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The upcoming serialization deadline and the United Kingdom's departure from the European Union could result in supply bottlenecks.
The European pharmaceutical industry and regulators are worried about an imminent worsening of the persistent problem of shortages of medicines in the region. Although both agree that regulations are partly to be blamed for a likely rise in the number of incidents of drug scarcities, they have different views on the issue of how regulations are reducing the availability of medicines.
The industry contends that regulations, particularly those relating to pricing policies, are being applied too strictly so that it has become uneconomic to retain low-priced drugs on the market. The regulators reckon that shortages are occurring when regulations are not being used effectively enough to ensure that medicines remain available.
The first half of 2019 could be a crunch time for medicines supplies in Europe as a result of a new packaging regulation coming into effect, which is aimed at combating counterfeit drugs, and the United Kingdom’s official departure from the European Union triggering legal changes that will have a big impact on pharmaceutical supply chains. The implementation of rules on the identification of individual medicine packs under the EU’s Falsified Medicines Directive (FMD) will be followed by Brexit, where the UK will no longer be a member of the EU’s single market. Supply bottlenecks could start to form before the two events through to their aftermath.
“Both FMD and Brexit will come into operation within a couple of months,” Adrian van den Hoven, director general of Medicines for Europe, representing generic medicines and biosimilars producers, said at the 17th Regulatory and Scientific Affairs Conference, which took place in London on 25–26 Jan. 2018. “Are we going to risk a total regulatory overload within a six-month period from the end of this year to the spring of 2019 during which the supplies system could become clogged up?” he asked.
A large part of the conference focused on the issue of shortages of medicines and the impact of the FMD packaging legislation and Brexit on their availability.
“The evidence that the root causes of medicines shortages are economic, including unsustainable pricing and reference pricing policies, is overwhelming,” Marc-Alexander Mahl, head of the generic-drug business of Fresenius Kabi and president of Medicines for Europe, told the meeting. He noted that claw- and pay-back measures used by governments to limit public sector overspending on pharmaceuticals were also partly to blame. A claw- or pay-back is a tax imposed when there is overspending within a budget so that the total net expenditure is kept within the budget’s limit.
In Romania, 2000 medicines had been withdrawn because of reference pricing and a claw-back tax, while in Portugal, there had been a “drastic reduction” in the number of hospital drug suppliers due to the impact of a pay-back scheme, according to Mahl. He cited the conclusion of a 2016 report (1) by the European Commission on the fiscal sustainability of funding healthcare. “While overspending is recovered via the claw-back tax, it has led to withdrawals of generic medicines from the market,” the report said (1).
Not only have generic-drug companies struggled to cope with the downward pressures on their profits and sales revenues, but they also have to cope with the expense of running complex supply chains in a high-volume, low-margin business, Mahl highlighted at the meeting. He pointed out that a large generic-drug company in Europe may have as many as 25,000 marketing authorizations, with more than 800 supply-chain employees working with more than 2000 partners and shipping products to up to 50,000 locations. At the same time, generic-drug companies have to invest in R&D to launch new products, formularies, and biosimilars to ensure competition and wider pharmaceutical access in the market, he said.
Meanwhile, the regulatory demands on generic-medicine producers at the EU and national levels are increasing, particularly with requirements to keep marketing authorizations up to date. Typically, 75% of the EU regulatory fee budget of a generic-drug company is taken up by the maintenance costs of marketing authorizations. Partly as a result of the number of variation approvals nearly doubling in four years, maintenance fees had risen by an average of 45% annually per marketing authorization in 2011–2014, Mahl said. He explained that one way to prevent medicine shortages would be to improve regulatory efficiency so that the administrative and cost burdens of keeping products on the market can be reduced. There should be a flat fee structure for the approval of variations. He also suggested that there should be a lower authorization and maintenance fees for older molecules that still serve a medical need.
A study in 2017 (2), cited at the conference, showed that national competent authorities (NCAs), which license medicines under the EU decentralized approval procedure, were making more flexible use of regulations to deal with shortages. But the report (2), carried out by the heads of medicines agencies (HMA) representing NCAs, indicated also that often, rules being applied by national authorities were aiming to be even more restrictive.
Governments have introduced procedures for banning exports of essential medicines at times of acute shortages. Regulatory authorities are also wanting to monitor more closely pharmaceutical plants liable to production disruptions, through measures such as risk-management plans. Finland, for example, has legislation that obliges manufacturers and wholesalers to store additional life-savings medicines for periods of three to 10 months (2). On the other hand, national authorities are being flexible with the enforcement of regulations when dealing with shortages. They are, for example, relaxing language rules on labels and patient leaflets in order to import replacement medicines from other countries. They are also giving emergency authorizations to bring in medicines from abroad.
Within the EU regulatory network for medicines, extending from the European Commission and European Medicines Agency to the HMA and the Co-ordination Group for Mutual Recognition and Decentralized procedures for human medicinal products (CMDh) at the national level, there are moves to adopt more uniform approaches to medicines availability. An HMA/EMA Task Force on medicines availability, which was set up in late 2016, has started meeting regularly since the middle of 2017. It comprises representatives of the HMA, EMA, the European Commission, and the chairs of the CMDh and its veterinary equivalent.
Kristin Raudsepp, co-chair of the task force, told the conference that it would be addressing issues such as the detection of potential supply disruptions and ways of avoiding shortages. Among the actions planned by the task force was the development of a definition of medicine shortage. The task force also wanted to “develop a concept of reportable shortage and agree on a common set of reporting requirements [as well as] develop metrics that could be used to measure a shortage,” Ruadsepp said.
Currently, among the major factors influencing the availability of medicines, is the number of authorized medicines that are either not being marketed or are no longer marketed in the EU. In addition, supply chain disruptions are affecting availability. These disruptions could result from difficulties with failed approvals of GMP-standard manufacturing or other safety or quality problems and the effects of parallel trade. Raudsepp, who is director-general of Estonia’s State Agency of Medicines, said that in her own country’s market, 60% of authorized medicines are not available. With those that are being marketed in Estonia, there are approximately 100 medicines experiencing shortages each year, with an average shortage period of 100 days in 2016. “Every [type] of medicine may be in shortage,” she said. “We have had cases of shortages for vaccines in the national vaccination scheme, for cancer treatment, and life-saving hospital medicines.”
Among the options for dealing with the issue of authorized medicines not being placed on the market was the use of regulations to require companies to make authorized products available, Raudsepp said. The European Commission is planning to send out a questionnaire to stakeholders on the implementation of article 81 of the 2001 EU directive on medicinal products (3).
Article 81 stipulates that the holder of a marketing authorization for a medicine and its distributors “shall, within the limits of their responsibilities, ensure appropriate and continued supplies of that medicinal product to pharmacies and persons authorized to supply medicinal products.”
Some participants at the conference pointed out that authorized medicines may not have been put on the market for economic reasons. There may not be the production capacity for manufacturing them. Also, with the FMD packaging regulation and Brexit looming on the horizon, it was not the time for considering the use of regulations to force companies to make products available.
The conference was warned that there was a danger, which due to its cost and complexity, pharmaceutical companies may not be able to meet the deadline for the implementation of the FMD packaging legislation. The regulation introduces pack identification of medicines involving the use of individual pack barcodes and anti-tamper devices within an “end-to-end” system under which the serialization and other data on each pack can be verified by a pharmacist with a scanner at a dispensing point connected to a central data bank. According to Philippe Drechsle, chair of Medicines for Europe’s FMD task force, a recent survey of the readiness of Medicines of Europe members for the legislation found that the most compliant company reached only a 55% state of readiness while other companies are at a level of 30% or even less (4).
Moreover, Brexit could result in a number of medicines no longer being available in the EU because of the need to obtain UK-based authorizations or because the UK was the original reference member state (RMS) under the mutual recognition procedure. These authorizations will have to be transferred to an EU state to remain valid after the UK’s departure. Both the FMD regulation and Brexit look highly likely to divert for awhile efforts to tackle the underlying causes of medicine shortages in the EU.
1. European Commission’s Directorate General for Economic and Financial Affairs and Economic Policy Committee, “Joint Report on Health Care and Long-term Care Systems & Fiscal Sustainability” (Brussels, October 2016).
2. Heads of Medicines Agencies, “Availability of Medicinal Products for Human Use” (Brussels, 29 May 2017).
3. European Union Directive, “Community Code Relating to Medicinal Products for Human Use,” 2001/83/EC (Brussels, 6 Nov. 2001).
4. Philippe Drechsle, “Falsified Medicines: Practical Implementation of the Falsified Medicines Directive in a Nutshell-How is the System Set Up to Detect Falsified Medicines in the Supply Chain?” presentation at the 17th Regulatory and Scientific Affairs Conference (London, United Kingdom, 25–26 Jan. 2018).
Pharmaceutical Technology Europe
Vol. 30, No. 3
When referring to this article, please cite it as S. Milmo, “Tackling Medicine Shortages in Europe,” Pharmaceutical Technology Europe 30 (3) 8–9 (2018).