SFL Newsletter - July 2017

One year EMA’s PRIME scheme; progress towards meeting unmet patient needs

To accelerate the development of medicines that target an unmet medical need, the widely publicized EMA PRIority MEdicines (PRIME) scheme was launched in April 2016 and represents a step towards a more influential and pro-active role for the EMA.

PRIME was developed in line with the European Commission’s priorities and EMA’s 2020 strategy. It is a voluntary scheme based on enhanced interaction with developers of promising medicines and is somewhat based on the FDA Priority Review scheme, which was launched in 2007. Early dialogue and support of development plans are intended to bring these medicines to patients earlier, without compromising high evaluation standards or patient safety.

In a workshop held in May 2017, EMA gathered relevant stakeholders to reflect on the first 12 months of the scheme’s implementation. In the first year, 96 PRIME eligibility assessments were processed. The requests covered a wide range of product types and therapeutic areas. Of the 20 eligible products, 12 were advanced therapies, 5 chemical-based medicines, 2 biologics and 1 vaccine. 12 of the granted requests represent orphan medicines and 1 in 3 eligible products targets a disease for which no treatment exists. The main reasons for denial of requests were insufficiently robust data (in 70% of cases), inadequate justification of therapeutic advantage (40%) and development of the therapy already being too far advanced for early engagement (20%).

Regarding therapeutic areas, most PRIME-eligible medicines are developed for oncology and hematologic diseases, followed by medicines used in neurology, gastroenterology, immunology, endocrinology and psychiatry. The nature of unmet needs dictates that PRIME is usually more relevant for rare diseases and neglected tropical diseases. EMA considers these figures as proof of the PRIME concept and will continue apace.

The procedure particularly benefits SMEs and applicants from the academic sector. Compared to big pharma companies, they can apply for PRIME at an earlier stage of development and request a fee waiver for scientific advice.

The experienced team at SFL can assist you in both the preparation of PRIME eligibility assessments and in performing a gap analysis to reduce the risk of rejection.

MDR/IVDR: a new era for medical technologies

The new regulations on medical devices (MDR) and in vitro diagnostic medical devices (IVDR) introduce new classification rules and extension of concepts, creating a binding legal Regulation on medical technology products for the first time. The Regulations took ten years of fraught political process to adopt, with the result being highly complex measures to be implemented.

In the MDR, the definition of “medical device” now includes certain devices with no intended medical purpose and devices manufactured utilizing non-viable tissues/cells of human origin. In addition, classification rules are explicitly formulated for: nanomaterials, medicinal products administered via inhalation, substance-based products and active therapeutic devices with a diagnostic function. The scope of the IVDR has also grown, and now covers companion diagnostics.

The MDR & IVDR will have a significant impact on the industry, notably due to:

  • The mandatory appointment of a person responsible for regulatory compliance, in each company
  • Increasing number of audits, as a responsibility of notified bodies (NBs), have been enhanced (e.g. one audit per year mandatory for certain classes of devices)
  • Unique Device Identifier to be applied on alldevices
  • A significantly higher bar for pre- and post-market data, especially for high risk class devices and implants
  • Potential delays in the conformity assessment procedure, where involvement of expert panels is required
  • Increased obligations pertinent to post-market surveillance, especially for higher risk devices whose manufacturers will need to prepare periodic safety update reports

NBs will have increased responsibilities towards all economic operators (manufacturer, authorized representative, importer, distributor). A re-certification procedure is imposed for NBs, as well as for all devices; since there is no “grandfathering” rule, it is highly likely that many NBs will not be re-certified. If your NB is not re-certified, the certificates they issued will not be valid anymore and, as a manufacturer, you have to contract another NB.

For the MDR and IVDR, product manufacturers will need to comply with the new Regulations by May 2020 and May 2022, respectively. Certificates issued by NBs under the current legislation during the transition period will continue to be valid until maximum 2024. However, requirements in the MDR and IVDR, related to post-market surveillance, market surveillance, vigilance, registration of economic operators and of devices, shall apply as of the application date (namely 2020 and 2022, respectively).

There are many emerging and critical needs for manufacturers with the new MDR/IVDR. SFL can assist you with customized training on the Regulations and provide strategic advice on developing your products in compliance with the new requirements.

Head of Drug Safety & Pharmacovigilance joins SFL

Dr. Conxita Barajas-Diaz has joined SFL as Head of Drug Safety and Pharmacovigilance. Dr. Barajas-Diaz brings many years of experience in drug safety, having worked on all functional levels with both European and US pharmaceutical companies and in consultancy. She is a highly experienced EU Qualified Person for Pharmacovigilance (EU QPPV) for medicinal products and has been involved in the oversight of vigilance activities for medical devices and advanced therapy medicinal products.

Dr. Barajas-Diaz is an associate professor at Barcelona University and University of Alcalá in Madrid, where she initiated postgraduate studies in Pharmacovigilance (PV) and is a coordinator of seminars in PV for the pharmaceutical industry. Together with the Spanish Health Authorities, she participates in elaboration of Good Pharmacovigilance Practices for the pharmaceutical industry.

Dr. Barajas-Diaz will support SFL clients with their PV requirements, including acting as EU QPPV and PV auditor, and lead the SFL internal PV System. She will be providing expertise and support in a range of PV topics, including benefit/risk assessments, risk management planning and mitigation, signal detection and training. Along with the multidisciplinary SFL team, the appointment of Dr. Barajas-Diaz fosters SFL’s expertise in strategic management, the writing of periodic evaluation reports (PBRERs), medical reviews, audits and quality topics in PV.

For assistance on projects including drug safety and PV topics, please contact the SFL team.

SFL opens new affiliate in Vienna, Austria

SFL is pleased to announce the creation of a new company SFL Regulatory Services GmbH in Vienna, Austria. The Vienna office has been established in order to continue and expand SFL’s EU activities and interactions with the EMA. SFL’s already established UK entity will continue to serve as a future contact point to the MHRA. The SFL team will continue supporting clients from offices in Basel, Barcelona, Brussels, London and Vienna.

EMA’s new pediatric PK guideline – concept paper open for public consultation

The EMA guideline on the role of pharmacokinetic (PK) studies in pediatric drug development has been in force since 2007, when the Pediatric Regulation was implemented. The goal of this guideline is to promote a more effective use of medicines in pediatric patients by assisting applicants in the development of medicinal products for the pediatric population, particularly for very young patients. During the last decade, many applications for pediatric indications have been submitted to the EMA and the national regulatory agencies. Numerous Pediatric Investigation Plans (PIPs) have been approved under this procedure. Based on the wealth of information and experience gathered through the procedure, and along with scientific developments in the last decade, a revision of the pediatric PK guideline has been proposed by EMA.

The revision will mainly target optimization of the study design and use of current PK modeling methods to support pediatric drug development. Due to the difficulty of demonstrating efficacy and safety in pediatric patients in clinical studies, PK data obtained in adults needs to be presented and used in an optimal manner. The revision will, therefore, highlight the appropriate methods for scaling PK from adults to children and between different pediatric subpopulations. Further changes relate to dose finding and dose selection. Considerations on dosage adaptation, individualized dosing, pediatric age categories and simulation-based approaches to optimize study design are identified for update in the revision of the guideline.

The concept paper on revision of the guideline is currently open for public consultation, and the deadline for submission of comments is 31 July 2017. Following the receipt of comments and consolidation, the draft guideline itself will be released for 6 months external consultation in Q4 2018. Interested stakeholders affected by the revision include the pharmaceutical industry, regulatory agencies, pediatricians and other healthcare professionals, medical societies and academia. The revision will have a significant impact on applications for pediatric drug development and the design, conduct and analysis of studies in PIP proposals.

To stay on top of the latest guideline revisions and for assistance in the development and preparation of PIP submissions, contact the SFL team.

RDAF: Swiss Invalidity Insurance (IV/AI) and rare diseases

Industry stakeholders, patient organizations, public health authorities and medical professionals from the field of rare diseases met at the Rare Disease Action Forum’s (RDAF) multi-stakeholder meeting in May. They discussed access to therapies for children and young people with rare diseases, and the Swiss Federal Council’s proposal for revision of the Swiss Invalidity Insurance (IV/AI) framework.

The proposed revision of IV/AI was presented from the perspective of patient organizations, with a focus on relevant aspects for children with rare diseases. One of the issues discussed included the process to update the list of congenital defects (GGL). This list is said to result in some shortfalls, notably when it comes to the procedure of inclusion or exclusion of a congenital defect.

Participants were also updated on the Swiss National Concept for rare diseases, whose four implementation pillars were said to be progressing well. Notably, it was mentioned that a Swiss structure for the coordination of rare diseases (KOSEK) would be set up this year, which was done on 22 June 2017. In addition, the topic of Swiss participation in the EU European Reference Networks (ERN) for rare diseases, which were launched in March 2017, was discussed.

Participants were presented with the view of a hospital’s tariff management department, where the billing of healthcare services provided to address rare conditions can be challenging. Finally, two university professors and medical doctors presented their experience in treating patients with rare diseases, under both the reimbursement scheme of the IV/AI and under health insurance.

The purpose of the RDAF is to serve as a multi-stakeholder platform to exchange ideas and define actions on how to raise awareness of rare disease and improve access to innovative therapies for patients with rare diseases in Switzerland. If you are interested to become member of RDAF please contact its secretariat, which is run by SFL.

Formal Brexit negotiations finally underway but uncertainty for medtech and pharma industries remains

Formal Brexit negotiations between the UK and the EU started on 19 June, yet the veil of uncertainty brought upon the medtech and pharma industries will remain for as long as it takes to reach a final agreement.

The EU27 agreed its negotiation priorities unanimously, and within a matter of minutes, on 29 April 2017. Among other aspects, the directive for the EU’s negotiation emphasized the priority of safeguarding rights of EU and UK citizens and settling the so-called Divorce Bill before further negotiations concerning trade can begin. In addition to the time lost for the UK general election, this agreed sequence of events puts negotiations on a knife edge by delaying discussion of future relations and potential recognition of common standards. For the healthcare industry, the undetermined period of time before negotiations on trade and product legislation can start is highly concerning, as it postpones discussion of outcomes for when the UK finally leaves the EU.

The EMA is also preparing for Brexit and, together with national regulatory agencies, agreed on distributing the workload efficiently to ensure a smooth transition. Much, in fact, will depend on the EMA’s relocation process and the extent to which it disrupts operation. The Council set the selection criteria for the new home of the agency, and the final decision is said to be scheduled for November 2017.

In a Q&A published on 2 May 2017, the EMA warned companies that many activities currently based in the UK may need to be moved to EU territory. It said that the marketing authorization holders, orphan designation holders, the Qualified Person for pharmacovigilance, and the batch release site should ideally be all based in an EU country. One key question that will be addressed during the Brexit negotiations is whether industry players will need to undergo two different procedures to obtain an approval in the EU and the UK to put a product on both markets. There do not seem to be compelling arguments for the UK to develop an independent approval system, but it is unclear whether the government can commit to implementing all amendments to EU legislation in future, and on time.

The future of the UK-based medical device industry and Notified Bodies (NBs) operations are also subject to uncertainty. Access to the single market for UK medical device companies cannot be taken for granted, as it will depend on the outcome of the negotiations. In the worst-case scenario, companies may be forced to comply with two different legislations and have two NBs in order to market their products in the EU and UK, and UK based NBs would need to have a branch in the EU in order to certify products for the single market.

The SFL team is ready to support you to ensure the continuity of your operations during this challenging period.

EU chemicals agency decides that bisphenol A (BPA) is a hormone disruptor

The European Chemicals Agency (ECHA), the body responsible for implementing the REACH Regulation restricting use of hazardous chemicals, decided on 16 June that bisphenol A (BPA), widely used in the medical device sector, is an endocrine disruptor.

With the addition of BPA to its candidate list of Substances of Very High Concern (SVHC), the substance itself and products containing it will be further restricted. In January of this year, BPA was already added to the list for reason of reproductive toxicity. BPA is clearly an area of concern for ECHA and the member state committee, especially France which proposed it for consideration.

While the most notable concerns of Green groups and environmental scientists are around use of BPA in food and beverage containers, which is a non-essential use, it will also impact critical medical devices where BPA may be fundamental to the performance of the device.

The inclusion of a substance in the candidate SVHC list creates legal obligations to companies manufacturing, importing or using such substances.

The Medtech & Pharma Platform 2017; building bridges between stakeholders in life sciences

The annual meeting of the Medtech & Pharma Platform aims to create bridges between key stakeholders from the life sciences sector and to foster greater cooperation between the medtech and pharma industries. This year’s Medtech & Pharma platform meeting will take place in Basel on 26 and 27 October.

In addition to its exhibition and networking opportunities, the event offers a conference with high level speakers on topics including: global regulatory trends, recent technology developments and approaches facilitating access, experience design, affordability of medical products in emerging markets, as well as connectivity and management of healthcare data.

Speakers at this year’s Platform include Mr. Athos Gianella-Borradori (Chugai), Ms. Patricia Mayer (IPM Global), and Mr. Adrian von Muralt (Novartis)

For the full program, and to register for attendance, please visit the Medtech & Pharma Platform website at www.medtech-pharma.com

SFL Newsletter - March 2017
International Rare Disease Day in Switzerland; “Collaboration is crucial!”

On 4 March 2017, ProRaris and Lausanne’s hospital center (CHUV) joined forces to organize the 7th International Rare Disease Day in Switzerland. Rare Disease Day offers an important opportunity to address some of the main challenges currently limiting the effective management of rare diseases: lack of awareness and prioritization.

The event brought together patients, their relatives and experts in public health, scientific research and the health industry to discuss the importance of reference centers for provision of specialized diagnosis and care. With SFL acting as the secretariat of the RDAF (Rare Disease Action Forum), a SFL representative attended the event.

Speakers Prof. Jean-Blaise Wasserfallen, medical director of CHUV and Anne-Francoise Auberson, president of ProRaris, outlined major developments and accomplishments in Switzerland in the last year. Both emphasized the need for further initiatives related to the rare disease environment. In line with the meeting’s focus, Prof. Wasserfallen highlighted the importance of interdisciplinary and interinstitutional collaboration.

Presentations focused on four collaborative projects, which served as examples of successful multi-stakeholder approaches: an internet portal and helpline (Portail Romand), Reference Center for Osteogenesis Imperfecta (SVOI), the Rheumatology Department for children and the Reference Center for muscle diseases at CHUV.

Round tables were held to discuss specific challenges that the rare disease patient community faces. The first round table of the day was dedicated to the “bench to bedside” loop for orphan drugs, and highlighted the roles of different stakeholders in the process. An interesting discussion reflected on the experiences of patients, the pharmaceutical industry and the Swiss public health institution. It was concluded that further steps in accelerating access to rare disease treatments require closer integration and collaboration of all interest groups.

The topic of the second panel discussion was the relationship between rare disease patients, industry and health insurance providers. It underlined the need for holistic and homogenous procedures for rare disease practices in Switzerland. In the last section of the conference, an update on the status of the national concept for rare diseases was given by Ms. Esther Neiditsch of the Federal Office of Public Health and Agnes Nienhaus of medical universities’ association Unimedsuisse. The latter association is responsible for the development of a National Coordination Platform for Rare diseases.

Overall, the discussions at the 7th International Rare Disease Day encouraged all stakeholders to engage and collaborate in creating incentives to improve diagnosis, provision of care, and development of new medicines and technologies.

The EU In-Vitro Diagnostic Regulation – eventually adoption is near

The In Vitro Diagnostic Regulation (IVDR) moved closer to its final adoption during March. Given that the European Commission published its original proposal in September 2012, the IVDR (along with the Medical Devices Regulation [MDR]) has been one of the longest running legislative procedures in the history of the European Union.

The latest version of the legislation was published by the Council of the European Union at the end of February 2017. This text, legally consistent and fully translated into all EU languages, was in preparation for the last six months.

Following publication, the Council voted to formally approve the text on 7 March 2017. The European Parliament’s Environment, Health and Food Safety Committee voted to adopt the IVDR text itself on 21 March. Now, just the formality of the plenary vote of the whole Parliament in 4 April remains to enact the IVDR.

In terms of implementation timelines, there are still some steps to go for the legislation. The IVDR is expected to be published in the Official Journal of the European Union in May 2017. Consequently, the new Regulation could enter into force in June 2017, together with the MDR. Five years after entry into force (i.e. June 2022), most provisions of the IVDR will enter into application. The MDR will be fully applicable by June 2020 following a three-year transition period.

Compared to the June 2016 version, there are no major changes concerning the likely final text of the IVDR. The regulatory assessment process remains largely the same as proposed in 2016, as are the rights and responsibilities of the key regulatory and market stakeholders. Nevertheless, there are a few changes that IVD manufacturers should be aware of.

Compared to the 2016 version, these changes mainly concern the transitional period and provisions. Starting from the date of application, the requirements in the IVDR will apply to all devices on the market or put into service. Even though manufacturers can use the transitional period to place devices on the market according to the old In Vitro Diagnostic Directive (IVDD), they will need to comply with some requirements of the new IVDR from when the IVDR becomes applicable.

Other minor changes comprise more specific definitions and technical clarifications, such as timelines for publishing documents on the different databases.

To further clarify and specify some details in the regulation and make it work in practice, a series of delegated and implementing acts is expected to be adopted by the Commission in the coming years. In such a detailed legislation, it will be important to follow developments closely even after the Regulation enters into application.  

The SFL team can help you to follow the next steps in the adoption and implementation of the IVDR and MDR and assess the impact on your products and development plan.

ECJ Decision on TÜV Rheinland liability for defective certified products

In the context of defective[1] breast implants produced by a French company, which later went bankrupt and could no longer be held liable, the European Court of Justice (ECJ) had to establish if the Notified Body[2] appointed to certify the medical devices for compliance with EU standards, TÜV Rheinland, could be directly held liable by end users.

The ECJ had to determine what legal obligations incurred to these Notified Bodies, and whether end users enjoyed correlative rights.

The ECJ outlined what the Notified Body must[3] and may do. The Notified Body must be “alert” when faced with evidence that a medical device might not comply with the requirements laid down in Medical Devices Directive 93/42/EEC (MDD) and mustact with all due diligence” when engaged in a procedure relating to the EC declaration of conformity. The Notified Body must, therefore, do something; the final concrete action is, however, left at the discretion of the respective Notified Body. In terms of surveillance, a Notified Body may “carry out unannounced inspections, to examine devices and/or to examine the manufacturer’s business records”.

Put simply, the ECJ answered “no” to end users enjoying correlative rights. The ECJ reiterated its position that a directive which imposes surveillance obligations on Notified Bodies does not confer correlative rights on end users. Also, end users are not conferred rights despite one of the objectives of the directive being to protect injured parties.

This is “especially [true] if the directive does not contain any express rule granting such rights”.  

Nonetheless, the court underlined that the legislation on liability for defective products does not preclude Member States from recurring to other systems of (non-)contractual liability, for instance based on fault. The impact of the Decision is somewhat limited as the MDD is due to be replaced by new MDR in mid 2020.

This jurisprudence pushed for the introduction of enhanced responsibilities on behalf of both manufacturers and the Notified Bodies through the IVDR and MDR, as well as for the introduction of a Unique Device Identification (UDI), for a precise track of devices and their manufacturers.

To keep track of requirements for certification of medical devices, please consult SFL team.

[1] Due to use of substandard industrial-grade silicone.

[2] The “notified body” in question is TÜV Rheinland AG (“TÜV”, in the following), an independent German company that certifies products and processes for their compliance with statutory specifications and other relevant performance benchmarks and standards. See http://www.tuv.com/en/corporate/home.jsp

[3] See paragraph 41 of the judgment, according to which the notified body is under an obligation to “Analyze the application for examination of the design dossier lodged by the manufacturer, which must describe the design, manufacture and performance of the product in question and […] ascertain whether the application of the quality system contemplated by the manufacturer ensures that the products fulfil the relevant requirements under that directive. Moreover, […] the notified body must satisfy itself that the manufacturer duly fulfils the obligations imposed by the approved quality system.”

Changes afoot on EMA’s policy on access to documents

In recent years, there has been an apparent need for an updated policy on transparency of information and access to documents underlying the European Medicines Agency’s (EMA) granting of marketing authorizations.

The growing demand of important stakeholders and the general public for more information and greater transparency can create tension with IP rights and marketing authorization holders (MAHs). This is underlined by several legal proceedings raised against the EMA regarding the provision of data considered to be “commercially confidential”. Since October 2016, upon marketing authorization application (MAA) submission, the EMA publishes Clinical Study Reports (CSRs) as part of a drive for transparency.

In February 2017, the EMA published a proposed revision to its original policy on access to documents of 2010 for public consultation. The policy is in accordance with Regulation (EC) No 1049/2001, which grants citizens a right to access EU documents. Stakeholders can submit comments until 18 May 2017.

To enhance the EMA’s capabilities in creating transparency, in addition to EU official documents, the proposal (ref.: EMA/729522/2016) aims to include corporate documents in the range of documents to be disclosed.

According to the EMA’s proposal, the policy shall be reviewed within 3 years or at an earlier stage if considered necessary. Supplementary documents to the policy comprise a new table with the access rules related to corporate documents (ref.: