Provisionally yours

Author: Grant Bamde

The development of new medicines and expanding the use of existing medicines is a resource-intensive process, where it can take a number of years to complete the clinical trials necessary to establish safety and efficacy of a medicine for use in patients. In recognition of this, many regulators have the capacity to expedite the availability of promising medicines where an unmet clinical need exists (e.g. EMA Conditional Approval). One such route for obtaining earlier market authorisation for prescription medicines in Australia is the Provisional Approval pathway offered by the Therapeutic Goods Administration (TGA).

The Provisional Approval pathway has the potential for prescription medicines that provide a major therapeutic advance for Australians to gain market entry up to two years sooner in comparison to the current standard registration pathway. A provisional approval allows for the time-limited provisional registration of medicines on the basis of preliminary clinical data where the TGA consider the benefit of early availability of the medicine outweighs the risks inherent in the fact that additional confirmatory data is still to be provided.

Although the clinical data provided as part of a submission for provisional registration may be preliminary, the provisional approval pathway is not a second-tier route for regulatory approval for a medicine with insufficient evidence. Comprehensive non-clinical data on safety, quality data and compliance with Good Manufacturing Practice as is needed for the standard registration process is also required to support a provisional registration. Additionally, to utilise the provisional approval pathway applicants must provide a clear plan to submit comprehensive confirmatory clinical data on the safety and efficacy of the medicine within six years of the commencement provisional registration.

The provisional registration period of prescription medicines approved via this pathway is two years, which may be extended by a period of two years up to two times, corresponding to a maximum possible provisional registration period of six years. If a sponsor is not able to demonstrate that they have met the conditions imposed on the provisional registration, the registration will automatically lapse at the end of a specified period. Once confirmatory clinical data to establish safety and efficacy of the medicine are available an application can be made to convert a provisional registration to a full registration.

What medicines are eligible for provisional approval?

Prior to making a submission for provisional approval, it is necessary to make an application for a provisional determination to establish the proposed medicine meets the eligibility criteria for provisional approval. Eligibility criteria are designed to ensure that only medicines providing the most benefit to patients will be provisionally approved.

To qualify for a provisional determination the product proposed for registration must be for treating a serious condition and either be a new medicine or a new use for an existing medicine. The product must also represent a major therapeutic advance for treating the condition based on the preliminary data available and compare favourably in terms of safety or efficacy against existing therapeutic goods used for the condition. The criteria also require sponsors to demonstrate that they can provide additional clinical data to confirm safety and efficacy as early as possible within the provisional registration period.

The TGA strongly encourages applicants who consider their medicine suitable for provisional approval organise a pre-submission meeting with the health authority to discuss an application for provisional determination. Ideally, this pre-submission meeting should be around six months prior to the planned submission date.

How is the provisional approval pathway different to the standard registration process?

The provisional approval pathway is similar to the standard prescription medicines registration process, however, there are some differences taking into consideration the uncertainty associated with preliminary clinical data. Since the risks and benefits of the medicine need to be established by preliminary data, a higher level of scrutiny and deliberation may be required to understand uncertainties, particularly where there may be an absence of evidence. As a result, the provisional registration process has a similar evaluation time in comparison to the standard pathway as the TGA weighs up the benefits and risks of earlier availability of these medicines. Medicines undergoing assessment by the provisional registration process are not eligible for a priority or accelerated review.

For provisional registration applications, it is likely that the dossier will consist of a combination of completed and ongoing pivotal or supporting clinical trials which may be in progress during evaluation. Unlike the standard registration process, it may be possible to provide new information from these trials during the evaluation period, where this information is likely to influence the registration decision, but this must be agreed with the TGA before submission. During the evaluation via the provisional registration process, there is also closer coordination between the different evaluation areas within the TGA to ensure that any emerging safety signals are identified and managed. The TGA are also able to seek external expert advice on issues concerning the submission earlier and more frequently in comparison to the standard registration process.

During the provisional registration period, it is necessary to comply with the relevant conditions of registration which were agreed at the time of registration. However, additional activities such as the ongoing collection and submission of confirmatory data on safety and efficacy, continual assessment of the medicines benefit-risk profile and enhanced post-marketing monitoring are likely to apply until the product transitions to full registration.

The Provisional Approval pathway is not appropriate for all products, however, where there is a high unmet medical need and early clinical data is both promising and convincing it can provide a path that will allow patients earlier access to medicines that treat life-threatening or seriously debilitating conditions.

If you are considering an opportunity for your drug to be authorised in Australia and think that it meets the criteria for the Provisional Approval pathway, please reach out to Brandwood CKC for assistance or further information.

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The contents of this article/presentation are solely the opinion of the author and do not represent the opinions of PharmaLex GmbH or its parent AmerisourceBergen Corporation. PharmaLex and AmerisourceBergen strongly encourage readers/listeners to review available information related to the topics mentioned herein and to rely on their own experience and expertise in making decisions related thereto.

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