FormalPara Key Points

Facilitated regulatory review pathways became available in Australia in 2017–2018.

This is the first survey of industry sponsors regarding their use and perceptions of these pathways, which were found to be beneficial to industry in providing earlier access of novel therapies to Australian patients.

1 Introduction

International regulatory alignment and collaboration, convergence, recognition, reliance, work sharing arrangements and facilitated regulatory pathways (FRPs) are widely used by, and are considered best practice among, national regulatory authorities (NRAs) globally in the regulatory review of pharmaceutical products, facilitating timely access to novel medicines for patients [1,2,3]. In Australia, FRPs were first introduced in 2017 with priority review (PR) and 2018 with provisional approval (PA) as part of the Medicines and Medical Devices Regulation review (MMDR)—a comprehensive reform which aimed to cut red tape and increase flexibility in regulatory review processes, commensurate with risk and aligned with global best practices [4, 5].

FRPs can have major implications for patient safety and outcomes, clinical guidelines and practice, health policy, pricing and reimbursement. A number of publications have analysed approval timelines in FRPs, outlined characteristics of FRPs, discussed the appropriateness of use of these pathways for different types of medicines as well as their added clinical value and sponsor compliance with post-registration requirements in other markets [6,7,8,9,10,11]. However, there appears to be limited structured study to evaluate industry experience, perceived benefits, shortcomings or proposed improvements to utilising these pathways. This has been noted in relation to the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) FRPs [12]. In Australia, the FRPs were developed in consultation with a wide and representative range of stakeholders (including approximately 48% of the submissions coming from the industry, followed by 18% and 17%, respectively, from health care professionals or professional bodies, and consumer organisations. Government, regulator and external organisations were also consulted with). However, approximately 5 years after implementation, despite a growing number of products being approved via these pathways and over 100 FRP determinations approved between 2017 and 2021, there has been no published data on the stakeholders’ perceptions on how these pathways are operating from their perspective.

Both PR and PA are intended for prescription medicine new chemical entities (NCE) or new indications. Additional qualifying criteria for PR include for a life-threatening or seriously debilitating condition where there are no registered competitors or the medicine provides significant benefit and it provides a major therapeutic advance. Additional criteria for eligibility for the PA pathway include for treating a serious condition and provides a favourable comparison against existing therapeutic goods or there are no competitors and it provides a major therapeutic advance and the company provides evidence of a plan to submit comprehensive clinical data within a specified timeframe.

For each pathway, the sponsor submits a determination application, and the Therapeutic Goods Administration (TGA) assesses the product against these eligibility criteria. An approved determination is a prerequisite for submission of an application for registration [13,14,15]. The level of clinical evidence necessary for PR submission is identical to the standard pathway—substantial evidence of safety and efficacy and a complete dossier. PA is based on early clinical data (e.g. phase II clinical trials) demonstrating evidence of significant therapeutic improvement and advance and is subject to time-limited post-approval data provision to the TGA [16, 17]. In a previous publication, an analysis of the PR and PA pathways was performed and the extent of utilisation by the pharmaceutical industry, elements and duration of approval processes, types of products that have been submitted via these pathways and their associated therapeutic areas were assessed [5].

1.1 Objectives

In this study, a survey was undertaken with the objective of obtaining the industry’s perspective on key aspects of the FRPs in Australia. The industry survey outcomes may help inform future TGA directions in regulatory science and supports potential alignment between regulatory processes and Australia’s HTA processes. The information may be useful to international and local sponsors planning to submit for medicine registration in Australia as it outlines the expected benefits, areas of regulatory burden, potential delays and issues from a user perspective.

2 Methods

2.1 Scope

In the survey, we solicited opinions of regulatory professionals from the Australian pharmaceutical industry based on their submission experience with the three main registration pathways for prescription medicines—PR, PA and standard pathway. Key parameters included overall satisfaction, regulatory burden, availability and ease of use of guidelines, regulator support, perceived shortcomings, impact on company strategy and recommendations for improvement. The standard registration pathway was included in the survey and evaluated across the same parameters, as it existed prior to, and remained unchanged by, the reform and is a useful comparator [18].

2.2 Ethics Approval

Approval from the Human Research Ethics Committee (HREC) was obtained from the University of New South Wales (UNSW) (Ethics approval: HC200821). A Participant Information Statement and Consent Form (PISCF) was embedded into the online survey. Only completed responses were analysed in this study.

2.3 Survey Design and Participants

The survey comprised 44 questions designed using a skip logic depending on the relevance of a particular question to a respondent. For instance, questions relating to PR were skipped for a respondent who had no experience with the pathway. Most questions had a section for free-text comments. The survey was developed in accordance with the recommendations of the OECD Measuring Regulatory Performance: A Practitioner's Guide to Perception Surveys and was reviewed by all researchers for relevance, completeness and wording [19]. The survey questionnaire is available in the electronic supplementary material. The survey was conducted using the Qualtrics platform and distributed via independent industry bodies, including Medicines Australia, ARCS Australia Ltd, a targeted pharmaceutical media outlet MedNews (Australian Pharmaceutical and Medicine News) and targeted emails to the Heads of Regulatory Affairs (RA) departments. The data collection period for the survey was from 25 July 2021 to 15 October 2021.

Eligible participants had submission experience with application(s) for registration of medicine(s) using at least one of the three pathways. The eligibility criteria were conducive to identifying participants who were well informed and possessed experience in the regulatory space of interest, thus helping to obtain a balanced, knowledge-based view and minimise bias.

2.4 Data Analysis

Survey results and publicly available data were analysed using descriptive statistics. Free-text survey responses were manually grouped by the researchers into key themes.

3 Results

In total, 16 respondents participated in the survey and completed the questionnaire in its entirety. As listed on the TGA website, 42 sponsors had a PR or PA determination approved as of October 2021. Thirteen of the 16 survey respondents in this survey had experience submitting via PR, PA or both pathways, thus making this sample size of 31% (13/42) representative of the industry segment of companies using the FRPs.

The demographic profile and professional background of the participants are summarised in Table 1, including the age (30 to ≥ 60 years old), gender (M/F, 9/7 [56/44%]), workplace (15/16 [94%] in multinational company), company size in Australia (7/16 [44%] with < 100 employees; 6/16 [37%] with 100–250 employees; 3/16 [19%] with 500–1000+ employees), roles (13/16 [81%] as RA Manager or Director), and duration of employment in the Regulatory Affairs field (13/16 [81%] for 10–15 years or longer).

Table 1 Demographics and professional background of the survey participants
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As indicated, all respondents were highly experienced, senior Regulatory Affairs professionals. All 16 respondents had experience submitting via the standard pathway, nine had experience with PR, ten with PA, and three respondents had standard pathway experience only.

Fifteen out of 16 participants 15/16 (93.7%) were working for multinational companies with the number of employees varying from under 100 to over 1000 in Australia, with portfolios covering a wide range of therapeutic areas, including alimentary tract and metabolism, blood and blood forming organs, cardiovascular system, dermatological, genitourinary system and sex hormones, anti-infectives for systemic use, anti-neoplastic and immunomodulating agents, musculoskeletal system, nervous system, respiratory system, or sensory organs. The companies’ portfolios included new chemical entities (NCE), new biological entities, gene therapy and in vitro diagnostics.

All respondents indicated excellent awareness of the Australian regulatory reforms and the MMDR, including the expedited registration pathways (PR, PA) and collaborative arrangements with overseas regulatory authorities, such as Project Orbis (which included the Regulatory Agencies of Australia, United States of America, Canada, Singapore, Switzerland, Brazil, United Kingdom, and Israel), the Access Consortium (Australia, Canada, Singapore, Switzerland, United Kingdom), and Comparable Overseas Regulator reliance pathways (COR)-A and COR-B. Two participants were not aware of the Project Orbis registration option (in one of the two instances, the company was not developing oncology products). Additionally, one participant reported being involved in the development of the reform guidance through TGA working groups.

3.1 Overall Satisfaction with the Pathways

The highest satisfaction was observed towards the PR pathway with 8/9 (89%) respondents indicating positive satisfaction (from extremely satisfied to slightly satisfied), whereas only 1/9 (11%) indicated a slightly dissatisfied experience. In comparison, 11/16 (69%) and 6/10 (60%) respondents showed a positive level of satisfaction with the standard and the PA pathways, respectively (Fig. 1). For PA, the responses were somewhat ambivalent, with 6/10 (60%) respondents expressing satisfaction with the pathway, 1/10 (10%) neutral, 2/10 (20%) slightly unsatisfied and 1/10 (10%) extremely unsatisfied, so 30% of respondents indicated a dissatisfied experience with the use of the PA pathway. By contrast, only 13% expressed dissatisfaction with the standard pathway. Free-text comments were provided by two respondents, who stated that the length of time taken for approval using the standard pathway remains a challenge and could be subject to improvement.

Fig. 1
figure 1

Overall satisfaction with pathways (left) and ease of use of the pathways (right). PR priority review pathway, PA provisional approval pathway

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3.2 Ease of Use

Most respondents found the standard and PR pathways relatively easy to use, with 12/16 (75%) and 7/9 (78%), respectively, indicating a positive level of ease of use, followed by 3/16 (19%) and 1/9 (11%) being neutral, with 1/16 (6%) and 1/9 (11%) being negative. However, the perception of the respondents was less favourable towards the PA pathway. Only 3/10 (30%) were positive whereas 6/10 (60%) were neutral, that is, neither easy nor difficult to utilise, and 1/10 (10%) was negative on this parameter (Fig. 1). A free-text comment was provided by one respondent indicating that the current execution of the standard pathway activities by the Regulator resulted in increased unpredictability.

3.3 Availability and Usefulness of the TGA’s Instructions and Guidelines

Overall, the respondents perceived that there were more guidelines available for the standard pathway than for the PR or PA pathways. For the PR and PA pathways, fewer participants, 4/9 (44%) and 6/10 (60%) respectively, indicated a high amount of guidance, followed by 44% and 40% who indicated a moderate amount only. One respondent stated that only a modest amount of guidance was available for the PR pathway (Fig. 2). In comparison, 14/16 (88%) respondents indicated a high amount (‘a great deal’ or ‘a lot’) of guidance available for the standard pathway, followed by 2/16 (13%) respondents who considered the amount of available guidance was moderate. Most of the respondents found the guidelines for all pathways useful, with 94%, 89% and 80% indicating a positive level of usefulness for navigating the standard, PR or PA pathways, respectively. One participant provided a free-text comment with positive feedback that guidelines and instructions for the standard pathway have improved over the years, becoming more specific and providing steps to navigate the process.

Fig. 2
figure 2

Availability of instructions and guidelines. PR priority review pathway, PA provisional approval pathway

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3.4 Level of Regulatory Burden Experienced in the Use of Regulatory Pathways

Overall, higher regulatory burden was perceived in PR and PA, with 3/9 (33%) and 5/10 (50%) participants, respectively, regarding the burden as high (‘a great deal’ or ‘a lot’) compared with 3/16 (19%) respondents for the standard pathway. For the PR pathway, 4/9 (44%) considered the regulatory burden moderate, compared with 2/10 (20%) for the PA pathway. For the standard pathway, most participants 10/16 (63%) indicated a moderate level of regulatory burden (Table 2). The respondents’ perceptions of regulatory burden with using the PA pathway were ambivalent with opinions ranging from high to no burden. Two factors were noted to contribute to the higher regulatory burden seen in using the PA pathway: the necessity to submit a registration application via the standard pathway if the later stage (typically phase III) data is positive and the necessity to maintain the TGA provisional registration even where the product is not marketed, for instance due to inability to secure reimbursement based on partial clinical data. The higher level of regulatory burden associated with the PR pathway was attributed by one participant from a large multinational company to some unique Australian requirements of the priority review designation. For the standard pathway, the timelines in the later stages of review were noted by one participant from a mid-sized multinational company to be tight and potentially difficult to manage.

Table 2 Level of regulatory burden in the use of a pathway
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3.5 Regulator's Level of Support and Clarity of Criteria

In this study, most participants considered the level of support from the Regulator adequate across all three pathways, that is, neither too much nor too little (81% for the standard pathway, 67% for the PR and 90% for the PA pathway). This might be attributable to the regulatory authorisation of many therapeutic products in the European Union (EU) or US prior to their registration in Australia. Therefore, the early enhanced regulator involvement occurs in these jurisdictions, making TGA’s level of involvement at later stages sufficient. In Australia, engagement and dialogue between the applicant and Regulator prior to submission for registration is facilitated via pre-submission meetings with the TGA. Such meetings aim to develop a common understanding of the proposed prescription medicine, clarify supporting documentation requirements and help plan the submission activities and resourcing. The TGA provides advice on existing studies, data sets or the proposed dossier content and format. However, unlike the FDA or EMA, the TGA does not engage in enhanced early dialogue at the product development stage or offer scientific advice or protocol assistance. Most respondents indicated that the determination criteria for the FRPs are generally clear: 8/9 (89%) for PR determination, and 9/10 (90%) for PA determination.

3.6 Impact of the Pathway on the Timeliness of TGA Approval

All respondents perceived that the PR pathway was effective in accelerating the approval process for eligible prescription medicines. Fifty-six percent of respondents (5/9) thought the PR pathway extremely expedited the registration timelines while 33% (3/9) thought it did so moderately (Fig. 3). One respondent provided a free-text comment on this parameter based on their experience before and after the COVID-19 pandemic. The PR pathway could be classified as extremely expedited as TGA were delivering an outcome in approximately half the time of the standard pathway prior to COVID-19. However, during the pandemic the TGA was adhering to the milestone plan which only offered a more moderate acceleration (3 months) compared with the standard pathway.

Fig. 3
figure 3

Timeliness of approval for provisional approval (left) and priority review (right) pathways

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The responses for the PA pathway were more ambivalent, with 6/10 (60%) respondents stating that the timelines were expedited. On the contrary, 40% (4/10) of respondents indicated the pathway did not offer an advantage over the standard pathway, and one (10%) participant felt it was even slightly slowing the process down (Fig. 3). Two respondents noted that the legislated timelines using the PA pathway were identical to those for the standard registration pathway.

3.7 Impact on Submission Strategy of Companies

All respondents reported that the introduction of the new pathways in Australia had affected their companies’ submission strategies, with over 90% (15/16) indicating they had used one or both FRPs (Fig. 4). Fourteen respondents (88%) indicated that their companies planned to use or continue the use of the TGA’s FRPs in the future.

Fig. 4
figure 4

Impact of FRP implementation on company (left) and extent of use (right). PR priority review pathway, PA provisional approval pathway

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Most participants reported a positive impact on their company from the introduction of these new pathways: 7/9 (78%) for PR and 7/10 (70%) for PA. Approximately one-fifth of the respondents in each pathway thought it made neither a positive nor negative impact on their company. One of the respondents who indicated an extremely positive impact commented this was due to their company being able to supply urgent medicines for the current pandemic. This may also be the case for other respondents who indicated a positive impact, as there was a dramatic increase in COVID-19-related products registered via the provisional pathway in 2021 [20]. One respondent indicated that the PA pathway provided no advantage in terms of market access or availability to patients and lacked commercial viability due to the inability to use the TGA provisional approval to secure reimbursement. It was noted that using the PA pathway offers only a modest Intellectual Property (IP) advantage, as the data exclusivity period of a specific product commences upon TGA’s provisional approval and would typically be approaching expiration by the time a full approval is achieved.

Just over half of the respondents (8/15 [53%]) indicated that they always, or actively, looked for opportunities to use either of the FRPs to obtain registration of new products and new indications, as they considered the best strategy was to maximise the speed to market and access for patients. One respondent stated that eligibility for FRPs has become a strategic decision-making process. Another participant stated that every new asset or indication was assessed for potential against the new pathways, which were then utilised where eligibility criteria were met and the company was willing to expend the required internal resource to make use of these pathways. On the contrary, 2/8 (25%) respondents indicated their company’s experience with the PA pathway was negative; in one case the Regulatory Affairs department generally advises against the use of the PA pathway.

Eight out of fifteen (53%) respondents indicated that the use of FRPs resulted in shorter review timelines, which affected their submission strategy. The PR pathway was sought where possible, particularly where it leads to an earlier Pharmaceutical Benefits Advisory Committee (PBAC) cycle of review for potential reimbursement. One participant stressed specifically the value of the TGA’s Comparable Oversees Regulator (COR)-A process, which had been used multiple times with the fastest approval of a new indication within 5 months. The FRPs were reported by respondents to provide more choices and options for global regulatory collaboration via the Access consortium and Project Orbis initiatives. They also resulted in increased planning, including strategies to launch, and allowed Australian submissions to be prioritised due to reduced resource burden needed to support applications.

3.8 Further Improvements

We received several suggestions for further improvements to the PR and PA pathways (Table 3). Improvements proposed for the PR pathway were classified into those related to the determination step, and those pertaining to the evaluation process. The improvements proposed for the PA pathway indicate its usefulness and desirability are reduced due to the lack of viable reimbursement options since the HTA bodies are reluctant to accept positive review outcomes due to higher uncertainty associated with these expedited pathways. Multiple respondents proposed modifications to the delivery of post-approval commitments and provided suggestions for shortening review timelines.

Table 3 Priority review and provisional approval pathways: proposed improvements
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4 Discussion

The effectiveness of FRPs in facilitating earlier access to novel medicines for patients (such as the COVID-19 vaccines and therapeutics) and streamlining the development and evaluation processes has been extensively discussed and documented in other jurisdictions. Several studies have analysed and evaluated approval timelines for FRPs within tier one and two NRAs, including the TGA [5, 7,8,9, 11]. However, research into industry perceptions of the value of these expedited regulatory programs is limited. Recently, Bujar et al. systematically characterised the perceived value of four key FRPs based on industry experiences, including US FDA’s Breakthrough Therapy Designation and Fast Track, EMA’s PRIME scheme and PMDA’s Sakigake [12]. Our survey is the first study to solicit perceptions and opinions from the pharmaceutical industry towards the use of the Australian TGA’s FRPs. The survey results have shown that the industry is thoroughly familiar with and keeps up to date with the changes implemented by the TGA, is open to the new developments and keen to use the new registration routes, which provide more flexibility, efficiency and speed. The number of products registered via the PR and PA pathways is gradually increasing in Australia [5]. Based on the reported level of overall satisfaction with the pathways and the impact on sponsors, the reform outcomes and the resulting introduction of the new registration options are seen as positive, useful and beneficial developments.

During the current COVID-19 pandemic, when flexible approaches and speedy registration of vital products became a necessity, the FRPs provided advantages to companies and Australian patients, allowing timely access to novel and highly needed therapies. However, it is important to take into consideration that COVID-19-related changes in the regulatory landscape and the extensive use of the PA pathway could make its use more positive and impactful for companies. Therefore, some of the positive industry users’ perceptions reported in the survey might be temporary and circumstance related. In support of this, the number of products registered via the PA pathway rose sharply from five in 2020 to 11 in 2021, of which seven were for COVID-19-related indications. The COVID-19-associated products approved via the PA pathway enjoyed an impressively short mean time to approval of 61 TGA working days (excluding company time), compared with 196 days for non-COVID-19-related provisionally approved products in the same year [5].

The changes in the regulatory landscape have not only affected the companies which utilised the newly available pathways but have also impacted the strategies of the sponsors who have not yet used an FRP. In our survey, three respondents had experience submitting via the standard pathway only (but not PR or PA). Of these, one respondent indicated that their company has not utilised FRPs, however their introduction has affected strategy aspects such as timing, global interaction and reimbursement approaches.

Most respondents emphasised that the efficiency, shorter timelines and earlier access for patients are the main considerations behind their companies’ willingness to utilise the TGA’s FRPs in the future. Greater harmonisation with other global jurisdictions is also a positive contributing factor. Having in place accessible, efficient and useful guidelines, opportunities for applicant—Regulator dialogue where necessary and alignment with international requirements have been identified as enablers of predictability in the regulatory review process [21]. The results of the survey indicate positive perceptions on these three aspects.

5 Limitations

The survey was completed by a limited number of participants, and while it is currently representative of the companies which use the FRPs and potentially of the industry at large, the FRPs continue to be utilised by an increasing number of sponsors and it will be beneficial to re-measure stakeholders’ perceptions over time.

Nearly all participants were from multinational companies. Therefore, there may have been an underrepresentation of local Australian industry stakeholders. Furthermore, results may have been affected by the timing of the survey administration. The survey was conducted in a year which saw a surge in provisional approvals for COVID-19 products. These therapeutic goods enjoyed an impressively short time to approval and stakeholders’ experience with PA non-COVID-19 related indications may be different.

Within the TGA, resource allocation to prioritise and bring to market in a timely manner the COVID-19-related products may have affected the resourcing of other pathways and products, as indicated by one respondent noting that approvals via the PR pathway had slowed down. This reported slowing down is not evident from the publicly available data on NCE registrations, however it may be beneficial to study the timelines for approval of new or extended indications or new combinations of registered prescription medicines which may be eligible for PR to observe any differences. While the survey was reviewed and confirmed to be comprehensive and adequate by a Regulatory Affairs professional, and ample opportunity was given for participants to provide comments, there is a possibility that certain significant questions were not asked, and associated feedback not collected.

The FRPs in Australia have only been available since 2017 (PR) and 2018 (PA), with a limited number of approved determinations submitted and applications approved. Up until the end of 2021, the TGA had approved 55 PR and 47 PA determinations, submitted by 42 applicants. Therefore, each respondent’s company only had a limited number of instances where a product was registered via an FRP. Due to this limited experience, current perceptions of a pathway may not be fully formed or accurate and may change as additional products are evaluated through these pathways.

6 Conclusion

The FRPs have been a transformative and positive development in the Australian regulatory landscape; however, there remain opportunities for further improvements. Some of these opportunities have been highlighted by this study and may help inform future regulatory decisions. This study has collected feedback from industry users on multiple key aspects of pharmaceutical medicine registration processes, as well as recommendations for improvement. We hope this feedback will inform future directions for both regulatory science and increased integration between regulatory and reimbursement processes in Australia.