that they will be facing the already existing market which will be monopolised by the originator.

In order to succeed in the biosimilars market a company will need to have significant financial resources in order to fund the requisite R&D budget to produce the products.  This may make the opportunity more appealing to already-established large pharmaceutical companies who have the resources to undertake projects of this nature and the desire to go head to head with one of its competitors.

However the biosimilar market expands, whether it be through big pharma or through small dedicated entities it looks set to do so, with the regulators now clarifying the position regarding marketing authorisation and a few positive authorisations given the biosimilar market may soon be underway.

 

Rachel Bunn and Juliet Nutland

Waterfront Solicitors LLP 

 

© Waterfront Solicitors LLP 2006