Generative AI in drug development

March 11, 2024

AlphaFold, Artificial Intelligence, BioNeMo, Boston Consulting Group, chemical-physical characteristics, data infrastructure, data sources, deep learning, drug development, drug discovery, drug repurposing, economic impact, ESMFold, Exscientia, Forbes, generative AI, generative AI model, genomic data, governance, inClinico, Insilico Medicine, machine learning, McKinsey and Co., molecular structures, MoLeR, MoLFormer-XL, MoLFormers UI, MolMIM, multiple skills, Mutual Information, National Human Genome Research Institute, NVIDIA, Pharma.AI, Pharmaceutical Technologies, receptor binding, regulatory requirements, responsible AI, SMILES notation system, unstructured data

by Giuliana Miglierini

Generative AI is perhaps the more advanced form of artificial intelligence available today, as it is able to create new contents (texts, images, audio, video, objects, etc) based on data used to train it. Applications of generative AI are not limited to, for example, the famous ChatGPT chatbot used to write complex texts, or to algorithms producing incredible images.

Generative AI is becoming a new paradigm in drug discovery, as it promises to greatly reduce both time and costs to develop new molecules, or to repurpose already existing ones for new indications. A fundamental goal for pharmaceutical companies, given that the average cost of developing a new medicines is estimated at $2.6 billion.

Algorithms can be trained on chemical-physical characteristics and 3D shapes of molecules in order to generate completely new molecules of interest for a certain application, and/or to predict their behaviour in the biological context (e.g. binding to a specific receptor). We resume the current status of implementation of generative AI in the field of drug development.

Quintillions of data
It seems ages since the first full sequencing of the human genome was completed in year 2000. Since then, vast amounts of genomic and other biological data have rapidly accumulated. To give an idea, the National Human Genome Research Institute estimates between 2 and 40 exabytes (i.e. quintillions) of data available within the next decade. The number becomes even more larger when considering other domains relevant to drug development, including chemical structures and properties, complex biochemical pathways, 3D protein structures and receptors, data on the efficacy and toxicity profile of already approved medicines and candidates in the pipelines, etc.
No matter to say, the parallel growing interest in artificial intelligence that characterised the last twenty years has turned fundamental for the availability of new technologies able to digest, extract and analyse these extremely large datasets.
Machine learning and deep learning algorithms represented just the first step towards this goal. Generative AI came as a consequence, its birth is attributed to a paper by Ian Goodfellow et al., published in 2014.

Opportunities and challenges of generative AI for drug discovery
The implementation of generative AI in the pharmaceutical and medtech sectors may lead to the an estimated economic value of $60-110 billion/year, says the report by McKinsey and Co. “Generative AI in the pharmaceutical industry: Moving from hype to reality”.
More specifically, McKinsey analysed 63 generative AI use cases in life sciences, calculating the potential economic impact for different domains. The higher values ($18-30 bln) are expected for the commercial domain, followed by research and early discovery ($15-28 bln) and clinical development ($13-25 bln). Less impacted appear enterprise ($8-16 bln), operations ($4-7 bln) and medical affairs ($ 3-5 bln).
Implementation of generative AI may prove not a so easy exercise for pharma companies, as it has to fit within an already complex organisation and with the strict regulatory requirements typical of the pharmaceutical lifecycle. An important message comes from the analysis from McKinsey: it is of paramount importance to exit the hype climate surrounding generative AI and understand exactly what it can and cannot be done.
The question is highly complex to be solved, and it requires multiple skills (data scientists, researchers, medical affairs, legal, risk and business functions) jointly working to set up the solution more suited to each company. The availability of a proper data infrastructure is just the first step, the chosen generative AI model has to be adapted to the complexity of the specific case of use, focusing on key applications to avoid disruption of the business.

According to an analysis by Boston Consulting Group, generative AI may prove useful to include also unstructured data among those used as data sources by the pharmaceutical industry. Possibly a challenging goal to achieve, as data access and management must fulfil regulatory requirements, for example in relation to the possibility to use data generated in clinical trials to support regulatory approval.
Governance of generative AI must also reflect the key principles established in the EU for AI systems, i.e. they “must be ‘safe, transparent, traceable, non-discriminatory and environmentally friendly,’ as well as ‘overseen by people, rather than by automation, to prevent harmful outcomes’.”

The need to integrate generative AI with human activities would probably call companies to redesign core processes. To this instance, selection of the more suited AI infrastructure and platform may turn critical for success of the initiative. Integration with already existing AI tools and flexibility are among other main features to be kept in mind. Not less important is the choice of the right partners, that should fit with the strategic business goals.

Many algorithms already available
The first AI applications based on deep learning algorithms were used, for example, to predict the sequence and structure of complex biological molecules. It was the case of the AlphaFold Protein Structure Database, which contains over 200 million protein structure predictions freely available to the scientific community. Other algorithms of this kind are ESMFold (Evolutionary Scale Modeling) and and Microsoft’s MoLeR, specifically targeted to drug design.
A more recent generation of generative AI are IBM’s MoLFormers UI, a family of foundation models trained on chemicals which can deduce the structure of molecules from simple representations. MoLFormer-XL screening algorithm, for example, was trained on more than 1.1 billion unlabelled molecules from the PubChem and ZINC datasets, each represented according to the SMILES notation system (Simplified Molecular Input Line Entry System). As reported by IBM, MoLFormer-XL is able to predict many different physical, biophysical and physiological properties (e.g. the capacity to pass the blood-brain barrier), and even quantum properties.

Mutual Information Machine (MIM) learning is the approach used by NVIDIA to built its MolMIM algorithms, a probabilistic auto-encoder for small molecule drug discovery. The NVIDIA BioNeMo cloud service uses these models to deploy a generative AI platform to create molecules that, according to the company, should fulfil all properties and features required to exert the desired pharmacological activity.

Not only big players: many new companies were born specifically to support the creation of generative (often end-to-end) AI platforms for drug discovery. Among the main ones, Insilico Medicine’s Pharma.AI platform is being used to build a fully self-generated pipeline comprehensive of 31 programs and 29 targets. The more advance product under development targets the rare disease idiopathic pulmonary fibrosis and is currently in Phase 2 in the US and China. The company’s inClinico AI data-driven multimodal platform to calculate the probability of success of single clinical trials proved useful to predict outcomes of Phase 2 to Phase 3 trials and to recognise weak points in study design.

UK’s based Exscientia, founded in 2012, is an AI-driven precision medicine company. Among its main achievements is the creation of the first functional precision oncology platform to successfully guide treatment selection and improve patient outcomes. The more advanced product in its pipeline is GTAEXS617, an oncology product targeting CDK7 in advanced solid tumors.
These are just few main examples, you can learn more on companies focused on AI for drug discovery in these articles published on Forbes and Pharmaceutical Technologies.

Approvals and flops in drug development in 2023

February 12, 2024

Abrysvo, approvals of new medicines, Arexvy, arpraziquantel, Artificial Intelligence, asundexian, ATMP, atrial fibrillation with stroke risk, BEN-2293, beta-thalassemia, Casgevy, cerebral glioma, clinical development, Columvi, commercial performance, CRISPR/Cas-9 gene therapy, dabrafenib, diabetic macular edema, diffuse large B-cell lymphoma, Duchenne muscular dystrophy, eczema, efruxifermin, Elevidy, elranatamab, Elrexfio, ema, epcoritamab, EU-Medicines for all, European Medicines Agency, evobrutinib, exagamglogene autotemcel, failure clinical trials, fexinidazole Winthrop, fibrosis, Fierce Biotech, Finlee, glofitamab, HIV vaccine, izokibep, momelotinib, multiple sclerosis, myelofibrosis, non-small lung cell carcinoma, Omjjara, oncology, psoriasis, refractory multiple myeloma, respiratory syncytial virus, Rezpeg, schistosomiasis, severe sickle cell disease, significant unmet need, sitravatinib, Spexotras, strong therapeutic benefits, talquetamab, Talvey, tarcocimab tedromer, Tepkinly, trametinib, Trinity Annual Drug Index, Trodelvy, trypanosomiasis

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.

EC Communication (part 1): How to address critical medicines shortages

October 27, 2023

Artificial Intelligence, Communication, critical medicine shortages, Critical Medicines Alliance, digitalisation of the regulatory system, distribution of medicinal products, EFPIA, ema, EMVS, ERCC, EU Commission, EU funds, EU guidance on procurement of medicines, EU joint procurement for antibiotics, EU Mechanism for Demand Signalling, European Medicines Verification System, European Response Coordination Centre, European Shortages Monitoring Platform, European Voluntary Solidarity Mechanism, harmonisation of pack sizes, HERA, Joint Action, list of key antibiotics, manufacturing capacity, Medicines for Europe, medicines shortages, MSSG Solidarity Mechanism, MSSG Toolkit, national procurement rules, PGEU, pharmaceutical supply chain, regulatory flexibilities, rescEU stockpile mechanism, shortages of critical antibiotics, Single Market for medicines, State aid projects, Stella Kyriakides, strategic autonomy, strategic EU reserve of essential medicines, supply obligations, UCPM, Union Civil Protection Mechanism, Union list of critical medicines

by Giuliana Miglierini

As announced on 3 October in the speech given by Commissioner Stella Kyriakides at European Parliament Plenary Session, the EU Commission has published on 24 October its Communication on medicine shortages and strategic healthcare autonomy.

The planned actions are firstly targeted to prevent and mitigate on the short-term critical medicine shortages, thus avoiding the reoccurrence of situations such as those experienced in the 2022. Mid- and long-term actions have been also addressed to support the strategic autonomy of the European pharmaceutical supply chain. Among these is the creation of a Critical Medicines Alliance, to start operations in early 2024.

“Improving the management of critical shortages of medicines and ensuring a steady security of supply for the EU has been our priority since day one. We need a single market for medicines in the EU and a new approach to better tackle shortages of critical medicines. Today we are putting forward collective actions to work closer with the industry and help Member States improve the security of supply for the coming winter and in the long-term.” said Stella Kyriakides, Commissioner for Health and Food Safety.

In this first post, we will examine actions in the field of medicines shortages, leaving the medium and long-term ones to a following article (part 2).

Prepared for future winters

The first goal of the EU Commission is to avoid situations of shortages of critical antibiotics such as those that occurred last year. To this instance, the Health Emergency Preparedness and Response Authority (HERA) and the European Medicines Agency (EMA) have already identified key antibiotics potentially at risk of critical shortages in the winter season, also in future years.

Immediately after the release of the Communication by the Commission, EMA published the details of the announced new European Voluntary Solidarity Mechanism for medicines, the MSSG Solidarity Mechanism.

The mechanism was developed by EMA’s Medicines Shortages Steering Group (MSSG), on the basis of the informal experience made during the pandemic. In case of critical shortages escalated to the MSSG for coordination at European level to request assistance, other member states may be of help through the rescEU stockpile mechanism to redistribute medicines from available stocks. The activation of the Union Civil Protection Mechanism (UCPM), via its 24/7 available European Response Coordination Centre (ERCC), aims to coordinate and logistically support the voluntary transfer of medicines, and it should represent the last resort, after the interested member state had exhausted all other possibilities.

The MSSG also developed a Toolkit including recommendations on how to tackle shortages of critical medicines. Among others are the monitoring of available stocks, supply and demand, interactions with marketing authorisation holders and manufacturers for increasing the manufacturing capacity and for the fair distribution of medicinal products, the implementation of regulatory flexibilities and actions aimed to improve communication to the public and international cooperation with other regulators to early identify critical shortages.

The other actions to tackle shortages

The first version of the Union list of critical medicines is expected to be released by the end of 2023. It will allow the development of further actions, on the basis of the analysis of the vulnerabilities of the supply chain of selected medicines to occur by April 2024.

In addition to the practical recommendations relative to demand forecasting at national level, the Commission is working on an EU Mechanism for Demand Signalling that should better support the collective EU public sector in its decisions. A new European Shortages Monitoring Platform for reporting information regarding available stocks and shortages of medicines is expected to start operating in 2025. Many future actions shall be supported using artificial intelligence to extract information about trends in demand and supply from existing data.

At the regulatory level, a new Joint Action has been announced for early 2024 to promote the effective use of flexibility as well as of measures applied at national level (i.e. magistral preparations of local pharmacies). Regulatory flexibilities may include, among others, the quick authorisation of alternatives, the approval of alternative suppliers of raw materials or finished products, or the temporary extension of shelf-life.

Another initiative announced for 2024 should see the issuing of an EU guidance on procurement of medicines, better detailing the already existing tools and practices supporting the security of supply. In the meantime, an EU joint procurement for antibiotics and treatments for respiratory viruses should be activated for the incoming winter.

The Communication contains some recommendations for member states and the pharmaceutical industry. The former are called to monitor and fully enforce the supply obligations of companies, to develop effective communication plans, and to consider how national procurement rules and criteria can increase security of supply. Industrial stakeholders should continuously monitor the evolution of demand and supply of critical medicines, assuring to the full the supply obligation under EU law. Early communication of critical situations to regulators should also occur, as well as the implementation of recommendations, both on regulatory flexibilities and on the elements of the pharmaceutical revision that could already be applied.

Comments from the stakeholders

The interested pharmaceutical associations promptly reacted to the EU Commission’s Communication.

EFPIA particularly welcomed the structural measures to address the industrial dimension of medicines shortages in the medium and long term, as the Critical Medicines Alliance. The development of solutions targeting the specific root causes of shortages, and measures aimed at mitigating shortages in the short term should be “proportionate and provide efficient, workable solutions that serve public health needs”. EFPIA asks for the industry to be included in the design and implementation of new processes and highlighted the “missed opportunity” represented by sharing of the information stored in the European Medicines Verification System (EMVS).

“In response to Member State and Parliament calls for a Critical Medicines Act, this communication is a positive first step for the security of supply of medicines. Medicines for Europe will partner with the EU to implement these important reforms”, said Medicines for Europe President, Elisabeth Stampa. The associations ask, among others, for a strategic EU reserve of essential medicines, and EU funds and State aid projects to incentivise investments in greener and more secure manufacturing processes for essential medicines and active pharmaceutical ingredients (APIs). Digitalisation of the regulatory system and harmonisation of pack sizes and presentations would be also helpful.

European community pharmacists also welcomed the Communication, as it may help to avoid new, severe medicine shortages like the one experienced last winter. “PGEU’s annual survey confirms that shortages exist in all EU countries across all types of medicines, causing detriment to patients’ health, waste of resources and frustration. Every day, we spend hours managing shortages and finding solutions to guarantee continuity of treatment for our patients”, commented PGEU President Koen Straetmans. As for the common strategic approach to stockpiling, according to PGEU it should be guaranteed that stocks will not be to such an extent as to jeopardize the general supply of medicines, nor they should generate unnecessary waste.

EuropaBio, representing the biotech industry, positively commented on the Communication and highlighted that EU actions should not be limited to essential medicines, but should target also the growing dependency on third countries for innovation medicines.

EU’s Industrial Forum, the future of advanced manufacturing technologies

October 6, 2023

access to capital, advanced manufacturing, Artificial Intelligence, biomanufacturing, Blueprint Alliance for Advanced Manufacturing, CAR_T cells biomanufacturing, circularity, data availability, data economy, data protection, due diligence, EU Single Market, EU sustainability goals, EU Taxonomy, EuropaBio, European Commission, European manufacturing data space, Free Trade Agreements, impact assessment, Industrial Forum, Industrial Strategy, industrial technologies, IP rights, netzero industry, Pact for Skills, public investment, readiness, report, REPowerEU, Skills, standardisation, state aids, supply chain resilience, VET practices

by Giuliana Miglierini

The expert group “Industrial Forum” is a multistakeholder body created by the European Commission to support the implementation of the Industrial Strategy launched in March 2020 and its following update of May 2021. Its members include Member States authorities, NGOs, industrial representations, research institutions and social partners representing different industrial ecosystems.

Its recently published report is the result of the structured dialogue among members on how to accelerate the deployment of advanced manufacturing technologies (AMTs) across the European industry. Among members which participated in the drafting of the document is also EuropaBio on behalf of the biomanufacturing industry.

Europe is leader in advanced manufacturing

Advanced manufacturing is based on the integration and convergence of the most advanced industrial technologies, i.e. automation, robotics, artificial intelligence and digitally connected solutions. New processes, new products as well as new business models based on this new approach are deemed to represent a fundamental competitive factor in the next few years.

Europe is currently well position in the ranking on “future of production” readiness, with 18 out of 25 countries considered by the World Economic Forum to be leading the change in manufacturing. Despite this, according to the report many efforts are still needed to accelerate the implementation of advanced manufacturing technologies in the EU, so not to be superseded by other fast-evolving competitors.

In order to achieve this challenging goal, the Industrial Forum identified seven different areas of attention, each of which is addressed by specific recommendations based on a SWOT analysis.

The seven areas of recommendation

The transition to new manufacturing models should, first of all, meet the EU sustainability goals established by the European Green Deal: the “net-zero industry” plan for renewables and industrial efficiency technologies is confirmed as a priority action, together with the expansion of the use of REPowerEU. The Commission is working on new energy savings directives, which should be timely implemented. Circularity of manufacturing processes and products is another main goal of EU’s industrial policies, to be supported by a set of new fit-for-purpose rules. A more rapid uptake of advanced manufacturing technologies should also be supported by both the availability of specific public procurement guidance and a targeted communication of the environmental benefits of European clean technologies.

The second area of action addresses how to improve access to capital, a key factor in ensuring the timely implementation of advanced manufacturing technologies. This may include a better use of public investment, as well as a cautious application of state aid instruments specifically targeted at later stages in the innovation and deployment process. The potential of these new technologies for sustainability should also be recognised within the upcoming EU Taxonomy de-legated acts.

The resilience of supply chains could be tackled by the rapid implementation of AMTs. In order to achieve this goal, the Industrial Forum highlighted the need for workable and proportionate rules on Due Diligence. No less important is the negotiation and activation of new Free Trade Agreements with third countries (such as the EU-Mercosur FTA). A critical area refers to the improvement of EU semiconductor capacity. According to the report, incentives and funding aimed to increase the supply chain resilience should be exempt from directing specific outcomes. The European institutions should also better support the local and regional industrial supply chains. Secure access to critical raw materials should be pursued by leveraging the trade policy.

The building of an EU Single Market is a main goal of the European Commission, also in the pharmaceutical field. Its freedoms should be safeguarded by narrowing down the scope of the Single Market Emergency Instrument, while promoting mitigation measures for advanced manufacturing. The Industrial Forum also recommends the availability of a single platform to provide companies with all the needed information to expand and/or export. Furthermore, a Single Market test should be included in the impact assessments of national laws to minimise the occurrence of gold-plating phenomena. New standards for AMTs would also be needed, an area which according to the Industrial Forum should conjugate an enhanced flexibility in standardisation requests and timely delivery in standard setting. Digital product standardisation should also be promoted, and adhesion to the New Legislative Framework should be ensured.

Data is a fundamental asset of the new economy. Recommendations in this area include supporting existing initiatives to create a strong European manufacturing data space, as well as ad-dressing the protection of both personal data and intellectual property rights and trade secrets. As artificial intelligence (AI) will assume an increasingly relevant role in future advanced manufacturing processes, the Forum recommends the development of clear, focused criteria on high-risk AI, while avoiding unnecessary regulation of industrial AI.

The availability of data should be pursued through the identification of a method for data collection in the advanced manufacturing category. It would also be important to generate trusted data sets at the European level for advanced manufacturing deployment, global competitive position, and economic / environmental / societal gains.

Many new skills will be needed in the next few years to handle the expansion of AMTs. To this instance, the Industrial Forum highlighted the importance to promote the harmonisation of Vocational Education and Training (VET) practices and qualification systems and to encourage women and girls to study STEM subjects and working in manufacturing. Other recommendations re-fer to the possibility of developing a Pact for Skills partnership and the proposal of a Blueprint Alliance for Advanced Manufacturing. A better entrepreneurial culture in Europe should also be promoted, as well as capitalisation on European creative industries.

Examples of biomanufacturing

Weaknesses to biomanufacturing identified by the Industrial Forum include the fact that it is still an emerging production process compared to chemical manufacturing. The report also mentions existing regulatory barriers, mainly linked to a process rather than product approvals pathway. Furthermore, significant investments in biomanufacturing are primarily located outside Europe. Possible risks identified by the report also refer to biomanufacturing being excluded or overlooked in key policymaking e.g. taxonomy supporting biomanufacture and sustainable financing.

The report includes two examples of AMTs linked to the health and agrifood sector. Chimeric antigen receptor T cells (CAR-T) represent one of the main areas of innovation in cancer treatment over the past two decades, in which the patient’s immune cells are engineered to produce the final immunotherapy. Many pharmaceutical companies are building specialised manufacturing facilities for CAR-T therapies within Europe, a biomanufacturing process which is highly complex and patient-specific, and requires long term investments, skills development, and integration into the European Union industrial base.

Biomanufacturing may also be applied to the production of vitamin B2 (riboflavin), that multi-step chemical synthesis is complex, requires hazardous agents and has low yields (~60%). Biotechnologies allow for the one-step production of vitamin B2, starting from vegetables as carbon sources and using a genetically modified bacterium (Bacillus subtilis) or fungus (Ashbya gossypii).

EMA’s reflection paper on AI in the pharmaceutical lifecycle

September 22, 2023

AI, Artificial Intelligence, BDSG, benefit-risk ratio, CHMP, clinical trials, combination products, conditional marketing authorisations, CVMP, data integrity, data processing pipeline, data protection, data-driven regulation, discovery, early regulatory interaction, efficacy studies, ema, EMA Innovation Task Force, ethical aspects, GLP Data Integrity, GLP Principles to Computerised Systems, good pharmacovigilance practices, governance, HMA, human supervision, interactions with regulators, ITF, lifecycle, machine learning, MAH, manufacturing, marketing authorisation holders, ML, model architecture, non-clinical development, patient safety, Pharmacovigilance, post-authorisation phase, post-marketing surveillance studies for veterinary medicines, precision medicine, public consultation, quality risk management, Reflection paper, risk-based approach, safety studies, SAWP, scientific advice, Scientific Advice Working Party, SOPs, Standard Operating Procedures, Summary of product characteristics, technical aspects

by Giuliana Miglierini

The rapidly evolving role of artificial intelligence (AI) and its possible application in the pharmaceutical field led the European Medicines Agency (EMA) to publish a draft Reflection paper on the use of AI along the entire lifecycle of both human and veterinary medicines.

The Reflection paper summarises the current view on the possible use of AI and machine leaning (ML) technologies and is open to public consultation until 31 December 2023. Comments, together with the outcomes of the joint HMA/EMA workshop to be held on 20-21 November 2023, will support its finalisation, as well as the possible development of new guidance. The initiative aims to identify the aspects of AI/ML use that would fall within the remit of EMA or of the single National Competent Authorities (NCAs) in charge of the dossiers’ assessment.

The document is part of the effort to improve the European Medicines Regulatory Network’s capability in data-driven regulation set forth by the joint HMA-EMA Big Data Steering Group (BDSG), and it has been developed in coordination with EMA’s CHMP and CVMP committees.

“The use of artificial intelligence is rapidly developing in society and as regulators we see more and more applications in the field of medicines. AI brings exciting opportunities to generate new insights and improve processes. To embrace them fully, we will need to be prepared for the regulatory challenges presented by this quickly evolving ecosystem” said Jesper Kjær, Director of the Data Analytics Centre at the Danish Medicines Agency and co-chair of the BDSG.

“With this paper, we are opening a dialogue with developers, academics, and other regulators, to discuss ways forward, ensuring that the full potential of these innovations can be realised for the benefit of patients’ and animal health” added Peter Arlett, EMA’s Head of Data Analytics and Methods, co-chair of the BDSG.

The main contents of the Reflection paper

The Reflection paper addresses the use of AI/ML with a dedicated chapter for each one of the steps, part of the overall lifecycle of a medicinal product. The interactions with regulators are then explored, as well as the different technical aspects to be taken into consideration. The final chapters discuss the governance of AI/ML applications, the integrity, and ethical aspects to be considered and how to address data protection.

The increasing use of AI technologies is based on the wide availability of big amounts of data produced and captured in electronic format on a routine basis. This data can be analysed by machine learning algorithms to inform the training of other systems able to analyse data and take actions with some degree of autonomy in order to achieve specific goals. These latter systems are the truly intended AI algorithms, those use is under discussion also in the field of regulatory decision making.

The Reflection paper recalls how the diffusion of these new technologies carries with it also some new risks, due to the “exceptionally great numbers of trainable parameters arranged in non-transparent model architectures”. Measures should thus be taken to ensure the safety of patients and the integrity of data, as well as to avoid the integration of bias into AI/ML applications.

The contents of the Reflection paper may also refer to combinations between a medicinal pro-duct and AI/ML-including medical device, as in such occurrence EMA is involved in the assessment of the characteristics of the device.

In general terms, existing guidelines, best practices, and recommendations relative to model in-formed drug development and biostatistics also apply to AI/ML; the adjacent methodology guidelines which may be relevant to this instance are listed in the document. The Reflection paper warns readers about the differences between the human and veterinary regulatory domains, suggesting that another reflection document specific for veterinary may be developed in future.

A risk-based approach

The usual risk-based approach typical of pharmaceutical development should be used to identify risks throughout the entire AI/ML tool lifecycle, including regulatory impact. According to the Reflection paper, the level of risk may depend also on the context of use and the degree of influence the AI technology exerts.

Developers should always seek early regulatory interaction and scientific advice, especially in cases where the AI/ML system may impact on the benefit-risk ratio of the medicinal product un-der development. To this instance, the EMA Innovation Task Force (ITF) is responsible for pro-viding early interaction on experimental technology, while scientific advice and qualification of novel methodologies in medicines development is provided by the Scientific Advice Working Parties (SAWP) of the CHMP for human medicines and of the CVMP for the veterinary ones.

As for all other steps of pharmaceutical lifecycle, the final responsibility for the suitability and use made of AI/ML algorithms, as well as their compliance to ethical, technical, scientific, and regulatory standards (GxP standards) and to current EMA scientific guidelines falls under the Marketing Authorisation Holders (MAHs) or applicants.

According to the Reflection paper, risks referred to in the discovery step may be limited, but they may impact the final evidence presented for regulatory review, thus principles for non-clinical development should be followed. This second step may include, for example, AI/ML modelling approaches according to the 3R principles. Regulators would expect to receive Standard Operating Procedures (SOPs) for AI/ML applications in preclinical studies; advisory documents on Application of GLP Principles to Computerised Systems and GLP Data Integrity should be also considered where appropriate. A pre-specified analysis plan would be needed for preclinical data potentially relevant for the assessment of the benefit-risk balance.

In the field of clinical trials, ICH E6 and VICH GL9 on human and veterinary GCPs should also be applied to the use of AI/ML. In particular, regulators expect the full model architecture and description of the data processing pipeline would be made fully available for comprehensive assessment should a model be generated for clinical trial purposes, as they would be considered parts of the clinical trial data or trial protocol dossier.

From precision medicine to pharmacovigilance

Particular considerations may be needed for applications of AI/ML in precision medicine, to individualise treatment according to the patient’s characteristics. AI/ML application supporting indication or posology decisions should be referenced in the Summary of product characteristics and their assessment falls under medicines regulation, representing a high-risk use both from the patient and regulatory perspectives. Close human supervision is also expected for AI applications used to draft or translate product information documents.

Many are the possible applications of AI/ML in the manufacturing of medicinal products, where they should follow the usual quality risk management principles (ICH Q8, Q9 and Q10) to guarantee safety, quality, and data integrity. New recommendations are also expected from EMA.

In the post-authorisation phase, AI/ML tools can effectively support efficacy and safety studies and post-marketing surveillance studies for veterinary medicines, as well as pharmacovigilance activities. Good pharmacovigilance practices should always be respected, and the used model should be validated, monitored and documented under the responsibility of the MAH. For conditional marketing authorisations, AI/ML applications should be discussed within a regulatory procedure unless details are agreed already at time of authorisation.

Trends for the future of the pharmaceutical manufacturing

April 21, 2023

AI, Annex 1, Artificial Intelligence, aseptic manufacturing, automation, bioavailability, biological medicines, collaborations, Connect in Pharma, connected devices, data integrity, data scientists, data security, data sharing, diabetes, digital tools, digitalisation, drug delivery systems, dry powder inhalers, eco-friendly drug delivery systems, energy efficient technologies, Industry 4.0, inhalation technology, injectable medicines, Internet of Medical Things, investments, IoMT, machine learning, MDR regulation, nasal delivery devices, partnerships, patient adherence, patient compliance, patient safety, Pharmaceutical development, pharmaceutical manufacturing, pharmaceutical packaging, realtime collection of data, recycled materials, regulatory compliance, report, reusable devices, secondary packaging, sensors, single-use devices, supply chain data sharing, survey, sustainability, tech-driven innovation, trianing

By Giuliana Miglierini

The technological evolution of pharmaceutical manufacturing towards the full implementation of the Industry 4.0 paradigm is rapidly advancing. Digitalisation of productions is supported by the wide spread of automation, devices connected to the Internet of Things, and machine learning algorithms able to keep entire processes under control. Looking at pharmaceutical development, new types of treatments are emerging, also requiring a retuning of current approaches. Results from a survey among experts and industry insiders (56 respondents from 13 different countries) run by Connect in Pharma show new challenges are to be faced in the incoming years by the pharmaceutical industry in order to maintain its market position.

The combined value of the global pharmaceutical market in 2022 is estimated to be approx $650 billion. The main component reflects pharmaceutical manufacturing (US$ 526 billion in 2022, data Insight Slice), while the global pharmaceutical packaging market value is roughly US$131 billion (data Fact.MR).

Many different factors supporting the transformation of pharmaceutical manufacturing have been identified by Connect in Pharma, ranging from ageing of population to Covid19 and Ukraine crisis, to climate change and pressures on energy costs, up to the shortage of healthcare professionals. The final conclusions and opportunities identified by the report indicate new partnerships and collaborations (mainly with startups, and small and medium-sized companies) will remain fundamental to support competitiveness, together with growing investments in tech-driven innovations. Involvement of patients and healthcare professionals in identifying unmet needs and optimal solutions is another item to be considered in order to increase adherence to therapy, suggests the report.

Digitalisation still waiting to full exploit its potential

Innovation in automation and digitalisation of processes has been introduced in the pharmaceutical sector at a slower pace compared to other industrial sectors, due to its higher regulatory barriers. About one third (28%) of respondents to the survey indicated their companies are developing artificial intelligence (AI) or other digital tools for application in the manufacturing and packaging process. The main drivers towards the implementation of such systems are more efficient data collection, reduction of manufacturing down times and human errors, and the use of machine learning to support continuous manufacturing. Better workflow integration and anticounterfeiting, and the ability to share supply chain data with regulators are also relevant. These are all objectives that would need to provide new specific training to the workforce, e.g. on AI or tools for augmented reality.

One of the main barriers that, according to the report, is still slowing down the full potential of AI and digitalisation in the pharmaceutical industry is represented by the need to comply to regulations, including data integrity and security. The human factor may also prove relevant, as many people (including top management) may be reluctant to accept this change in technology. The availability of data scientists with a deep knowledge of the pharmaceutical sector is another critical point to be addressed.

Advances in drug delivery technologies

Connect in Pharma’s report also shed light on some drug delivery technologies that, despite not being an absolute novelty, are gaining relevance for the development of new products and treatments.

The moving of pharmaceutical pipelines towards a continuously increasing number of new biologic / biosimilar products, including mRNA-based and gene therapies, requires the availability of manufacturing and packaging capacities able to accommodate the specific needs of such often very unstable macromolecules. New drug delivery systems have been developed in recent years to provide answers to this need, among which is inhalation technology.

Dry powder inhalers and nasal delivery devices are the preferred formulations for the 50% of respondents to the survey that indicated actions are ongoing to develop new products using inhalation technologies. According to the report, these devices might prove particularly useful to deliver drugs that need to rapidly pass the blood-brain barrier in order to become effective, as well as for the delivery of vaccines. Fast absorption and higher bioavailability compared to other routes of administration are other elements of interest for inhalation technologies, which is also believed to be able to contribute to the reduction of carbon footprint.

Once again, the regulatory environment resulting from the entry into force of the EU Medical Devices Regulation (especially for drug-device combination products), together with the need to demonstrate patient safety and satisfactory bioavailability of these devices, are among the main barriers to their development, says the report. Inhalation technologies may also give rise to a new generation of delivery devices connected to the Internet of Medical Things (IoMT).

Another major trend identified by Connect in Pharma refers to the development of new drug delivery systems for injectable medicines (50% of respondents). This area is greatly impacted by the entry into force of the revised Annex 1 to GMPs, on 25 August 2023, that will increase the requirements for aseptic manufacturing. According to the report, main areas of innovation in this field may include new devices for injectable drug delivery, namely targeted to diabetes (the leading area of innovation), intravitreal ocular injection, autoimmune diseases, oncology, respiratory therapy, and pain management.

Connected devices

Diabetes is a highly relevant field of innovation also with respect to the implementation of connected devices, those embedded sensors and electronics allow for the real-time collection of data on self-administration of the therapy by patients, and their forwarding to health professionals. AI algorithms further enhance the potential of connected devices delivering diabetes treatments, as they support the real-time monitoring of insulin concentration in blood, and the consequent level of insulin delivered by the device. According to Connect in Pharma, other positive characteristics arising from the use of connected devices refer to the possible increase of patient adherence and compliance to treatment, resulting in improved patient outcomes and more personalised treatment.

Regulatory barriers are once again a main burden to the wider spread of connected devices, says the report, due for instance to the ultimate control over the sharing of data, and the choice if to implement single-use or reusable devices. Manufacturing costs, cybersecurity, and patient hesitancy are other hurdles identified by respondents to the survey.

The challenges for sustainability

The green policies put in place especially in the EU are calling industry to revise its processes and products to decrease their environmental impact, improve sustainability of manufacturing and packaging processes, so to eventually meet the climate targets fixed for 2050. According to the report, the global healthcare sector would be responsible for 4.4% of global net emissions. Connect in Pharma’s survey indicates 66% of involved companies are working to implement more sustainable practices. These may include for example the use of recycled materials in secondary packaging, the implementation of energy efficient technologies, and the development of more ecofriendly drug delivery systems. Costs have been identified as the main barrier to transition, together with the lack of common definitions. According to some of the experts, a wider use of data to monitor manufacturing systems and processes may help in improving the overall efficiency and in lowering the carbon footprint. Transport, for example, has a great impact on the sustainability of packaging.

A concept paper on the revision of Annex 11

November 18, 2022

AI, algorithms, Annex 11, Artificial Intelligence, audit trail review, backup, Cloud, Computerised System, Concept paper, CSA, ema, FDA, GMP, Good Manufacturing Practice, guideline, ICH Q9, machine learning, ML, Pharmaceutical Inspection Co-operation Scheme, PIC/S, qualification, Quality System Software, revision, validation

This concept paper addresses the need to update Annex 11, Computerised Systems, of the Good Manufacturing Practice (GMP) guideline. Annex 11 is common to the member states of the European Union (EU)/European Economic Area (EEA) as well as to the participating authorities of the Pharmaceutical Inspection Co-operation Scheme (PIC/S). The current version was issued in 2011 and does not give sufficient guidance within a number of areas. Since then, there has been extensive progress in the use of new technologies.

Reasons for the revision of Annex 11 include but are not limited to the following (in non-prioritised order):

The document should be updated to replace relevant parts of the Q&A on Annex 11 and the Q&A on Data Integrity on the EMA GMP website
An update of the document with regulatory expectations to ‘digital transformation’ and similar newer concepts will be considered
References should be made to ICH Q9
The meaning of the term ‘validation’ (and ‘qualification’), needs to be clarified
Guidelines should be included for classification of critical data and critical systems
Important expectations to backup processes are missing e.g. to what is covered by a backup, what types of backups are made, how often backups are made, how long backups are, retained, which media is used for backups, or where backups are kept
The concept and purpose of audit trail review is inadequately described
Guidelines for acceptable frequency of audit trail review should be provided
There is an urgent need for regulatory guidance and expectations to the use of artificial intelligence (AI) and machine learning (ML) models in critical GMP applications as industry is already implementing this technology
FDA has released a draft guidance on Computer Software Assurance for Production and Quality System Software (CSA). This guidance and any implication will be considered with regards to aspects of potential regulatory relevance for GMP Annex 11

The current Annex 11 does not give sufficient guidance within a number of areas already covered, and other areas, which are becoming increasingly important to GMP, are not covered at all. The revised text will expand the guidance given in the document and embrace the application of new technologies which have gained momentum since the release of the existing version.

If possible, the revised document will include guidelines for acceptance of AI/ML algorithms used in critical GMP applications. This is an area where regulatory guidance is highly needed as this is not covered by any existing regulatory guidance in the pharmaceutical industry and as pharma companies are already implementing such algorithms.

The draft concept paper approved by EMA GMP/GDP IWG (October 2022) and by PIC/S (November 2022) and released for a two-months consultation until 16 January 2023.

Draft topics for the first IHI calls for proposals

May 27, 2022

AI, algorithms, Artificial Intelligence, call for proposal, cross-sectoral collaboration, cross-sectoral sources, decision-support system, digital platform, drug-device combination products, early diagnosis, early feasibility studies, EFS, European Health Data Space, FAIR principles, harmonised methodology, harmonised standards, health technology innovation, heterogeneous health data, high unmet public health need, hubs of clinical excellence, IHI, image-guided technologies, imaging equipment, IMI federated databases, Innovative Health Initiative, interoperability, joint decision making process, machine learning, multi-modal therapeutic approaches, multi-omic platforms, neurodegenerative diseases, next generation imaging, patient datasets, patient imaging, patient-adapted interventions, patient-centred tools, personalised interventions, personalised oncology, PREM, prognosis, PROM, re-usable data

by Giuliana Miglierini

The Innovative Health Initiative (IHI) published on its website the first draft topics which may be part of the first two calls for proposals, scheduled in June 2022. Interested parties may start the activities needed to build and formalise the research consortia, taking into consideration that the announced topics are draft, pending their approval by the IHI Governing Board and their final version may differ from the drafts.

IHI call 1 shall focus on innovative technologies for the development of decision-support system for improved care pathways, next generation imaging, personalised oncology and access and integration of heterogeneous health data in areas of high unmet public health need.

IHI call 2 shall address cardiovascular diseases and the development of a harmonised methodology to promote early feasibility studies.

The draft topics of IHI call 1

Innovative decision-support systems are important to make available improved care pathways for patients with neurodegenerative diseases and comorbidities. The actions to be undertaken include the enhanced cross-sectoral and sustainable collaboration between healthcare industries, academia and other stakeholders in order to exchange data (through the new European Health Data Space), analytical tools and material for training and professional development of personnel.

Earlier diagnosis should lead to more clinically effective interventions and reduced hospitalisation and facilitate the adherence to therapy. Clinical outcomes are expected to support a better patient stratification, which is needed to develop more patient-adapted interventions, therapeutics and cost-effective pathways for the management of neurodegenerative diseases. Among the expected outcomes is the development of a re-usable, interoperable, easily adaptable, and scalable digital platform, initially targeted to support patients in this therapeutic area, but further expandable in the future to other areas of interest. The action should also involve the development of agreed standards and guidelines to support data collection and operational features of the digital platform. New algorithms may provide (near) real time feedback on health interventions and support the constant monitoring of the patient’s status.

The second topic is focused on the development of high-quality tools, high-quality data, advanced patient imaging and image-guided technologies and processes for improved early diagnosis, prognosis, staging, intervention planning, therapy and management of cancer. Imaging can be part of new combined cancer therapies (e.g., theranostics, chemotherapy, targeted therapy including immunotherapy, radiotherapy and/or surgery). The call should also include the development of improved validation and evaluation methodologies specific to artificial intelligence (AI)and machine learning (ML), with a particular attention to the creation of new solutions that automatically link images to clinical data. This could be applied, for example, to develop minimally invasive interventions guided by medical imaging, or image-driven planning and predictive tools.

The third topic is also aimed to tackle cancer through the development of personalised interventions. This action should contribute to break down silos that are often still characterizing medicine and technological areas. The availability of harmonised approaches should lead to safe and effective innovative health technologies, to the integration of future products, services and tools and the development of more patient-centred tools. Here again, an expected outcome is represented by a dynamic platform for R&I collaboration across different sectors and stakeholders, focusing on the early stages of applied clinical research on cancer and on the testing and validation of multi-modal therapeutic approaches, including novel or emerging technical and clinical concepts and the possible contribution arising from in vitro diagnostics.

Topic 4 of IHI 1 addresses the integration of future products, services and tools along the healthcare pathway to better respond to specific patients’ needs. The availability of interoperable, quality data which reflect the FAIR principles (Findability, Accessibility, Interoperability, Reusability) is central to this action, as well as the development of advanced analytics/artificial intelligence supporting health R&I. Among the main expected outcomes is the long-term access to diverse types of data enabled by the linkage and integration of novel and cross-sectoral sources. Access to interoperable tools should also become possible for citizens and patients to support the self-management of health and the joint decision making process between healthcare professionals and patients.

The draft topics of IHI call 2

Cardiovascular diseases (CDV) remain one of the main causes of death; the development of new tools for the primary and secondary prevention of CDV is the main focus of Topic 1, to be pursued by the identification of existing comprehensive CVD and heart failure (HF) patient datasets, in order to facilitate the diagnosis of atherosclerosis and HF. These data shall be also integrated with those captured by diagnostic tools (e.g., wearables, imaging devices, bio samples/biopsies).

Classical diagnostic screening, in-vitro- diagnostics, ‘multi-omic’ platforms (e.g. genomic, transcriptomic, proteomic and multimodality imaging data), continuous glucose monitoring (CGM) data, continuous electrocardiogram (ECG) from wearable, HF and activity data, wearable devices and digital health applications are all possible sources for the data. Projects may also leverage data in currently available IMI federated databases in compliance with the GDPR regulation governing protection of personal data.

The utility of already existing or new biomarker combinations shall be assessed to detect patients at risk, also making use of AI models to analyse data. Validated data referred to patient reported outcome and experience measure (PROMs and PREMs) may also be considered for use in the clinical setting.

The second draft topic is targeted to establish a harmonised methodology to promote the diffusion of Early Feasibility Studies (EFS) among healthcare professionals. Once again, the availability of digital technologies easily accessible by patients shall be key to this action. Among expected outcomes are the improvement of the quality of clinical evidence on health technology innovation generated through earlier clinical experience, together with the increase of the attractiveness of clinical research for healthcare technologies in the EU.

These activities are essential to enable the fast translation of innovation into the clinical practice, improving access to patients especially where there are only limited or no alternative therapeutic options. This approach to the development of innovative technologies may also benefit regulators and health technologies assessment (HTA) bodies, as well as notified bodies. All stakeholders involved in clinical practice and research may contribute to the early generation of quality data, so to achieve a better understanding of diseases management and treatment options and to support the future development of new medical guidelines.

The creation of hubs of clinical excellence to attract investment may also be considered under this topic, with involvement of developers of medical devices, drug-device combination products, imaging equipment, in-vitro diagnostics, and SMEs.

Trends in the development of new dosage forms

April 16, 2022

3D printing, advanced therapies, APIs, Artificial Intelligence, auto-injectors, bioavailability, biological macromolecules, biological medicines, capsules, chewable gels, compliance, confectionery-derived dosage forms, continuous manufacturing, controlled-release, cross-contamination, digital pills, dosage forms, effervescent tablets, excipients, extendedrelease formulations, extrusion, Felicity Thomas, fictional coating, fixed-dose combinations, formulation, geriatric patients, high potency APIs, i.v. administration, infusions, injectable medicines, intranasal dosage forms, isolators, lipid nanoparticles, lyophilisation, micronisation, mini-tablets, multi-particulates, nanomilling, nanotechnology, oral solid dosage forms, orally disintegrating tablets, OTC, over-the-counter medicines, paediatric patients, parenteral administration, PAT, personalised dosage forms, Pharmaceutical Technology, process analytical technologies, RABS, self-administration, small molecules, soft gel, spray drying, stability, tablets

by Giuliana Miglierini

Oral solid dosage (OSD) forms (i.e. capsules and tablets) historically represent the most easy and convenient way for the administration of medicines. Recent years saw an increasing role of new approaches to treatment based on the extensive use of biotechnology to prepare advanced therapies (i.e. cellular, gene and tissue-based medicinal products). These are usually administered by i.v. injections or infusions, and may pose many challenges to develop a suitable dosage form, as acknowledged for example by the use of new lipid nanoparticles for the formulation of the mRNA Covid-19 vaccines.

The most recent trends in the development of new dosage forms have been addressed by Felicity Thomas from the column of Pharmaceutical Technology.

The increasing complexity of formulations is due to the need to accommodate the peculiar characteristics of biological macro-molecules and cellular therapies, which are very different from traditional small-molecules. Bioavailability and solubility issues are very typical, for example, and ask for the identification of new strategies for the setting up of a suitable formulation. The sensitivity of many new generation active pharmaceutical ingredients (APIs) to environmental conditions (i.e. temperature, oxygen concentration, humidity, etc.) also poses many challenges. Another important target is represented by the need to improve the compliance to treatment, to be pursued through the ability of patients to self-administer also injectable medicines using, for example, specifically designed devices. The parenteral administration of medicines has become more acceptable to many patients, especially in the case of serious indications and when auto-injectors are available, indicates another PharmTech’s article.

According to the experts interviewed by Felicity Thomas, there is also room for the development of new oral solid dosage forms for the delivery of biological medicines, as well as for OSD forms specifically designed to address the needs of paediatric and geriatric patients.

Some examples of technological advancements

Productive plants based on the implementation of high containment measures (i.e. isolators and RABS) are widely available to enable the entire manufacturing process to occur under “sea led” conditions, thus allowing for the safer manipulation of high potency APIs and the prevention of cross-contamination. Process analytical technologies (PAT), digital systems and artificial intelligence (AI) can be used to improve the overall efficiency of the formulation process. This may also prove true for previously “undruggable” proteins, that thanks to the AI can now become “druggable” targets denoted by a very high potency (and a low stability, thus asking for specific formulation strategies).

Advances in material sciences and the availability of new nanotechnology can support the development of oral formulations characterised by improved efficacy and bioavailability. To this instance, the article mentions the example of new softgel capsules able to provide inherent enteric protection and extended-release formulation. Functional coating, non-glass alternatives for injectables, and new excipients may also play an important role in the development of new formulations, such as controlled-release products, multi-particulates, orally disintegrating tablets, intranasal dosage forms, fixed-dose combinations.

The ability to establish a robust interaction with the suppliers enables the development of “tailor-made” specifications for excipients, aimed to better reflect the critical material attributes of the drug substance. The ability to formulate personalised dosage forms may prove relevant from the perspective of the increasingly important paradigm of personalised medicine, as they may better respond to the genetic and/or epigenetic profile of each patient, especially in therapeutic areas such as oncology.

Not less important, advancements of processing techniques used to prepare the biological APIs (for example, the type of adeno-viral vectors used in gene therapy) are also critical; to this regard, current trends indicate the increasing relevance of continuous manufacturing processes for both the API and the dosage form.

Injectable medicines may benefit from advancements in the understanding of the role played by some excipients, such as polysorbates, and of the interactions between the process, the formulation and the packaging components. Traditional techniques such as spray drying and lyophilisation are also experiencing some advancements, leading to the formulation of a wider range of biomolecules at the solid or liquid states into capsules or tablets.

New models for manufacturing

API solubility often represents a main challenge for formulators, that can be faced using micronization or nano-milling techniques, or by playing with the differential solubility profile of the amorphous vs crystalline forms of the active ingredient (that often also impact on its efficacy and stability profile).

As for the manufacturing of OSD forms, 3D printing allows the development of new products comprehensive of several active ingredients characterised by different release/dissolution profiles. This technology is currently represented, mostly in the nutraceutical field, and may prove important to develop personalised dosage forms to be rapidly delivered to single patients. 3D printing also benefits from advancements in the field of extrusion technologies, directly impacting on the properties of the materials used to print the capsules and tablets.

Artificial intelligence is today of paramount importance in drug discovery, as it allows the rapid identification of the more promising candidate molecules. Smart medical products, such as digital pills embedding an ingestible sensor or printed with special coating inks, enable the real-time tracking of the patient’s compliance as well as the monitoring “from the inside” of many physiological parameters. This sort of technology may also be used to authenticate the medicinal product with high precision, as it may incorporate a bar code or a spectral image directly on the dosage form. Dosage flexibility may benefit from the use of mini-tablets, that can be used by children as well as by aged patients experiencing swallowing issues.

The peculiarities of the OTC sector

Over-the-counter (OTC) medicines present some distinctive peculiarities compared to prescription drugs. According to an article on PharmTech, since the mid-‘80s the OTC segment followed the dynamics characteristic of other fast-moving consumer packaged goods (FMCG) industries (e.g., foods, beverages, and personal care products), thus leading to a greater attention towards the form and sensory attributes of the dosage form.

The following switch of many prescription medicines to OTC, in the ‘90s, reduced the difference in dosage forms between the two categories of medicinal products. Today, the competition is often played on the ability to provide patients with enhanced delivery characteristics, for example in the form of chewable gels, effervescent tablets for hot and cold drinks, orally disintegrating tablets and confectionery-derived forms. The availability of rapid or sustained-released dosage forms and long-acting formulations, enabling the quick action or the daily uptake of the medicine, is another important element of choice. Taste-masking of API’s particles is a relevant characteristic, for example, to make more acceptable an OSD form to children; this is also true for chewable tablets and gels, a “confectionery pharmaceutical form” often used to formulate vitamins and supplements.

ACT EU: the EU’s vision for the future of clinical trials

February 4, 2022

academics, ACT EU, Artificial Intelligence, clinical research, clinical trials, Clinical Trials Information System, Clinical Trials Regulation, coordinated scientific advice, CTIS, decentralised trials, decisional evidence, EFPIA, ema, EMRN, EU CTR Coordination Group, European Commission, European medicines agencies network strategy, European Pharmaceutical Strategy, GCPs, HMA, IVDR, KPIs, multi-stakeholder platform, patient-oriented medicines development, safety monitoring, working parties

by Giuliana Miglierini

Just few days before the entry into force of the new Clinical Trials Regulation and of the Clinical Trials Information System (CTIS) on 31 January 2022, a new initiative has been announced to completely renew the European framework governing how clinical trials are designed and run. The strategic document ACT EU (Accelerating Clinical Trials in the EU) has been jointly developed by the European Commission, the European Medicines Agency (EMA), the Heads of Medicines Agencies (HMA) and national regulators with the aim to strengthen the European Union as a leading “focal point” for clinical research at the international level.

ACT EU shall support the achievement of the goals established by the European Pharmaceutical Strategy and the European medicines agencies network strategy (EMANS) to 2025. The initiative will be co-led by the European Commission, EMA and HMA; the proposed governance shall find inspiration on the model already in use by the Clinical Trials Information System, with an EUCTR Coordination Group with an adapted mandate and composition. The individual domains which form the overall matrix will be coordinated by the relevant functions available within the network. The formal public communication phase on ACT EU will start after the official endorsement of the initiative by HMA and EMA.

Six objectives and ten priorities of action for 2022-2023

The ACT EU strategy identifies six different goals for the future of European clinical research. Its leading role shall be optimised through a unified European position on clinical trials at the international level, a better ethical oversight and integration of ethics committees into the clinical trial and medicines regulatory lifecycle. Large-scale multinational clinical trials with broader geographical scope shall be incentivised, while reducing the administrative burden for sponsors and investigators.

A special attention will be paid to the generation of decisional evidence for unmet medical needs, rare diseases, and on vaccines and therapeutics for public health crises and pandemics. A truly high level and coordinated scientific advice is indicated as an important element in order to support the trial and marketing authorisation processes. The strategy confirms the need to adopt new patient-oriented medicines development and delivery models with pro-active engagement of all the stakeholders. The availability of an improved capacity both at the development and regulatory level is also deemed important to achieve the goals of the initiative.

These challenging objectives shall be pursued in years 2022-2023 through the activation of a set of ten specific priority lines of action. An initial exercise to map already existing initiatives within the European medicines regulatory network (EMRN) will be run, that will represent the basis for the consequent development of a governance rationalisation strategy. This might include, for example, the alignment of different expert groups and working parties in the EMRN and ethics infrastructure.

The smooth implementation of the Clinical Trials Regulation shall be monitored using a set of Key Performance Indicators (KPI), still to be developed; the modernisation of the good clinical practices (GCPs) should occur under specific ICH’s guidance. The attractiveness of Europe for larger, multinational trials should specifically address studies run in the academic setting. Furthermore, the academics and non-profit organisations may also play a leading role in the analysis of data arising from clinical trials.

Further actions will include the availability of a multi-stakeholder platform, including patients, and the engagement in the initiative of all enablers by mean of a targeted communication campaign. A tighter coordination of different aspects relevant to the planning of new clinical trials, i.e. the scientific advice on the trial approval and the design of the study, has been also announced. The increasing use of artificial intelligence and/or machine learning technologies in the clinical domain and issues pertaining complex and decentralised trials, as well as the interface between the In Vitro Diagnostics Regulation (IVDR) and the Clinical Trials Regulation will benefit of new targeted methodological guidelines.

As for safety monitoring of clinical trials, the priority is to start its integration into a pre- and post-marketing safety monitoring framework. At the educational level, the competences needed to face this challenging scenario for the future of clinical trials in the EU will require the activation of specific training curricula, inclusive of modules on drug development and regulatory science with links to universities and SMEs.

Four principles to guide all actions

The complexity of the ACT EU initiative will require also the development of a new approach to make available the resources needed to smoothly run all the planned activities, possibly including the exploitation of the expertise external to the European medicines regulatory network. The strategy indicates the intention to adopt a collaborative and integrative approach, so to achieve a large research impact in the EU.

To this instance, the four principles “Do, Require, Influence, Support” have been identified to guide the execution and coordination of the projects, the requirement of specific guidance to address the expectations on applicants/developers/researchers, the availability of key publications and leadership to support the transformation phase at all levels (including patient, the academic, etc.), and stakeholders interactions suited to support all the above mentioned objectives.

The initial mapping of existing activities should also led to the identification of the budget needed for meetings, inclusive also of the activities relative to stakeholder engagement, training, and communication. Any other activities falling outside the optimisation of the already existing ones would be self-funded by the respective organisations (EC/NCA/EMA).

Comments from EFPIA

According to EFPIA, the announcement of ACT EU represents the beginning of an exciting new phase for clinical research in Europe. The industrial association highlights that the innovative design of many clinical trials, especially the complex ones, requires an increased efficiency.

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Artificial Intelligence Archives - European Industrial Pharmacists Group (EIPG)

Generative AI in drug development

Approvals and flops in drug development in 2023

EU’s Industrial Forum, the future of advanced manufacturing technologies

EMA’s reflection paper on AI in the pharmaceutical lifecycle

Trends in the development of new dosage forms

ACT EU: the EU’s vision for the future of clinical trials

News from EIPG