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The European Union has a challenging task ahead as it strives to harmonize regulations on advanced therapy medicinal products.
The European Medicines Agency is approving a growing number of advanced therapy medicinal products (ATMP) despite claims that their commercialization is being hampered by increasingly complex regulatory and standards requirements. The creation of ATMPs by a 2007 European Union regulation (1), backed by a specialist committee for advanced therapies (CAT) within EMA, aimed to boost development of medicines derived from progress in cellular and molecular biology.
Initially, the regulation seemed to have little impact on the number of advanced medicines on the market after the start of its implementation in early 2009. By mid-2013, there were only four marketing authorizations from 10 applications in the three ATMP categories of gene therapy, somatic cell therapy, and tissue engineering.
Over the past few years, however, there have been signs of a surge in ATMP development. The number of medicine applications recommended by CAT to be classified as advanced therapies rose by 26% in 2014 (2). In late 2014, EMA recommended for EU approval the first advanced therapy medicine containing stem cells. It is also the first drug for the treatment of moderate to severe limbal stem cell deficiency (LSCD), a rare eye condition due to physical or chemical burns to the eyes that can result in blindness.
At the same time, the quality, safety, and efficacy rules under existing and proposed EMA guidelines on ATMPs have been becoming more complex. One reason is that expanding knowledge about the new therapies has raised new concerns, particularly relating to issues regarding the quality of starting materials and drug substances. The regulators have gradually become more aware of the biological variability and intricacy of ATMPs. This tightening of standards seems to be deterring big pharmaceutical companies rather than small- and medium-sized enterprises (SMEs) from developing advanced therapy products.
In a 2014 report (3) on the application of the 2007 regulation, the European Commission, the Brussels-based EU executive, found that the majority of ATMP research was being done by small companies and entities. Approximately 70% of sponsors of ATMP clinical trials were SMEs or not-for-profit organizations, while large pharmaceutical companies accounted for less than 2%.
The report concluded that because there are “still many unknowns” with advanced therapies, “it is important to put in place adequate controls to prevent detrimental consequences for public health” (3). Nonetheless, it is also acknowledged that “too burdensome requirements” could have adverse consequences for public health because they could prevent the marketing of valid treatments for unmet medical needs.
One onerous requirement is the amount of data needed on starting materials, such as the source and history of cells, and their detailed characterization. In addition, a complete description, including source, characteristics, and testing details, of all materials used during the manufacture of products is needed. Some developers of ATMP products complain about the regulators making demands for data that existing analytical technologies cannot yet provide. There have also been complaints about EMA wanting unnecessary high levels of purity in cell-therapy treatments, especially those comprising mixtures of undifferentiated cells.
Another matter of contention has been EMA’s insistence that marketing authorization applicants for tissue-engineered products must demonstrate through pharmacokinetics the longevity or persistence of their medicines. “From the point of view of our members, pharmacokinetics does not include longevity, but resorption, distribution, and excretion of a drug,” Matthias Wilken, head of European drug regulatory affairs at the German Pharmaceutical Industry Association (BPI), told BioPharm International. “The requirement to demonstrate longevity might lead to extensive clinical studies that would be an undue burden to pharmaceutical entrepreneurs,” he explained.
Also in some cases with ATMPs, the regulators are seen as taking too much of a “generic” approach to advanced technologies and not making a strong enough distinction with conventional pharmaceuticals. “The assessors and members of EMA scientific committees often come from the field of conventional medicinal products,” said Wilken. “Initially, there was a lack of understanding of the peculiarities of ATMPs. But this [understanding] is getting better, as is shown, for example, by the fact that EMA, along with the Commission, is currently working on tailoring GMP requirements for ATMPs.”
The big regulatory differences between ATMPs and chemical-based pharmaceuticals is the greater emphasis needed with biological products on quality issues, mainly because with many of them, there are gaps in knowledge about ways of managing their risks. However, EMA has acknowledged the limitations of applying uniform rules to ATMPs by adopting a risk-based approach that allows the products to be assessed on a case-by-case basis.
The distinct approach needed for ATMPs has been highlighted by the latest EMA guidance (4) on advanced therapies, which covers the quality, preclinical, and clinical aspects of gene therapy. The draft guideline (4) on gene therapy was issued in May 2015 for a period of public consultation ending in August. It replaces a guidance note (5) published in the early phase of gene-therapy development in 2001.
Since the 2007 ATMP regulation was implemented, EMA has had to deal with three applications for gene-therapy authorizations, only one of which has so far been successful. “[From a quality perspective], there were no major changes or inconsistencies in the 2001 guideline that required an immediate revision,” an EMA spokesman informed BioPharm International. “However, some updates were necessary, for example, to reflect novel methodologies for testing and characterization, and also to ensure cross references to new legislation and guidelines that were developed separately.”
Quality and safety
Also, the format of the sections on quality and manufacturing aspects in the revised guideline has been changed to follow that in the harmonized Common Technical Document (CTD) for marketing authorization application dossiers, according to EMA. “This is expected to be helpful for the small developers of gene-therapy products when compiling their dossiers,” said the EMA spokesman. As a result, 40% of the 42-page draft guideline covers quality matters, 30% non-clinical issues, many of which relate to assessing risks linked to quality management, and only 10–15% to clinical development.
A lot of the obligations in the guideline requirements relate to the quality of the components in the vectors or delivery systems of the products. Details of the quality of all starting materials and their sources have to be provided, including virus seed as well as mammalian and bacterial cell banks. All raw materials used during manufacture have to be tested and characterized.
Partly due to the detailed EU quality and safety requirements for advanced therapies, companies developing ATMPs are critical of an exemption to EU rules granted to hospitals involved in R&D and the manufacture of the products. Hospital-based research and production in the sector are increasing rather than contracting in Europe. This trend is mainly because some EU states are using these hospitals as ATMS development centers at the core of national regenerative medicine programs.
The United Kingdom, which is seeking global leadership in the sector has, for example, a network of cell therapy centers of excellence based in leading hospitals. “The establishment [of these centers] is essential if we are to build a concentrated critical mass of knowledge, skills, and therapeutic know-how,” according to a UK government-commissioned report on regenerative medicine (6).
Under the 2007 EU regulation on ATMPs, member states are allowed to give hospitals exemption from the legislation as long as the hospital’s advanced therapies are being provided on a “non-routine basis” to its own individual patients. Some organizations are calling for the “non-routine” provision, which is open to different interpretations, to be extended to cover products only when a fully validated, EU-approved advanced therapy alternative cannot be used.
“While the hospital exemption rule allows the early development and delivery of ATMPs that meet an otherwise unmet clinical need in a patient, the exemption should only be used to deliver a product if there is no licensed alternative, with proven efficacy and safety, available,” says Michael Werner, executive director of the US-based Alliance for Regenerative Medicines, a global advocacy group representing stakeholders in the ATMP sector.
Its European arm has been among the leading critics of criteria applied for the exemption, particularly those relating to manufacturing standards. Sceptics about the potential of exempted hospital-based development systems contend that they encourage the avoidance of the strict EU data requirements because the hospitals have to adhere only to national quality and safety standards, although these standards should be consistent with those at the EU level.
Even the European Commission in its report (3) on the impact of the ATMP regulations concedes that the exemption can enable hospital-based centres to have lower development costs than commercial ATMP organizations because of the advantages of being subject to less rigorous standards. A major objective behind the EU’s ATMP regulation was the introduction of harmonized standards across Europe. The way the hospital exemption is operating shows that there is still some distance to go before full harmonization is achieved.
1. EC 1394/2007 Regulation on advanced therapy medicinal products (Brussels, November 2007).
2. EMA, Annual Report 2014 (London, April 2015).
3. European Commission, Report in accordance with Article 25 of EC 1394/2007 on advanced therapy medicinal products (Brussels, March 2014).
4. EMA, Guideline on the quality, non-clinical and clinical aspects of gene therapy medicinal products–draft (London, March 2015).
5. EMEA, Note for guidance on the quality, preclinical and clinical aspects of gene therapy medicinal products (London, April 2001).
6. UK Department of Health, “Building on our own potential: a UK pathway for regenerative medicine,” Report of Regenerative Medicine Expert Group, March 24, 2015 (London).
About the Author
Sean Milmo is a freelance writer based in Essex, UK, email@example.com.
Article DetailsBioPharm International
Vol. 28, No. 7
When referring to this article, please cite it as S. Milmo, "Unravelling the Complexity of EU's ATMP Regulatory Framework," BioPharm International, 28 (7) 12–14 (2015).