Later this year, the European Medicines Agency (EMA) will issue new guidance, following a report on shortages (the EMA Report), to provide more transparency and to assist national agencies in dealing with this shortage of medicines.
This new guidance will have practical implications, including additional administrative and information burdens for all stakeholders, and is likely to benefit certain groups.
The growing problem
On 23-28 May, members of the World Health Organization debated how to deal with the global shortage of medicines, including the safety and accessibility of medication for children.
Recent industry reviews (EAHP surveys) have highlighted the high weekly incidence of shortages of oncology and anti-infectives, particularly in hospitals in Europe. Further EU-wide study groups looking at hospitals and other treatment centres will therefore start in 2016 to refine previous data.
In response to these reviews, and in meetings with key associations, the EMA had previously considered the following two options:
- Making shortage readiness evaluation an element of the EMA’s review of a Site Master File
- Incorporating shortage readiness into sections of Chapter 1 of the EU Guidelines to GMP on annual product review.
The EMA may still consider implementing one of these options.
The EMA is likely to establish single points of contact at national and European levels to facilitate the coordination of alerts and also the resolution of shortages. The EMA may also publish a proposed EU-wide definition of ‘shortage’ for national agencies to consider when implementing its guidance.
In 2015 it had suggested this could be: ‘Medicine shortages that affect or are likely to affect more than one European Union (EU) Member State, where the European Medicines Agency has assessed the shortage and provided recommendations to patients and healthcare professionals across the EU.’
Industry stakeholders had suggested: ‘A crisis situation caused by the inability of any Marketing Authorisation Holder to supply a drug with a specific Active Pharmaceutical Ingredient to a market over an extended period of time resulting in the unavailability of this medication for patients.’
What could be the impact of these proposals?
EMA’s proposed role
The EMA already coordinates and provides guidance to support EU-wide harmonisation in several areas. It also consults with national regulators and other international regulators including the FDA, which in 2012 published new regulations (the Food and Drug Administration Safety and Innovation Act) requiring manufacturers to inform each other and FDA about the risk of shortages, not just about existing shortages.
In Europe, the EMA pragmatically seeks to set out how best to identify the point in a supply chain where a manufacturing or quality problem is likely to trigger a significant disruption to supply. Once a manufacturer or national regulator has informed the EMA that it has identified such a ‘weak link’ or risk, the EMA plans to provide guidance on when and how manufacturers and other stakeholders should report a situation that could lead to a shortage in one or more countries in Europe, and also in other markets.
The EMA does not intend to regulate or identify how the supply of medicines within a Member State should be managed: that is a matter for the national authorities.
Role of national authorities
National authorities retain exclusive responsibility for the regulation of supply of medicines in their own countries, and most already impose an obligation of continuity of supply of medicines on wholesalers and manufacturers. However two-thirds of authorities in Europe do not use a standard definition of what constitutes a medicine shortage, and this leads to delays in information about the risks of cross-border shortages.
Ahead of the EMA’s planned guidance, authorities in some Member States have been implementing their own proposals on how to identify and provide further information about shortages of medicines.
For example, France will implement a new law that imposes new duties on holders of marketing authorisations, as well as wholesalers and distributors, to inform the competent authority (ANSM) of the risk of a shortage of medicines that are of ‘major therapeutic importance’. Data about such risks will be published on the ANSM website. This affirms the role of all stakeholders – pharmacists, wholesalers, distributors, Responsible Persons and holders of marketing authorisations – in identifying, managing and disclosing any disruption to supply of medicines in France.
Introducing new monitoring, reporting and data transfers… may not lead to faster resolution of shortages
An innovative element of the new law is that supply chain stakeholders must submit proposals to ANSM for resolving shortages at around the same time as ANSM is informed of these shortages. This will involve a level of coordination and sharing of data between stakeholders that previously was not formally required, and will raise questions as to the confidentiality of data and the causes of these shortages. It will lead to the increased use and disclosure of risk-management plans, and discussions about the liability of individual members of a supply chain to take remedial steps.
In other countries, national authorities are relying on existing legal procedures to deal with shortages: in April 2016, for example, the Athens Public Prosecutor started a criminal investigation into the causes and actors of certain failures to supply, after complaints by patients and pharmacists.
Other countries such as Spain, the Netherlands, Italy and Belgium have already created national databases, containing published information about likely or actual shortages. Germany, France and England also have similar databases, although they either limit what is included or do not make them publicly available at all.
Power to review national regulator proposals
Stakeholders should bear in mind that the EU Commission has the power to require national authorities to make changes to their plans: for example, in May 2016 the EU Commission gave two months’ notice to Portugal and Slovakia to amend steps introduced to limit the impact of exports on shortages.
In Portugal, wholesale distributors of medicinal products for human use were asked to notify the Commission of their intention to export medicines considered to be ‘at risk of shortage’ by the authorities, and to provide information on the export operations that had been carried out. In Slovakia, wholesale distributors were asked to notify the Commission of all exports of human medicines, and are also required to wait for 30 days for a tacit clearance by the state authority.
The Commission deemed that these requirements did not set out clear and transparent criteria to estimate risks of a potential shortage due to parallel trade.
Likely impact of future EMA proposals
It is widely acknowledged there are multiple reasons for shortages: logistic, economic and qualitative. There has been a limited assessment of the likely consequences of further regulating shortages within individual countries or across the EU.
Introducing new monitoring, reporting and data transfers for orders and deliveries across supply chains that are already complex will lead to increased costs for stakeholders. It may not lead to faster resolution of shortages.
Communicating in detail with patients, prescribers and possibly with health insurers will involve preparation and consultation time that has a real cost for healthcare professionals.
Additional duties on marketing authorisation holders to monitor supply and report to national authorities in their national language will also not address production issues that may be outside their control.
Stakeholders are already meeting costs to comply with new anti-counterfeit regulations. National regulators may not have the resource to deal with multiple short- or longer-term supply chain disruption that may be caused by an event outside their country or region.
Proposals for resolving shortages, as approved by regulators, may lead to the use of more expensive medicines and additional charges for additional returns, warehousing and deliveries.
There may also be benefits as well as risks for patients, associated with switches in their medication, that are likely to lead to an increase in reports of adverse events. These switches already occur, and it is hoped a public database will enable better evaluation and implementation of the supply of alternative treatments. While patients are likely to receive more information about shortages, this could also raise anxiety about continuity of treatment, which is important in therapy areas such as oncology.
Patients and healthcare groups agree with EFPIA about the need to seek more accurate supply and demand data to verify regulatory compliance, and to identify potential supply shortages at an early stage.
Proposals for securing continuity of supply of medicines for patients within and outside Europe are important. They should include assessments of their implications for all stakeholders.