“[..]Develop a regulatory strategy for this novel vaccine[..[Critically discuss the potential regulatory incentives as well as obligations[..]Critically discuss the regulatory aspects that need to be considered to achieve this aim.”
Introduction
Breast cancer represents a quarter of all cancers and is the highest cause of female mortality (Majeed et al., 2014) Breast cancer has several subtypes with differing prognosis and clinical features (Debiasi et al., 2018) Trastuzumab represents the current Standard of Care (SoC) and has shown to improve progression-free survival (PFS) and overall survival (OS) (Slamon et al., 2001).
Human epidermal growth factor receptor 2 (HER2) is a major contributor to the growth and progression this disease (Majeed et al., 2014), leading to reduced survival (Yarden, 2001) and is thought to be overexpressed in up to a quarter of all cases globally (Arteaga et al., 2011). Amplification of HER2 is related to more severe disease characteristics (Ross et al., 2009) and can lead to treatment resistance in some regimens (Hanna et al., 2017) and reduced treatment response to endocrine therapy (Montemurro et al., 2011) HER2-targeted therapies have been shown to dramatically improve survival outcomes for this subset of patients (Lower et al., 2008), which include trastzumab (Hudis, 2007). Studies show that trastuzumab in combination with other agents has significantly improved clinical outcomes (Papazisis, Habeshaw and Miles, 2004; Nishimura, Okumura and Arima, 2007). The emergence of treatment resistance also represents a clear problem in this patient population and the use of combination therapies may provide a way to manage acquired resistance (Luque-Cabal et al., 2016) Metastatic HER2-positive disease represents a clear unmet need for combination HER2-targeted therapies which will be the basis of the development of the regulatory strategy.
Regulatory Levers
MHRA Innovation Office: PIM and EAMS
This regulatory lever allows sponsors to understand how to progress their novel therapeutic through the regulatory environment. Guidance is provided individually and jointly with NICE to provide support through the drug development and manufacturing process (MHRA, n.d.). Advice of future-proofing compliance of supranational regulation can also be provided to safeguard the marketability of the product and allows views from other UK regulators such as the Human Tissue Authority to be represented (Richards and Hudson, 2016).
Early Access to Medicines Scheme (EAMS) allows innovative drugs to reach patients who need them. The first stage is a Promising Innovative Medicine (PIM) designation which provides evidence that the candidate drug may be eligible for EAMS. PIM designation helps to facilitate interactions with patient access stakeholders and the MHRA may notify the NHS and HTA bodies of this designation to provide further interactions and more holistic approach to the approval and testing of this product (MHRA, n.d.). 73% of PIM designation applications have been successful (MHRA, 2019) which represents a promising statistic. The EAMS designation leads to a fast review process and positive decisions are made publicly available, which can raise the profile for the developing product. There is a fee for this submission and the sponsor must make their product available to patients free-of-charge and as no funding will have been allocated, the costs associated with this scheme may be a hurdle for smaller companies (O'Connor, McDonald and Lam, 2017). However, the opportunity to provide benefit to those in need and gather RWE makes this an attractive regulatory option to pursue.
EAMS approval is not a guarantee of success. Provenge (sipuleucel-T) was EAMS approved in 2010 some 4 years, the developing company filed for bankruptcy due to poor sales (Elvidge, 2014).
EMA Innovation Task Force, PRIME and Accelerated Access
PRIority MEdicines or PRIME scheme allows for early discussions and interaction with the EMA and provides early rapporteur appointment and expert advice on the drug development plan and regulatory strategy. Sponsors are also able to get an indication of the likelihood of being granted AA, which would speed up the approval process. However, this early access must be balanced with more rigorous pharmacovigilance activities and safety monitoring, which the sponsor must ensure is being maintained. Although only 18 out of 63 PRIME requests were granted for oncologic products (EMA, 2019a), this is likely due to the failure to demonstrate a major therapeutic advantage to SoC (EMA, 2018). This is not anticipated to be a problem for the investigational product in question. AA also allows for discussion with the regulatory bodies regarding GMP and GCP so that these checks can be brought into the overall development plan, reducing potential delays and issues (EMA, 2016a).
When looking at the parallel scheme at the FDA nearly 90% of these approvals did not represent improved clinical outcomes (Kim and Prasad, 2015), which shows a shortcoming of PRIME and AA schemes and goes some way to explain why PRIME designated drugs often have to provide clinical data over a longer period of time and larger patient population (EMA, 2018). Additional studies may have been planned if this occurs.
Joint Advice HTA bodies and EMA
The Committee for Medicinal Products for Human Use (CHMP) and Scientific Advice Working Party (SAWP) provide guidance to sponsors to ensure that the appropriate investigations are carried out, preventing major objections being raised when marketing authorisation is sought. The EMA also offers discussions alongside with European Network for Health Technology Assessment (EUnetHTA) for sponsors to develop their data gathering plans to support marketing authorisation and reimbursement applications (EMA, 2019b). This regulatory lever provides an invaluable opportunity to smooth the regulatory process and reduce risk associated with the drug development plan for the sponsor and their stakeholders.
UK Accelerated Access
The UK Accelerated access scheme aims to mirror the EMA scheme and also provides health authorities the opportunity to define the medical needs of the healthcare system If companies develop drugs to meet this need, a permanent dialog begins which guarantees accelerated for the drug, while its benefit:risk ratio is uncertain (Accelerated Access, 2016). This clearly provides an opportunity to safeguard reimbursement of development costs and to provide patients with unmet need to efficacious products. It is assumed for that this product is not eligible for this scheme due to the current SoC in established practice. Additionally, this scheme is more focussed on the post-Brexit landscape (Parliament. Health and Social Care Committee, 2018) and is therefore out of the scope of this assignment. However, it would form a central part of the regulatory strategy if the context was different. PDCO and PMEAG: Paediatric Investigation Plan Paediatric scientific advice is free of charge at any stage of development for a paediatric medicinal product. These levers aim to increase the availability of paediatric medicinal products to reduce off-label use products in children (EUPATI, 2016). Paediatric studies could be waived for this classes of drugs and this need should be established early. Furthermore, the potential use of this product in adolescents would encourage the development of a PIP as planned. PIP approvals are led by the adult indication. 93% of new oncology treatments have relevant activity in paediatric cancers but, half of these have received waivers (Vassal, Geoerger and Morland, 2013). Given the large proportion of paediatric oncologic agents used in adult indications, there is a clear argument for PIP work to be completed.
Benefits of this lever are 6-month extension of the patent and through the Paediatric Use Marketing Authorisation (PUMA), products receive 10 years of data exclusivity and market protection, partial fee exemptions from the centralised application process and the ability to use the same branding on the paediatric formula to the adult product (EMA, n.d.) however, it can be challenging to design and conduct the necessary studies due to wide variations in epidemiology and physical development of the paediatric populations.
Regulatory Strategy
Following Phase 1b, there is evidence of efficacy, with regards to the immunologic response with co-administration of trastuzumab and evidence of good tolerability with regards to low level observed toxicity. Due to the disease prevalence, this product is not eligible for orphan designation which limits some regulatory pathways but, still provides plenty of scope for engagement and uptake of other incentives. A graphic summary of the regulatory strategy from Phase 1b to Marketing Authorisation is provided as Figure 1. Figure 2 shows the planned studies for widening the approved indications.
Regulatory initiatives can accelerate the approval of the investigational product and safeguard trial participants from unnecessary exposure to activities that would not support licencing. The collaboration between regulators, Health Technology Assessment (HTA) bodies and patient groups ensures that the product has good uptake and fulfils the requirements of these three key groups. Scientific and protocol advice ensures that studies are planned with regulatory and HTA compliance in mind, streamlining the commercial process, reducing costs & resources and ultimately, mitigating regulatory risk. If the product is ineligible for any of the schemes applied for, development should continue and scientific advice should still be sought from the regulators although, this may come with a financial cost. Notwithstanding, this would be an important opportunity to ensure compliance and smooth approval process.
Figure 1 – Regulatory strategy and drug development scheme from phase 1b to marketing authorisation
Figure 2 – Regulatory strategy and drug development scheme from marketing authorisation to target indication widening.
Period 1 – Following Phase 1b
A Paediatric Investigation Plan (PIP) should be developed. This will be done in concert with advice from the EU’s PDCO and UK’s PMEAG to ensure that study design and indications are feasible and meet regulatory requirements. Advice will be sought on the possibility of a waiver on paediatric studies due to breast cancer being an adult malignancy however, the inclusion of adolescent studies will be planned for. The Paediatric studies will not be actioned until the close of the Phase III trial but must be planned for and designed at this early stage. PDCO will advise on any need for reformulation for example, selection and volume of diluent used and a potential recommendation for dose finding PK-modelling. A mass-balance assessment, to determine potential Drug-drug interactions and to profile the pharmacokinetics of the drug as well as, in-vitro drug-drug interaction studies should be carried out. Population PK modelling and PK/PD modelling related to efficacy and safety parameters (EMA, 2017) may also be initiated depending on scientific advice.
Engagement with EMA’s Innovation Task Force (ITF) will provide scientific advice and guidance on protocol design for Phase II study. ITF will also advise and guide through the application for PRIME designation, as a novel therapy and provide guidance for the application of Accelerated Assessment (AA). AA designation will allow faster access to patients for the investigational product (EMA, 2016a) and provide an opportunity for the sponsor to reassure stakeholders, at this early stage of development where additional funding is likely to be needed. Methods and plans for post-marketing RWE collection should also be discussed at this early stage.
MHRA’s Innovation Office will be engaged to provide further scientific and protocol advice for the design of Phase II study and to guide through the application of PIM designation and subsequent EAMS process.
Companion Diagnostic/biomarker verification is not thought to be needed due to the number of approved and validated companion diagnostics for HER2 overexpression in breast cancer that can be readily utilised (Myers, 2016). However, this must be confirmed during opportunities for scientific and protocol advice.
Period 2 – Phase 2 Trial
Initiation of the Phase II trial. This trial will enrol adults who over express HER2 with limited/no co-morbidities and generally stable health conditions. The design will be a single arm, dose ranging study with aims to confirm safety profile seen in Phase I and to assess exposure-efficacy and exposure-safety relationships to support dosing levels in the pivotal Phase III trial.
Period 3 – Phase 3 Study Design and Advice
Following the Phase II trial, scientific and protocol advice will be sought jointly from the EMA and EUnetHTA to guide acceptable Phase III studies (EMA, 2019b). HTA bodies and patient groups will advise on acceptable Patient Reported Outcomes (PRO) measures to be used in the trial to support reimbursement activities and provide meaningful information to patients. Joint scientific advice will also be sought form MHRA and NICE for the same reasons and will provide further guidance to ensure regulatory compliance when submitting the marketing authorisation application.
MHRA EAMS work will also commence at this point, where select patients will be provided with the investigational drug, on an on-going basis due to the high unmet need. These patients are provided the drug free-of-charge (MHRA, n.d.) and will provide the sponsor with useful real-world evidence (RWE) to support marketing applications and to provide reassurance to stakeholders.
Period 4 – The Pivotal Phase 3 Trial
The Phase III trial is initiated. This is a 2-arm trial involving adults that overexpress HER2 with limited co-morbidities. It will compare standard of care (SoC), trastuzumab alone against the SoC + the investigational vaccine. Primary endpoints measured will be Progression Free Survival (PFS) and Overall Survival (OS) with a secondary endpoint of the PROs previously agreed with the regulators, HTA bodies and patient groups and the clinical benefit rate (CBR) as this can provide a measure of disease stabilisation (Amiri-Kordestani et al., 2016). There will be a parallel ‘all-comers’ compassionate study of adults that overexpress HER2 that will run with wider inclusion criteria to maximise potential benefit offered to patients in this disease area. This compassionate study will not be part of the marketing authorisation application but will provide RWE to support this application and provide efficacy and safety evidence to stakeholders. It also provides an opportunity for RWE gathering of safety signals to reduce uncertainty in the benefit:risk ratio of this product.
Period 5 – Marketing Authorisation
This is where centralised marketing authorisation is sought from the EMA due to the product being a therapeutic vaccine for the treatment of cancer. AA should have already been granted due to previous co-ordination through the PRIME initiative which will mean a faster decision on approval can be expected.
Conditional approval, through the Adaptive Pathways scheme will be sought, to allow for the drug to be licenced as quickly as possible, providing benefit patients. This approval will be for a limited indication of a well‐defined patient subgroup with a high medical need that will expand as more evidence of efficacy and safety is gathered over the next year (EMA, 2016b). This conditional approval will be converted into a full marketing authorisation once the EMA is satisfied that the required benefit:risk ratio has been established. The conditional marketing authorisation path is integrated within the PRIME scheme and so should provide unnecessary hurdles to be approved.
Following marketing authorisation, the PIP will be initiated, and paediatric studies will begin. This will be staggered trial design (ICH, 2017) starting with older adolescents before moving into younger children, if required by PDCO and PMEAG. The aims of these studies will be to determine any chance of ‘late effects’ from the drug on future growth and development. Period 6 – Life-cycle Management and Post-Marketing
Following the conditional approval, further studies will be undertaken to expand the patient population and effectively manage the drug life-cycle. These will include a the planned for, paediatric-use marketing authorisation (PUMA) and a basket trial to determine efficacy in other cancer areas where HER2 is over-expressed, a geriatric study, special population studies in those with impaired organ function. Efficacy of the treatment as a monotherapy and efficacy in non-HER2 over-expressors can be sought to further widen the target indication. If efficacy is shown in other cancer indication, further paediatric work may be carried out to support PUMA indication expansion and investigations into younger patients. RWE collection will be achieved through multiple data sources such as, electronic health record data and clinical/patient registries and the Clinical Practice Datalink (CPRD) will be carried out to collect further safety and efficacy data from real-world use to reduce uncertainty and to marketing expansion from conditional to ‘full’ marketing authorisation (Cave, Kurz and Arlett, 2019). The cost of these ongoing studies and analysis will need to be planned for.
Common issues surrounding poor-quality or incomplete data, as well as the potential for bias in data interpretation will be mitigated by following the EU’s Innovative Medicines Initiative (IMI) GetReal (IMI, 2017).
Executive Summary
Figure 3 - Table to provide executive summary of drug development plan and regulatory strategy.
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