Pharmaceutical Strategy Archives - European Industrial Pharmacists Group (EIPG)

A concept paper on the revision of Annex 11


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 Read more

What happens after IP loss of protection


by Giuliana Miglierini What does it happen under a competitiveness perspective once intellectual property (IP) protection for medicinal products expired? And what is the impact of the new entries on generics and biosimilars already in the market? The role of competitor Read more

The FDA warns about the manufacture medicinal and non-pharmaceutical products on the same equipment


by Giuliana Miglierini A Warning Letter, sent in September 2022 by the US FDA to a German company after an inspection, addresses the possibility to use the same equipment for the manufacturing of pharmaceutical and non-pharmaceutical products. The FDA reject Read more

A study on medicines shortages from the European Commission

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by Giuliana Miglierini

The study on medicines shortages commissioned in March 2020 by the European Commission upon request of the European Parliament and Council has been published; the document, prepared by a consortium led by Technopolis, suggests 16 possible policy measures – both legislative and not-legislative – that the Commission may consider while drafting a new legislative proposal to govern the issue, expected to be announced at the end of 2022.

According to the current EU pharmaceutical legislation (Directive 2001/83/EC), marketing authorization holders (MAHs) have to submit – two months before the temporary or permanent interruption of supply of a certain medicinal product – a pre-notification to the relevant national competent authorities (NCAs) (Article 23a, a part in the case of exceptional circumstances).

The mandate to continue supply to cover the needs of patients, and respective responsibilities of MAHs and wholesale distributors are established by Article 81 of the same directive.

The new study will support some of the achievements set forth in the Pharmaceutical Strategy; another action undertaken to reduce the impact of shortages in the EU is represented by the EU Executive Steering Group on Shortages of Medicines Caused by Major Events, an initiative set up in March 2020 with the contribution of the Commission, EMA and member states.

The Commission study on shortages by Technopolis confirms that current market framework conditions for off-patent medicines play against supply resilience – said Rebecca Guntern, President ad-interim of Medicines for Europe, commenting the release of the study –. As long as healthcare systems only focus on the cheapest possible price for off-patent medicines and do not reward investments to ensure robust supply chains, the only option for companies is to be the cheapest or to leave the market.

The main outcomes of the study

The study on shortages focused its attention on medicines for human use marketed in the EU/ EEA in the period 2004-2020. The main objectives of the exercise include the identification of shortages’ root causes and specific characteristics, the assessment of the adequacy of the current framework (at EU and national level) and of possible solutions to address the problem.

Data from the shortages registries kept by national competent authorities (NCAs) of 22 EU’s countries was only available for years 2007-2020. Commercial data on pharmaceutical sales from IQVIA MIDAS was also used, and extensive consultation with stakeholders was run under different formats.

Central to the 16 recommendations highlighted in the study is the establishment of a centralized and harmonised EU-wide definition of medicine shortages, as well as of harmonised reporting criteria. The latter should aim to collect sufficiently detailed information on key parameters (e.g. product details, MAH, details on the shortage and impact).

Different definitions, systems for notifications and type of information requested are currently in use in the various member states; even the definition of “shortage” agreed in 2019 by EMA and HMA was not considered by stakeholders adequate to differentiate between critical and non-critical shortages. According to the report, this fragmented situation doesn’t allow for the sharing of data and comparative analysis between countries, thus resulting in the overall inefficiency of the system.

Attention should be paid also to the creation of a EU-wide list of medicines subject to critical shortages; specific policies and regulations may be developed on this basis to improve their availability. Medicines typically experiencing shortages are older, off-patent and generics drugs with low profit margins; the main therapeutic areas involved include pain, hypertension, infections and oncology.

The creation of dialogue platforms at the national level is also envisaged, where to exchange the point of view of different supply chain stakeholders (including patients and healthcare providers). The study highlights the high burden shortages create on pharmacists and physicians looking for the best possible treatment alternative for their patients. A possible way to address this issue would see the availability of information about alternative medicines in shortage databases. In many cases, this type of occurrence is referred just to some countries within the EU, thus suggesting inequitable distribution and access rather than global supply issues may play a major role in shortages.

Understanding the root causes

Limited reporting is a key point to be solved in order to improve the understanding of root causes of shortages. According to the study, a reductionist approach to reporting is often used; this makes fully evident just acute causes (e.g. a problem at the production site), but leaves unattended more systemic issues (e.g. consolidation of manufacturing, resulting in a very limited number of production sites) and market-related factors (e.g. single-winner procurement practices).

Quality and manufacturing issues account for approx. half of all cases of shortages, suggest the report; among commercial reasons are market withdrawals and unexpected increases in demand. The information available for the analysis was judged insufficient to exactly asses the potential risks linked to outsourcing of manufacturing activities (including the production of APIs) and parallel distribution.

The proposed recommendations ask for greater transparency of industry supply quotas as well as parallel traders’ and wholesalers’ transactions. Suppliers should establish adequate shortage prevention and mitigation plans; legal obligations for MAHs and wholesalers are suggested in order to maintain a safety stock of (unfinished) products for medicines of major therapeutic interest at EU-level.

A new legislation to tackle shortages

The provisions set forth by Articles 23a and 81 of the Directive have been transposed differently into the single national legislations, often well before the establishment of the shortages registries. Several EU’s countries have acted on their own to strengthen the system, for example establishing mandatory reporting on stock levels and export restrictions. Nevertheless, according to the study available data are not sufficient to draw final conclusions on the costs and efficacy of stock keeping obligations on the level of (notified) shortages in the countries where they were introduced.

A more pro-active approach to the management of medicines shortages by MAHs and distributors may be supported by the availability of a EU-wide and uniform legislation governing financial sanctions to be applied if notification requirements and/or supply responsibilities are not met. Other suggestions include the adoption of common principles for the introduction of national restrictions on intra-EU trade, and the availability of greater flexibilities for emergency imports of specific products in case of market withdrawals and other critical shortages. As for procurement, the study indicates the opportunity to address public procurement tenders also considering the incorporation of requirements for more diversified, multiple tenderers and thereby supply sources.

From a regulatory perspective, the document highlights the opportunity to reduce costs and simplify administrative procedures for the submission of post-approval changes. The availability of an accelerated mutual recognition procedure (MRP) within the EU is also suggested, together with a more efficient use of the Repeat Use Procedure. Improved flexibility should be a target also with respect to the EU-wide regulation governing medicines packaging and labelling, so to allow for the use of digital leaflets and multi-country/multi-language packaging and labelling.


The opportunity for repurposing of oncology medicines

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by Giuliana Miglierini

Rare cancers, which account for approx. 22% of new cases in Europe, represent an area of low business interest for the pharmaceutical industry, due to the limited number of patients compared to the very high costs to develop targeted treatments. It is thus important to consider the possibility for already existing medicines to be repurposed for a new indication. Lower costs of development and risk of failure, and a shorter time frame to reach registration are upon the main advantages of repurposing compared to de novo development, highlights the Policy Brief presented during the Joint meeting of EU Directors for Pharmaceutical Policy & Pharmaceutical Committee of 8 and 9 July 2021.
The experts addressed more specifically the possibility to achieve non-commercial repurposing of off-patent cancer medicines, which are commonly used off-label to treat patients not responsive to other more innovative types of therapies.

The issue of non-commercial development
The request of a new indication for an already marketed medicine has to be submitted by the Marketing authorisation holder (MAH). This greatly hampers the access to noncommercial repurposing by independent research institutions, as they would need to find an agreement with the MAH, the only responsible for all the interactions with regulatory authorities, at the central (EMA) or national level.
Considering the issue from the industrial point of view, this type of external request may prove difficult to be answered positively, when taking into consideration the very low return on investment that can be expected from a repurposed off-patent medicine. Even EU incentives schemes, such as those on data exclusivity and orphan designation, may not be sufficiently attractive for the industry. Current incentives schemes, for example, allow for an additional year of exclusivity in case of a new indication for a well-established substance, a 10-year market exclusivity
plus incentives in case of an authorised medicine granted with orphan designation, or the extension of the supplementary protection certificate for paediatric studies (plus 2 years market exclusivity for orphans).
The following table summarises the main issues and potential solutions involved in the setting of a specific reference framework for the repurposing of off-patent medicines for cancer, as reported in the WHO’s Policy Brief.

Table: Short overview of issues and solutions in repurposing of off-patent medicines for cancer
(Source: Repurposing of medicines – the underrated champion of sustainable innovation. Copenhagen: WHO Regional Office for Europe; 2021. Licence: CC BY-NC-SA 3.0 IGO)

Many projects active in the EU
The European Commission started looking at the repurposing of medicines with the 2015-2019 project Safe and Timely Access to Medicines for Patients (STAMP). A follow-up phase of this initiative should see the activation in 2021 of a pilot project integrated with the new European Pharmaceutical Strategy.
Several other projects were also funded in the EU, e.g. to better train the academia in Regulatory Science (CSA STARS), use in silico-based approaches to improve the efficacy and precision of drug repurposing (REPO TRIAL) or testing the repurposing of already marketed drugs (e.g. saracatinib to prevent the rare disease fibrodysplasia ossificans progressive, FOP). A specific action aimed to build a European platform for the repurposing of medicines is also included in Horizon Europe’s Work programme 2021 –2022; furthermore, both the EU’s Beating Cancer Plan and the Pharmaceutical Strategy include actions to support non-commercial development for the repurposing of medicines.

According to the WHO’s Policy Brief, a one-stop shop mechanism could be established in order for selected non-commercial actors, the so-called “Champions”, to act as the coordination point for EU institutions involved in the funding of research activities aimed to repurposing. This action may be complemented by the support to public–private partnerships involving research, registration and manufacturing and targeted to guarantee volumes for non-profitable compounds.
Among possible non-profit institutions to access funding for repurposing research in cancer are the European Organisation for Research on Cancer (EORTC) and the Breast Cancer International Group. An overview of other existing initiatives on repurposing has been offered during the debate by the WHO’s representative, Sarah Garner.

How to address repurposing
Looking for a new indication is just one of the possible points of view from which to look at the repurposing of a medicine. Other possibilities include the development of a new administration route for the same indication, the setup of a combination form instead of the use of separated medicinal products, or the realisation of a drug-medical device combination.
A change of strategy in the war on cancer may be useful, according to Lydie Meheus, Managing Director of the AntiCancer Fund (ACF), and Ciska Verbaanderd.
Keeping cancer development under control may bring more efficacy to the intervention than trying to cure it, said ACF’s representatives. The possible approaches include a hard repurposing, with a medicine being transferred to a completely new therapeutic area on the basis of considerations about the tumor biology and the immunological, metabolic and inflammatory pathways, or a soft repurposing within the oncology field, simply looking to new indications for rare cancers.
From the regulatory point of view, a possible example for EMA on how to address the inclusion of new off-label uses of marketed medicines is given by the FDA, which may request a labeling change when aware of new information beyond the safety ones.

The Champion framework
The Champion framework, proposed as a result of the STAMP project, is intended to facilitate data generation and gathering compliant to regulatory requirements for a new therapeutic use for an authorised active substance or medicine already free from of intellectual property and regulatory protection.
A Champion is typically a not-for-profit organisation, which interacts with the MAH in order to include on-label what was previously off-label, using existing regulatory tools (e.g innovation offices and scientific and/or regulatory advice). The Champion shall coordinate research activities up to full industry engagement and would be responsible for filing the initial request for scientific/regulatory advice on the basis of the available data. The pilot project to be activated to test the framework will be monitored by the Repurposing observatory group (RepOG), which will report to the Pharmaceutical Committee and will issue recommendations on how to deal with these types of procedures.

AI to optimise the chances of success
Artificial intelligence (AI) may play a central role in the identification of suitable medicines to be repurposed for a target indication, as it supports the collection and systematic analysis of very large amounts of data. The process has been used during the Covid pandemic, for example, when five supercomputers analysed more than 6 thousand molecules and identified 40 candidates for repurposing against the viral infection.
AI can be used along drug development process, making it easier to analyse the often complex and interconnected interactions which are at the basis of the observed pharmacological effect (e.g drug-target, protein-protein, drug-drug, drug-disease), explained Prof. Marinka Zitnik, Harvard Medical School.
To this instance, graphic neural networks can be used to identify a drug useful to treat a disease, as it is close to the disease in “pharmacological space”. The analysis may also take into account the possible interactions with other medicines. This is important to better evaluate the possible side effects resulting from co-prescribing; annual costs in treating side effects exceed $177 billion in the US alone, according to Prof. Zitnik.