According to section 16H of the Therapeutic Goods Regulation 1990, a medicine, vaccine or in vivo diagnostic agent is an orphan drug if the intention of the drug is to treat, prevent or diagnose a rare disease; the drug must not be commercially viable to supply to treat, prevent or diagnose any other disease or condition1.
A drug has to be designated as an orphan drug before any application for product registration is lodged2. Orphan drugs are eligible for the waiver of application and evaluation fees but only if designation is received prior to submitting an application to register an orphan drug on the ARTG3. However, full fees will apply to all variations to an orphan drug (i.e. applications submitted under s. 9D)4. TGA’s target timeframe for orphan drug designations application is 20 working days from receipt to a decision being made5 but they recommend starting orphan drug designation process 2-3 months before the intended pre-submission planning process6.
Orphan drugs are evaluated for quality, safety and efficacy in the same way as other registered medicines7. There are no special considerations given in relation to the timelines for evaluation of orphan drug applications – TGA adheres to their timelines as with any other non-designated drugs.
Sponsors have to invest considerable amounts of money for discovery, intermediate steps of preclinical & clinical research before it can go for regulatory bodies for a review and if all steps are successful, finally to the market8. Since orphan drugs by definition, are used to treat small and very specific populations who suffer from rare diseases and conditions5, we can safely assume that the financial cost weigh far greater on the scale than immediate financial benefits to be gained compared to other similar drugs that could be used by a wider population for more common diseases. Although TGA assigns these drugs the same timelines as any other application in the same category, the application and evaluation fees are waived. This reduces some cost to the sponsor while making sure that an incentive is provided by the TGA to invest into the needs of a small population of end users.
A separate orphan drug designation application has to be made for every new indication even if the molecule/active ingredient of the medicine is the same (see Phenasen example below)
Table of As2O3 Orphan Drug Designation approvals3: (Phebra operated as Pharmalab in the past.)
|Drug||Date of designation||Indication||Dose||Sponsor|
|Arsenic trioxide injection||21/08/03||For the treatment of patients with acute promyelocytic leukaemia, who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy.||Pharmalab Pty Limited|
|Arsenic trioxide injection||8/6/04||For the treatment of patients with acute promyelocytic leukaemia.||Pharmalab Pty Limited|
|Arsenic trioxide||24/02/11||For the treatment of acute promyelocytic leukaemia.||Tablets and oral liquid||Phebra Pty Ltd|
I chose to write about Arsenic trioxide since the company I work for manufactures it in Australia. It is sold under the trade name Phenasen® by Phebra. As seen from the above information taken from the TGA website, arsenic trioxide injection was first designated as an orphan drug in 2003. According to the description of indication, it was given this designation for second line treatment of acute promyelocytic leukaemia (APML). Again in 2004, another orphan drug designation was approved for the same drug, but this time, to be used in first line treatment for the same disease. Thus we see that a change in indication (in this case, an extension of indication) for the same drug requires a separate orphan drug application, although no aspect of the drug itself may have been changed.
From our understanding of orphan drugs and TGA’s policy of waiving application and evaluation fees for their registration, we can conclude that when a Category 1 submission was submitted for an extension of indication for As2O3, TGA would have waived both the application and evaluation fees of $27,500 & $109,9009 respectively. The post-marketing requirements for orphan drug products are the same as for other registered medicines10.
From the last row in the table above, we can see that a third application for an orphan drug designation for As2O3 was approved in 2011. The indication is the same as the approval in 2004 for first line treatment of APML but this time, it was given for a new dosage form.
A drug will be given an orphan drug designation if it satisfies the conditions set forth for the designation. Presence of a drug on TGA’s orphan drugs list does not mean that it is being sold in the market already; there may be drugs that have been given this designation but have not completed the registration process. Therefore, this list should not be consulted when deciding whether a drug is available in the market for a rare disease.
- The extension of indication application for first line treatment of APML by As2O3 was eventually approved by TGA in 201511
- As2O3 approval by TGA for first line therapy of APML marked the first time in the world that As2O3 was given approval for first line treatment of APML (Checked on FDA & EMA websites).
- ‘Orphan drugs’, Therapeutic Goods Administration, 2016, https://www.tga.gov.au/orphan-drugs (accessed 22/08/2016)
- ‘Guidance 2: Fees and charges for prescription medicines’, Therapeutic Goods Administration, 2016, https://www.tga.gov.au/book/27-when-evaluation-fees-are-waived-or-reduced-prescription-medicines (accessed 20/08/2016)
- ‘Orphan drugs’, Therapeutic Goods Administration, 2016, https://www.tga.gov.au/orphan-drugs (accessed 20/08/2016)
- ‘Applications for orphan drug designation’, Therapeutic Goods Administration, 2016, https://www.tga.gov.au/book-page/related-information (accessed 20/08/2016)
- ‘Applications for orphan drug designation’, Therapeutic Goods Administration, 2016, https://www.tga.gov.au/book-page/what-will-happen-application-designation (accessed 20/08/2016)
- ‘Applications for orphan drug designation’, Therapeutic Goods Administration, 2016, https://www.tga.gov.au/book-page/how-apply-orphan-drug-designation (accessed 20/08/2016)
- ‘Applications for orphan drug designation’, Therapeutic Goods Administration, 2016, https://www.tga.gov.au/applications-orphan-drug-designation (accessed 20/08/2016)
- ‘Learn About Drug and Device Approvals’, U.S. Food and Drug Administration, 2016, http://www.fda.gov/ForPatients/Approvals/default.htm (accessed 20/08/2016)
- ‘Fees and charges: summary – from 1 July 2016’, Therapeutic Goods Administration, 2016, https://www.tga.gov.au/book-page/prescription-medicines-1 (accessed 20/08/2016)
- ‘Applications for orphan drug designation’, Therapeutic Goods Administration, 2016, https://www.tga.gov.au/book/export/html/190328 (accessed 20/08/2016)
- ‘Australian Public Assessment Report for Arsenic trioxide’, Therapeutic Goods Administration, 2016, https://www.tga.gov.au/sites/default/files/auspar-arsenic-trioxide-151216.pdf (accessed 20/08/2016)