Periodic Reporting for period 2 - PEARRL (Pharmaceutical Education And Research with Regulatory Links: Innovative drug development strategies and regulatory tools tailored to facilitate earlier access to medicines)
Periodo di rendicontazione: 2018-05-01 al 2020-08-31
Europe’s pharmaceutical industry is facing unprecedented challenges in the development of new medicines due to long development timelines, high failure rates and the increasing costs of testing new drug candidates. Solutions are urgently needed to streamline ‘molecule-to-market’ timelines to ensure that patients have access to breakthrough therapies as early as possible, while keeping prices affordable.
The PEARRL Project developed innovative development strategies for oral medicines as well as regulatory tools to facilitate early access to them. One highlight was the application of molecular modeling techniques to choose the optimizing drug formulations to improve the drug’s absorption from the digestive tract. This approach can replace the traditional “trial-and-error” approach of choosing excipients. Another highlight was the design of laboratory tests to predict how medicines are absorbed in certain patient types such as those with ulcerative colitis and in children. Moreover, by combining the results of these tests with sophisticated computer models describing the absorption of drugs, it became possible to predict the influence of a drug’s formulation on its therapeutic effectiveness. All three aspects significantly advance both the optimization and streamlining of oral drug development.
The project brought together 18 leading European institutions, including 9 representatives from the pharmaceutical industry, 5 academic institutions and 4 regulatory agencies in a multi-sectorial consortium. 15 Early Stage Researchers (ESRs) were recruited, all of whom have either graduated with their PhDs or are finalizing their dissertations. These scientists will now serve as “communication bridgers” between industrial development and regulatory science, helping new medicines to be brought to the market faster, with lower failure rates and reduced overall costs.
The PEARRL Project developed innovative development strategies for oral medicines as well as regulatory tools to facilitate early access to them. One highlight was the application of molecular modeling techniques to choose the optimizing drug formulations to improve the drug’s absorption from the digestive tract. This approach can replace the traditional “trial-and-error” approach of choosing excipients. Another highlight was the design of laboratory tests to predict how medicines are absorbed in certain patient types such as those with ulcerative colitis and in children. Moreover, by combining the results of these tests with sophisticated computer models describing the absorption of drugs, it became possible to predict the influence of a drug’s formulation on its therapeutic effectiveness. All three aspects significantly advance both the optimization and streamlining of oral drug development.
The project brought together 18 leading European institutions, including 9 representatives from the pharmaceutical industry, 5 academic institutions and 4 regulatory agencies in a multi-sectorial consortium. 15 Early Stage Researchers (ESRs) were recruited, all of whom have either graduated with their PhDs or are finalizing their dissertations. These scientists will now serve as “communication bridgers” between industrial development and regulatory science, helping new medicines to be brought to the market faster, with lower failure rates and reduced overall costs.
The first research objective in PEARRL was to develop innovative ‘bio-enabling’ formulation development strategies to provide the solutions required to ensure efficient oral delivery of new drug candidates. The second objective was to find more accurate biopharmaceutic tools to screen prototypes to arrive at the optimal lead formulation. The third research objective was to couple these biopharmaceutical tools with in-silico models that can predict the formulation performance in the target patient population. These three research objectives were structured as three research Work Packages (WP).
WP 1 was focused on designing innovative ‘bio-enabling’ drug formulations. In terms of key achievements in WP1, sixteen research manuscripts on bio-enabling formulation design have already been published, with a further six research papers currently undergoing PEER review. Notable examples of the novel formulation technologies developed in PEARRL include the use of lipophilic salts (ESR 1), modified polyelectrolyte matrices (ESR 2) and supersaturated Lipid based formations (ESR 14) to improve oral absorption. In addition, more rational ‘industry-ready’ approaches to formulation screening have been advanced for amorphous solid dispersions (ESR 4), drug polymer interactions (ESR 5) and precipitation inhibitors (ESR 3). Finally, novel computational tools to predict formulation design have also been developed (ESR 1, 2, 3, & 5).
The primary objective of WP2 was to develop new in-vitro testing approaches that predict which formulation will perform optimally in patients. ESR 7 successfully optimized in-vitro test conditions for assessing the impact of food on drug product performance; ESR 9 developed an in vitro porcine biorelevant media for predicting drug product performance in the preclinical pig model; ESR 10 has optimised ‘small scale’ approaches for high throughput screening; ESR 11 completed an in-vivo study in healthy adults as an approach to more reliably predict dosing in infants and ESR 13 designed an in vitro-in silico-in vivo framework as a regulatory approach for conducting virtual bioequivalence trials. All ESRs co-authored at least one review article relating to their project and one to four research articles.
WP3 aimed 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 predicting the drug performance in the desired patient population. The research in WP3 focused on appropriate models to predict drug absorption in children (ESR 12) and patients with intestinal diseases such as Crohn’s and coeliac disease (ESR 15). Appropriate media were developed to assess drug performance in children and adults with intestinal diseases. ESR 6 utilized advanced in-vitro biopharmaceutic tools to investigate the gastrointestinal behavior of two enabling formulations (aprepitant and etravirine) and combined these data with PBPK models to explain the drug levels in patients for both drugs. ESR 8 built a PKPD model for zolpidem and applied it to answer questions such as “why does zolpidem have lower absorption when given with meals”. ESR13 also used the model to create a “safe space” for the dissolution behavior of zolpidem products, which would ensure therapeutic equivalence for this common sleep medicine. In total, twelve peer-reviewed research papers were published in WP3 in leading journals, with a further five research articles already submitted for peer review.
WP 1 was focused on designing innovative ‘bio-enabling’ drug formulations. In terms of key achievements in WP1, sixteen research manuscripts on bio-enabling formulation design have already been published, with a further six research papers currently undergoing PEER review. Notable examples of the novel formulation technologies developed in PEARRL include the use of lipophilic salts (ESR 1), modified polyelectrolyte matrices (ESR 2) and supersaturated Lipid based formations (ESR 14) to improve oral absorption. In addition, more rational ‘industry-ready’ approaches to formulation screening have been advanced for amorphous solid dispersions (ESR 4), drug polymer interactions (ESR 5) and precipitation inhibitors (ESR 3). Finally, novel computational tools to predict formulation design have also been developed (ESR 1, 2, 3, & 5).
The primary objective of WP2 was to develop new in-vitro testing approaches that predict which formulation will perform optimally in patients. ESR 7 successfully optimized in-vitro test conditions for assessing the impact of food on drug product performance; ESR 9 developed an in vitro porcine biorelevant media for predicting drug product performance in the preclinical pig model; ESR 10 has optimised ‘small scale’ approaches for high throughput screening; ESR 11 completed an in-vivo study in healthy adults as an approach to more reliably predict dosing in infants and ESR 13 designed an in vitro-in silico-in vivo framework as a regulatory approach for conducting virtual bioequivalence trials. All ESRs co-authored at least one review article relating to their project and one to four research articles.
WP3 aimed 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 predicting the drug performance in the desired patient population. The research in WP3 focused on appropriate models to predict drug absorption in children (ESR 12) and patients with intestinal diseases such as Crohn’s and coeliac disease (ESR 15). Appropriate media were developed to assess drug performance in children and adults with intestinal diseases. ESR 6 utilized advanced in-vitro biopharmaceutic tools to investigate the gastrointestinal behavior of two enabling formulations (aprepitant and etravirine) and combined these data with PBPK models to explain the drug levels in patients for both drugs. ESR 8 built a PKPD model for zolpidem and applied it to answer questions such as “why does zolpidem have lower absorption when given with meals”. ESR13 also used the model to create a “safe space” for the dissolution behavior of zolpidem products, which would ensure therapeutic equivalence for this common sleep medicine. In total, twelve peer-reviewed research papers were published in WP3 in leading journals, with a further five research articles already submitted for peer review.
In order to maximise the impact of PEARRL related research, the consortium arranged for a special ‘PEARRL’ themed issue in Journal of Pharmacy and Pharmacology (Wiley) which was published in 2019. Eleven scientific reviews were prepared jointly among the ESRs, focusing on identifying knowledge gaps in PEARRL-related research area, with a view to addressing these in PEARRL research. The key impact of these review articles was to provide new critical perspectives on optimal oral drug product development strategies for the industry. To date, over fifty peer-reviewed scientific publications have been published by the PEARRL consortium members. In addition, fifteen papers are undergoing various stages of peer review and are due to be published over the coming months. Compared to a target of nineteen (as originally planned) this confirms both (1) the excellence of the ESRs and (2) the success of the consortium members in disseminating the scientific results generated in PEARRL. The outcomes from PEARRL align with our societal commitment to facilitate earlier access to breakthrough medicines. The results achieved have already led to innovations 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 address, in very significant ways, the need for the pharmaceutical industry to accelerate ‘molecule to market’ timelines for oral medicines and thereby reduce overall costs. The unique training programme developed in PEARRL provided ESRs with higher employability prospects. The collaborations among beneficiaries achieved in PEARRL are driving further research opportunities. For example, two new EU research consortia involving existing and new beneficiaries, have already been successfully established: InPharma https://cordis.europa.eu/project/id/955756 and AGePOP https://cordis.europa.eu/project/id/956146. All ESRs will be exemplary future ambassadors, not only for PEARRL, but also for the EU MSCA ITN programme.