clinical development Archives - European Industrial Pharmacists Group (EIPG)

Lessons learnt to transition from Horizon 2020 to the new FP10


by Giuliana Miglierini The European Commission published the ex post evaluation of Horizon 2020 (H2020), the FP8 framework programme for research and innovation (R&I) run in years 2014-2020. The report identifies several areas of possible improvement, which may be taken into Read more

Approvals and flops in drug development in 2023


by Giuliana Miglierini Approvals and flops in drug development in 2023 The European Medicines Agency published its annual highlights, showing 77 medicines were recommended for marketing authorisation, and just 3 received a negative opinion (withdrawals were 19). In 2023 some highly expected Read more

Webinar: Oral Colon Drug Delivery - Design Strategies


EIPG webinar Next EIPG webinar is to be held on Wednesday 21st of February 2024 at 17.00 CET (16.00 GMT) in conjunction with PIER and University College Cork. Anastasia Foppoli, will discuss on the various approaches and the general aspects Read more

Approvals and flops in drug development in 2023

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by Giuliana Miglierini

Approvals and flops in drug development in 2023

The European Medicines Agency published its annual highlights, showing 77 medicines were recommended for marketing authorisation, and just 3 received a negative opinion (withdrawals were 19).

In 2023 some highly expected candidates under clinical development failed to meet the fixed endpoints, as reported by Fierce Biotech. The impact of the Covid-19 pandemic reduced the commercial performance of medical products launched in 2020, highlights the Trinity Annual Drug Index. We summarise the main features emerging from the three documents.

The approval of the first CRISPR/Cas-9 gene therapy

The only advanced therapy medicinal product (ATMP) recommended by EMA in 2023 represents a true innovation in the therapeutic arsenal to treat transfusion-dependent beta-thalassemia and severe sickle cell disease. Casgevy (exagamglogene autotemcel) is the first-in-class CRISPR/Cas 9 gene therapy approved, targeting specific mutations in the genome of patients that affect the production or function of haemoglobin.

EMA recommended in 2023 39 medicines based on a new active substance never authorised before in the EU. Generics and biosimilars were about a third of the approved products (14 and 8, respectively). On the other hand, 17 products received an orphan designation. Other new medicinal products followed different dedicated regulatory pathways, such as Prime (3) or accelerated assessment (3). One product received approval under exceptional circumstances, other 8 a conditional marketing authorisation.

Oncology continues to represent the most attractive therapeutic area for pharmaceutical R&D, with a total of 14 new medicinal products.

Elrexfio (elranatamab) and Talvey (talquetamab) were approved for the treatment of adult patients with relapsed or refractory multiple myeloma, a rare cancer of the bone marrow that affects plasma cells. Two other new medicines – Columvi (glofitamab) and Tepkinly (epcoritamab) – were approved for the treatment of diffuse large B-cell lymphoma, an aggressive cancer of the lymphatic system. The treatment of myelofibrosis, a rare blood cancer that affects the bone marrow, can benefit from the approval of Omjjara (momelotinib). Cerebral glioma in paediatric patients from one year of age is the target of the combination of Finlee (dabrafenib) and Spexotras (trametinib).

Among other particularly innovative products recommended for approval by EMA are two vaccines to protect against lower respiratory tract disease caused by respiratory syncytial virus, Abrysvo (bivalent, recombinant) targeting small infants via immunisation of the mother during pregnancy (and over-60 adults), and Arexvy (recombinant, adjuvanted), representing the first vaccine for active immunisation of adults aged 60 years and older.

EMA also recommended two medicines for use in countries outside the EU, under the regulatory procedure “EU-Medicines for all” (EU-M4All). Arpraziquantel (arpraziquantel) targets schistosomiasis, a neglected tropical disease caused by parasitic trematode worms and affecting an estimate of 50 million young children. Fexinidazole Winthrop (fexinidazole) is already in use from 2018 to treat human African trypanosomiasis, a disease caused by the parasite trypanosoma brucei gambiense and also known as sleeping sickness. The CHMP extended the indications to include treatment of the more acute and lethal form of the disease caused by trypanosoma rhodesiense.

The main failures in clinical R&D

Pharmaceutical R&D may also lead to failure of the clinical development for candidate products. A selection of the more significant flops in 2023 as for clinical trials has been published by Fierce Biotech on its website.

An already FDA approved gene therapy product is also included in the list, Sarepta’s Elevidy for the treatment of Duchenne muscular dystrophy, as its phase 3 Embark study didn’t meet the primary endpoint. The product is now under further scrutiny by the FDA. As for vaccines, a major failure refers to Janssen Pharmaceuticals’ HIV vaccine and its phase 3 Mosacio study, that was terminated as it was not expected to meet the primary endpoint. According to Fierce Biotech, Johnson & Johnson would have ended the development of the HIV vacci-ne and completely revised the infectious disease R&D unit. Failure to meet the expected benefit (3.5-month overall survival) in the phase 3 Sapphire trial impacted also sitravatinib, a spectrum-selective kinase inhibitor developed by Mirati Therapeutics to overcome resistance to checkpoint inhibitors in the treatment of non-small lung cell carcinoma. Tarcocimab tedromer is an anti-VEGF antibody biopolymer conjugate developed by Kodiak Sciences to treat diabetic macular edema, and that did not meet the primary endpoint in a phase 3 trial compared to the approved therapy. The same occurred to evobrutinib, a BTK inhibitor from Merck KGaA to treat multiple sclerosis, that failed the comparison with the reference product in two phase 3 studies. The failure of the potential blockbuster factor-XIa inhibitor asundexian, developed by Bayer for treatment of atrial fibrillation with stroke risk, was due to an observed “inferior efficacy” com-pared to the standard treatment Eliquis. The failure of efruxifermin (a FGF21 analog) in a phase 2b study aimed to treat fibrosis in cirrhotic MASH patients was attributed by Akero Therapeutics to the fact enrolled patients may have reached a too advanced state of disease for the treatment to be effective. The failure of Nektar Therapeutics’ phase 2 clinical trial in lupus with Rezpeg (rezpegaldesleukin) is a less typical occurrence, as it was due to errors made by the industrial partner Eli Lilly in the analysis of data from a phase 1b trial in eczema and psoriasis. Lilly admitted the errors and was then sued by Nektar.

The land of unicorns also crashed down when izokibep, a small protein developed by Acelyrin, failed the primary endpoint against placebo. The company had received a $540 million IPO, to then see its shares value decreasing by 58%. The failure was attributed to a programming error by a CRO, which according to Fierce Biotech is under investigation by the sponsor. The potential of artificial intelligence in supporting drug discovery may also be impacted by the failure of BEN-2293, a topical pan-Trk inhibitor in eczema developed by Benevolent AI which failed to meet the secondary endpoints of the safety-focused study.

The commercial performance of products approved in 2020

The commercial performances of novel drugs approved in 2020 are the focus of the Trinity Annual Drug Index.

Oncology represented in 2020 the leading indication (29% of the total 58 unique FDA drug and biologic approvals), followed by neurology (16%). The combination of the two therapeutic areas marked a net increase compared to 2017 (45% vs 34%, respectively). Half (9/17) of the new pro-ducts approved in Oncology were small molecules, mainly mutation directed. A quarter (24%) of the new medicines were monoclonal antibodies. The antibody drug conjugates Trodelvy, in particular, was the highest performing Oncology drug overall.

The strong impact of the Covid-19 pandemic on the pharmaceutical industry in 2020, with many shifts of priorities in development and the need to manage shortages and disruptions of the supply chain, led to a lower commercial performance of the new products launched com-pared to 2016-2019. Good commercial results were obtained only by new medicines addressing significant unmet need or providing very strong therapeutic benefits.

The Trinity Annual Drug Index also highlights that approx. 21% (12/58) of approved products in 2020 constituted a “first launch” for their respective companies. None of them surpassed their forecast expectations, and approx. a half significantly underperformed.


The new MHRA’s framework for clinical studies

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By Giuliana Miglierini

The repositioning of the United Kingdom as a global leader for clinical development of medicinal products can now benefit of the complete renewal of the framework regulating clinical studies run in the country. Announced in March 2023 by the Medicines and Healthcare products Regulatory Agency (MHRA), the new set of measures represents the deepest reform of the sector in the last 20 years. The new package is based upon results of the public consultation run in Q1 2022 in partnership with the Health Research Authority (HRA) and the Department of Health in Northern Ireland, which collected more than 2,000 responses.

As stated in the foreword of the final document, which details the government’s consideration of responses to individual questions, the main objective of the reform is for the UK to capitalise on the opportunity offered by the country’s new position in the global clinical trial landscape. Furthermore, it represents just the initial step of UK’s new regulatory approach, which may include for example a wider use of real-world evidence, novel analytics and data tools. International collaborations are also deemed important, e.g. with the FDA’s Project Orbis and the Access Consortium (Australia, Canada, Singapore and Switzerland) and the International Council for Harmonisation of Technical Requirements for Pharmaceuticals of Human Use.

Our world-first Covid-19 approvals showed how important it is to ensure that regulation is flexible and agile. This overhaul of the clinical trials legislation will do just this – it will move us away from a one-size-fits-all approach to the regulation of clinical trials and help to streamline approvals by removing granular and duplicative regulatory requirements”, said MHRA Chief Science and Innovation Officer Marc Bailey.

According to the Health and Social Care Secretary Steve Barclay, the reform will make the UK more attractive for scientists and researchers. “These changes will help speed up clinical trials, without compromising on safety, and encourage the development of new and better medicines for patients. They come after the government announced additional funding of £10 million for the MHRA to accelerate the delivery of cutting-edge treatments including cancer vaccines”, he said.

The main goals of the reform

Patients are central to the UK’s reform of clinical trials. While efficacy and safety of new medicines under development remain the main target, great attention should be paid to reduce health disparities. To this instance, the MHRA announced the issuing of new guidance on how to ensure diversity of participants enrolled in trials, so to overcome imposed targets or arbitrary quotas. The improved attention to diversity would also support the delivery of trial results more adherent to the effective prevalence and clinical need across the population.

Flexibility and proportionality of the regulatory environment is another key objective of the reform. According to the final document, regulatory requirements should adapt to the current risk of the trial, and researcher should become subject to an overarching duty to consider proportionate approaches to clinical development.

Simplification of regulatory procedures is also expected, for example in the case of studies characterised by a risk similar to that of standard medical care. In this instance, regulatory review of the study protocol should not be needed anymore, substituted by simple “notification scheme” to enable approval.

As said, the attractiveness of the UK as a leading destination for international trials should be supported by streamlined and efficient application processes. This goal should include a new legislative action to integrate the regulatory and ethics reviews of clinical trial applications. Results from a pilot phase will be taken into consideration, as they proved possible to halve the approval times and cut the time from application to recruiting a first patient by 40 days.

All activities relating to clinical development should reflect the ICH Good Clinical Practice (GCP) principles for trial conduct. Regulatory timelines for approval are expected to compete at the international level, so to encourage sponsors to choose the UK as the preferred site to conduct multinational trials. According to the MHRA, the review of an application should take a maximum of 30 days in general, with a maximum of 10 calendar days for a decision to be granted once the regulator has received any final information. As for GCPs, compliance should also extend to service providers of electronic systems that may impact on patient safety.

Sponsors should also benefit from greater flexibility to respond to questions raised by regulators. In particular, the reform aims to amend the Request for Information (RFI) receipt, so that the sponsor has access to RFIs as they are ready rather than waiting for all requests to be made together.

The reform takes in consideration also the possible impact of incoming innovation, for example different types of trials and innovative study designs (e.g. decentralised trials). New guidance should be provided to set out specific details, thus avoiding any duplication. Guidance should be also provided on how to involve patients; family members or carers having a direct experience of the health problem in the design and conduct of a trial.

Transparency of the entire process should be supported by the compulsory registration of the trial in a World Health Organisation public register. A summary of results should also be published within 12 months of the end of the trial, and trial findings should be mandatory shared with trial participants.

Comments from the industry

We welcome the MHRA and HRA’s commitment to work with our industry to codevelop new regulatory guidance and their pragmatic approach to patient & public involvement and trial diversity. We look forward to working with them to make the UK an attractive destination for clinical trials.”, said Richard Torbett, ABPI Chief Executive.

On 19 May, ABPI further commented from is blog the current situation of clinical development in the UK. According to the association representing the British pharmaceutical industry, enrolment to industry trials decreased by 44% between 2017 and 2021, while UK’s global ranking for phase III trials dropped to the 10th place (from the previous 4th). ABPI also reports revenues and cost savings to NHS England from life sciences companies of more than £10,000 for every patient recruited onto an industry clinical trial between 2016 and 2018.

In view of the release of the independent review commissioned by the government to former innovation minister Lord O’Shaughnessy, ABPI has identified three main steps necessary to support the international competitiveness of UK’s clinical trials sector.

Rapid and smooth regulatory procedures are at the first place, with the request not to delay from the 60 days target for combined regulatory and ethics review, comprehensive of the administrative processes of costing and contracting a clinical trial. Early scientific and regulatory advice and sufficient resources for the MHRA to clear the current backlogs and codevelop new regulatory guidance would be also important.

ABPI also highlights the often-experienced difficulty in recruiting a sufficient number of patients. The suggestion for the government is to take inspiration from UK’s leading position in early-phase (phase I) industry trials in order to improve investment in late-phase trial infrastructure. To this instance, health real-world data may prove important to support the search for eligible patients in a larger population.

According to the industrial representative, the UK is also lacking a nationwide clinical research dashboard to describe its performance in clinical research to global sponsors. This should include metrics on volume, speed, quality, impact, and innovation.