Australia: The Omnitrope Experience ... Is it STOP or GO for Follow-On Biologicals in Australia?

The recent developments regarding Sandoz's attempts to register Omnitrope have raised significant questions in relation to the regulatory processes available for follow-on biologicals ("FOBs") across the world's largest pharmaceutical markets. At its simplest, it has highlighted several issues which need urgent clarification for many pharmaceutical manufacturers. More so, it has exposed the world's largest and pre-eminent regulatory authority, the US Food and Drug Administration (the "FDA"), as lacking the legal authority to deal with an application by a generic pharmaceutical manufacturer for a FOB.

A FOB is a product made through biotechnological means, and referable to a marketed biological product. In this way it is conceptually similar to a generic chemical medicine. However, the comparison between FOBs and reference products is somewhat more difficult. Generally speaking, biological products possess a significant degree of variability. The properties of the molecule (primary to quaternary structure, the length of sequences, glycosylation etc.) may vary enormously between products. Further, in many cases the end product consists of a complex mix of whole and derivative molecules. Accordingly, no two biological products can ever be absolutely identical.

This inevitably leads to problems when submitting an application for a FOB via any abridged registration process. Ordinarily, a generic pharmaceutical manufacturer may submit an application via an abridged process by proving that its generic chemical product has the same active ingredient, composition and is bioequivalent to a marketed reference product (normally the innovator's product). If this is proved, then the generic pharmaceutical manufacturer may rely on pre-clinical and clinical testing data of the innovator, thereby saving significant time, resources and money. However, as Sandoz discovered for its Omnitrope applications, it is exceedingly difficult (if not impossible) for an FOB to satisfy the requirements for recognition as a "generic medicine" given their innate variability.

Omnitrope, Sandoz's "generic" somatropin, listed for registration as a FOB in the EU, the US and Australia. The different responses from these three regulatory agencies demonstrate just how significant the divide is in the current approval mechanisms and procedures for FOBs. It indicates how ill equipped many of the world's largest regulatory agencies were to deal with FOB registrations.

The EU has a centralised pharmaceutical approval process amongst member countries. The chief industry body responsible for the regulation of pharmaceuticals is the European Medicines Agency (the "EMEA") (although the European Commission ("EC") has the final say on all pharmaceutical approvals). At the time Sandoz applied for registration of Omnitrope, the EU was undergoing significant changes in its regulatory environment for FOBs (termed "biosimilars" in the EU). Particularly relevant were the amendments to Directive 2001/83/EC in 2004, the primary Directive for the regulation of pharmaceuticals. Prior to the implementation of these amendments, Sandoz's Omnitrope received an unfavourable assessment from the EMEA.

The amended Directive 2001/83/EC now permits the registration of "similar biological medicinal products", recognising the need for an approval mechanism for FOBs. A series of Guidelines assessing similar biological medicines have followed. Accordingly, it would appear that the EU is now (comparatively) well placed to receive applications for FOBs.

The EMEA has now granted Sandoz a favourable assessment for Omnitrope, and on 18 April 2006 the EC gave Sandoz the green light for marketing approval.

In contrast, the regulatory situation is far from resolved in the US. Operating under the directives of several statutes, the FDA draws a distinction between the regulation of chemical entities and biological products. Chemical based drugs are evaluated by separate divisions and under separate sections of code to that of biological products. Accordingly, separate laws and regulations apply to these two classes of products. Of importance however, is that only chemical entities have regulations in place to allow generic approvals.

As a consequence, after extensive analysis of Sandoz's Omnitrope, the FDA notified Sandoz that it was unable to proceed with its application. It released a press statement stating that "the agency has completed its review of Omnitrope and did not identify any deficiencies in the application", and further that, the FDA was "unable to reach a final decision on the application due to uncertainty regarding scientific and legal issues."

Sandoz sued the FDA. On 10 April 2006, the US District Court for the District of Columbia ruled that the FDA must decide whether or not to approve Sandoz's Omnitrope application. The FDA is yet to decide on the Sandoz application. It maintains that further legislation is needed to clarify the law in relation to FOBs and to provide actual legal authority to the FDA to approve them. Clearly a white paper to provide the FDA with a position on the regulation of FOBs is long overdue. Until implemented, applicants seeking to register a FOB in the US will face considerable hurdles to approval.

Unlike the FDA, Australia's Therapeutic Goods Administration ("TGA") operates on the basis that therapeutic products are therapeutic products no matter how they are derived. Accordingly, each new product applying for registration will be assessed using a similar framework, without extensive dichotomies to determine procedures. The TGA's flexible internal guidelines have enabled them to avoid the stalemate of the FDA. Consequently, Sandoz's Omnitrope application in Australia met with no legal impediments to approval. Omnitrope was reviewed, and found to have a favourable risk-benefit profile. Shortly after, the TGA gave Sandoz the green light for marketing approval.

Despite the successful registration of Omnitrope, this issue is not completely resolved in Australia. The TGA has stated that it will assess each individual application for a FOB on a case-by-case basis, and normally only after the applicant has met with the TGA on one or more occasions so as to clarify data requirements. Clear and further guidelines are needed by the TGA to grant FOB manufacturers a concise understanding of what is needed from them, both in terms of approval process and clinical and non-clinical data. However, with few Australian FOB applications on the horizon, these are unlikely to be released in the short term.

The experiences of Sandoz with its Omnitrope application indicate just how big the divide is between the EMEA and the FDA in the current regulation of FOBs. Current pilot schemes combining FDA and EMEA consideration and resources for pharmaceutical applications may serve to smooth some of these differences. However, both the agencies and generic pharmaceutical manufacturers will still need to properly understand the current state of play for future FOB applications for each market. Clearly, much more effort is needed from the FDA even for this process to be internally understood. Considering the number of biological products that globally come off patent soon or are no longer protected by patent, this is an issue that needs definitive answers quickly.

For Australian manufacturers, the message is that the TGA is well placed to develop or adopt further guidelines to handle such applications if and when the need arises in Australia. The existing framework is sufficiently robust to simply incorporate any new or adopted EU guidelines into the process.

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