ema Archives - European Industrial Pharmacists Group (EIPG)

Generative AI in drug development


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 Read more

PGEU annual medicine shortages report


by Giuliana Miglierini The situation of medicine shortages is getting worse, with many countries which in 2023 experienced more issues than the previous years, according to the PGEU annual report on medicine shortages. Community pharmacists are on the front line Read more

EMA’s pilot scheme for academic and non-profit development of ATMPs


by Giuliana Miglierini Advanced therapy medicinal products (ATMPs) are often developed by academic and non-profit organisations, because of their high level expertise in the biotechnological techniques that underpin many new therapeutic approaches. On the other hand, these organisations often lack Read more

EMA’s pilot scheme for academic and non-profit development of ATMPs

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by Giuliana Miglierini

Advanced therapy medicinal products (ATMPs) are often developed by academic and non-profit organisations, because of their high level expertise in the biotechnological techniques that underpin many new therapeutic approaches. On the other hand, these organisations often lack sufficient understanding and experience to face the complexity of the regulatory development.

To improve the possibility for non-commercial developers to access regulatory and scientific support related to promising ATMPs addressing unmet medical needs, a pilot was launched by EMA in September 2022. Three projects have been already selected to participate to the pilot. ARI-0001, a chimeric antigen receptor (CAR) product based on patients’ own T-cells, developed by the Hospital Clínic de Barcelona, was the first project to access the pilot. The product was granted eligibility to the PRIME scheme in December 2021, and is targeted to treat patients older than 25 years with relapsed/refractory acute lymphoblastic leukaemia.

The second call closed in December 2023 and saw the participation of 11 candidates, among which two new academic organisations were selected. The Berlin Center for Advanced Therapies (BeCAT) – Charité is developing TregTacRes, a gene therapy based on modified T-cells, for use as add-on therapy after transplantation. Fondazione Telethon’s gene therapy Telethon 003 (etuvetidigene autotemcel) targets the Wiskott-Aldrich syndrome, a rare, life-threatening immunodeficiency.

The new phase of the project will now recruit a total of 5 new participants by the end of 2024. The first results of the pilot are expected in 2025.

How to apply
Interested academic organisations can find all information together with the ATMP Pilot Application Form on the dedicated EMA webpage; applications are open up to the end of April 2024. The email address [email protected] is also available to request more information or to express interest in participating. A guideline document on fee incentives for scientific advice, marketing authorisation (MA) applications and pre-authorisation inspections for academic participants is available, together with Q&As on the pilot.

Pre-selected candidates will be invited to a meeting with EMA’s Innovation Task Force (ITF) to provide further information on their projects before final selection. At this stage, interactions between EMA and applicants would mainly take place via the online platform IRIS. Therefore, interested organisations will need to register to the platform and request a research product identifier (RPI).

Requirements and procedure for the application
Academic developers active in the EU can apply to the pilot provided they have already generated some proof-of-principle data on the interested ATMP. The academic status of the organisation will be checked by EMA during the selection phase. Applicants may include public/not-forprofit hospitals or research organisations and hospitals, Higher Education Institutions (HEI), public-private partnerships/consortia, and international research organisations, provided they are establish in the EU. In case of projects comprehensive of non-EU participants, the principal investigator has to be located in the EU, and clinical trials must include EU patients. The academic sponsor must be free from operating agreements with any pharmaceutical company, and it can freely operate via intellectual property rights on the product.

The support provided by EMA aims to ensure that development activities would meet regulatory standards as for quality, safety and efficacy of the ATMP product. A smooth path towards the submission of the MA application based on existing regulatory procedures and tools should therefore be possible. The pilot also aims to identify potential gaps in existing tools and procedures, from the perspective of academic sector developers.

Key principles used to select the new participants are listed in the Q&As document. As for individual ATMPs under development, they must address an unmet medical need, represent a major therapeutic advantage over existing treatments, or offer a new option in orphan areas. Previous eligibility to the PRIME scheme is not a prerequisite to apply for the pilot. The Q&As also specify that there is no direct link between the product having received an hospital exemption (HE) and access to the academic pilot.

Preliminary clinical evidence in patients is needed to support the application, as well as information on the mechanism of action gained by non-clinical studies. A sufficiently mature quality development, to be assessed against the pharmaceutical process and the planned GMP manufacturing process, should be also available to better support later stage clinical development and/or a MA application in the EU.

The academic sponsor must also have full access to the data related to the development and manufacture of the product, e.g. control of critical starting materials. The knowledge needed to successfully interact with EMA may be ideally provided by a specific person (also a consultant) appointed by the sponsor and with experience in the field of product development and regulatory affairs.

Benefits and fee reductions
Selected academic organisations will benefit by a dedicated EMA’s point of contact in the relevant therapeutic area office. A EMA Support team may be also appointed to provide regulatory and scientific support depending on the stage of development and nature of the program. Activities to be part of the pilot may include preparatory teleconferences to check planning, identify potential needs for additional support and complement interaction mechanisms under existing tools. The optimisation of pre-submission meetings is another goal of the pilot, together with debriefings before and/or after regulatory interactions. A particular attention will be payed to the regular assessment of the level of maturity of the projects, including co-decisions and stopping points.

EMA will also provide financial support to the selected academic applicants for the activities concerning the five selected ATMPs. More in particular, the Agency will grant the same incentives as for micro-, small- and medium-sized enterprises, with respect to fees established by the Council Regulation (EC) No 297/95 and its Implementing Rules.

To qualify for the fee incentives, selected academic organisations must continue to fulfil all the above mentioned criteria for accessing the pilot also at the time of the request for a fee incentive related to a procedure or service to be provided as a part of the pilot itself. To this instance, applicants shall submit a declaration to EMA, inclusive of the fulfilment of requirements and establishment in the European economic area.

Incentives for academic organisations participating to the pilot include a 90% fee reduction for both initial scientific advice and follow-up, and pre-authorisation inspections. MA applications for designated orphan medicinal products for human use will benefit a 100% fee reduction, while MA applications not covered under this occurrence will see deferral of payment until the notification of the final decision on the MA for the concerned ATMP is issued.

The document on fee incentives specifies also that remuneration of national competent authorities for those activities shall not be reduced.

The granting of fee incentives will follow EMA’s verification of the documentation submitted by the applicants. After confirmation by the Agency the applicant qualifies for the fee reduction, participants to the pilot will have a six months period to submit their requests for scientific advice and/or marketing authorisation. Ex–post controls and prove of evidence confirming the fulfilment of criteria for the fee reduction may also be required at any time until the finalisation of the concerned procedure.


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 first Union list of critical medicines

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by Giuliana Miglierini

The first version of the Union list of critical medicines was published on 12 December 2023 by the European Commission, the European Medicines Agency (EMA) and the Heads of medicines Agencies (HMA).

The initiative is part of the actions planned according to the Pharmaceutical Strategy and the Communication on addressing medicine shortages in the EU. A Q&As documentwas also published to illustrate the main features of the list, together with the methodology to identify critical medicinesto be included in the list (see the dedicated webpage of EMA’s website). The first version of the Union list of critical medicines is comprehensive of approx. 200 active substances, selected starting from a pool of more than 600 referred to in the national lists of critical medicines of Finland, France, Germany, Portugal, Spain, and Sweden. These six countries were chosen as their lists were based on criteria aligned with those agreed for the Union list. The process also comprised consultations of key stakeholders, including patients and healthcare professionals’ organisations and industry associations.

The list will be updated annually, and further references will be added in 2024. The final list will also include the separate assessment of the vulnerability of the supply chains to be run by the European Commission.

The Union list will not replace existing national lists of critical medicines, that will continue to support national policy decisions. EU member states may also use the Union list to create their own national lists, if not yet available.

Ensuring an uninterrupted supply of critical medicines is essential for a strong European Health Union. With the publication of the first Union list of critical medicines today, we are delivering on our promise to accelerate work in this area and to take every possible measure to avert the risk of shortages for our citizens”, said Stella Kyriakides, Commissioner for Health and Food Safety.

A list to prevent shortages

The Union list of critical medicines represents a warning about the importance of avoiding shortages for specific medicines, as they would highly impact both patients and healthcare systems. No immediate effect is expected on shortages, but the risk might decrease in the longer term.

The Union list specifies human medicines (both innovators and generics, vaccines, and medicines for rare diseases) those continued supply is considered a priority in the EU. It will be used by the EU Commission, EMA and HMA for the definition of proactive measures to strengthen the supply chain and minimise the risk of supply disruptions (see more on EMA’s webpage on Availability of critical medicines).

The Union list of critical medicines will also serve as the basis for the Commission to run the analysis of vulnerabilities, followed by recommendation of suitable measures in consultation with the Critical Medicines Alliance (we wrote about this part 1 and part 2). The Commission may issue recommendations for companies to diversify suppliers or increase production within the EU. Incentives to invest may also be used to favour the resilience of European manufacturing. As for procurement, strong contractual obligations for delivery may apply.

Medicines included in the Union list will also be prioritised for actions by the European medicines regulatory network, in charge of monitoring their availability and implementing measures to minimise the risk of supply disruptions. To this instance, existing processes and structures will be used as defined in the mandate of EMA’s Medicine Shortages Single Point of Contact (SPOC) Working Party and EMA’s Executive Steering Group on Shortages and Safety of Medicinal Products (MSSG).

No additional obligations have been introduced by now for marketing authorisation holders and national competent authorities. This will be a topic of discussions during the final phase of negotiations on the proposed revision of the EU pharmaceutical legislation.

The methodology to select critical medicines

The therapeutic indication and the availability of alternative medicines are the two main criteria for the insertion of a certain medicinal product in the Union list of critical medicines. Additionally, it has to be classified as critical in at least one-third (33%) of EU/EEA (European Eco-nomic Area) member states.

National lists of critical medicines may differ from one another, reflecting differences of the internal evaluation criteria used to assess criticality. For example, some products are marketed just in some countries, or alternatives are available in some countries and not in others. Furthermore, the Union list is still incomplete, as some important medicines have not yet been assessed at the central level. The Union list does not include as well products mentioned in the WHO list of essential medicines. Orphan medicines are included in the Union list if they meet the above-mentioned assessment criteria.

The document on methodology further clarifies the governance of the process and the matrix for identifying medicines to be included in the Union list of critical medicines. The methodology was created starting in 2021 (European Commission Structured Dialogue initiative), finalised by the HMA/EMA Task Force on the availability of authorised medicines for human and veterinary use (HMA/EMA TF-AAM), and finally adopted in June 2023.

The medicinal product criticality is evaluated on the basis of a risk assessment. As for therapeutic indications (criterion 1), all authorised medicines in a member state should be classified, irrespective of their marketing status. Criterion 2 refers to the availability of alternatives, and only authorised medicines marketed in the respective member state should be classified.

A low, medium or high-risk level is assigned for each of the two above-mentioned criteria, thus resulting in a risk matrix. The exercise allows to assign the medicine in one of the following categories: critical medicines, medicines at risk, other medicines.

Medicines considered at high risk with respect to their therapeutic indication refers to products those use may have very serious implications for the health of individual patients or public health (general life-threatening acute conditions, specific life-threatening acute conditions, or irreversibly progressive conditions). Evaluation parameters include the fact the disease is potentially fatal, irreversibly progressive or, if left untreated, will pose an immediate threat to the patients. Furthermore, the treatment must be administered immediately or within regular dosing intervals, and the product has to be part of a national disease control program.

Appropriate alternatives are identified according to the fact they are authorised for the same therapeutic indication and are available on the market in the respective member state. Furthermore, alternative treatment has to be clinically possible, without negative impact on the patient’s health and providing the same quality of care standard. As for criterion 2, high risk cri-tical medicines refer to products for which no appropriate alternative is available, or only one appropriate alternative (product) on ATC level 4 or 5 (same active substance or alternative is within the same ATC level 4 group or in another ATC level 4 group) is available.

Public consultation for the review of HERA

We inform all interested EIPG’s members that the public consultation for the review of the Health Emergency Preparedness and Response Authority (HERA) is open until 19 February 2024 and it can be accessed through the dedicated webpage of the EU Commission website.

The consultations aim to assess how HERA’s mandate and tools contributed to achieve EU’s political objectives, and how the Authority complements the work of other EU bodies and responds to the current health challenges.


The drug shortage situation – EIPG’s point of view

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by Maurizio Battistini

The shortage of medicines has been a major concern in the countries of the European Union, and elsewhere, for more than 10 years, so much so that the Economic Community has devoted a great deal of effort and increasing attention to this problem in an attempt to mitigate its impact on patient health.

Several factors can be identified as being at the root of the shortage of medicines, some of which intersect with each other, mainly concerning aspects with technical, qualitative, regulatory, forecasting, supply, speculative and economic implications.

EIPG has made its contribution to the various attempts to contain the phenomenon by participating in task forces, round tables and convenings dedicated to identifying the root causes of the issue and, through gap analysis, the consequent mitigation measures. Overall, strengthening the risk-assessment approach to assess and define the risk level of individual deficiencies or the causes to which they pertain in order to rationalize and focus mitigation interventions and identify their level of acceptance with a proactive approach.

Before defining the particularly deserving aspects to be emphasised and consequently acted upon, it is important to mention those that represent, in the opinion of EIPG, but are not limited to, the elements on which priority action should be taken. In analysing the problem, one cannot in fact fail to take proper account of the fact that medicines are not such without their active ingredients and that, for diseases with the widest spread, there are equivalent medicines and alternative therapies. On the basis of the latter assumption, it is understandable that the definition of a shortage of medicines should be restricted to cases where no equivalent medicines or alternative therapies with different medicines are available, so as to concentrate efforts to solve the problem only on those conditions that are worthy of attention because they are not limited to the unavailability of a specific product or to situations for which it is possible to identify an alternative treatment (defining a list of critical medicines and defining risk assessment criteria for assessing whether a product should be on the list or not).

The operation required to bring the production of active ingredients back to Europe, recognising their strategic and central role in the composition of medicines for the entire community and patients, takes longer. The relocation of the manufacturing of active ingredients to third countries, which has been taking place for several years now for mainly economic reasons, has led to the dependence of many other countries, including mainly those of the Union, on supplies that today has the occasional impact that we know of, but which could become much more serious if not systemic. We have been hearing about reshoring the production of active pharmaceutical ingredients for some time now, but so far there do not seem to be any concrete initiatives for its implementation.

As mentioned above, EIPG identified the revision of the definition of drug shortages and the reallocation of strategic production of active pharmaceutical ingredients in Europe as a main key action to mitigate the impact of drug shortages.

Although it is not an aspect of primary interest to the European industrial pharmacist community, EIPG recognises the economic aspects as playing an important role in the origin of shortages, particularly with regard to the low price paid for certain categories of medicines, which induces manufacturers to abandon the manufacture of low-profit products, and the discrepancies in the price of medicines that exist in the different countries of the Union, discrepancies that, coincidentally, make the countries where prices are the lowest or even where volumes are not so attractive as to devote production to shortages.

Having made this necessary digression on the aspects requiring corrective action at source, there are, however, other, mostly ‘occasional’ causes on which to intervene, where possible, in a proactive manner or by means of reaction instruments capable of reducing the impact of shortages. In this regard, some of the elements covered in the introductory part of this discussion, namely: technical-qualitative, regulatory, forecasting and speculative, are taken up and detailed.

As far as the technical quality aspects are concerned, given the vastness of such occasional events in the production cycle of a medicine, a separate, dedicated discussion should be devoted to them. In addition to a few examples, please refer to the chapter ‘Shortages Originating from Manufacturing‘ in the text ‘Pharmaceutical Supply Chains – Medicines Shortages‘ published by Springer and written by the same author as this article. The book, authored by experts in the field, provides an insight of relevant case studies and updated practices in Pharmaceutical Supply Chains (PharmSC) while addressing the most relevant topics within the COST Action Medicines Shortages (CA15105) and it covers uncertainty and risk aspects of supply chain management, carefully combining the scientific level with a pedagogical approach. In industry, proactive strategies such as the adoption of reserve stocks or back-up establishments can be adopted to make up for medicine shortages on an emergency basis, although the expense of sustaining these prudential approaches remains the main problem.

In a number of situations, shortages can occur due to underestimated sales forecasts or problems with the supply of raw materials, and in particular APIs.

A particular case in point is parallel trade, which by its very nature can have such contrasting effects that it has been dubbed ‘The double face of the parallel trade’. While on the one hand, this method is useful in dealing with shortages in a relatively short time (import in the country where the shortage needs to be filled and export from the country where the availability exists), on the other hand, it has often encouraged the migration of products from countries where they are cheap to others where they guarantee a higher margin, in which case it could be the source of the problem and not its solution.

Last but not least, it should be pointed out that the phenomenon of shortages has an economic implication, as it is more likely to affect drugs with low profitability or movements of drugs from countries with low margins or sales volumes to those with high margins or higher market shares.

Heads of Medicines Agencies and the European Medicines Agency on improving availability of human and veterinary medicines invited the EIPG to attend the key stakeholders’ table at the Workshop on Shortages Prevention Plan held on 1 and 2 March 2023. The EIPG was represented by Jane Nicholson and Maurizio Battistini. Staff from the EMA, the European Commission and members of national authorities presented their current initiatives and future plans. Representatives from the research and generics industry, wholesalers, pharmacists from the EIPG and PGEU, and several organizations representing patient groups had the opportunity to present and discuss ideas for shortage prevention, permanent market withdrawals, and shortage communication and transparency.

The meeting had breakthrough sessions on biosimilars (the EMA is publicly encouraging their use) immunoglobulins and veterinary medicines. The EIPG commented on the low prices of medicines that cause shortages and called for more accurate definitions of ‘medicine shortages’ and to focus efforts on essential product shortages where there is no equivalent medicine or alternative therapy to ensure patient access to adequate treatment.

Shown below is the action plan that EIPG submitted to the group at the meeting; an action plan that largely reflects what is the topic of this article.

  • Establish pro-active risk management plan
  • Prepare list of medicinal products of clinical importance that lack therapeutic alternatives • Undertake regular checks on market availability of alternative products especially those with low pricing due to cap measures
  • Criticality in the procurement of all starting materials with particular attention to APIs
    • How to mitigate?
  • Quality and manufacturing aspects that could have an impact on medicines’ shortages
    • How to manage them preventively?
  • Appropriate agreements on quality and capacity of CMOs
  • Need to review quality management systems throughout life cycle (including those for older products)
  • Consideration of batch release and transportation impact on the time to deliver products to the market
  • Review impact on production planning of potential weaknesses in sales forecasting

Everyone in industry agrees that problems of shortages are complex with no quick solutions, and it was interesting to hear staff from Agencies agree that one of the main problems of shortages for older products is the impact of low pricing of products by national healthcare systems. Also, product dumping of medicines at an extremely low price was mentioned as occurring in some countries and everyone present agreed this must not be tolerated. There were 100 participants in the main meeting room at the EMA and 200 who were connected online.

In opening the meeting, Emer Cooke Executive (Director EMA) explained the aim was to inform stakeholders about the HMA/EMA Task Force activities and deliverables and share stakeholders’ perspectives on ongoing and planned initiatives to address availability issues. She explained the long-term position of the EMA is to focus on prevention and to become more proactive, particularly since the EMA after Covid was given an extended mandate for emergency situations. The EU joint action for shortages has been launched to improve capacity at national level and the single point of contact (SPOC) working party is really helping to ensure suitable structures are in place to assist with shortages. The EMA is working with the European Commission, DG SANTE (medicinal products unit, quality, safety and innovation) and DG HERA (intelligence gathering, analysis and innovation unit) both of whom made presentations during the meeting.

In October 2023, released documents about Commission steps up actions to address critical shortages of medicines and strengthen security of supply in the EU.

The work done by the European community is aimed at addressing the shortages of the most critical medicines by emphasising the role of logistical aspects but overlooking certain critical elements that go beyond supply chain management and concern the upstream management of the concrete problems for which medicine shortages continue to occur (root causes). For the time being, the Commission seems to be oriented towards a predominantly top-down approach, even if there are spaces where opportunities for a multidisciplinary discussion involving all stakeholders in the supply chain are offered. However, it remains important to note that the Community is taking an active interest in the problem albeit adopting containment measures aimed at containing the problem rather than solving it at its root.

Given the role entrusted to Italy to find solutions to this important problem, the author is convinced that the face-to-face meeting that EIPG will have in Rome with the Italian Medicines’ Agency, on the occasion of the EIPG’s Annual General Assembly, will serve as a constructive basis for working together to find longer-term solutions to medicines’ shortages main causes.

Reference: Battistini, M. (2019). Shortages of Medicines Originating from Manufacturing. In: Barbosa-Povoa, A., Jenzer, H., de Miranda, J. (eds) Pharmaceutical Supply Chains – Medicines Shortages. Lecture Notes in Logistics. Springer, Cham. https://doi.org/10.1007/978-3-030-15398-4_5


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

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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.



The New Pharmaceutical Legislation

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by Jane Nicholson

To celebrate the 70th Anniversary of the foundation of the Belgian Association of Industrial Pharmacists (UPIP-VAPI) a Seminar on “The New Pharmaceutical Legislation” was held on 8th September in the European Parliament. The meeting was arranged in conjunction with the General Assembly of the European Industrial Pharmacists Group (EIPG) with attendance from participants of at least 15 European countries.

Frank Peeters, President of UPIP-VAPI opened the meeting and Alexia Rensonnet, a Board Member, described the new legislation as the largest reform in the past 20 years. The existing directive and regulations are to be replaced by new legislation with the objective of creating a single market to ensure all patients have timely and equitable access to safe, effective and affordable medicines whilst continuing to offer an attractive and innovation friendly market for suppliers.

Lilia Luchianov, Policy Officer at DG Sante – European Commission, said that the new legislation envisaged a leaner regulatory environment through simplification, regulatory modernisation and digitalisation. There will be access to both innovative and established medicines and incentives for innovation so that European companies remain globally competitive. Regulatory responsibilities will be shared between the EU and Member States. As well as changes to the General Pharmaceutical Legislation there will be changes to the Orphan and Paediatric legislation. Pre-authorisation support and a faster approval process including “targeted approach” rather than the current “one size fits all” are proposed.

The proposed reduction of protection for innovative products and the market launch conditions were questioned by several participants. Some of the current challenges for the Commission were said to be that pricing, reimbursement and procurement are a national competence.

In response to the current growing concerns on shortages, the Commission’s suggestions include the publication of an EU list of critical medicines, improved coordination of monitoring, earlier industry notification of shortages and withdrawals, improved industry shortage prevention plans, stronger coordination by the EMA and more legislative powers for the Member States and the Commission. During the discussion period Maggie Saykali, Director of the European Fine Chemical Group challenged the Commission to provide economic conditions for the manufacture in Europe of raw materials used by the pharmaceutical industry. Rather than dependence on China or India, European supply of raw materials would enormously improve security of supply of pharmaceuticals as well as improve worldwide environmental sustainability.

Par Tellner, Director of Regulatory, Drug Development and Manufacturing for the European Federation of Pharmaceutical Industries and Associations presented EFPIA’s views on the proposed revision to the pharmaceutical legislation. Whilst he welcomed the opportunities for regulatory modernisation such as simplification of the EMA structure by reducing the Scientific Committees from 5 to 2 and abolishing product licence renewals there are a number of challenges ahead. These include the notable reduction of research and development incentives, the added burden for industry to implement environmental risk assessments and the actual root causes of non-availability of medicinal products in the markets of Europe.

Jean-Paul Pirnay, head of LabMCT, Queen Astrid Military Hospital presented the past present and future of bacteriophage therapy. Wherever you find bacteria, you find phages which have been used since 1923 with the establishment of the Phage Institute in Tblisi (GEO). Although abandoned in the West many years ago, the Russian USSR has kept using phage therapy. Some isolated laboratories have been further developing and using phages and it has been shown that you need a handful of phages to target one bacterial spp.

Jean-Paul’s laboratory has helped establish a phage bank in a controlled environment. A single phage API can be produced according to a monograph. Individual phages can then be mixed together to target a particular bacterium. 100 seriously ill patients with resistant bacteria have been treated in 35 hospital of 29 cities and 26 phages were found to be needed. Eradication of the target bacterial infection was found in 61% of cases. In addition, phages were found to be synergistic when used with antibiotics. Jean-Paul considers commercially viable broad spectrum phage cocktails may be produced in the future.”

Geert Verniers (Lector SCM and Researcher BM-expertise center VIVES University) and his colleague described the use of Drones in the transportation of medicinal products,biological samples and tissues. With traffic congestion on roads causing gridlock around many hospital centres and personalised medicines needing urgent delivery from one area to another, the use of drones for professional transportation is compelling. Various significant points for consideration were discussed. These included the type of drone, drone pilots and Cargo Ports, the design of routes and the complexity of regulation, environmental impact, vibration problems and temperature control.

Following a lengthy discussion period, Frank Peeters thanked the speakers for their interesting contributions and all those responsible for this meeting being held in the European Parliament.


EMA’s 3-year work plan for the Quality domain

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by Giuliana Miglierini

The European Medicines Agency has released the input notes made by the GMDP Inspectors Working Group (IWG) as for the drafting of the 3-year workplan for the Quality domain. The document, which reflects the objectives of the Network Strategy and Regulatory Science Strategy, addresses many aspects which may affect the overall efficiency of the pharmaceutical supply chain, both at the routine and specific level.

The document identifies a number of strategic goals aimed at improving the overall integrity and resilience of the pharmaceutical supply chain and the product quality, and to optimise the im-pact of new technologies. Description of the tactical goals follows, i.e., the projects and actions to be activated in order to reach the above-mentioned strategic objectives.

Improved traceability of the supply chain

Strategical goals include the enhancement of traceability, oversight and security for both the human and veterinary medicine supply chain. Four different actions are planned at the tactical level, starting from a better sharing of information regarding manufacturers, distributors, pro-ducts and their respective compliance. To this instance, actions to improve EudraGMDP records are expected.

Inspections of the repositories system should also be tackled by means of a liaison with the Ex-pert Group in inspectional procedures. The implementation of the new Veterinary Regulation should be addressed paying attention both to GDP for veterinary medicines and active substances. Improvement of the inspection capacity may benefit from the development of a specific training curriculum for GDP inspectors; to this instance, the IWG suggests a possible collaboration with PIC/S, through the EU4Health Joint Action 11 and the associated Work Programme 6.

Enhanced inspector capacity

Another strategic goal set forth by the GMDP IWG aims to improve inspector capacity building at EU and international level. To this regard, suggested actions include the support to the international API programme, comprehensive of the provisions of the new Veterinary Regulation related to API inspections and controls. Veterinary specific GMP guideline annexes 4 and 5 should be harmonised in collaboration with PIC/S. The collaboration should also include ongoing initiatives on inspection reliance, in order to better identify barriers preventing member states from accepting inspection results from other trusted authorities. PIC/S and the International Coalition of Medicines Regulatory Agencies (ICRMA) should also collaborate with the GMDP IWG to reach an agreement on shared definitions, best practices and harmonised approaches for distant assessment and hybrid inspections. The pilot programme for sterile inspections should be also finalised, with participation of all member states. Routine assessor-inspector joint inspections are suggested, as well as a training course specific to the new Annex 1.

The development of a harmonised, EU level guidance on data integrity is the tool identified by the GMDP IWG to reinforce responsibility of marketing authorisation holders (MAHs) for product quality. This goal may be achieved by adapting the current guidance published in the form of Q&As into Chapter 4 and Annex 11 of the GMP Guide, in collaboration with the WHO and PIC/S. A better attention on MAHs responsibilities and to the supervision of API manufacturers should also build upon the recommendations contained in EMA’s lessons learnt report (LLE) on Nitrosamines.

Critical manufacturing sites and new technologies

The review of long-term risks resulting from dependency on limited number of manufacturers and sites should support a better supply chain resilience. The review should be aimed to the identification of sites manufacturing a significant number of products or producing medical pro-ducts for a significant number of markets within the European economical area (EEA). The GMDP IWG also suggests performing cooperative supervision of these sites between member states and other strategic partners.

A better understanding of the possible implications resulting from the introduction of new manufacturing technologies has been also deemed important to regulate the new supply chains. To this instance, the indication of the IWG is to consider if a specific GMP annex would be re-quired in order to support the adoption of new and innovative technologies. As for decentralised manufacturing, this topic should also be evaluated in the GMP Guide to medicinal products other than advanced therapies.

Amendments to current guidelines

The document of the GMDP IWG details the specific guidelines that would need consideration in view of the proposed interventions.

Many actions are planned to achieve their objectives by the end of 2023. More specifically, the IWG expects to provide the EU Commission with the final text of the GMP for novel veterinary medicinal products and for autogenous veterinary vaccines. GMPs should be also revised to include Nitrosamines LLE recommendations to MAHs, so to ensure adequate quality agreements are in place with manufacturers.

The same deadline should apply to the development of specific training material on ICH Q9, addressing risk identification and risk management. This action would support EU members of the Expert Working Group (EWG) and should be coordinated with the dedicated PIC/S expert circle. A similar action is planned with respect to ICH Q12 on lifecycle management and ICH Q7 (GMP for active substances), as well as to other quality guidelines for veterinary medicines. The GMDP IWG is also expected to support the EWG in developing the new ICH Q13 guideline on continuous manufacturing.

Annex 15 on the Qualification and Validation may be revised by Q2 2024 in order to include considerations on new technology in facilities, products and processes, including also the possible extension of LLE recommendations to APIs.

The end of 2024 is the date indicated for the review of GMPs for advanced therapy medicinal products in order to include the new provisions of the revised Annex 1. The same deadline applies to the possible revision of Annex 16 on the certification by a Qualified Person and batch release, in order to provide further guidance on batch traceability according to LLE recommendations. The end of next year may see also the drafting of the final text of Annex 4 on the manufacture of veterinary medicinal products other than the immunological ones, based on comments received on the concept paper and the resulting draft text. A similar action is planned for Annex 5 on the manufacture of immunological veterinary medicinal products.

Chapter 4 (Documentation) and Annex 11 (Computerised systems) of the GMP Guide should be revised to assure data integrity in the context of GMP. The proposed deadline for these actions is Q1 2026.

Support to scientific advice and communication

A specific chapter of the GMDP IWG document is dedicated to actions deemed to support scientific advice activities. In this case too, target dates are provided for the completion of the different actions. These include the provision to the EU Commission of scientific advice on GMP standards to be included in the implementing act on GMP for veterinary medicinal products and active substances.

At the international level, the IWG plans to continue its efforts to reach a better convergence through existing mutual recognition platforms and programmes and to support the EU Commission to establish and maintain mutual recognition agreements. Collaborations with ICRMA, the EDQM, Chinese and Indian regulators should be also continued, as well as the dialogue with interested parties and stakeholders.


EMA’s recommendations to prevent medicines shortages

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By Giuliana Miglierini

Continuity of medicinal product supply is still representing a key issue for European countries. The HMA/EMA Task Force on the Availability of Authorised Medicines for Human and Veterinary Use has published a new guidance document in the form of recommendations for the industry on best practices to be adopted to prevent shortages of human medicines.

The recommendations are targeted at marketing authorisation holders (MAHs), wholesalers, distributors and manufacturers. The specific role of each actor is detailed, and highlights are provided on how to optimally approach the prevention and mitigation of shortages. The document refers to the harmonised definition of shortage agreed by EMA and HMA, i.e. “A shortage of a medicinal product for human or veterinary use occurs when supply does not meet demand at a national level“.

Different players for different roles

The pharmaceutical supply chain is characterised by many different actors, each of which plays a specific role in the development, manufacturing and distribution of medicinal products.

Marketing authorisation holders are the ultimate responsible for the monitoring of all activities needed to timely produce and distribute their products. This means MAHs should oversight the entire supply chain, from suppliers of active ingredients (APIs) to end users, in order to continually align demand with supply, evaluate the actual impact of a shortage, and establish the more suitable prevention or mitigation strategies. According to the guidance, reference should be made to the “ISPE Drug shortages prevention plan – Holistic view from root cause to prevention” in order to build a suitable quality culture integrated into product lifecycle; compliance to ICH Q10 is also recommended.

Manufacturers include both APIs suppliers and producers of the medicinal product, which should possess a in depth knowledge of their processes and issues that may impact on product availability. This is even more true for contract manufacturing organisations (CMOs), as a problem with their manufacturing capacity may impact many different customers. Wholesale distributors have general visibility of stock levels and product flow and can identify early signals of a potential medicine shortage. They are subject to national laws as for their obligations to ensure continuity of supply to patients.

As for institutions, national competent authorities (NCAs) are responsible for the coordination of the response to a shortage by means of regulatory tools and strategies. Existing regulatory flexibility can be used, while NCAs cannot intervene in pricing, sourcing, and clinical practice. NCAs are also responsible to communicate actual shortages from their websites.

EMA’s responsibilities relate to shortages of centrally authorised products and coordination of the EU response to supply issues due to major events or public health emergencies. The Agency is also responsible for the publication of a public catalogue for shortages assessed by the CHMP and/or PRAC committees, and for the publication of information on critical shortages monitored at EU level.

National health service providers are responsible for the setting up of policy and operational aspects needed to guarantee the timely access to medicines (i.e. reimbursement schemes, purchasing arrangements, clinical guidelines, etc.). In case of a shortage, they are called to indicate available alternatives, and to issue specific clinical guidance for healthcare professionals if needed.

The overall sustainability and accountability of health systems is the major goal for national Ministries of Health, to be tackled by mean of legislative initiatives. End users include healthcare professionals responsible for appropriate prescribing and for the identification of available alternatives in the case of a shortage affecting their patients. Timely information to patients, in particular for specific diseases, may be provided by patients representative groups, which may also collect feedback on the impact of shortages for patients.

Ten recommendations to prevent shortages

The guidance highlights the importance to notify as soon as possible to NCAs any potential or actual shortage, in order to timely face the increased demand for alternative product suppliers. To this instance, MAHs and wholesalers are in the best position to monitor available stocks and report at early stages about possible issues.

An improved transparency would be needed as for the provided shortage information, to avoid patients’ concerns and the consequent risk of stockpiling and to avoid duplication of efforts. To this instance, MAHs are called to provide all available information requested by the notification form, including also multi-country information (e.g. related to API suppliers).

MAHs should also have a shortage prevention plan in place, addressing the entire life cycle of the specific product from sourcing of raw materials to manufacturing capacity and distribution. Wholesale distributors are also called to develop similar plans focusing on their specific role. Prevention plans should include an analysis of vulnerabilities and risks of interruption of supply, the assessment of the robustness of the supply chain arrangements and controls as well as of the need of revalidation, and the availability of a medicine shortage risk register to identify products of clinical importance by therapeutic use and availability of alternatives.

MAHs and wholesalers should also have a shortage management plan to be activated in case of issues with the availability of a certain product. To this instance, the capacity of available alternative manufacturing sites is critical, including CMOs which should always be kept timely informed by MAHs. A possible approach suggested by the guidance sees the development of a dashboard to continuously monitor signals for potential supply disruption. Procedures to identify true shortage points would also be needed to overcome the current limitation of the automated order systems.

The punctual implementation of Pharmaceutical Quality System according to ICH Q10 and ICH Q12 is also deemed fundamental to prevent any delay related to regulatory procedures that may impact on product availability. Product quality reviews (PQRs) are suggested as a possible tool to capture appropriate data and trends for continuous improvement.

The overall resilience of the supply chain should be supported by the justification of the adoption of the just-in-time supply model, particularly when limited alternatives are available. MAHs and wholesalers should guarantee the availability of suitable contingency stocks to face any unexpected delay.

Sub-optimal communication among different stakeholders should be also addressed by means of an improved cooperation, including a two-way communication system extending also to potential or actual shortages. Critical points of attention are identified in the intra-company communication between different departments, those between local MAH representatives and manufacturer, and the availability of information on stock levels to entities entitled to supply medicines to the public via ordering portals. Specific criteria for communication, together with the description of key processes and supply chain maps should be developed by each stakeholder.

Stockpiling is another critical practice to be avoided in order to ensure the fair and timely distribution of medicines. To this instance, healthcare professionals are called not to order or dispense more stock than normal in case of shortage, while MAH stock allocation practices between different countries should also take into account the clinical need of patients, and not just economic factors. Parallel trade should be also avoided as far as possible. NCAs should duly justify any decision to limit this practice, while companies should seek advice from their relevant authorities of the exporting country in case of critical shortages.