A review of medicines and medical device regulation in 2015 has recommended that the TGA implement expedited pathways for promising new drugs.13 This would enable the TGA to grant provisional approval of a new drug on the basis of early data, if the immediate availability of the drug outweighs the risk that additional data are still required. Similar pathways currently operate in Europe, Canada and the USA.14
In response to the review, the TGA released two consultation papers in 2017. The first aimed to seek opinions on enhancements to the current Medicines Vigilance Framework in order to better identify and address medicine safety concerns.15 Specifically, the Black Triangle Scheme, similar to that already operating in Europe, will be introduced to identify newly available drugs requiring increased vigilance. This will alert clinicians and consumers that these drugs are subject to additional monitoring and prompt them to report adverse events to the TGA. This may improve the rate of reporting in the postmarketing phase to help identify rare adverse events. Changes are also being proposed for the product information to improve the accessibility of prescribing information.15
The second paper asked for discussion of a provisional approval pathway.16 This pathway is designed to permit the clinical use of ‘promising’ medicines for patients with unmet clinical needs earlier than would normally be allowed. Provisional approval would be granted with significantly less clinical data than currently required. Decisions are likely to be made before phase III trials have been designed. This is important as many clinical trials fail from lack of efficacy, safety concerns, or a combination.17 Other phase III trials may meet the primary end point, but find mortality is worse, as seen with evolocumab and fibrates.18,19
In order to obtain full registration, sponsors must submit confirmatory data on efficacy and safety. However, there is the real possibility that a promising drug is never given full approval because subsequent trials do not confirm a benefit. By then the drug may have been used in clinical practice for up to two years under provisional approval. Increased pharmacovigilance will therefore be essential for these new drugs.
Safety concerns
Bypassing the traditional premarket approval process moves the experimentation phase of drug development into the real world. Under provisional approval, drugs will be applied in clinical practice before their comparative safety and efficacy are known and without the stringent follow-up and protection afforded by clinical trials. While there will be increased emphasis on pharmacovigilance in the provisional pathway, including random audits, these mechanisms have not yet been fully scrutinised and may not provide enough protection for patients.
Sponsors are legally mandated to report all negative outcomes they become aware of, but there is no imperative for them to actively search for adverse events. As reporting by clinicians will remain voluntary it is likely that there will be significant under-reporting of adverse reactions to provisionally approved drugs. However, adverse events from specialist-only drugs such as immunotherapies may have a higher rate of detection and reporting due to hospital reporting systems.
Postmarketing safety concerns have been raised with the provisional approval process implemented in Canada, a process similar to that proposed in Australia. There is a statistically significant risk that drugs approved under this mechanism will receive a serious safety warning or be removed from market compared to those approved by a standard review process.20
Despite these concerns we are still not entirely certain how the provisional approval pathway will be implemented in Australia by the TGA. At present, the TGA is yet to announce its complete plans for monitoring the safety and efficacy of these provisionally approved drugs. The TGA already has the power to impose conditions on the registration of a new drug. For example, an existing condition of registration of new drugs has been the requirement for a risk management plan.21 The TGA will undertake monitoring to ensure the contents of these plans, such as collecting additional safety data, are carried out.15