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Who we are

Xendo is a leading consultancy and project management organisation in the fields of (bio)pharmaceutical products, medical devices and healthcare. Thanks to our multi-disciplinary, knowledge driven approach, Xendo can deliver a broad palette of services to the life sciences industry, applying the right colour to projects we participate in. For over 25 years we have successfully completed thousands of national and international assignments for start-ups as well as for the largest, established multinational companies and organisations. Over 220 experienced and highly educated professionals offer their expertise ranging from strategic advice and project management to auditing, operational support and training; providing a full-colour spectrum.

Our clients

The spectrum of our fields of expertise is as broad as the range of clients we work for, enabling us to cater to the varied needs and wishes of the Life Science industry. We bring our palette of services to companies, ranging from start-ups to multi-national organizations, to provide them with robust solutions. Whether they are a (bio)pharmaceutical or medical device company, a hospital or a pharmacy, a manufacturer or a laboratory, we match their colour.

15-06-2017
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#Adverse Drug Reactions related to mortality and morbidity

Adverse Event Reaction related Mortality and Morbidity: Drug-Drug interactions and Overdoses

Abstract

Adverse Drug Reactions (ADRs) are a major contributing factor to morbidity and mortality resulting in 6.5-10.9% of hospital admissions and mortality rates of 0.15-2.9%. A considerable number of ADRs are preventable particularly those caused by drug-drug interactions and overdoses. Preventive measures such as adhering to Risk Management Plans (RMPs), ongoing Pharmacovigilance (PV) awareness training for healthcare professionals and patients could help reduce the prevalence rates of ADRs.

Introduction

Adverse drug reactions are an acknowledged factor contributing to morbidity and mortality universally and have caused the withdrawal of 28 drugs from the US market between 1976 and 2007. The World Health Organization defined an ADR as any noxious, unintended or undesired effect of a drug that occurs at doses normally used in humans for the prophylaxis, diagnosis, or therapy. ADRs are classified into two major groups:

  • type A are predictable reactions from the known pharmacological action of the drug, and usually dose-dependent
  • type B (idiosyncratic) are unpredictable and independent of the dose e.g. allergic reactions.

Other minor categories include:

  • type C which are chronic and are dependent on dose and time
  • type D which are delayed reactions
  • type E which covers withdrawal
  • type F for unexpected failure of therapy (Hinson et al., 2010).

This paper discusses ADR rates of morbidity and mortality and ADR prevalence factors with a particular interest in Drug-Drug Interactions (and overdoses. Preventability of the ADRs is also discussed.

Results

  • Hospital admissions due to ADRs vary in literature, with estimates of 3% in the Netherlands and Germany, 6.5-8.8% in the UK, 5.8% in Italy, and 12.8% in Greece.
  • Mortality rates due to ADRs are estimated from 0.1-2.9%. A retrospective eight-year (1999-2006) study conducted in the US of >2 million deaths revealed that 2341 deaths (0.1 per 100,000) were ADR-related deaths. In 2005, drugs were the leading cause of death estimated at 739, 936 per year.
  • The socio-economic healthcare costs associated with ADRs are very high, £466m/year in the UK annually, and A$946 200 in Australia are related to ADR hospital admissions.
  • A significant percentage of ADRs are considered preventable with varying estimates of 40-77% in literature. Overdoses contributed to average 30% of ADRs while drug-drug reactions 4-32%.
  • Factors contributing to ADR prevalence and/or susceptibility include: increase in the number marketed drugs, type of drug, increase in aging population, pregnancy, gender, disease state, genetics, ethnicity, polypharmacy, and urbanization.
  • Type A are commonly reported, as such are preventable by either dose adjustment or avoiding drug interactions.
  • Medications errors, off-label use, misuse and abuse are potential causes of ADRs that are usually excluded from ADR studies. However, Iatrogenic deaths in the US cause up to 7.8 million deaths per 10years, and medication errors were estimated at 14% fatality rate.


Conclusion

ADRs remain a significant contributing factor to morbidity and mortality worldwide despite increased awareness, past mistakes or experiences, and stricter regulations. The figures are likely to increase if preventive measures are not exercised. Most reported ADRs are Type A (predictable and dose dependent) and as such could be prevented. Drug-drug interactions and overdose contribute to a significant portion of preventable ADRs. The most promising prevention approach by far is precision medicine which combines genetic analysis with factors such as behavioural, functional, environmental and lifestyle information.

Read the full article.

This publication was written by:

Angella Angiji - Associate Consultant 

12-06-2017
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#Dutch Biotech Event

Xendo CEO André van de Sande moderating a session about Strategies for growth for Life Sciences companies at the recent Dutch Biotech Event. Synthon and Merus shared their insights about their successful company strategies.

29-05-2017
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#UPDATED: MD & IVD CLASSIFICATION CHART

UPDATE

We have updated our Medical Device and In Vitro Diagnostic classification chart due to the huge success of the previous version. Have a look at the chart and feel free to ask us if you have additional questions.

Various drafts of the Medical Device Regulation and the In Vitro Diagnostics Regulation have been published back in 2016, already giving indications into which direction the regulations would evolve, upgrade the requirements compared to the respective directive and their effect on the technical documentation and thus the medical device manufacturers.

Recently, on May 5, 2017, the final text of the European Medical Device Regulation 2017/745 (MDR) and the In Vitro Diagnostic Regulation 2017/746 (IVDR) have been published in the Official Journal of the European Union. Consequently, both regulations come into force on May 26, 2017. Three years later, the application for the MDR will take place on the date of May 26, 2020 and the IVDR will follow two years later.

The MDR will combine the Active Implantable Medical Devices Directive (90/385/EEC -- AIMD) and the Medical Devices Directive (93/42/EEC -- MDD) into one regulation. The IVDR will replace the In-Vitro Diagnostic Medical Devices Directive (89/79/EC -- IVDD).

The update of the tech documentation will start with the verification of the classification of your medical device or in-vitro diagnostic. Compared to draft publications of the regulations, the classification rules have been further upgraded with respect to numbering.

To assist you in your efforts to classify your IVD or Medical Device we have put together the criteria according to these novel regulations in an updated flowchart.

Contact: Marc Klinkhamer - Principal Consultant

16-05-2017
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#NeeS: The roadmap ends in 2018. Are you prepared?

Submissions in NeeS (Non-ectd electronic Submission) format will soon be history with the possibility of submitting in this format ending definitely for all procedures in the EU member states end of 2018.

Currently, electronic submissions of dossiers for human medicinal products in the EU are acceptable in two formats: NeeS (Non-ectd electronic Submissions) and eCTD (electronic Common Technical Document). eCTD differs from NeeS in that an eCTD dossier contains two XML files (index.xml and EU-regional.xml) providing a backbone to the dossier, and a util folder, together allowing easy navigation through the dossier and replacement of documents, while navigation through a NeeS is based on an electronic Tables of Content, bookmarks, and hypertext links.

eCTD was first established in 2002 and became mandatory for all centralized electronic submissions to EMA by 2010. The National Agencies, however, allowed a longer transition period to transfer national, decentralized procedure (DCP) and Mutual Recognition Procedure (MRP) dossiers from NeeS to eCTD.  For new marketing authorization applications submitted via the DCP and MRP, eCTD format has become mandatory since 2015 and 2017 respectively, while variations for older approved dossiers can still be submitted in NeeS. The European Medicines Regulatory Network eSubmission Roadmap, adopted in 2014 and modified in February 2017, describes the transition from NeeS to eCTD (v.3.2).

Source: eSubmission Roadmap

From 1 January 2018 onwards, eCTD will be mandatory for all CP, DCP and MRP submissions. The eSubmission Roadmap has been extended for national procedures, but European national submissions for new applications will be required in eCTD format from 1 July 2018 as well and the NeeS roadmap will definitely end on 1 January 2019 with eCTD being required for all submissions, including those for nationally registered products. This implementation date set should be strived for by all National authorities (see Annex 2 to the HMA eSubmission Roadmap). 

Although this is not a strict requirement, authorities will request transferring the existing dossier to eCTD format prior to submission of a new variation or update. The creation of an eCTD is done via a baseline submission, usually only covering the Quality part (Module 3) of the dossier. A baseline submission is a compiled submission of the current status of the dossier, i.e. resubmission of currently valid documents that have already been provided to an agency but in another format (TIGes Harmonised Guidance for eCTD Submissions in the EU Version 2.0 August 2011). The advantage to the company of creating a baseline eCTD first is that this will provide a well-structured overview of the information already contained in the dossier. As a result preparing the individual future submissions will require less work and allow a more efficient planning.

To prepare for the upcoming deadlines, companies are advised to assess their current situation by following these steps:

For products registered through MRP/DCP:

  • Identify all your products with at least one registration by DCP or MRP.
  • Identify for these products by when variations, safety updates or renewals are to be expected.
  • Check the current format of Module 3 of the dossier i.e. already in eCTD, (partly) in NeeS, paper scans, and CTD format or previous NtA (Notice to Applicants) format.
  • For dossiers already completely available in NeeS, the transfer to eCTD is relatively easy and can be done within short time.
  • For dossiers available in the old NtA format, the dossier has to be converted to CTD using the NtA-CTD correlation table. The correlation table works well for simple situations e.g. one formulation, one strength. In more complex situations, a critical look needs to be taken at the way information is provided in the dossier and a decision to be made on how to arrange the CTD dossier; Restructuring information in an efficient way avoids unnecessary dossier changes and variations in the future.
  • If applicable, harmonization of different dossiers in different countries for the same product can be taken into consideration as well.
  • Performing a conversion creates the opportunity to simultaneously make an inventory of possible non-compliances with current standards or internal procedures in the Quality module of the dossier. Although within the baseline submission, no content change is allowed, having such an inventory supports decisions on future updates and applications in new countries.     
  • Make a priority list of products for which the dossier will need to be converted to eCTD.
  • Create a work plan and assess whether you have the tools and resources to conduct the conversions.

For products registered through National Procedures:

  • Follow-up on announcements from National Agencies on the implementation of the mandatory use of eCTD in National Procedures on a local level based on the eSubmission Roadmap.  
  • List all your products registered nationally and follow the steps above, taking into account that the period for transition is one year longer for these products. However, depending on the number of products and possible different dossiers in different EU member states, creating a work plan on time is still advisable.
  • Having a work plan, the necessary internal/external resources ready and the required it-tools helps you to implement the eCTD conversion strategy, facilitating a timely implementation and compliance with the regulations. Performing proper planning and processing the eCTD conversion correctly from the start is certainly worth the investment.

Please see http://esubmission.ema.europa.eu/ectd and www.xendo-de.com/en-656/e-submissions.htm for more information.

Of if you have any questions don't hesitate to contact us.

Authors: Patricia Baede, Liesbeth Hoff & Almut Holz

08-05-2017
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#NEW: Japanese Translations

Or as you might know it in English: Pharmacovigilance, Regulatory Affairs, Quality Management & Lean Six Sigma.

Since 2001, Xendo has built up extensive experience in Japan and has provided above solutions to over 30 large and medium-sized Japanese (bio) pharmaceutical companies. And besides our regular visits to Japan, we have also established an affiliate in Tokyo in 2010. For years, we have been a trusted partner for audits, inspections, training, and other global activities regarding Pharmacovigilance, Regulatory Affairs, Quality Management & Lean Six Sigma. And conducting these audits and giving inspection training in the EU style, has proven to be very effective.

Thanks to our success in this region, the new Xendo website couldn't be left without Japanese content. So, to be able to better cater to the needs of our Japanese relations, our website now offers Japanese translations for several of our services. We would like to invite you to have a look!

SERVICES

Pharmacovigilance Regulatory Affairs Quality Management & Lean Six Sigma
ファーマコビジランス 規制関連業務 品質管理 & リーンシックス・シグマ

05-05-2017
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#A comprehensive 6-step route towards a cost-effective CE-mark

“Using the current directives while preparing for the new medical device regulation and IVD regulation

Medical devices in Europe

Modern medicine strongly depends on the use of medical devices for purposes of both care and cure. Medical devices have become a vital part of modern healthcare and practically no diagnosis or treatment is possible without them. Types of medical devices range from large capital hospital fixed equipment, through high-technology implants, surgical and monitoring equipment, to more familiar products such as wheelchairs, sticking plasters, syringes, incontinence aids, and spectacles.


In the medical device industry, the success of a novel medical device launch can often determine the positioning of the company for the coming years. Having a great product is essential and a good starting point, but is not enough to ensure it succeeds in the market. One of the most important determinants is obtaining a so-called CE mark before the device can circulate on the single European market. According to the European directives, a CE-mark (‘Conformité Européenne’, i.e. European Conformity) is mandatory for medical devices placed on the European Union single market. The CE-mark indicates product’s compliance with EU legislation and thus, implicates that these devices meet EU safety, health, and environmental protection requirements. By bearing a CE-mark, the medical device is considered as a product with sufficiently proven performance and safety for application in clinical practice and enables free marketability in the European Economic Area. Thereby the manufacturer declares, on his sole responsibility, conformity with all of the legal requirements to achieve CE-marking.

Throughout this article the manufacturer will appear and the definition is as follows: ‘manufacturer’ means the natural or legal person with responsibility for the design, manufacture, packaging and labelling of a device before it is placed on the market under his own name, regardless of whether these operations are carried out by that person himself or on his behalf by a third party.


The requirements to obtain a CE-mark vary among the different types of medical devices and may result in a significant expense with respect to certification (resulting in costs of thousands up to million Euros) and long process (varying between a couple of months and several years). Preparation in an early development process is, therefore, essential to deal efficiently with this burden and warrant making the right legal choices; this last point will prevent costly changes in the design of the device in the latest stage of the development process (to minimise the risk of non-compliance with the requirements of Notified Bodies (NB) and thus to minimise costs and time).


Currently, medical device and in vitro diagnostic developers need to demonstrate that their medical device meets the requirements of respectively Directive 93/42/EEC and Directive 98/79/EC (in this article the active implantable medical devices are out of scope) . These Directives describe the approaches that have to be followed in order to obtain CE marking. However, the regulatory landscape is about to change significantly. In 2020, Europe’s Medical Device Regulation (MDR) and in 2022 In Vitro Diagnostic Regulation (IVDR) will come fully into force, which will impact all medical device and in vitro medical device developers, respectively. Even though the final version has not been approved yet (expected May 2017), it is clear that Europe’s new MDR and IVDR will bring substantial changes to the way medical device manufacturers bring their devices to the European market, and how they maintain compliance throughout the product’s lifecycle. 

Figure 1. Transition period new MDR and IVDR.

This article will not deal with the changes that will take place but will explain the ins and outs of the current legislation. The reason for this is that during the transition period (Figure 1), which is between the publication date of the MDR and IVDR and May 2020 (MDR) and May 2022 (IVDR), it is still possible to CE-mark devices according to the current legislation, i.e. the Medical Device (93/42/EEC) and In Vitro Diagnostic Directives (98/79/EC). Especially for start-ups it could be strategically beneficial to CE-mark their products according to the current legislation and make the switch to the future legislation at a later stage.   In this way, the increased regulatory burden that is imposed by the MDR will be spread over several years and also time to market could be shortened. Also, manufacturers that have products on the market and want to expand their product portfolio could take advantage of this approach; for example, the In Vitro Diagnostic industry will be faced with major changes and it could be advantageous to continue using the IVDD and wait until the dust has settled. Because the CE-marking process is often regarded as a confusing, costly and complex procedure which takes up a lot of a company’s precious time, this article will discuss the most important steps and will provide more clarity and an overview in the complex matter of CE-marking. 

Legislation of medical devices in Europe


Figure 2 represents the steps in chronological order on how to develop and CE-mark your product. These steps include (1) identifying the directive(s) applicable to the device by identifying the type of your device, as there are different directives for each different type of device; (2) verifying the device-specific requirements and (harmonised) standards, as each type of medical device is further specified within classes or lists; (3) identifying if an independent conformity assessment from a notified body is required, as for some medical devices the involvement of a notified body is required (see 1.3); (4), further designing and developing the medical device and checking its conformity since each design of a device has to be carefully verified and validated according to the EU directives; (5) drawing up and keeping required technical documentation available, which has to be presented on request to the appropriate national authorities or sent to a notified body for review; (6) affixing of the CE-mark to the device and generating a declaration of conformity, as the CE-mark must be affixed accordingly, visibly, legibly and indelibly to the product or its data plate and the identification number of the notified body must be displayed if involved.

Figure 2. Steps to undertake in order to obtain a CE-mark.

1. Identifying directives applicable to the device

First, the appropriate directives, standards, and requirements must be identified since the requirements to obtain a CE-mark vary amongst the different types of medical devices. To determine the appropriate directives, one must first determine the appropriate type of medical device. Medical devices are divided into three categories; medical devices (MD), in vitro diagnostic devices (IVDs) and active implantable medical devices (AIMDs) each with their own EU directive (93/42/EC, 98/79/EC and 90/385/EC respectively).

Medical devices; 93/42/EC. According to 93/42/EC, a ‘medical device’ means any instrument, apparatus, appliance, software, material or another article, whether used alone or in combination, including the software intended by its manufacturer to be used specifically for diagnostic and/or therapeutic purposes and necessary for its proper application, intended by the manufacturer to be used for human beings for the purpose of:

  • diagnosis, prevention, monitoring, treatment or alleviation of disease;
  • diagnosis, monitoring, treatment, alleviation of or compensation for an injury or handicap;
  • investigation, replacement or modification of the anatomy or of a physiological process;
  • control of conception,

and which does not achieve its principal intended action in or on the human body by pharmacological, immunological or metabolic means, but which may be assisted in its function by such means.


IVD; 98/79/EC. According to 98/79/EC, an ‘in vitro diagnostic medical device’ means any medical device which is a reagent, reagent product, calibrator, control material, kit, instrument, apparatus, equipment or system, whether used alone or in combination, intended by the manufacturer to be used in vitro for the examination of specimens, including blood and tissue donations, derived from the human body, solely or principally for the purpose of providing information:

  • concerning a physiological or pathological state, or
  • concerning a congenital abnormality, or
  • to determine the safety and compatibility with potential recipients, or
  • to monitor therapeutic measures.

Specimen receptacles are considered to be in vitro diagnostic medical devices. ‘Specimen receptacles’ are those devices, whether vacuum-type or not, specifically intended by their manufacturers for the primary containment and preservation of specimens derived from the human body for the purpose of in vitro diagnostic examination. Products for general laboratory use are not in vitro diagnostic medical devices unless such products, in view of their characteristics, are specifically intended by their manufacturer to be used for in vitro diagnostic examination.

AIMD; 90/385/EC. This category of devices fall outside the scope of this article and will not be further dealt with. However, it is important to determine if the device can be defined as an AIMD or not.

2. Verifying the device-specific requirements and harmonised standards

After the right category of device has been selected, the appropriate device-specific requirements have to be determined. The medical device categories are further subdivided into classes or lists for each medical device directive. The applicable class or list for both MDs and IVDs has to be determined in order to verify which tests are required to obtain a CE-mark.

2.1. Medical devices

The MDs are classified in either Class I (including Is & Im), Class II (IIa or IIb) or Class III that covers the highest risk devices. The classification rules are set out in Annex IX of the directive 93/42/EC. These rules include:
how long the device is intended to be in continuous use,
whether or not the device is invasive or surgically invasive,
whether the device is implantable or active,
whether or not the device contains a substance, which in its own right is considered to be a medicinal substance and has action ancillary to that of the device.

2.2. In vitro diagnostic medical devices

The IVDs are categorised in either self-testing, list A, List B or other/general devices. To verify the category of the medical device, the flowchart presented in Figure 3 can be used.

Figure 3. Flowchart for verifying the classification of IVDs.

2.3 (Harmonised) standards

In order to generate evidence for conformity of the medical device to the applicable directive and specific requirements for each class of devices, multiple verifications, and validation studies must be executed and documented. Although the directives do not prescribe a specific methodology on how to perform these studies and leave the choice to the manufacturer, it is best to follow widely accepted methodologies described in standards (that can, for example, be obtained via the European Commission). For example, if a medical device is a sterile product, then the sterilisation process must be validated and for different sterilisation processes specific standards do exist; they are most often published by the well-known ISO organisation. In case a standard has been adopted by either CEN or Cenelec (Commission of the European Union) they are considered to be harmonised. The advantage of such a harmonised standard is that when a medical device (i.e. its design and the required manufacturing and packaging processes) is in conformity with a harmonised standard, the compliance with the essential requirement is presumed.

3. Involvement and selection of a notified body

3.1. Notified body

After identification of the type of device and its class or list, the manufacturer should determine the involvement of a notified body (NB) as a third step in the procedure. For low-risk medical devices the involvement of a NB is not required, as explained in the next paragraph.
A notified body is an organisation which is accredited by a competent body to verify whether a medical device meets the essential requirement of the applicable directive and eventually provides a CE-certificate. Each member state of the European Union specifies its own competent body (-ies) to enact the directive within its territory. Each competent body selects its own NBs in each state, where the competent body controls the NBs. These NBs are registered at the EU New Approach Notified and Designated Organisations (Nando) information system. Today, around sixty NBs are present in the European Union.

To obtain a CE-certificate that allows the manufacturer to CE-mark the device, the manufacturer must apply at a NB for many types of medical devices. As observed in Table 1, this is mandatory for MDs class IS, IM, IIa, IIb and III, IVD list A, B and self-tests, which are all part of the high-risk IVDs. The manufacturer can, however, apply to any NB in the EU that is capable of carrying out the desired procedure, regardless of which Member State that NB is established in.

Part of the activities of the NB is to assess the quality management system of the manufacturer by performing an audit. Besides NBs, also so-called registrars can perform this activity and even issue a certificate of compliance to the applicable standard, i.e. the ISO13485 standard. Although it is allowed to use a registrar for this, the disadvantage is that the registrar cannot issue a CE-certificate that is required for CE-marking. Also, the registrar charges additional prices and, therefore, it is recommended to use a registrar for assessment of the quality management system.

Table 1. Conformity routes of medical devices and in vitro diagnostic devices.

The selection of a NB should be a performed with utmost attention. Quality and costs amongst different NBs can differ and in addition, it should be taken into consideration that not all NBs can assess all categories of medical devices and in vitro diagnostics. The following aspects could enhance the proper NB selection:

  • Consider any future plans; not all NBs have a worldwide presence. If you might consider expanding to other markets in the future, it is recommended to choose a NB which is present in these markets.
  • Size of NB; in general, people have more attention for established brands. Large NBs have, in general, more experience and could be used as a promotional tool for your device. However, small NBs normally work faster and at lower prices compared to large NBs. 
  • Analysis of service; in terms of timing, service of a NB is very important, even in the future. The service of a NB must be analysed in order being sure of receiving proper service in the future.
  • Special administrative charges; NBs can charge special administrative and renewal fees. It is better being informed up front about these fees to avoid surprises.
  • Experience of NB; ask the NB if they are experienced with the type of device. If they are familiar with this type, the certification might go quicker.

For the conformity assessment, different routes can be chosen from. In most of the cases, the Annex II route is chosen because this allows the manufacturer a greater freedom to operate. The differences between the routes are mostly determined by the level at which the NB is involved in the assessment of the device’s design and the way it is secured that produced devices are appropriately controlled.

3.2 Self-certification

For certain medical devices (MDs class I and low-risk IVDs) the CE-certification by a notified body is not mandatory. The manufacturer can continue the following steps independently, ending in a self-certification that will be described later on in this article.

4. Further design and development of the medical device (including required clinical data)

4.1 Regulatory strategy before finalising design and development of the device

The design and development process of a medical device is one of the most important steps, because it will render to documented evidence by which the safety and performance of the device is guaranteed. Especially for devices where the involvement of a NB is required and that are at higher risk, it advisable to start with a regulatory strategy before finalising the design and development of your device. The requirements for CE-certification by a notified body and an overview of these steps to meet the requirements can be preliminarily reviewed by the notified body. After agreeing on this strategy by both partners, the manufacturer and the notified body, agree on this strategy, including the category and classification of the medical device, the manufacturer can finalise the design and development of its device. Discussing this strategy before finalising the design and development of the device will notably shorten the duration of the official CE procedure since it will prevent non-compliance with the NB requirements.

In addition, compliance with quality management system requirements described in the ISO13485 standard ensures the manufacturer’s ability to meet customer and regulatory requirements. This will not only facilitate the CE-certification process but also provide added value for the reputation of your company.

4.2 Verification testing

Besides a structured and standardised approach for the design and development process, including proper design inputs and application of risk management, also the verification testing to be performed is essential. Because of the variety of medical devices, including in vitro diagnostics, is enormous, it is impossible to go into detail into this topic here. In general, ample attention should be given to topics such as sterility, biocompatibility, electrical safety, electromagnetic compatibility and usability (of course only if they are relevant to the medical device in development). Each and every verification test must be documented, meaning that pre-approved protocols and reviewed and approved reports should be generated. Verification testing is also sometimes referred to as bench testing and can be done in the facilities of the manufacturer or outsourced to third parties. In the latter situation, the manufacturer should keep in mind in the case of outsourcing the final responsibility remains with the manufacturer.

4.3 Clinical evidence (clinical data)

The testing of the medical device (or the in vitro diagnostic) by the user in the actual situation where the device will be used is named design validation or clinical validation. It is required to obtain clinical evidence based on actual data to demonstrate compliance with the essential requirements described in the applicable directive. Guidance on how to obtain clinical evidence can be found in the guidance documents Meddev 2.7/4 and Meddev 2.7.1. The collection of clinical data can be completed by execution of a clinical investigation unless it is duly justified to rely on existing data. Naturally, such justification will have to be based on a proper clinical evaluation. In general, the higher the risk class of a medical device, the higher the chance is that clinical investigations with the device should be executed. By comparison with suitable comparators, additional clinical investigations may be feasible to support the existing clinical evidence. The provided clinical data, for all types and/or classes of medical devices, must consist of:

  • A critical evaluation of the relevant scientific literature which is related to the safety, performance, design characteristics and intended purpose of the device, where there is demonstration of equivalence to the device of which the data relates and the data adequately demonstrates compliance with the relevant essential requirements, or;
  • A critical evaluation of the results of all performed clinical investigations, or;
  • A critical evaluation of the combined data provided from the two points mentioned above.

Safety and performance can often be demonstrated by other means. However, for IVDs in list 2 and MDs class III, in particular, data must be generated to:

  • Verify that the performance characteristics of the device are those intended by the manufacturer under normal conditions, and
  • Determine any undesirable side effects under normal conditions of use. These side effects must be assessed whether these effects constitute risks when weighed against the intended performance of the device.

Thus, a clinical investigation on a non-CE-marked device must be designed to prove that the performance claimed by the manufacturer can be demonstrated and that the device is judged to be safe to use on patients. A clinical investigation on a non-CE-marked device must at least be considered when:

  • The device is an implantable or Class III medical device.
  • The introduction of a completely new concept of a device into clinical practice where components, features and/or methods of action, are previously unknown.
  • Where an existing device is modified in such a way that it contains a novel feature particularly if such a feature has an important physiological effect; or where the modification might significantly affect the clinical performance and/or safety of the device.
  • A device incorporates materials previously untested in humans, coming into contact with the human body or where existing materials are applied to a new location in the human body or where the materials are to be used for a significantly longer time than previously, in which case compatibility and biological safety will need to be considered.
  • A device, either CE-marked or non-CE-marked, is proposed for a new purpose or function.
  • An in vitro and/or animal testing of the device cannot mimic the clinical situation.
  • There is a new manufacturer especially of a high-risk device.

Alternatively (in particular for line extensions to products or for products already on the market outside the EU), clinical data may include a complaints analysis in combination with a literature compilation with an expert summary, post-market surveillance data, and so on and this might be sufficient. Clinical evaluation is based on the assessment of the risks and the benefits, associated with the use of the device, through either:

  1. a compilation of relevant scientific literature, that is currently available as well as, where appropriate, a written report containing a critical evaluation of this compilation (the “literature” route). For this, the manufacturer must demonstrate the equivalence of the device to which the data relates and the device(s) for which conformity is being assessed. Furthermore, the applicability of the literature data for the device being assessed have to be demonstrated; or
  2. the results of all clinical investigations relevant to the device in question (the “clinical investigation route”); or
  3. a combination of I. and II. mentioned above. Where the clinical evaluation is based on such a combination, it should include an overall assessment. This assessment should take account of market experience, if available. It is important that the manufacturer relates the data to the specific device, having regard to the hazards identified.

5. Technical documentation

After these steps, the technical file can be created which includes general aspects of the device, device description, essential principles and evidence of conformity, risk management, summary of design verification/validation, manufacturer information for process and accessories, and labeling. The summary of design verification/validation includes the required evidence which differs for each type of medical device.
Depending on the strategy chosen, the technical file can contain more or less of the original verification and validation documents. If the original document is not included, then providing a summary and making reference is acceptable. A reason to keep the technical file lean and mean is that will be easier to maintain throughout the lifecycle of the medical device. On the other hand, reviewers could always ask for the original documentation, which could result in a slower review process.

The technical file is handed over to the NB for review In addition to this review, the NB will also audit the manufacturer on site in order to assess the quality management system and the processes for manufacturing and packaging. Also, on-site audits for critical subcontractors are often part of the review.

6. Affixation CE-mark

6.1 Declaration of Conformity

After completion of technical file, the manufacturer should generate a Declaration of Conformity (DoC). In case the medical device classification required the involvement of a notified body, there is the logical prerequisite that the review and approval process by the NB should have been successful and a CE-certificate issued. With the DoC generated, the manufacturer then affixes the CE-mark. As mentioned in the beginning of this article, the CE-mark must be affixed visibly, legibly and indelibly to the product or its data plate and the identification number of the notified body must be displayed if involved.

Once the device is correctly CE-marked it does not need the additional approval to be marketed in the EU, EEA or Switzerland as the CE-marks represents free movements in these states. However, these states can request the manufacturer to register the device and can require device information in the respective language. Thus, in case if the device will be marketed in a state other than registered the national authorities should be contacted.

6.2 Eudamed

One final note should be made for those medical devices for which there is no NB involvement; these devices need to be registered at Eudamed, the European databank for medical devices. Eudamed is a secure web-based portal acting as a central repository for information exchange between national Competent Authorities and the Commission in accordance with the Medical Devices Directives. The information in it is not publically available. It also contains data on devices where a NB was involved and the information is entered by the NB self.

Conclusion

Within this article, the complex CE-marking process is simplified by providing a comprehensive  6-steps route towards obtaining a CE-mark. Even though the current legislation will be replaced, it could be a strategic choice to continue to comply with the Directives during the transition period and switch over to the Regulations at a later stage. Essential steps, such as verifying the applicable directives by defining the appropriate class/list of your device, should be addressed before finalizing the design and development of your device. It should be noted that discussions with a notified body (if relevant) is of utmost importance before undertaking this finalization step. Neglecting advice from NBs can result in unnecessary (high) costs and time. After finalizing the design and development, collecting clinical data regarding the safety and performance of your device is a crucial next step in convincing NBs. However, it should be noted that the CE-marking process is a rigorous complex procedure that should be implemented in an early development stage and often warrants additional advice from experienced consultants, such as provided by Xendo. In addition, the CE-marking process is expected to get more complicated with the new Regulations that will come into force in May 2020. A comprehensive overview of this process will be published mid-2017 by ttopstart and Xendo

Provided by

Contact ttopstart if you need assistance with financing crucial development steps, such as to cover the costs of the regulatory approval procedure, of your medical device (e.g. finding relevant subsidies and applying for them).

&

Contact Xendo if you need assistance with the regulatory approval procedure. This includes defining the appropriate strategy and planning for your device and setting up the required quality management system.

Authors

Michelle van Wijk - Consultant

Marc Klinkhamer - Principal Consultant
ttopstart is a science and business consulting company that serves leading researchers and innovative companies in the fields of life sciences, medical technology and health. ttopstart is specialised in the markets life sciences, medical technology and healthcare. ttopstart empowers biomedical innovators by supporting them with convincing VCs, subsidy providers, strategic partners and other stakeholders around the world to invest in their product. We want to enable their success in tackling the challenges associated with disruptive healthcare innovations, for the benefit of patients.

25-04-2017
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#6 Quick Tips About Excel Sheet Validation (GAMP)

Are you using Excel spreadsheets? And are these used for GxP activities? Are these Excel sheets used again and again, as a template? Ever thought about validating such templates? Is the person who built your spreadsheet a genius with Excel, but doesn’t know how to validate? Want to use spreadsheet templates but validation issues are holding you back?

And what does an umbrella have to do with it?

Caricature by George Cruikshank (1792-1878) entitled ‘The Umbrella’ and dating from 1820.

It is fairly common that a spreadsheet template is created to do calculations which otherwise should be done by hand or calculator. Spreadsheet examples for GxP related matters range from a simple template for calculations of impurity in a sample to a highly complex spreadsheet for statistical analysis of clinical studies including Visual Basic for Application macros. Such spreadsheets may contain critical data, such as laboratory information, and may be used for making critical decisions.

Many companies think a spreadsheet template is just a calculator and don’t realize that you should actually think of it as an application. In fact, records generated by the calculations are electronic records and must therefore comply with EU’s Annex 11 and FDA's 21 CFR Part 11.

Did you know that by creating a spreadsheet template you are now considered to be a software developer? Your in-house developed software might even be a GAMP software category 5 application. The GAMP software category defines the extend of activities required to validate your spreadsheet.

But enough to scare you off, no need to be afraid. A good road map and some tips and tricks can help you on your way through the rough landscape of spreadsheet validation. Here we go!

  1. First of all, relax, you don’t need to show all your calculations are accurate and validate Excel itself. What you do need to show, is that the calculations in the spreadsheet are the right calculations. Now, how do we do that? Well, you’re halfway if you already know about validation and the ‘V-model’. Also embrace the GAMP guide. That’s ISPE's guide for Validation of Computerized Systems in the Pharmaceutical industry; the Good Automated Manufacturing Practice (GAMP). The GAMP guides you through the process and even gives you practical instructions on how to write the validation documentation.
  2. With all your experience, regulations and guidelines in mind, develop the spreadsheet that includes all necessary requirements. Think of the following aspects:
    • Use of the spreadsheet must be restricted to the intended user. So place the template on a (server) location with access limited to selected users. And protect the spreadsheet with a password that allows users to open the spreadsheet (as read only).
    • You want to protect the spreadsheet against any undesired changes, so lock all cells within the spreadsheet (except the cells in which the user needs to give input). So the user cannot change cells with formulas, constants, labels etc.
    • And give the input cells a color to make the spreadsheet more clear and easier to understand for users.
    • Make use of drop down menus or data entry limits to prevent entry mistakes.
    • Is the calculated result presented in the right way? Does it have the correct number of decimal places; is the unit of measure displayed?
    • You can create an audit trail to log what has changed when using the spreadsheet to make it more compliant to the EU’s Annex 11 or FDA's 21 CFR Part 11.
    • Like any application, implement a version number to the spreadsheet, which also comes in handy for change control.
    • When a user fills the (validated) spreadsheet template with data, the resulting spreadsheet file with data is an electronic record. So, just like the template, make sure these files are stored on a (server) location with access limited to selected users.
  3. Prepare all validation documentation. Depending on the impact on Patient Safety, Product Quality and Data Integrity and the complexity of the spreadsheet the GAMP can help you to find out what you need to do. Here you get the so called ‘GAMP software category’.
  4. During validation, manually verify the reliability of the spreadsheet. Verify the spreadsheet calculations by entering expected values and extreme values and verifying the behavior of the spreadsheet, or comparing the data with already known data.
  5. Make sure all necessary supporting Standard Operating Procedures are present, such as procedures for Change and Configuration Management, Backup and Restore, and Archiving and Retrieval. Also provide Working Instructions how to use the spreadsheet template for each type of user.
  6. After successful validation celebrate your success and release the spreadsheet for use. Any changes should go via Change Control and the actions for revalidation can be determined based on a Risk Assessment.

So, please don’t be afraid of spreadsheet validation anymore. It is actually very much doable.

However, we do have to make a remark: an Excel spreadsheet template is built upon the spreadsheet application Microsoft Excel. Which is principally not designed for regulated environments. So if the spreadsheet software changes, the spreadsheet template might be subject to validation again and should therefore be accessed with each update. For example, Office 365 is a platform that is continuously improving and expanding and implements updates each month. Knowing this, also consider using dedicated software, such as laboratory data systems, for your calculations.

What did the umbrella have to do with it? Here's your answer!

Definition of ‘gamp’, found on: https://en.oxforddictionaries.com/definition/gamp

If you have any questions don't hesitate to contact us!

Blog by: Nynke Noort - Consultant



07-04-2017
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#Bend or break: increased regulatory burden for medical device Own Brand Labelling

For medical device Own Brand Labelling (OBL) manufacturers, the regulatory requirements in Europe will change significantly with consequently major impact on the way of doing business. Right now the rules are changing and it will be a bend or break situation.
Private-label products or services are typically those manufactured or provided by one company and sold under another company's brand. This approach is used by a great variety of organizations and also within the medical device industry. In short, the OBL sells the device, while the design, manufacturing, and packaging of the medical device are executed under the full responsibility of the Original Equipment Manufacturer (OEM).

Until now, compliance to the European Medical Device Directive 93-42/EC (MDD) is secured by a CE Certificate of the product of the OEM, which is the objective evidence that the medical device complies with the requirements of the MDD. The OBL only has to generate an abbreviated Technical File (TF), based on which a Notified Body (NB) can grant a CE Certificate to the product of the OBL. The prerequisites for this approach, are that the OEM product is not modified by the OBL, the labelling is essentially identical between the OBL and OEM product and the intended use is also the same. Recently, however, a different view on conformity assessment of OBL medical devices has been developed.

EU Recommendation


It all started with the European Commission recommendation “on the audits and assessments performed by notified bodies in the field of medical devices” that was published four years ago in the Official Journal of the European Union (L253/27-35, September 25th, 2013, 2013/473/EU). Though the recommendation on unannounced inspections was thought to be non-mandatory, many manufacturers were surprised by these audits. Additionally, this recommendation zooms in on the OBL/OEM situation, as can be read in a separate paragraph with the title “General advice in case of outsourcing of the production via subcontractors or suppliers”. It is remarkable to read that the OBL’s approach described above is no longer valid according to the Commission, because “manufacturers do not fulfil their obligation to have at their disposal the full technical documentation and/or of a quality system by referring to the technical documentation of a subcontractor or supplier and/or to their quality system" (meaning, a simple statement that the OEM holds the documentation is not deemed sufficient).

Following this recommendation, the British Medicines and Healthcare Products Regulatory Agency (MHRA) published a draft guidance on this particular OBL/OEM topic last year (Own Brand Labelling, Version 1.0, April 22nd, 2016). In this guidance, the Commission’s recommendation was fully embraced by the MHRA. In the introduction, it is also stated that review of an abbreviated Technical File was not deemed feasible not only by the British authority but also by the other EU Member States. The MHRA is quite clear and detailed on the responsibilities of the OBL with respect to compliance to the current MDD, and any OBL manufacturer will recognize that this will increase the workload of its regulatory department. The MHRA ends the guidance with a cliffhanger:“MHRA recognizes that in some cases Notified Bodies will take different views regarding own brand label and original manufacturers.”. This draft guidance was replaced just last month by a final guidance. Although the title has changed to “Virtual Manufacturing replaces Own Brand Labelling for medical device manufacturers” (Version 1.0, March 2017),the goal of the guidance remains unchanged. So the main question right now is: What are the Notified Bodies doing about this??

What now?


Although it is too early to speak of a game change, it is apparent that (some) Notified Bodies are already following suit to the Commission’s recommendation and the MHRA guidance. This is understandable because both institutions are of high reputation. It is also understandable from another perspective; the current legislation for medical devices will soon be succeeded by the so-called Medical Device Regulation (MDR). The MDR is much more detailed and clearer on many issues than the MDD. One of these issues is that the text of the Medical Device Regulation (MDR) supplements the lack of clarity in the Medical Device Directive on the roles and responsibilities of an OBL. Article 10(4) of the Regulation does not leave much room for the OBL, as it reads “Manufacturers of devices other than custom-made devices shall draw up and keep up to date technical documentation for those devices.”; no exceptions are granted for the OBL. The Regulation will be published in May this year and it is not expected that there will be any changes in this part of the proposed text as known today. So it is understandable that Notified Bodies will already tune their conformity assessment approach to the successor of the MDD.

One of the reasons to generate the MDR is given in the preamble of this regulatory document: “At the same time, this Regulation sets high standards of quality and safety for medical devices to meet common safety concerns regarding these products”, which is easily understood when one recalls the fraud case in France regarding leaking breast implants and the turmoil it created throughout Europe. The MDR will fully replace the current medical device legislation, i.e. the MDD, within a three-year transition period. During this transition period, a medical device manufacturer has the choice to either comply with the MDD or with the new MDR, and the CE Certificate issued by the Notified Body will refer to the chosen legislation. But it can be expected that some Notified Bodies will already enforce the stricter OBL obligations defined in the MDR, the MHRA guidance, and the Commission’s recommendation, even if the OBL manufacturer chooses to comply with the MDD and likes to continue their business as usual.

Steps to take


As a result, the OBL manufacturer should be planning for additional regulatory work in the three years to come or even sooner. The regulatory effort should be spent to the following main topics:

  • the current abbreviated Technical File for the medical device product should undergo an overhaul, with more emphasis and details on amongst others risk management;
  • a detailed quality agreement with the OEM needs be made up (not only the general aspects regarding distribution and pricing need to be spelled out);
  • detailing the various roles and responsibilities of both the OBL and EOM;
  • the OBL should engage in performing activities for Post Market Surveillance (whereby not only a reactive approach is followed but also a pro-active).

Continuing business as usual will not seem to last much longer; CE Certificates for new products or renewals will most probably be taken care of by Notified Bodies in a way that differs substantially from the past.

Concluding, regulatory burden for medical devices put on the European market by an Own Brand Labeler will increase in the future and this future is near. The OBL could argue that this increased effort will not increase the safety of the products, but the Notified Bodies decide in the end, and their new direction has become clear recently. Because the activities involved will require a substantial lead time, it is time to act now in case of the medical device OBL manufacturer.

Author: Marc Klinkhamer - Principal consultant