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Pharma companies are concerned they may have to postpone plans for the commercialization of new combination products because of delays in obtaining marketing authorizations because of a lack of clarity about approval rules.
Pharmaceutical companies in Europe involved in the development of integral drug-device combinations (DDCs) were left on tenterhooks in August 2018 after the European Medicines Agency (EMA) revealed it would be cutting back work on guidelines on the authorization of certain unspecified groups of medicines (1). The announcement raised fears among companies that they would have to postpone plans for the commercialization of new combination products because of delays in obtaining marketing authorizations due to a lack of clarity about approval rules.
Developers of integral DDCs, which range from pre-filled syringes to complex electro-mechanical devices, have been waiting for a crucial guideline for more than a year on procedures for the assessment of device components in combination products under the European Union’s Medical Devices Regulation (MDR), which is replacing the 1993 Medical Devices Directive (MDD).
When it comes into effect in May 2020, the MDR will require, for the first time, integral DDCs to have their drug device components evaluated by specialist organizations, called notified bodies (NBs), for certifying device standards. The legislation contains large gaps in information about the process for the assessment of DDCs by NBs, which can be filled only by an EMA guideline. The agency started preparing a draft of the guideline in early 2017.
“There is currently no understanding of how the process to support this new requirement (for an NB opinion on a device) would work,” stated the Brussels-based European Biopharmaceutical Enterprises (EBE) in a reflection paper published in July 2018 (2). “In turn, concerns are being raised that this [information gap] could impact approval timelines and unduly delay important medicines getting to market.”
Biopharmaceuticals producers, of which EBE is a leading European representative, are particularly worried about problems with approvals of combination products under MDR because of the growing number of biologicals, such as monoclonal antibodies (mAbs), being delivered through DDCs.
The views expressed by EBE, which is a branch of the European Federation of Pharmaceutical Industries and Associations (EFPIA), are also being echoed by other associations, such as Medicines for Europe, representing generic-drug producers, and MedTech Europe, the medical device manufacturers’ association.
Unfortunately for the pharma and medical device sectors anxious about uncertainties regarding requirements under the MDR, EMA is facing a period of upheaval due to the United Kingdom’s departure from the European Union in March 2019. The agency is currently having to complete the relocation of its headquarters from London to Amsterdam, Netherlands, over the next five months and also cope with an expected 35% reduction of staff. As a result, it is temporarily reducing its activities, including the drawing up of guidelines, between November 2018 and June next year.
The agency, however, disclosed in early October 2018 that it would carry on preparing the guideline on MDR, as well as a number of other guidelines on issues such as pharmacovigilance, anticancer medicinal products, and GMP guidance on manufacture of sterile products (3).
“EMA is aware of the concerns raised by the industry that came with the introduction of the new MDR, and in particular with Article 117 (requiring an NB opinion on combination products),” an agency spokesperson told Pharmaceutical Technology Europe.
“Work on seven guidelines which address either an urgent public/animal health need or are necessary to support and facilitate preparation for Brexit or the implementation of new or revised legislation will continue beyond 1 Nov. 2018. This includes the guideline on quality requirements of medicinal products containing a device component for delivery or use of the medical product.”
There have been other signs that the regulatory authorities are increasing their efforts to eliminate uncertainties on MDR. EMA now has a dedicated task force on MDR implementation as it affects the agency’s responsibilities for the centralized licensing of medicines, including DDCs, in the EU. There have also been informal talks on MDR between industry representatives and officials of the European Commission, the EU executive that has overall responsibility for the regulation’s implementation.
“We are still hoping to make more progress than this,” Barbara Freischem, EBE’s executive director, told Pharmaceutical Technology Europe.
Other obstacles remain once the draft of the EMA guideline has been completed, possibly by the end of this year. The draft has to go through a consultation process with stakeholders and other interested parties, whose comments will have to be considered when the guideline is finalized, probably well into 2019, two years after the adoption of MDR.
It is unclear what impact the guideline will have on national agencies or competent authorities (CAs) in EU member states, which approve combination products in their own markets, and to what degree of urgency they will be moved forward with the implementation of MDR.
Competent Authorities for Medical Devices (CAMD)-an association representing national medical device licensing agencies, many of whom also approve medicines-has given a “low” priority to guidance for combination products on the “appropriate level of interaction with relevant authorities” (4).
Industry believes that there needs to be a clear relationship between regulatory authorities, NBs, and combination product manufacturers for the approval procedure to work properly.
Most of the more than 30 objectives listed in a CAMD roadmap, which also covers companion diagnostics, have been allocated a “medium” or “high” priority.
There have also been delays in an EU-wide procedure for raising the efficiency of NBs by requiring that each one be certified according to new, tougher standards. This process is likely to result in fewer notified bodies being accredited to do MDR assessment work, particularly on DDCs and other combination products.
“We don’t know whether there will be sufficient NBs and whether those that are available will have the capability to evaluate combination products like DDCs,” said Freischem.
Accredited NBs will have to have been designated to conduct conformity assessments on drug device combinations. DDC manufacturers will then be free to choose one of these designated notified bodies to evaluate their products.
The EBE has suggested that the process of NB evaluation could be made easier for both the medicine and device manufacturers, as well as the notified bodies, by basing the EMA guideline on an already existing guideline, issued by the agency in 2011 (5). This guideline is for combination products comprising advanced therapy medicinal products (ATMPs), such as gene and cell therapies.
The seven-year-old guideline would provide, according to EBE, a framework for a tiered, risk-based approach within MDR to combination products. Those using existing, well-known technologies might not, for example, be required to undertake an NB assessment. More complex and innovative products may not only need an NB evaluation but also an opinion of a group of experts.
Swissmedic, the medicines and devices licensing agency of Switzerland, a non-EU country that aligns its regulations with those of the EU, has already been preparing its own MDR-compliant legislation, which allows for an evaluation by experts.
With integral complex and innovative combination products, the suitability of the device component would be assessed by the Swiss equivalent of an NB or “some other type of expert opinion,” according to the agency (6).
EBE stresses the need for NBs to be clear about their responsibilities in the evaluation of DDCs, so the EMA guideline must be unambiguous about what data have to be provided by the medicine manufacturer. This requirement is particularly the case with information related to the compatibility of the drug to features of device components, especially materials.
The complications in drawing up a coherent procedure for assessing DDCs and other combination products under MDR are being blamed on the usual teething problems with new legislation but also on the fragmented nature of the EU’s system for certifying device component quality standards.
“You tend to get difficulties with gaps in information with most new legislation,” explains Freischem. “But with MDR, there is the added complexity of having a lot more NBs than there are competent authorities for approving medicines.”
Also, the MDR quality and related rules for devices have become more numerous and stricter. In an annex to the regulation, they stretch to more than 20 sections with multiple sub-sections.
DDCs are a fast-growing market with rapid advances in technologies that are inevitably causing regulatory difficulties when medicines and devices are covered by different quality standards and approaches.
While the quality of medicines is governed by good manufacturing practice (GMP) rules, quality of medical devices is mainly controlled by standards of the International Organization for Standardization (ISO) and sector bodies such as the International Electrotechnical Commission (IEC), which lays down standards for electrical and electronic products.
Digitalized or electrical devices often have to be assessed against several different standards. An electro-mechanical infuser, for example, can be covered by as many as six different ISO and IEC standards.
Bringing together different regulatory systems for approving as medicines DDCs and other increasingly complex combination products is likely to become a major challenge for regulatory authorities for some time to come.
1. EMA, “Brexit Preparedness: EMA to Further Temporarily Scale Back and Suspend Activities,’’ Press Release, 1 August 2018.
2. European Biopharmaceutical Enterprises (EBE) and European Federation of Pharmaceutical Industries and Associations (EFPIA), “An Industry Perspective on Article 117 of the EU Medical Devices Regulation and Impact on How Medicines are Assessed,’’ Reflection Paper (Brussels, 12 July 2018).
3. EMA, “Update on EMA’s Brexit Preparedness,’’ Press Release, 9 October 2018.
4. Competent Authorities for Medical Devices (CAMD), “CAMD Implementation Taskforce: Medical Devices Regulation/In-vitro Diagnostics Regulation (MDR/IVDR) Roadmap,’’ (17 Nov.
5. EMA, Procedural Advice on the Evaluation of Combined Advanced Therapy Medicinal Products and the Consultation of Notified Bodies in Accordance with Article 9 of Regulation (EC) No. 1394/2007. EMA/354785/2010 (London, 11 Feb. 2011).
6. Swiss Agency for Therapeutic Products (Swissmedic), “Requirements and Information Relating to Combination Products (Medicinal Products With a Medical Device Component) in the Form Application for Authorisation/Variation, Human Medicinal Products,’’ Press Release, 10 July 2017.
Pharmaceutical Technology Europe
Vol. 30, No. 11
When referring to this article, please cite it as S. Milmo, "Guidelines on Integral Drug-Device Combinations," Pharmaceutical Technology Europe 30 (11) November 2018.