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Pharmaceutical Education And Research with Regulatory Links: Innovative drug development strategies and regulatory tools tailored to facilitate earlier access to medicines

Periodic Reporting for period 1 - PEARRL (Pharmaceutical Education And Research with Regulatory Links: Innovative drug development strategies and regulatory tools tailored to facilitate earlier access to medicines)

Reporting period: 2016-05-01 to 2018-04-30

Europe’s pharmaceutical industry is facing unprecedented challenges in the development of new medicines due to longer development timelines, higher failure rates and increasing costs of testing new drug candidates. Solutions are urgently needed to streamline ‘molecule-to-market’ timelines to ensure earlier patient access to breakthrough therapies and reduce the cost of new medicines overall.

PEARRL is a European Training Network that develops innovative drug development strategies and regulatory tools designed to facilitate earlier access to new medicines. PEARRL research addresses key needs for getting new medicines to market faster. From antibiotics through to medicines which prevent gastric ulcers, to stem cell research, the research in the pharmaceutical sciences has made great strides over the last century. However, developing a new drug into a licensed medicine is a long, costly and complex process. Every stage of drug development requires extensive testing. Even so, at the end of the long process of drug development – often over 10 years - and after committing considerable human and financial resources, the new drug’s safety and efficacy in the desired patient population may not meet the stringent requirements for approval by regulatory authorities such as the European Medicines Agency (EMA).

The PEARRL project brings together 18 leading European institutions, including Pharmaceutical industry (9), academia (5) and regulatory agency (4) partners in a multi-sectorial team to deliver a unique research programme. 15 Early Stage Researchers (ESRs) have been recruited in PEARRL, to focus their research endeavours on developing innovative drug development strategies to enable accelerated approval, thus facilitating earlier patient access to new medicines.

The main research objectives of PEARRL are to develop novel bio-enabling formulations (‘better oral medicines’), new biopharmaceutics tools and predictive in silico methods to forecast drug levels in humans (‘streamlined development’), which together will serve as communication bridgers between industrial development and regulatory science (‘accelerated approval’). The key impact will be that new medicines will be brought to the market faster, with less failure rates and lower overall costs.
To address this, the research strategy in PEARRL provides a three-tier approach: (1) Adding innovative ‘bio-enabling’ formulation strategies to the existing palette to provide the versatility required to address the challenges presented by today’s drug pipeline; (2) finding fast and accurate ways to screen prototypes to arrive at the optimal lead formulation, and (3) coupling these biopharmaceutical tools with in silico models that can predict the formulation performance in the target patient population. This research strategy is reflected in three distinct Work Packages.

• WP1 is about the design of innovative ‘bio-enabling’ drug formulations. WP1 focuses on developing novel formulation technology to address an increasing trend for new drug candidate with poor solubility and consequently insufficient absorption from the intestine. Various types of bioenabling strategies are being studied including solid dispersion technology (FHNW & Pharmathen), mesoporous systems (Merck) and Lipid-based drug delivery systems (UCC & Janssen).
In terms of key results to-date, substantial progress was made in designing new ‘bio-enabling formulations’ by using additives with a molecular rationale for different solid dispersions (ESR 2, 3 and 4). A more rational formulation design has successfully led to the first lipid-based candidate formulations (ESR 1 and 14). Novel computational tools to predict formulation design have also been developed (ESR1, 2, 3, & 5).

• WP2 focuses on in vitro tools and in vivo models for screening novel bio-enabling formulations and for evaluating drug product performance in patients. The primary objective is to develop new in vitro testing approaches that predict which formulation will perform optimally in patients. The groups involved in WP2 are focused on designing bio-predictive in vitro testing conditions (JWGU, Pion, UoA, UCC); ‘small scale’ in vitro approaches for high throughput screening (Pion & UoA); in vitro testing conditions for evaluating products in special patient populations e.g. paediatrics, intestinal disease states (UBATH, UoA); suitability of pre-clinical pig models for predicting bioavailability in humans (UCC).
Significant progress has been made in Period 1. An intestinal luminal study in humans is underway (ESR7), the first pig study is completed with an associated research manuscript already published (ESR9), experiments with small scale in vitro setups are in progress (ESR10), an in vivo study in adults to predict drug performance in paediatrics is ongoing (ESR11) and in vitro experiments are in progress (ESR13).

• WP3 aims to provide the crucial link between the lab and the patient by integrating results obtained from WP1 and WP2 into Physiologically-based Pharmacokinetic (PbPK) models and ultimately to predict the drug performance in the desired patient population. Ongoing research in WP3 is focused on appropriate models to predict drug absorption in children (UBATH) and patients with intestinal diseases such as ulcerative colitis, Crohn’s and coeliac disease (UBATH & UoA). A novel in silico model has been developed at JWGU to simulate plasma profiles in patients.
Already at the end of Period 1, appropriate media have been developed to assess drug performance in children (ESR 12) and adults with intestinal diseases (ESR15). Initial experiments have indicated that solubility of key drugs differs between media of healthy and diseased patients. ESR 6 has generated solubility, dissolution and transfer model data for aprepitant, successfully developed a PbPK model for this anti-emetic drug and has been able to simulate plasma profiles for different dosing conditions successfully. ESR 8 has built a PKPD model for zolpidem and is applying it to different formulations of this hypnotic drug.
In order to maximise the impact of PEARRL related research, the consortium have arranged for a special ‘PEARRL’ themed issue in Journal of Pharmacy and Pharmacology (Wiley) to be published in late 2018. Eleven scientific reviews have been prepared jointly among all ESRs, focusing on identifying knowledge gaps in PEARRL related research area, with a view that these can be addressed in PEARRL research. ESRs have also published several conference abstracts and the first research manuscripts have recently been published.

The results achieved in Period 1 have already led to innovation in three key areas: namely, novel formulation technology, bio-predictive in vitro methods and patient-tailored in silico tools. Collectively, these new technologies and tools will address the needs of pharmaceutical industry for accelerating ‘molecule to market’ timelines for oral medicines and reduce costs overall (e.g. reduce failure rates, reduced in vivo testing). These results will contribute to the competitiveness of EU pharmaceutical industries. The outcomes from PEARRL will also align with societal obligations towards providing earlier access to breakthrough medicines to patients in need.