Reflector

	Growth in plasma-derived medicinal products is good news for drug developers and for patients-but it is generating a bitter turf war in Europe over how to source the starting material: human blood.

	Over the last decade, the use of plasma-derived medicinal products (PDMPs) has widened steadily, with the global market more than doubling to surpass $20 billion by 2016. Demand has leapt further ahead more recently, both with increasingly sophisticated usage of existing products, and with the emergence of new products and new indications. Most strikingly, the use of immunoglobulin has expanded dramatically from treating primary immune deficiency to other conditions, including multifocal motor neuropathy. New specialty plasma proteins have emerged, such as C1 esterase inhibitor for the treatment of hereditary angioedema, and strong surges in use are being seen for and prothrombin complex concentrate as well as alpha-1 antitrypsin. PDMPs are also now finding further uses in secondary immunodeficiency following new cancer treatments.

	The challenges in supplying the plasma required to sustain this evolution are sending shockwaves through what has for years been a tranquil and traditional corner of the healthcare scene in Europe. Here, in contrast to the US and other regions of the world, blood donors have volunteered their services with altruistic regularity in 1,400 blood establishments handling 20 million blood donations every year. And donors receive no compensation in many countries other than a cup of tea and a biscuit. The predominantly charitable or state organizations that collected blood, primarily for transfusion, also offer some supply of what is known as “recovered” plasma, for therapeutic uses, and also, to a lesser extent, for fractionation into the starting materials for PDMPs. But the advances in science, technology and clinical care-and the resulting demand for plasma-derived medicines-have rendered that model inadequate.

	Commercial operators have increasingly set up their own networks specifically for obtaining what is known as “source” plasma for PDMPs. And that is where the differences of approach are now generating real conflicts-between public and private interests, between voluntary and compensated donation, and ultimately between the relative weight to be given to the interests of patients and the interests of collection organizations.

	No one disputes the need for more plasma. The European Medicines Agency (EMA) guideline on PDMPs notes how “improvements in protein purification and molecular separation technology have made available a wide variety of products, with medical applications covering a large field, and the therapeutic value of these is unquestioned,” but that “the quantity of plasma for fractionation is limited by the number of donors.” The European Commission, which is trying to steer a middle course between the warring factions, notes that the current legislation is “limited in provisions that help achieve sufficiency,” and that “while the number of private plasma collection centers in the EU has increased in recent years, this is far from sufficient to keep up with increasing demand for plasma derived medicines.” Figures from The Marketing Research Bureau, a consultancy, show that just to meet European demand for polyvalent immunoglobulin, nearly four million liters of plasma had to be imported from the US in 2017 to complement Europe’s own resources of nine million liters. For 2025, the consultancy estimates that this gap will rise to nearly six million liters-more than a third of the total requirement of 15 million liters.

	But identifying a problem and agreeing to a solution are two very different challenges-and more particularly in the perennially complex world of European policy formation. The Commission is in the throes of revising its blood-products legislation, and both sides in the debate are ramping up their rhetoric to gain as much as possible from the outcome. The legal intricacies are too arcane to merit detailed attention here- suffice it to offer a couple of examples by way of illustration: PDMPs are covered by the basic 20-year-old EU rules on pharmaceuticals, and so too is any “plasma that is prepared by a method involving an industrial process;” they are also covered by the 15-year-old blood directive; and as if that were not enough, PDMP standards are set in a series of monographs from the European Pharmacopoeia-a separate authority under the aegis of the (also separate) Council of Europe. In addition, EU member states are allowed to apply their own more stringent requirements for PDMPs. Italy, France, and Spain choose to limit their collections of blood and plasma exclusively to domestic clinical needs.

	As the quest for higher volumes of plasma intensifies, the traditional blood donor centers say they want to see the law changed in a way that will give them greater protection against disruption from commercial interests.

	The European Blood Alliance (EBA), an association of non-profit blood establishments, is determined to defend its “voluntary and non-remunerated donation” model, and claims that a Council of Europe agreement- the Oviedo Convention-supports its rejection of financial gain from the human body and its parts. At present, private-sector collection and donor payment is not allowed in many EU countries. In a thinly coded message, EBA says “excellence in blood products supply chain cannot be characterized merely by high productivity and quality,” and it appeals over the heads of everyone else for decisions that will “contribute to a well-functioning professional healthcare system”-in other words, preservation of something like the status quo. It  recommends giving the Council of Europe’s currently non-binding guidelines a mandatory effect throughout the EU.

	Another public-sector based group, the International Plasma Fractionation Association, is similarly urging “a preference for and commitment to the ‘gift model’ of blood and plasma donation without remuneration” and the non-profit model. There are risks, it says, in a market-related supply system-not least an “erosion and/or fragmentation of a community-based donor population.” The answer to insufficient collection is, it says, for governments to boost the public-sector system.

	But the Plasma Protein Therapeutics Association (PPTA), which brings together private-sector manufacturers, as well as collectors of source plasma used for fractionation, sees major inefficiencies in the current arrangements. In addition to manufacturers of plasma-based products, PPTA’s EU members comprise an alliance of 14 organizations that collect around three million liters of plasma at 97 centers in Germany, Austria, Czech Republic, and Hungary-a good achievement, but not enough, it acknowledges. Top of its wish-list is 

EU action to promote a network of dedicated centers for collecting plasma specifically for PDMP manufacture in all EU countries. At present, the infrastructure is so patchy-with big gaps in access to the plasmapheresis equipment that permits higher volumes of source plasma collection-that the goal of European self-sufficiency will remain elusive, PPTA says. The group also wants the ban on payment in many EU countries to be lifted too. It points out that plasmapheresis is a more burdensome and longer process (up to 90 minutes per session) than the 15-minute process for a standard whole-blood donation-and that therefore it should at least be possible for some compensation for those donors.

	The accent in PPTA arguments is principally on patient needs: without plasma, many valuable treatments cannot be made available to them. In contrast, the public-sector arguments tend to focus on protecting the donor. But these are, in some ways, proxy arguments: at bottom, opening the door to payment and to private-sector collection is seen as threatening a fatal blow to the public sector’s voluntary state-run model; while the private sector perceives an attempt by the public sector to manipulate the review of European legislation in a way that would tie the industry’s hands with red tape in the guise of safety rules.

	The outcome will affect more than the interests of a handful of vested interests, because therapy for many conditions for many patients is reliant on adequate supplies of plasma-and at a time of increasing turbulence in international trade, and globalization of health threats, Europe’s patients may find themselves more than ever dependent on European-sourced plasma.

Reflector is Pharmaceutical Executive’s correspondent in Brussels

Articles

The collection of source plasma for new therapies igniting debate.

Blood Feud Divides Europe Over Plasma Shortfalls

	While the agencies that pay for medicines continue to struggle with the inadequacies of external reference pricing (ERP) systems that many of them rely on, parallel attempts to pry open the black box of managed entry agreements (MEAs) seem even more unproductive. A panel of experts working with the richest countries in the world has just been obliged to admit failure in its search for an easy key to unlock the secrets held by deals on payment for results or population-level coverage.

	“It is difficult to assess to what extent performance-based MEAs have so far been successful,” conclude the authors of a study for the Organization for Economic Cooperation and Development (OECD), because “little information is currently shared,” particularly on the products for which MEAs are in place, on the design of MEAs, or on their results, and there is a consequent “lack of evidence.”

	Advocates of tougher pricing controls on medicines will find little comfort in the findings of the OECD study, because it confirms what European discussions of ERP during 2019 already made clear: that as long as confidentiality remains the norm in pricing negotiations between drug firms and national payers, information and evidence is always going to be in short supply. The ambitions of European national payers to leverage a shift in focus from list prices to net prices are evident in the burgeoning regional groupings now emerging along the lines of the Beneluxa model, and were at the heart of last year’s ERP discussions in their Euripid grouping too (which this column covered in May 2019

). So far, the ambitions remain a long way from fulfilment.

	That is not to say that the concept of MEAs is called seriously into question in the study. These agreements between firms and healthcare payers can, in principle, allow for coverage of new medicines while managing uncertainty around their financial impact or performance, it concedes. And at least two-thirds of OECD countries and EU member states have made use of financial agreements designed to reduce prices and/or budgetary impact of medicines in OECD countries and EU member states without linking them to product performance.

	Many of them have also used performance-based agreements that link to payments or rebates, it says. The most common designs for agreements are patient-level payment-by-result (PbR), paying firms only for treatments to which patients respond, and population-level coverage with evidence development (CED), which aim to reduce uncertainty around comparative effectiveness or cost effectiveness.

	The problem is that it is hard to say whether these agreements do what they are intended to do. Few countries have formally evaluated their experience. And the confidentiality that surrounds these agreements is a permanent barrier to independent evaluation.

	There is little evidence in the public domain, admit the authors of the study-and such information as is available, including from expert interviews they have conducted-indicates that CED agreements have so far had a poor track record of reducing uncertainty around the performance of medicines, and PbR agreements “do not always generate evidence on product performance because data used for triggering payments are not always aggregated and analyzed.”

	As a result, some countries have recently reformed CED schemes, and some are discontinuing CED agreements altogether in favor of alternatives, notably with restricted or conditional coverage without an MEA, and with coverage initially restricted to certain indications or patient groups and only broadened if and when additional evidence becomes available.

	Where the advocates of tougher pricing controls may find more comfort-and pharmaceutical executives may entertain more reservations-is in the study’s suggestions that the situation is not without some hope of remedy. One of the avenues that the report recommends for exploration is “ensuring a minimum level of transparency of content, limiting confidentiality to those parts of MEAs that may be commercially sensitive (e.g., prices).” It also urges sharing information on results of MEAs, and how performance of products is measured within them.

	According to the study, this would benefit payers. It says it would reduce duplication of effort between countries; it would allow payers to learn from experience elsewhere to inform their negotiations with firms; and it could reduce uncertainty over results from small patient samples in the case of rare diseases. Greater transparency over the performance of products would also “be useful for other stakeholders with legitimate interests and the general public,” it says.

	The study also raises a hitherto less remarked issue. It suggests that reticence over the outcome of MEAs could have a dimension beyond the strictly technical. “The potential non-disclosure of results of clinical studies conducted under performance-based MEAs raises ethical concerns, as available information on the effectiveness of medicines could be withheld from the public.” 

	The ways forward that the study recommends amount to a radical change in current practice. If MEAs are to be more useful, “payers would need to change their policies in negotiations with pharmaceutical firms to ensure that information on future MEAs is not confidential,” it says-somewhat glibly, since abandoning confidentiality is not entirely within the exclusive gift of payers; companies would have to agree to it too.

	“There is significant interest in sharing of information on the existence of MEAs, on how product performance is measured, and in decisions made as a result of MEAs,” it continues. “Payers could agree on which information to share, in which form, and through which mechanism.

	Various mechanisms of information exchange are possible, including publishing information on existing websites, establishing new central repositories, and using existing initiatives for sharing of information on medicines and health technologies.”

	In what sounds like a belated-and even then possibly inadequate-acknowledgement that it does indeed take two to tango, the study does recognize that “further assessments might be necessary to determine which information is commercially sensitive and ought therefore to be protected.”

	But its optimistic attitude still seems to rather miss the point: “Changes to legislation might not be necessary in most countries to achieve greater transparency.” Legislation is unlikely to deliver the transparency aspired to. As this column has observed in the past, industry-and many national authorities who benefit from confidential agreements-are resistant to the extensive transparency that more radical commentators are mulling. And drug firms are on the record as saying that if they are forced to disclose net prices, they will stop making agreements that involve discounts, and provide their products only at list prices.

	Similarly, pricing authorities who currently obtain discounts in return for confidentiality agreements say they will not be able to afford the acquisition of expensive medical treatments if they are available only at list prices. It is hard to see the legislation that-in Europe at any rate-could compel either side to enter into agreements that they were strongly opposed to.

	So despite the meticulous engagement of the OECD’s researchers, the black box of MEAs remains almost as hermetic and opaque as ever. Something more than an academic review may be needed to advance meaningful discussion on revealing its innermost secrets.

https://www.oecd-ilibrary.org/social-issues-migration-health/performance-based-managed-entry-agreements-for-new-medicines-in-oecd-countries-and-eu-member-states_6e5e4c0f-en

http://www.pharmexec.com/new-flare-europes-external-reference-pricing-debate

New OECD study doesn’t shed much light on the effectiveness of managed entry agreements for drug access.

Unlocking the Black Box of Pharma Pricing in Europe

	The changing of the guard at the head of the European Union has not gone smoothly, but most of the pieces were in place before the end of 2019, and for anyone with an interest in health or patients or pharmaceuticals in Europe, 2020 could turn out to be a happy new year. But no promises.

	The new European Commission swept-or, more accurately, trailed-belatedly into office at the beginning of December, behind its new boss, Ursula von der Leyen, herself a last-minute choice, and until only weeks ago Germany’s minister of defense. This at least relieved the new European Parliament of the burden of repeating its cumbersome approval process for the candidates for the top Commission jobs, and permitted it at last to turn to its own affairs for the first time since it was elected in May. The European Council, too, managed to appoint a new full-time president on schedule, with Belgium’s former prime minister Charles Michel taking over the organization of EU summits and strategy from Poland’s former prime minister Donald Tusk.

	So much for the top management-which shouldn’t need adjusting now for another five years. What does it mean for health and for patients and for pharmaceuticals? For a start, it means the possibility of some consistent policymaking with a longer-term vision, instead of the haphazard and short-term responses that have characterized much of the EU’s approach to health until now. And within each of the principal EU institutions, there is some evidence of greater attention being paid to health issues.

	The new Commission has identified health as an important policy area, and Stella Kyriakides, the new health commissioner, a Cypriot psychologist, has been tasked with implementing an ambitious agenda. Drug firm executives have been gratified to see that the first item is to “ensure Europe has the supply of affordable medicines to meet its needs,” and to “support the European pharmaceutical industry to ensure that it remains an innovator and world leader.”

	Other main tasks include “effective implementation of the new regulatory framework on medical devices,” making the most of “the potential of e-health to provide high-quality healthcare” and the creation of a “European Health Data Space,” which is intended to promote health-data exchange and support research, covering “treatments, medicines, medical devices, and outcomes.” The health commissioner will also be in charge of setting up “Europe’s Beating Cancer Plan” to improve cancer prevention and care-and with a close link to the research mission on cancer envisioned for the EU’s seven-year, €80-billion Horizon Europe R&D program now under development.

	“Europeans expect the peace of mind that comes with access to healthcare and protection against epidemics and diseases,” said Kyriakides. And she recognized that this requires, among other things, investment in new technologies.

	The parliament, freed from seemingly endless debates over who was sufficiently qualified to become a member of the new Commission, has picked up its work on health matters energetically. The health committee- now 

one of the largest of the parliament’s dozen or so panels-has been engaged in developing a “strategic approach to pharmaceuticals in the environment,” in asserting its control over the management of the European Medicines Agency (EMA), and reviewing the EU’s legislation on blood, tissues, and cells. And late at night in the parliament’s last plenary session of 2019, MEPs sealed their approach to an optimistic resolution on “enabling the digital transformation of health and care.”

	Meanwhile in the Council, work will resume in the light of a widely supported initiative to bring an integrated approach to health policy. Finland’s strenuous efforts in the second half of 2019, during its stint in the rotating presidency chair, led to the adoption of a strategy entitled “the economy of well-being.” Its chief architect described this as a plan which would, among other things, allow digitalization and new technologies to “create the ground for innovations and growing businesses, which will help to promote public health and the availability of new medicines.” At the beginning of this month, Croatia took over chairship of EU’s health council. As a small and new member state, it will be less ambitious than its predecessor, but it has, nonetheless, already identified “promoting lifelong healthcare” as one of the priorities it will pursue.

	Over at the EMA itself, which moves into its new permanent home in Amsterdam this month, there is palpable relief that despite the immense Brexit-induced disruption of being abruptly uprooted from its London home, it has been possible to maintain something like business as usual on the agencies core activities. And there is a reasonable expectation that many of its other activities, suspended over the last two years as a result of strained resources, can gradually resume as staff numbers return to normal and the agency settles back into routine.

	But despite these favorable winds, the voyage into the future may not be entirely smooth sailing. A major strategic challenge was highlighted at the December meeting of the health council, by Margaritis Schinas, the commission vice president, whom von der Leyen has put in charge of “promoting our European way of life,” and who will be Kyriakides’ direct superior. The EU, he remarked, accounts for only 8% of the world’s population and only 20% of its GDP-but it currently accounts for 50% of the entire spending around the world on social security. This was a reality that the EU would have to take into consideration as it developed its strategy for continued access to health and social services, he indicated, underlining its significance for developing policies that maximized prevention.

	The broad support for Finland’s efforts to create an integrated EU health policy have already been subjected to some conditionality over the details by many member countries’ governments, who have insisted on the immovable primacy of national sovereignty on health. The logjam persists in the Council over plans for closer cooperation among national and regional health technology assessment bodies. Drug shortages have shot to the top of the news agenda and the subject is now gaining priority as a policy issue-with the link frequently made, irrespective of the logic, with the ever-incendiary topic of drug prices.

	Health ministers have given their backing to the concept of a new structure to seek solutions-and these range from simpler mechanisms such as improved sharing of information to elaborate discussions of repatriating active ingredient manufacture to Europe. All the time, a steady background drum beat of concern over balancing innovative medicine provision with healthcare budgets threatens to burst into a cacophony of outrage, with patients and health payers chorusing their disappointments. AIM, one of Europe’s most influential mutual insurance organizations, has recently intensified its attacks on industry practice, leveling accusations of “opacity” over “astronomical” drug prices at a meeting in the European Parliament in December.

	The concerns over what are seen as unjustified drug prices are also leaking into competition policy-where the EU has much stronger powers than in health. As a minor reminder of the breadth of the EU’s continuing reach into healthcare, the European Commission-in its role as the EU’s competition authority-approved just before the holiday break the takeover by Danaher of the biopharma business of General Electric’s Healthcare Life Sciences division. Margrethe Vestager of Denmark, who is back in the new Commission in charge not only of competition policy but also of digital strategy, had expressed her concerns that the deal could lead to  reductions in competition and innovation, and increases in prices and product shortages.

	Her anxiety was assuaged only by Danaher’s commitment to divest itself of some of its activities in molecular characterization, microcarriers, and chromatography resins and hardware in China, the US, France, and the UK. This will, she said, “preserve effective competition in the supply of inputs to the bioprocessing industry-to the benefit of patients.”

	But her services have indicated that the Commission is prepared to deploy its formidable powers more widely, and specifically in relation to drug prices if there is suspicion of anticompetitive agreements or abuses of dominance related to pharmaceuticals.

What to make of new momentum in advancing health agenda.

A Happy New Year for European Pharma Policy?

	Are drug firms going to be forced to launch their products in even the smallest EU markets? For years now, the smaller countries in Europe-and there are many of them-have grumbled about not having access to the full range of medicines that are on the market elsewhere. Why, demand regulators and patients in Cyprus or Lithuania or Slovenia, should they not benefit from the same treatment possibilities as are enjoyed by Germany or France or other big countries? The arguments have become increasingly heated recently, and have fused questions of availability with questions of price in a high-octane political cocktail.

	Sometimes the absences are the result of not being able to afford the price the manufacturer seeks-many of Europe’s smaller countries are also its less wealthy countries (although Luxembourg offers a striking exception). Sometimes companies defer launching in countries with lower prices where such a move would risk their price being dragged down in other markets through the reference pricing system widely practiced in Europe.

	And sometimes the logistics of launching in a small market-which will usually require tailor-made packs in one of Europe’s multiple local languages-discourage launch. Overall, smaller countries routinely complain that manufacturers simply don’t take the trouble to market everywhere.

	Concern over this European patchwork quilt of availability has elevated the subject to strategic review by the European Commission-and added intensity has been brought by the current controversies raging over high-priced new medicines, and by the blame-game underway over the growing European problem of drug shortages.

	The basis for the Commission involvement is that products authorized through Europe’s central procedure via the European Medicines Agency (EMA) are subject to obligations over launch. The Commission’s aim is to arrive at a clearer definition, with a view to seeing if companies can be compelled to market their products in every EU country. So it has set up a working group to explore the subject, and commissioned a study by Ernst & Young (EY), which is now nearing completion.

	At the heart of the discussion are the provisions in the EU’s 2004 legislation (Regulation (EC) No 726/2004) 

covering market launch of centrally authorized products, and particularly its clauses on validity of marketing authorizations. This specifies that in general “a marketing authorization shall be valid for five years,” may be renewed after five years on the basis of an EMA reevaluation, and once renewed, “shall be valid for an unlimited period” unless safety issues are raised. At the time, this was something of a novelty: until then, manufacturers had been obliged to renew every authorization every five years.

	There are other conditions too, however-notably a “sunset clause.” An authorization which is not followed by the actual placing of the medicinal product for human use on the EU market within three years “shall cease to be valid,” says the legislation. The cessation of validity is automatic, with no particular decision or administrative action required. Similarly, even when a product has been placed on the market, if subsequently it is no longer actually present on the market for three consecutive years, the authorization shall also cease to be valid.

	But the precise scope of those obligations has never been fully defined. What is under debate now is whether the sunset clause can be invoked as a threat against companies who fail to market their products everywhere in the EU. The precise scope of the obligations to launch has never been fully defined, so the arguments turn on the grey areas in the legislation. Notably, agreeing just what placing a product on the market entails: whether a launch is just a part of the EU market qualifies, or if the entire EU market must be covered. And how many pack sizes or presentations must be available to meet the requirement?

	But the underlying intentions of the legislation are also in question: just what did EU legislators want to achieve with the rules they put in place years ago? The initial logic behind the provision, according to the Commission’s working group, is that the sunset clause was a 

for granting manufacturers virtually unlimited validity on their authorizations. It was a device to prevent the authorities suffering the administrative burden of maintaining authorizations for products not actually marketed.

	The sunset clause gave the authorities a sort of get-out clause to intervene where manufacturers were not making use of their unlimited authorizations. But the working group also admits that there might be additional reasons, which play into the separate debates over pricing and over shortages. Was the motive of legislators also, suggests the working group, to encourage companies to place a product on the market in a timely manner after the authorization, or to avoid long interruptions of supply.

	That’s complex enough as a series of discussions. But in a classic example of the complexities of EU lawmaking, a further wrinkle was introduced when the legislation was being unveiled, nearly two decades ago. In effect, late changes to the rules provided something like a get-out clause for companies from the get-out clause for the authorities. The European Parliament and national ministers in the EU Council demanded changes that would allow the authorities to ignore their obligation to cancel unused authorizations “in exceptional circumstances and on public health grounds.” The circumstances can be, for instance, a product intended to treat a sporadic disease, which will not be sold until that disease breaks out; or leeway might be allowed to smaller firms that may need more time to find a partner for marketing a new product. As a result, authorities’ absolute power to invalidate an authorization for failure to launch was curtailed. This meant that companies could be free-with the blessing of the authorities-to persist with an authorization even without any launch.

	After studying the situation on the ground and working through all the permutations of the legislation in practice, the working group has reached an interim conclusion: there is “a flexible approach toward marketing authorization holders, who are in principle allowed to launch and cease marketing as they see fit.”

	This doesn’t mean that the law is entirely neglected. Companies are obliged to inform EMA of the actual marketing of an authorized product, and the agency has put in place a system to monitor the marketing status of centrally authorized medicinal products. When a three consecutive-year period without marketing has elapsed, EMA notifies the Commission accordingly.

	Some of the terms used in the sunset clause have-in distinct cases-been clarified by court interpretations, including what constitutes placing a product on the market. But because the clause itself has so far not been subject to an authoritative interpretation by the EU courts, which are the ultimate arbiters of EU legislation, there is still plenty of margin for debate about its power and its limits.

	The presumption so far has been that the EU market is served as soon as and as long as the product is placed on the market somewhere in the EU, which allows manufacturers to choose where and when they launch their products. But the working group has highlighted the need to see this the broader context of the legislation’s objectives-and it cites the Commission’s identification as the top priority of “a high level of public health protection, notably by making safe, innovative products available to patients as quickly as possible.” It goes on: “The flexibility provided should be read in the light of the general objectives of the regulation and cannot lead to situations which go against those objectives…assuring a high level of health protection (which includes availability).”

	The impending EY report is keenly awaited, as it is likely to influence the working group’s thinking on how the current rules should be changed.

European Commission working group is looking closely at marketing obligations for centrally authorized products.

Author | Reflector

Articles

Blood Feud Divides Europe Over Plasma Shortfalls

Unlocking the Black Box of Pharma Pricing in Europe

A Happy New Year for European Pharma Policy?

Who’s Going to Choose Where to Launch a Drug?