Orphan drugs in Australia

KEYWORDS:

• Orphan drug program
• review
• rare diseases
• oncology

The Australian orphan drugs program has the aim of encouraging research into, and the marketing of therapies aimed at the treatment of rare diseases. The scheme commenced in 1997, and is currently awaiting the outcome of a review into its processes. The review examined the functioning of the scheme to ensure it still fulfills its original purpose. This expert opinion piece will examine the possible outcomes into the review, which has been the subject of many submissions from patient support groups, medical professionals, and the pharmaceutical industry.

This summary of the current scheme is based on personal observation and involvement, firstly as a neurologist who diagnoses and treats rare diseases, and secondly as an advisor to government. The Advisory Committee on Prescription Medicines (ACPM), which I currently chair, advises the Therapeutics Goods Administration (TGA) about specific issues relating to the approval of medicines in Australia. The committee, made up of clinical experts in most fields of medicine, meets every 2 months, and provides clinical advice in relation to any matter the regulator may ask. New chemical or biological entities, major extensions of indication, or major changes to the product information will often be discussed.

Many of these applications involve orphan drug designation. It is likely that this trend will continue, and increase, as there has been a steady increase in orphan applications over the past years. The views expressed here are entirely my own, and I do not speak for the TGA, nor do I have any specific knowledge about the outcome of the review. Finally, the funding for orphan drugs, once approved by the TGA, which is a matter of great concern to patient groups, will not be covered in this review.

The Orphan drug program in Australia, was designed, as were others around the world, to provide incentives to develop and market products where the target population was small. In Australia, the current incentives include the waiver of fees for evaluation and registration. While other jurisdictions have included other potential incentives, such as grant programs or tax waivers, the Australian scheme does not currently involve other incentives apart from the waiver of fees.

These incentives in Australia are not inconsiderable: for a new chemical entity the fee for registration is $221,400AU, and for an extension of indication $131,600 AU using the 2014/15 rates. In addition, the waiver of fees also applies to the application to the Pharmaceutical Benefits Advisory Committee (PBAC), the committee which advises about the listing of the agent on the Pharmaceutical Benefit Scheme [1].

An orphan drug is currently defined, according to section 16H of the Therapeutic Goods Regulations 1997, as (1) a medicine, vaccine, or in vivo diagnostic agent is an orphan drug if it:

(2) must be intended to treat, prevent or diagnose a rare disease; or must not be commercially viable to supply to treat, prevent, or diagnose another disease or condition.

The regulation further stipulates that if the medicine has been refused approval on grounds of safety by any of the other major regulatory agencies (these are listed in the regulations, section 3) then it would not be granted orphan drug status.

An area of interest in this review of orphan drugs in Australia will be the use of the word ‘or’ in the above regulation. It has been argued that the intent of the original scheme was to encourage novel chemical or biological entities to be developed specifically for rare diseases, and the conjunction should have been ‘and’ rather than ‘or’ in the regulations. The current wording allows registered products to be legitimately classified as orphan drugs if the new intended market is a rare disease, even though the product may be highly profitable and used widely in another therapeutic category. This issue is further discussed in the following.

A second area of discussion in the review will be the definition of rare disease. Currently, under Regulation 2 of the Therapeutic Goods Regulations, a rare disease is defined as a disease or condition, likely to affect not more than 2000 individuals in Australia at any time.

When the scheme was introduced in 1997, the population of Australia was approximately 20 million, so 2000 patients represented an incidence of 1 in 10,000. The current population is now over 25 million, so the incidence has decreased. Globally, Australia has one of the more restrictive definitions, and patient thresholds for the definition of a rare disease compared to other countries are listed in Table 1. It should be noted that a similar trend is seen in other jurisdictions, which use an absolute threshold, e.g. the United States, where the orphan designation is less than 200,000 per year. In addition, diseases which now can be treated may, by definition, become non-rare by the fact that life expectancy will be increased. An example of such a disease is hemophilia A. In 2009–2010, nearly 1800 patients suffered from Factor VIII deficiency, and this group now numbers over 2000, thus exceeding the threshold of rare disease under the current definition.

Table 1. Comparison of the patient threshold definition for orphan drugs used by country.

Country/regulator	Patient threshold
Australia	Less than 2000 at any time (0.88 per 10,000)
USA	6.37 in 10,000
Switzerland	5 in 10,000
Singapore	37.7 in 10,000
EMA	5 in 10,000

EMA: European Medicines Agency.

It is highly probable that the definition of orphan drug will be expanded after the review. Rare Voices Australia, the peak body representing Australians with rare diseases, defines rare disease as one with an estimated prevalence of 5 in 10,000, combined with a high level of complexity [1]. Such a recommendation is in line with the current EMA threshold, and in my opinion, it is probable that this (or similar) will be the maximum future threshold definition.

The orphan drug program has been increasingly used by applicants since its inception. Since 1998, 287 applications were designated as orphan, with 14 designations per year from 1998 to 2008, but 27 per year from 2009 to 2013. It is anticipated that this trend will continue. Around half of the designations have been to treat neoplastic and hematological disorders [1].

A recent trend in orphan applications has been either using an approved product, i.e. an extension of indication, or classifying a new disease type, e.g. genetic variances in breast cancer [1]. The Cancer Council Australia and Clinical Oncology Society of Australia, in its submission to the review [2], highlighted the trend of using genetic markers to advise treatment decisions. For example, Axitinib, a selective tyrosine kinase inhibitor of vascular endothelial growth factor (VEGR-1, 2, and 3) in the treatment of renal cell carcinoma, is an orphan drug by virtue of the rarity of the mutation.

Early applications for orphan drug status were generally for a broad, whole disease indication. Some examples include Anagrelide ‘for the treatment of essential thrombocythemia’, which was registered in November 1999, or Imiglucerase approved for the ‘enzyme replacement for patients with a confirmed diagnosis of Gaucher’s disease’ registered in May, 1999. With the wider use of genetic markers and ‘personalized medicine’ more recent applications have involved narrow indications in a molecularly defined subset of a disease, or targeted to a very specific stage of a disease. Recent examples are adalimumab, registered in June 2014 for ‘the treatment of active Crohn’s Disease defined as a Pediatric Crohn’s Disease Activity Index (PCDAI) score >30 in pediatric patients (6–17 years of age) who have had an inadequate response to conventional therapy, or who are intolerant to or have contraindications for such therapies’.

Many of the applications for orphan status would be in the orphan category where the application uses subdivisions of a common disease entity with therapies based on targeted mutations in the disease. Therapies in the field of cancer and hematology appear the major user of this system of subdividing disease, with most activity in breast and lung cancer historically, but more recently in melanoma, renal cell carcinoma, and neuroendocrine tumors [1]. These highly specialized medicines for a small target group are becoming more common in major regulatory schemes, with around one-third of the new medicines approved by the FDA in 2013 being orphan drugs [3].

Many of the new orphan drugs in Australia already have an established market for non-orphan indications [1], and subsequently receive orphan drug designation for a new, specific indication. Some of the annual sales estimates for a selection of drugs with orphan and non-orphan indications, while complex to analyze, are presented in the ‘Orphan Drugs Program: Discussion paper’. These include sales of Rituximab of $53 million, adalimumab of $84 million and Bevacizumab of $41million AUD for the financial year 2013/2014. Annual sales estimates of some drugs with purely orphan indications include Imatinib $25 million, and Lenalidomide $19 million.

As noted earlier, in order to continue to support the development of therapies for rare diseases, and in order to maintain a system that is fair and equitable, the review into the orphan drug scheme was commenced in May 2015. Submissions were received from the pharmaceutical and research community, support and patient groups, consumer organizations and from other medical and pharmacy groups. The review proposed several areas for reform.

The three main areas proposed for possible reform included a redefinition of a rare disease (moving toward that of other regulators, see earlier), changing the definition of an orphan drug, and examining the model of financial incentives for orphan drugs. From a purely personal viewpoint, the definition of a rare disease will almost certainly be changed, and I suspect that the definition of orphan drug may be restricted to more tightly control the use of specific markers, or disease stage, in a more common disease. My personal feeling is that already approved drugs may not automatically be given orphan status because of its putative use in a new ‘orphan’ indication. This would bring the TGA into closer alignment with the EMA.

The final report and recommendations are not yet available, however are expected by the end of the year. It is awaited with interest by patients, industry, and the medical profession.

Declaration of interest

G Herkes is Chair of the Advisory Committee on Prescription Medicines for the Therapeutic Goods Administration (TGA). The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was not funded.