Regulators and Drug Makers Call for Greater International Regulatory Alignment

On the opening day of the Medicines for Europe (MFE) 18th Regulatory and Scientific Affairs Conference, held January 31 to February 1 in London, United Kingdom, representatives of the generics and biosimilars industry and regulators gathered to discuss the opportunities and challenges posed by the globalization of medicine development and manufacture.

In his opening remarks, Marc-Alexander Mahl, MD, president of MFE and executive vice president of the business unit for generic drugs at Fresenius Kabi, highlighted the fact that the upcoming year will be a particularly challenging one in Europe.

“Regulation in 2019 will be heavily impacted by politics,” he said, noting that not only will the upcoming withdrawal of the United Kingdom from the European Union be a particularly “massive project” to address, elections in Europe will result in a new Commission in the autumn. As they face down these challenges, stakeholders must keep in mind the mission of providing European patients with access to medicines and collaborate to optimize regulatory activity in order to achieve that mission.

In a panel discussion moderated by Adrien van den Hoven, director general of MFE, representatives of industry and regulatory bodies echoed Mahl’s calls for greater alignment.

David Gaugh, senior vice president of sciences and regulatory affairs of the US generics and biosimilars trade group the Association for Accessible Medicines, said that, from the American perspective, globalization provides opportunities to increase the efficient use of limited resources, particularly be reducing regulatory burden through reduction in the number of duplicative clinical studies for products.

According to Gaugh, reducing such studies could help companies to enter more markets with their products; the current need to replicate work for multiple territories can force the decision to abandon some markets because of the cost and work involved.

There are challenges to alignment, however; for example, FDA representatives have been clear, said Gaugh, that the Hatch-Waxman Act will not allow for a global comparator product for small-molecule generics. “We think there are ways around that,” he noted, saying that new legislation would be one way to address the problem.

Gaugh praised FDA Commissioner, Scott Gottlieb, MD, for his efforts to improve alignment, and for looking into the potential for global comparator products. However, he added that, while there have been past achievements in terms of regulatory alignment, such as EU and US mutual recognition of good manufacturing practice inspections, these achievements have been very slow, and he urged faster efforts.

Mahl, too, indicated that he believes that there are opportunities for greater convergence of regulatory standards, particularly between the European Union and the United States—such as establishment of similar standards for package leaflets—that could benefit all stakeholders and make the process of bringing a product to market less complex.

“Measures which just burden the manufacturing process without safety gains” are not desirable, Mahl said, adding that “what we need in generics and biosimilars is planning safety,” as uncertainty drives up costs and undercuts the promise of these drugs.

Deus Mubangizi, DrPh, group lead of inspection services on the World Health Organization (WHO)’s prequalification team, agreed about the need to reduce the number of repetitive studies conducted for generics and biosimilars, which he said may not always be science-based and may even border on being unethical.

“We approach this issue from the concept that safe, efficacious, good-quality, and affordable medicines should be available for everyone, not just a few,” he said, and explained that using a global reference product, which could facilitate global approval, is one key way to promote access.

However, he said, “We are all complaining about access … but we see a lack of exchange of information.” In his view, truly globalizing development will take greater data sharing from both regulators and companies. In the meantime, said Mubangizi, the WHO asks, “what are the work-arounds?” In its work on prequalification of reference products, while the FDA may not be able to share its data, the WHO has no restrictions on preparing reports created on FDA-approved products and sharing them with other WHO member nations to help facilitate the exchange of information.

Susanne Keitel, PhD, director of European Directorate for the Quality of Medicines, agreed that divergence of regulatory requirements “clearly is an issue,” and highlighted the need for harmonization. However, said Keitel, it is also time to question the current system employed in Europe: “We have to use the opportunity for globalization to lean back and look at our own system,” she said, to see if it is still appropriate for its purpose. In her view, it is time to reflect on whether what has evolved over time is adequate to today’s challenges.

Among Keitel’s other concerns regarding an increasingly globalized industry are maintaining the quality and reliability of a fragmented supply chain, especially as payers feel price pressures. It is becoming more important, she said, to invite payers into discussions about the price of drugs, because while payers feel price pressure to drive down costs as much as they can, “there are limits to the cost of medicines. We need to ensure quality.”

Also calling for reflection on the state of current regulation was Peter Bachmann, PhD, of Germany’s Federal Institute for Drugs and Medical Devices. Bachmann called current methods to show bioequivalence “medieval science,” and called for a rethinking of approaches to demonstrating equivalence that could potentially solve the problem of demonstrating the feasibility of generic to generic substitution of drugs, as happens in real-world practice.

Speaking from the pharma perspective Neeraj Sharma, MBA, head of Sun Pharma’s generics business in western Europe, said that, while “globalization” is not exactly a popular term in the current European political climate, he sees it as key to solving some key challenges; biosimilars made in Asia, he said, have had a crucial role increasing patient access to biologics, and increasing production capacity outside of Europe, especially for oncology and antimicrobial products, could alleviate drug shortages. Flexible supply chains, he added, could allow for quick, multicountry sourcing in response to fluctuations in demand or interruptions in supply.

Also speaking from the drug maker’s point of view was Frank van Strien, vice president of regulatory affairs at Synthon. According to van Strien, companies face significant challenges related to the kinds of studies they must undertake in different regulatory territories. He pointed to a generic glatiramer acetate (copaxone) product for which his company was required to undertake a phase 3 trial, but was advised not to submit information from the trial to the FDA. He called on regulators to develop greater reliance on other competent authorities as a way to reduce unnecessary testing of such complex products.

Finally, Guido Rasi, MD, executive director of the European Medicines Agency, agreed with the need to foster global development and availability of medicines, agreeing that regulators have a duty to keep pace with science, technology, and methodology. Yet he also underscored the need for regulators to involve other stakeholders in adapting to ongoing changes that affect medicines. Rosi called on regulators to start having more conversation with payers, providers, and especially patients, moving beyond considering just the views of health technology assessment bodies.

In summing up where Europe stands with its regulatory landscape, Rosi said: “bigger opportunity, bigger problems.”