TGA consultation a unique opportunity 12 min read
The Therapeutics Goods Administration (the TGA) is consulting with the public and industry to potentially reform regulatory and reimbursement frameworks, to incentivise the repurposing of existing medicines. Off-label use (where a medicine is used for a disease or medical condition for which it does not have marketing approval) is already lawful and common, and off-label prescribing can be medically important. Facilitating marketing approval for new indications for existing medicines is still a worthwhile objective, and the TGA has proposed options to encourage more regulatory and reimbursement applications for repurposing older medicines. Industry has the opportunity to reshape the future of repurposing medicines in Australia through making submissions on the TGA's proposals by 30 March 2021. With extensive experience in this area, we offer our insights on some of the TGA's proposed options.
- It is legal for physicians to prescribe medicines for off-label use, but not for suppliers to promote off-label uses.
- It is desirable that existing medicines are legally prescribed and used for indications for which they are safe and effective, and that suppliers can promote those medicines for those uses.
- A key barrier to seeking registration of repurposed off-patent medicines is that the return on investment is low, given the approval cost is incurred by one sponsor, while the benefits may be enjoyed by others.
- The TGA's suggestion to provide exclusivity periods for new indications of repurposed off-patent medicines for the first sponsor who seeks approval or Pharmaceutical Benefits Scheme (PBS) listing is interesting but may have practical limitations and unintended impacts for sponsors:
- It is not clear what type of exclusivity is contemplated for the sponsor seeking registration or PBS listing for a new indication. Will that be marketing exclusivity, data exclusivity or brand exclusivity?
- How will exclusivity work in the context of generic prescribing and generic substitution? Would doctors have to prescribe by brand and mandate no substitution, or would pharmacists have to check the indication before dispensing a generic? What incentives and penalties (if any) would apply?
- Depending on the nature of any proposed exclusivity, if the sponsor of a new indication is granted exclusivity for that indication, sponsors for the original indication(s) may be precluded from promoting or selling their product(s) for the new indication, thereby excluding the original sponsor from its existing off-label market.
- The European model is to grant a six-month patent term extension to originators that apply for additional paediatric indications. This encourages originators to obtain marketing approval for additional indications, but that would not assist in the context of new uses for already off-patent medicines or for non-paediatric indications.
- The main regulatory barriers to repurposing prescription medicines could be reduced by a variety of measures, including:
- encouraging applications by industry groups and associations (which would need to include providing exemption from competition law prohibitions on collaborative action and information sharing);
- reducing the evidentiary burden for seeking new indications for repurposed medicines; and / or
- reducing the substantial cost of an application for a new indication, by providing fee relief.
- The option of compelling the original sponsor to make an application for additional indications is radical and we anticipate it will face opposition from stakeholders.
- Notwithstanding the TGA has extended the time for submissions, now 30 March 2021, it is likely that there will be further consultation, as the TGA considers feedback, refines existing options and formulates new ones.
Executives, management and legal counsel.
The TGA has released a consultation paper, and is seeking input from the public and industry to understand the potential obstacles and incentives to repurposing medicines that may influence a sponsor's decision to extend an indication for an existing medicine, including for indications that are approved overseas, used for a less common disease, used off-label or are likely to be less commercially profitable.
Repurposing medicines offers potential to address existing, emerging and rare diseases. The TGA does not currently initiate applications for registration of repurposed indications. Rather, it relies on an Australian sponsor to make an application.
There are a number of regulatory challenges and barriers to repurposing medicines. A key one is a lack of exclusivity for off-patent medicines. Without a method of treatment patent for a repurposed indication (or 'second medical use'), there is little incentive for sponsors to incur the cost of a TGA application, as well as a Pharmaceutical Benefits Advisory Committee (PBAC) application, once a medicine is generic. This is because the approval cost is incurred by one sponsor, but without the exclusivity offered (for example) by a second medical use patent, the benefit is enjoyed by others. The TGA correctly identifies this as a key barrier and seeks to overcome it through various options proposed in its consultation paper.
COVID-19 pandemic – impetus for change
The impetus for the TGA consultation appears to be the COVID-19 pandemic, which has seen companies deploy considerable efforts to repurpose existing medicines as possible COVID-19 treatments. One example is Gilead's Veklury (remdesivir), which was originally developed to treat Ebola and provisionally approved by the TGA in July 2020 to treat COVID-19. Unlike remdesivir, off-patent medicine, dexamethasone, which was recommended based on clinical trial data, was not approved by the TGA and instead used off-label to treat COVID-19. Other medicines under investigation with variable trial outcomes include hydroxychloroquine, lopinavir with ritonavir and lopinavir with ritonavir plus interferon beta-1a.
Repurposing medicines is also a key issue being considered in the ongoing inquiry by the House of Representatives Standing Committee on Health, Aged Care and Sport into the approval of new drugs and novel medical technology. The purpose of the Parliamentary Inquiry is to ensure that Australia is well positioned to access new drugs in a timely manner and respond to emerging global trends.
The traditional framework for regulatory approval and reimbursement of medicines – comprising the TGA, which regulates marketing authorisation, and PBAC, which uses the Health Technology Assessment to make decisions around pricing and reimbursement – is being challenged by the need to respond to both rare conditions and unmet medical need. Reform is said to be needed to overcome the challenges to repurposing prescription medicines, including those observed in the TGA consultation paper.
As noted in the consultation paper, off-label use is lawful, common and medically important. This is evidenced by the National Health and Medical Research Council (the NHMRC) setting suggested tiers of evidence that can be relied on by practitioners to determine when off-label prescribing meets appropriate standards of safety and efficacy. The Council of Australian Therapeutic Advisory Groups provides guiding principles for quality use of off-label medicines. Off -label prescribing ensures that patients do not miss out on optimal, timely, more cost-effective or life-saving treatments because such treatments have not been submitted for 'approval' by the TGA for a particular indication or have not yet been 'approved'.
In this context, it is important to remember that TGA 'approval' is not approval for use of a medicine per se – it is a marketing approval. Despite this, some judges, politicians and the media incorrectly assume that off-label use is not permitted. Thus, part of the solution must be to clarify that use of a medicine for a particular indication may be legal and appropriate based on the clinician's judgment, whether or not marketing approval for that particular indication has been obtained.
Nonetheless, it is desirable that medicines are not only legally prescribed and used for indications for which they are safe and effective, but that they can be promoted by suppliers for those uses, thereby aligning what both the prescriber and what the supplier can do. This could also mitigate exposure to joint liability that a supplier may face for off-label use. Further, it is desirable for prescribers, particularly non-specialists, that they do not have to justify 'off-label' use or be concerned about potential legal claims or professional criticism arising from a lack of marketing approval for a particular use. It would also reduce potential consumer concern if the use for which a medicine has been prescribed is listed in the Consumer Medicines Information.
Care needs to be taken to ensure that a campaign to facilitate marketing authorisation of existing medicines for extended indications as proposed by the TGA does not suggest to patients or prescribing doctors that off-label use ,where it is appropriate, is illegal or dangerous.
To overcome the barriers to repurposing prescription medicines, the TGA has offered a number of potential options. Some are fit for purpose, some have practical limitations and others may impact sponsors' rights.
Companies are currently not incentivised to seek TGA approval for an extended indication of repurposed off-patent medicines because other sponsors of the same drug will benefit from that approval such that the return on investment is low or negligible. This barrier is particularly significant where repurposing medicines for a new indication is not straightforward. It may not simply be a matter of compiling existing studies. Rather, there may be a need to conduct clinical trials, reformulate the medicine, or combine the medicine with another medicine or device.
In Australia, while data exclusivity exists, it is only available for registered therapeutic goods containing a new active component that has not previously been included in the Australian Register of Therapeutic Goods. The data exclusivity regime does not apply to new indications, new dosage forms or combinations of existing compounds.
One of the proposed options is to provide exclusivity to the first sponsor:
- that seeks TGA approval for an extended indication for a particular use for a period of time; and/or
- that seeks PBS listing for the use of a particular medicine for an indication for a period of time.
The TGA consultation paper says that this could be particularly appropriate for non-commercially viable indications that have significant health benefits, although there would be the requirement for an agreed codified process to determine 'non-commercially viable' and 'significant public health benefits'.
It is suggested that this exclusivity could increase the viability for a sponsor for a generic medicine, even in a small market. Similar suggestions have made to the Parliamentary Inquiry by several pharmaceutical companies, which supported exclusivity for off-patent indications or an extension of the data exclusivity regime so that it is aligned with the regime in Europe, which offers 10 years' data exclusivity, and the United States, which offers 12 years.
While there would seem to be some industry support for an exclusivity period, it is not clear what type of exclusivity the TGA is suggesting – whether that is data, marketing or brand exclusivity.
In any event, there would seem to be practical problems associated with implementing the TGA's proposal in the current environment, which generally requires generic prescribing and permits generic substitution at the pharmacy level. Requiring patients to convey specialised and potentially complex information as to their indication is unlikely to be practicable, and requiring prescribers to specify the brand and prohibit substitution is contrary to the shift to generic prescribing. These considerations need to be factored into any proposed exclusivity regime, to ensure that any exclusivity provided in this context will actually achieve the stated object of encouraging the registration of additional indications for existing medicines.
It should also be recognised that in the case of off-patented medicines, exclusivity, if effective, could adversely impact suppliers that have been supplying medicines for treatment of relevant indication off-label, perhaps for decades. A competing supplier obtaining marketing approval would shut them out of their long-standing market.
Exclusivity does not come without difficulty but requiring a prescriber to prescribe by brand and prohibiting substitution by pharmacists may be the best way to overcome these observed difficulties.
Other alternatives to exclusivity (however formulated) may strike a better balance. This could include a right of first refusal for the first sponsor of an existing medicine, or a priority review incentive. In the latter case, a sponsor could be incentivised to obtain marketing authorisation for a new indication relating to a rare disease, if the sponsor was then entitled to priority review of a marketing authorisation for a different product. It could also include following a similar model to that adopted in Europe, which involves the grant of a six-month patent extension to originators that apply for additional paediatric indications. However, a model of this kind would not assist in the context of new uses for already off-patent medicines or for non-paediatric indications.
The high cost of making a TGA application and a PBAC application means that many potential sponsors may not be able to justify the cost against the likelihood of a meaningful return on investment, including by reason of the size of the market for the repurposed indication. We consider that the option proposed by the TGA to provide fees and charges relief would remove one of the key barriers to sponsors seeking regulatory approval for new indications.
Reducing the evidentiary burden
A hurdle in repurposing prescription medicines recognised by the TGA is the existence of evidence gaps and challenges in assembling 'regulatory quality' data to support an application to register a new indication. Once a medicine has received marketing authorisation, and particularly if it is generic, a lower level of evidence may well be sufficient to allow approval for an extended indication. For example, a literature-based submission may be sufficient in some cases. However, such submissions may not be appropriate, and the data requirements may need to be higher, where the medicine has a high level of toxicity, a narrow therapeutic index, tolerance or addiction issues, or major side effects.
Reducing costs may not be enough by itself. We consider that a number of the options raised in the TGA's consultation paper warrant further consideration, including:
- encouraging applications by industry groups and associations (which would also require consideration of providing exemption from competition law prohibitions on collaborative action and information sharing);
- making government-funded applications, or TGA-initiated applications; and
- providing research funding as an incentive to research institutes that submit data leading to an application for an extended indication.
Compulsion is not the answer
The option to potentially introduce legislative changes to compel a sponsor to make an application for an additional indication is radical and we anticipate will face opposition from stakeholders. Compelling a sponsor in this way may have significant repercussions, including potentially discouraging sponsors from choosing Australia as a place to market their products.
If there is anything to be learned from the COVID-19 pandemic, it is that collaboration between industry and government is essential to drive the development treatments for rare, emerging and existing conditions.
This TGA consultation presents a unique opportunity for industry to collaborate with government and shape the Australian regulatory framework in a way that will ensure both that investment in repurposed prescription medicines is feasible and that off-label use is encouraged. Submissions to the TGA are due by 30 March 2021. There is likely to be further consultation as the TGA considers feedback and formulates options. The Allens team is available to assist and provide further insights.