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MDR/IVDR: Highly-anticipated guidance documents you should not be waiting for
15-02-2018

#MDR/IVDR: Highly-anticipated guidance documents you should not be waiting for

The transition time for the two Medical Device Regulations is rapidly ticking away: economic operators shall be fully compliant with the MDR by May 2020, and with the IVDR by May 2022. Are you an economic operator – in other words are you a Manufacturer, Authorized Representative, Importer, Distributor, System/Procedure Pack Assembler or Sterilization Service Provider? Then you might be eagerly waiting for further guidance (in the broadest sense of the word) from Europe. Here’s what guidance you can expect – and why you should not wait for it.


Roadmap for implementation

In November 2017, the Competent Authorities for Medical Devices (CAMD) issued a roadmap for implementation of the MDR/IVDR. CAMD identified seven technical areas/work streams and one over-arching/cross-cutting area/work stream. For each technical area/work stream, a list of actions items and priorities for various working groups was defined. This list outlines the roadmap for these working groups, according to which they can develop the guidance that you need for effectively implementing the MDR and the IVDR. Here’s what you can expect.

1. Clinical evaluation and clinical investigation (for Medical Devices); Performance evaluation and performance studies (for In Vitro Diagnostic Devices)

Expect guidance documents and/or Implementing Acts on the topics of equivalence, well-established technologies, clinical evidence and performance evaluation.  Several templates will be developed, such as templates for Summary of Safety and Clinical Performance, Clinical Investigation Application Form, SAE/device deficiency reports and timelines, PMCF Plan, and PMCF Report (and their IVD equivalents). For IVDs, new Common Specifications will be developed to replace the current Common Technical Specifications. Guidance regarding companion diagnostics is also to be expected.

2. Scope and classification

With the revised classification rules for MDs and IVDs, guidance will be developed around classification rules and scope.  Common Specifications are to be expected regarding Annex XVI products (products without an intended medical purpose). Implementing acts will be developed on the topic of reprocessing single-use devices.  Also, expect guidance on the appropriate level of interacting with relevant authorities regarding combination products and companion diagnostics.

3. Notified bodies and conformity assessment

These are specific for Notified Bodies and not for Economic Operators, however for Economic Operators it will be interesting to see the development of these guidance documents as they will give insight in, for example, the different routes for conformity assessment, the definition of ‘significant change’, or the differences between IVD Class B and C conformity assessment procedures.

4. Post-market surveillance and vigilance

New guidance will be developed on requirements for vigilance reporting. Also, various templates are going to be developed, such as a new Manufacturer Incident Report (MIR) Form, Field Safety Notice (FSN) and Periodic Safety Update Report (PSUR).
In addition, terminology might change as nomenclature for Adverse Events and Patient Harm will be (re)defined.

5. Eudamed and Unique Device Identification

According to the CAMD roadmap, expect clear and early instruction to stakeholders on how to interact with the system.  Guidelines will be developed on the topics of UDI assignment, UDI carriers, UDI marking and registration.

6. Market surveillance

CAMD is going to develop guidance or infographics for Economic Operators clarifying expectations around economic operator obligations, responsible person, liability, interaction with Eudamed and registration requirements.

7. IVD-specific issues

Specifically for IVDs, you can expect guidance on how to assess Class D IVDs in the absence of Common Specifications.
As already covered in previous work streams, also expect template documentation for performance studies, as well as guidance for assessment of companion diagnostics, classification, the appropriate level of interaction on combination products with relevant authorities, the nomenclature for Adverse Events and Patient Harm, and vigilance reporting.

8. Over-arching and cross-cutting priorities

Expect further definition of the responsibilities for conformity assessment of parallel importers and reprocessing of single-use devices. Also, guidance will be developed on the clarification of the role of the Medical Device Coordination Group (MDCG) in the governance of the regulations. Action items are defined to ensure that Eudamed will go live as planned (March 2020). As covered in the Eudamed work stream, instructions will be released to stakeholders on how to interact with the system. Current status is that functional specifications for Eudamed are to be released in May 2018, which implies that the progress towards the go-live date is still on track.

In January of this year, transitional provisions have been released by the CAMD Transition Sub Group, in the form of FAQs for both the MDR and the IVDR, covering initial questions on the topics of Eudamed, placing on the market of MDR/IVDR-compliant devices until date of application, placing on the market of MDD/AIMDD/IVDD-compliant devices after date of application, and the “sell off” provision in the MDR/IVDR. Keep an eye on these FAQs, as they are intended to evolve and expand over time.


Don’t wait, act now

Are you an economic operator waiting for guidance from Europe? Then there is little doubt that the expected guidance documents will be instrumental to you in implementing the requirements of the MDR/IVDR. These guidance documents may come in various sizes and shapes:

Delegated Act        Common Specification
Although not mentioned in the CAMD roadmap, Delegated Acts may be prepared and adopted by the European Commission. These non-legislative acts are based on, for example, specific objectives, content, scope, and duration that have been set out in the original legislative act (like the MDR or IVDR), and are considered to supplement or amend the original legislation. In other words, a Delegated Act tells us more about what actually is considered the law. The use of harmonized standards is good practice in order to presume to be in conformity with the General Safety and Performance Requirements. But in case relevant harmonized standards are considered not sufficient, or perhaps even not existing, the Commission may adopt Common Specifications which will have the same use as the harmonized standards. Specifically, regarding IVDs, current Common Technical Specifications may be replaced by such Common Specifications.
MEDDEV-like guidance documents
Designed as non-legally binding guidelines, MEDDEVs were intended to promote a common approach to be followed with regards to the three Medical Device Directives (MDD, AIMDD, and IVDD). As these Directives have been replaced by the MDR and IVDR, new MEDDEV-like guidance documents will be prepared to provide guidance with regards to the MDR/IVDR requirements. These may simply be updates of existing MEDDEVs, or may be entirely new guidance documents.
Implementing Act Other guidance documents
A non-legislative act that is considered to be procedural: a practical implementation of the rules that already exist in the original legislation, and thus may result in practical things such as templates, procedures, deadlines etcetera. In other words, an implementing act tells us how to implement the original legislation. These include any kind of (non-legally binding) guidance not covered by the above, such as infographics or FAQs.

But even though these guidance documents are highly-anticipated, here is why you should not wait for them – or more appropriately: why you should stop doing nothing while waiting for them.


Three reasons why time is running out:

  1. Although the preparation of a number of guidance documents, for example in the technical area of Clinical Evaluation, has been set to the highest priority, timing is the problem: as the CAMD roadmap does not define specific timelines for the release of the various guidance documents, it is not clear as to when exactly these guidance documents will be released – so chances are that it might be too late if you still have to start implementing.
  2. Judging from the CAMD roadmap, the amount of work ahead for the involved working groups and other stakeholders is substantial. For a number of the discussed guidance documents, it may even be a matter of years rather than months before they will be released. In the meanwhile, the date of implementation of the MDR and the IVDR is coming closer and closer, leaving you with hardly any time to become fully compliant with the regulations should you decide to wait.
  3. An additional obstacle is Brexit. Tough divorce negotiations between Brussels and London and the time-consuming work for MedTech experts involved in this topic will surely not help swift implementation of the CAMD roadmap and could cause serious delay in release dates. To add to that, historically the UK’s MHRA has played an important role within the European Union in developing policy aimed to protect public health as well as to support innovation in medical technology. If the MHRA steps out due to Brexit, this may add even more delay to release dates or adversely impact policy development.

Get time back on your side

It’s clear that the time that is left for you to get all the work done should not be underestimated. And the road ahead may be full of questions. You may find yourself at a crossroads now: should you sit and wait for guidance to arrive with the risk of having insufficient time left to become compliant, or should you get up and start transitioning already based on current knowledge with the risk of having to adjust once new guidance arrives?

Your best option is to start now and anticipate as best as you can on what is to come instead of wait and react. Start building a transition program based on what you can use from current guidance documents. As soon as new guidance documents are released, use these to double check to which extent you already comply with the MDR/IVDR, and to which extent you will have to fill any remaining gaps. This will get you further and will save you more time than doing nothing at all.

As we pointed out in our previous blog on MDR, time is running out fast: the longer you wait with the implementation of the MDR/IVDR requirements, the higher the risk will be that you will lose money.

Blog by: Urville Djasim – Consultant at Xendo


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Gene therapy trials: a harmonized procedure across EU?
05-02-2018

#Gene therapy trials: a harmonized procedure across EU?

After the first clinical trial with a gene therapy medicinal product (GTMP) in 1989 and years of development and improvements, more and more GTMPs are now entering late-stage clinical trials and the first therapies have received market approval. In view of these developments, it seems that the field of Gene Therapy is about to pay-off and regarding the tremendous potential of emerging technologies (e.g. CRISPR-Cas), even more promising developments in the field of GTMPs seem to be ahead of us.

With the installation of a new Clinical Trials Regulation, the European Commission (EC) aimed to harmonize and thereby ease the application of clinical trials within the EU. However, the environmental legislative divergence between the Member States seems to neutralize the benefits of this Regulation for the clinical development of GTMPs.

CURRENTLY: DIFFERENT REQUIREMENTS FOR GTMPS ACROSS EU MEMBER STATES

In contrast to an application for market authorization, an application for a clinical trial is currently not harmonized in the EU and requires a separate submission in each Member State in which the trial will be conducted. In addition to all regular requirements of Directive 2001/20/EC, a GTMP trial is also subject to specific environmental legislation because it contains or consists of genetically modified organisms. This legislation requires an assessment of the potential risks for man and the environment. In the EU, two different Directives can apply to a clinical trial with GTMPs:

  • Directive 2001/18/EC, in which the trial is considered as deliberate release of a GMO into the environment (the GMOs are expected to be introduced in the environment),
  • Directive 2009/41/EC, in which the trial is considered as contained use of a GMO (the GMOs are expected to remain in dedicated rooms in the hospital).

All Member States have implemented these two Directives in their national GMO legislation and whether a clinical gene therapy trial is seen as deliberate release or contained use, differs among the Member States. Several Member States have chosen one of the Directives to apply to all gene therapy trials, which are performed in their country. However, in other Member States a clinical gene therapy trial is in one situation considered as deliberate release, while in another situation as contained use. In these Member States, it depends on the characteristics of the trial and the classification of the GMO used, which of the Directives applies.

Apart from the fact that each Member State has its own national legislation, they also have their own procedures and timelines for filing and assessing a clinical GTMP trial application. It goes without saying that the requirement for an environmental risk assessment combined with differences in legislation, procedures and timelines doesn’t exactly ease the path for a multicenter GTMP trial across several EU Member States and requires regulatory expertise and know how to coordinate and apply for such a clinical trial.

OBJECTIVE: HARMONIZED CLINICAL TRIAL APPLICATIONS IN EU

In 2014, the European Parliament launched a new Regulation (No. 536/2014) on clinical trials with medicinal products for human use, replacing the Clinical Trials Directive 2001/20/EC. Its objective is to harmonize the electronic submission of and the assessment process for clinical trials conducted in multiple Member States. In short, medical-scientific and product quality assessments will be centralized, but national issues like informed consent and compensation arrangements will still be evaluated separately by each Member State. Although this Regulation came into force directly after its publication in the Official Journal of the European Union, it won’t be applicable until the necessary EU portal and database are fully functional, which isn’t to be expected before the end of 2018.

REALITY: ENVIRONMENTAL LEGISLATION FOR GTMPS IS NOT COVERED

The new Regulation applies to all clinical trials with medicinal products for human use, and therefore includes GTMPs. Unfortunately, it doesn’t cover the requirements for the extensive assessment of the potential environmental risks. This means that the approval of a GTMP trial, in terms of its environmental safety, still resides at the level of the Competent Authority of each Member State with all its differences in national legislation, procedures and timelines. Consequently, gene therapy trials still face complex and non-harmonized regulatory requirements and procedures in EU.

CONCLUSION: NO BENEFIT FOR MULTINATIONAL CLINICAL GENE THERAPY TRIAL

Obviously, it would be most desirable if EU Member States could agree on the harmonization of the environmental legislation for clinical trials with GTMPs. Unfortunately, the EU Member States are widely divided in their GMO policy. This makes it unlikely that a centralized procedure for clinical trials with GTMPs, which also covers the environmental risk assessment, will come into effect in the near future, if at all. Until that time, one should consider carefully if a multicenter gene therapy trial in different EU Member States is really worth the effort to apply for the required environmental approval in each one of them.

PLANNING A MULTICENTER GENE THERAPY TRIAL: POINTS TO CONSIDER

  1. Limit the multicenter trial to a minimum of Member States (preferably one).
  2. If more than one Member State is required, choose your primary Member State based on your contact and previous experience with potentially qualified clinical centres.
  3. List the Member States with similar legislation for gene therapy trials as your primary Member State of choice, i.e. Member States with national environmental legislation that is based on the same Directive,
  4. Identify and contact the different involved parties in each Member State of choice to get insight in:
    1. the requirements for environmental approval
    2. the procedure of assessment
    3. the timelines that apply
  5. Select the Member States that most closely resemble the requirements, procedure, and timelines of your primary Member State of choice and that contain the most qualified clinical centres to perform your trial in.

If you're looking for additional experience and/or know how on GMO legislation and environmental risk assessments for clinical trials with gene therapies feel free to contact us and one of our experts will get back to you! We are familiar with the differences in national requirements and could support your company to navigate in this complex and non-harmonized playing field in order to design your regulatory strategy and work on a successful submission process

Blog by: Erik Schagen - Sr. Consultant at Xendo

Serialisation: What's it gonna cost you?
28-01-2018

#Serialisation: What's it gonna cost you?

Adapting packaging lines, implementing a new anti-tampering system, a 2D data matrix with a unique serial number, software adjustments, efficiency loss because of slowed production, and costs related to data exchange between European and national data banks. These terms probably sound dreadfully familiar to those involved in serialization.

Falsified medicines can easily be confused with their authentic counterparts but may contain ingredients of bad or toxic quality, or in the wrong dosage; posing a very real risk to patients.  This threat to global health is answered by a comprehensive strategy both at a European and international level in the form of serialization. The EU Directive: 2011/62/EU aka Falsified Medicines Directive (FMD) is intended to prevent the entry into the legal supply chain of falsified medicinal products; thus creating a safer environment for patients.

So how does it work?

The basic set-up is the following:

  • Manufacturers register packaging to the European system (EU-Hub)
  • EU-Hub Transfers data to the national systems (NMVS)
  • Pharmacy holders and wholesalers are connected to the national systems
  • Wholesalers perform risk-based sampling
  • Pharmacies scan the product to check the status of a serial number and sign them off
  • Competent authorities receive reports to enable research possible falsification

&

  • The patient is ‘assured’ a safer product

The scheme below gives a broad overview of how the system is designed.

Higher costs per packaging

Obviously, nothing is free and to no one’s surprise, the current hot topic is the price of medicines, which is bound to rise. The European Commission has already carried out an impact analysis in 2015 (Ecorys) to determine the effect of FMD on the price of drugs. They estimated a rise of up to 3 euro cents per packaging in general (so no differentiation between innovative drugs or generics etc.)

Other reports show significantly differing numbers like a report from CapGemini in which the additional costs of the FMD for the Dutch manufacturers of generic medicines are estimated at an average of € 0,17 per packaging.

Investments for manufacturing companies

As for the manufacturing companies that will be affected, the organization ‘Medicines for Europe’ has estimated that updating packaging and production lines will cost the average company 5 million with an additional 2 million annually for running and maintenance costs. According to their calculations serialization will cost the entire pharma industry 5 billion to update packaging and production lines and also 90 million the implement the EMVS accompanied with an equal amount annually to keep it up and running.

These additional costs that companies will be facing can vary to a great extent as they depend on factors like:

  • Adaptation of packaging processes with new packaging lines, set up and testing, artwork, and implementation of software and data-connections
  • Generation and management of serial numbers
  • Training
  • Registration dossiers
  • Higher stocks
  • Contribution to NMVS and EMVS
  • Project costs

Also, depending on total revenue, the number of products, and their presentations, FMD costs will vary per manufacturer. Especially for companies with relatively low volumes and/or low margins in a relatively small medicines market, costs will be ‘higher’ due to the vigorous investments (which have no guarantee of any possible payback). For instance, this will put a lot of pressure on generics and small scale companies, which may consequently choose to discontinue certain products or worse.

The intended result of increased patient safety will be paired with significant costs in any case and may even be too much to handle for some of the smaller companies. But how much exactly? Based on our experience we’ve come up with a calculation tool which should give you some insight into the ballpark figure to help you prepare.

RECEIVE OUR CALCULATION TOOL HERE.

Considerations

So, now you may have a ballpark figure, but what’s next? Preparing a business case, funding and actually getting started are the logical next steps. It might be helpful to consider using Lean Six Sigma as a methodology, this approach offers various tools that are well-suited for projects like these. And though compliance with the FMD is the primary objective you may very well be able to realise substantial savings in the process to compensate for these investments.

Feel free to contact us to find out how or any other questions you might have.

Blog by: Nick Veringmeier

How to organize a Kaizen (Lean Improvement Workshop)
10-01-2018

#How to organize a Kaizen (Lean Improvement Workshop)

Kaizen: The Japanese term commonly used for lean improvement workshops. Its meaning expresses what it’s all about: change for the better.

In life sciences, we tend to associate change with change control, which is usually justified because there are plenty common reasons why you need to be in control of every detail. But most of the time we don’t really change anything significantly at all because it’s ‘complicated’ and we go on like before.  In lean, change implies improving. Measuring and demonstrating success as you move on and leaving your current state behind for a new and improved one. The Kaizen specifically has proven itself in many different situations and in many businesses and has the very beneficial side-benefit that people feel heard, engaged and empowered.

For example, taking a number of people to one of their warehouses to "go see what’s actually going on there". They will probably experience that the people who actually work there are surprised when asked what could be improved. This is exactly the essence of Kaizen: not talking about but with your staff.  

What to improve

So to get started. The first step is identifying the area you want to improve on, or in lean terminology: define the problem. There’s plenty of formal tools to make the best choice like value stream mapping.  For instance, creating a complete map following a biopharmaceutical product including the receipt of materials, upstream and downstream processing, aseptic filling, release, and shipment to a customer. This map could show you that something like the water production is the actual bottleneck you’ve been looking for (and now you can improve it). Or it may be the time you need for batch record review or product release. Conclusions like these are usually the result of a Kaizen and are fully data-driven and, therefore, (most of the time) fully supported by the whole team. You can also brainstorm with a group of people and pick one improvement project. Most of the time people actually already know very well which areas can be improved on. Data-driven conclusions may be different from team-based intuition though, obviously.

Secure a sponsor

The next step is identifying your sponsor. If there is none who wants to support you, stop. Basically, there’s no way of organizing a proper Kaizen without sponsorship. Let’s say the event/deviation handling process in a packaging department needs to be improved and the involved Quality Officer doesn’t have time for the Kaizen.  As a result, he or she isn’t very likely to be engaged and in all probability not the most likely person to agree on the proposed improvements. Therefore, you need a sponsor to make sure that every stakeholder actively participates in the event and facilitate a unanimous agreement.

Prepare prepare prepare

After having made sure there is a sponsor it’s your role as facilitator to actually organize the Kaizen. Preparation is key, so agree with your sponsor on things like the definition of the problem, the scope of the Kaizen, would be considered a successful outcome, who’s on the team and the planning. Once these aspects are all settled, you can proceed with data collection.

Start with a plan and try to balance between the needed data and the effort to collect it. This depends mostly on what you want to improve, or in lean: what is problem? If you want to improve the workplace, like the warehouse, for example, observation is your best friend, in a QA release process data collection is more likely the preferred route and in other cases, you might want to focus on material movement. More generally, it may even be refreshing to actually observe what people are doing on their computer.

The Kaizen

At last, the day of your Kaizen has arrived. Make sure that all stakeholders show up and ask your sponsor for help to assure this. These sessions get cancelled occasionally simply because people don’t show up. At least you could tell yourself you’ve defined your first problem if that’s the case.

Your role as a facilitator is key during the Kaizen and you should try to focus on keeping the process going as planned. DMAIC is a very helpful tool here because you’ve already agreed with your sponsor upon the problem, scope, timelines, team, and Kaizen; thus, you already completed D(efine) and because you collected data, you also completed M(easure).



The kaizen is all about direct observation:  M(easure) and determine the root causes and complete the A(nalyses).  Flip-overs and post-its are most useful to support the analyze phase, e.g. to map the process and to prepare a fishbone, a cause and effect diagram which helps to identify root causes by visually displaying the many potential causes for a specific problem or effect.

To keep the process on track is one thing, to keep people on track is a completely different ball game:

  • People can become frustrated with each other in which case you’ll have to address this to some extent, otherwise people get disengaged.
  • Sometimes the subject matter experts seem to know everything about the topic at hand and tend to dominate team discussions. Unfortunately, there is a lot of “I think that”, “I believe that” or boldly “This is how it works” behavior in many companies. And because of this, you will need the data you previously collected to either confirm or reject statements.

Question, question, question and conclude. Make sure that everyone is heard and guide the entire group towards one eventual, consensual conclusion. Other “tools” you definitively need are enthusiasm, energy and humor.

In the traditional approach, all stages are done in five days but it depends very much on the company whether this is necessary or even realistic. You may also choose to end the Kaizen with root causes and solutions identified. In that case, implementation and control become part of business “as usual”.

Evaluation of the Kaizen

Make sure you get tangible and sustainable results. That’s critical. For sure, a properly executed Kaizen boosts team morale, but the hard work starts afterward. And this is all about project management and implementation. The reward, however, is an improved process with tangible results, e.g. errors decreased by 30%, lead time reduced with 40% and yield increased by 10%. And when the team experiences that their daily work has become easier, you can count on it that they won’t be able to wait for the next Kaizen to start.

Tip: If you’d like to experience Lean Six Sigma yourself have a look at our Lean Game of have a look at the Yellow and Green Belt training we provide with the Biotech Training Facility.

Blog by: Marc Stegeman - Certified Black Belt at Xendo

Meet us at Innovation for Health 2018
09-01-2018

#Meet us at Innovation for Health 2018

XENDO BIKE RAFFLE

Like last year, we will also be organising a raffle for one of our customized Xendo VANMOOF bikes! We are looking forward to meeting you there and don't forget to hand in your ticket at our booth!

INNOVATION FOR HEALTH 2018

Innovation for Health is the premier event on healthcare innovations in the Netherlands. It provides a unique opportunity to meet leading innovators, to catch up on the latest trends, to present cutting-edge innovations and to engage leaders and decision makers in healthcare innovation. Innovation for Health features renowned speakers, displays high impact innovations, highlights best practices and demonstrates inspiring developments in healthcare. By bringing together key players and stakeholders across the healthcare & Life Sciences spectrum, and fostering dialogue between research, markets, and policy makers, the event aims to contribute to the future of sustainable healthcare.

More info: https://www.innovationforhealth.nl/

Facing the challenges in clinical study vendor management
19-12-2017

#Facing the challenges in clinical study vendor management

Last year, announcements appeared on the FDA, EMA, and  WHO websites, that during regulatory inspections of a clinical contract research organization (CRO) in India serious violations were identified in the conduct of bioequivalence and bioavailability studies.

The outcome of these inspections didn’t just seriously impact the CRO, but also the pharmaceutical companies that subcontracted this CRO.

 “The inspection found significant instances of misconduct and violations of federal regulations, including the substitution and manipulation of study subject samples..” “the sponsor […] must repeat the bioequivalence/bioavailability studies […] at an acceptable alternate study site.” FDA, April 2016

“EMA recommends suspension of medicines over flawed studies…” “Bioequivalence studies performed at the site cannot be used to support medicines approval in the EU.” EMA, July 2016

 


Risks in vendor management

Present-day clinical studies are increasingly complex, more globalised, and making use of new technologies. As a result, vendors are often highly specialised and pharmaceutical companies (Sponsors) make use of many different vendors in one clinical study. In turn, these vendors often subcontract activities to third party vendors. Sponsors should understand that the use of all those vendors and their subcontractors can be very risky because if one of them fails to be compliant, it can have disastrous consequences for the development of your product.

According to Good Clinical Practice (ICH E6, section 5.2.1), the Sponsor always remains ultimately responsible for the quality and integrity of a study. In the revised ICH E6 (section 5.2.2) it’s stated that Sponsor oversight is not just limited to the vendors they contract, but it also includes the vendor’s third parties.

Some examples of risks in vendor management that might seem familiar:

  • Your company has a list of approved vendors, but… under time pressure, because it was requested because they know the vendor… the study team decides to contract an unapproved vendor or an approved vendor for unapproved services.
  • Your qualified vendor decides to change procedures or one of their vendors without notifying you, the contract giver. This may not seem like a big deal, but what if this change involves critical study activities or software?
  • During the vendor qualification audit, everything looked perfectly fine, but now your vendor doesn’t perform as expected... Serious breaches aren’t escalated, deadlines are missed, overall quality is low… 
  • Are we using Sponsor procedures, vendor procedures, or a combination? Confusion about the applicable procedures can lead to an inconsistent approach to study execution (document management, monitoring, reporting of deviations, etc.) and may finally lead to significant quality issues.
  • Use of different vendors does not only complicate the clinical study execution and (essential document) management. It may also lead to additional data integrity risks. Are you sure that clinical study data collected in different systems finally end up in one location? Are data still reliable when they are transferred from one system to another? Is a reliable analysis of all study data possible during or at the end of the study?

Mitigating the risks

Quality agreements between Sponsor and vendors to document the responsibilities and expectations to ensure the quality of a study are quite common nowadays. Sometimes it’s already part of the contract. But does this give the assurance, that there is a robust quality system in place for your clinical study and will it make sure you don’t face any surprises at some point during or even after the study?

Risks can be further mitigated by a carefully thought-out vendor oversight approach, considering the following aspects:

Formalise your vendor management approach.

Standardising your processes in selection, qualification, contracting, managing and even ending collaboration with vendors can support your company in adequate vendor oversight.  Assign a vendor manager or vendor management team, which can support your company in keeping vendor oversight. A vendor manager can manage the contracts, interact with quality assurance, and be involved in issue/conflict management.

Don’t underestimate the importance of good communication lines (and trust).

Make sure there is a detailed Sponsor-vendor and/or vendor-vendor communication plan in place. Open and transparent communication is essential for smooth execution, prompt handling in case of issues and a reliable study outcome. A relationship built on trust is essential. This is a two-way process: The vendor should be transparent and share potential issues; the contract giver should establish an open environment. Immediate repercussions will work counterproductive. Instead, focus on an action plan to mitigate any risks and improve any processes.

Vendor qualification and requalification are more than ‘just’ an audit.

  • In addition to auditing the vendor’s quality system, competencies and qualifications, experience and resources, have you considered the following? Try to assess the ‘soft’ aspects of vendor quality, such as communication, reliability, collaboration and quality awareness (the quality culture). Not easy to objectify, but you may have a look at repeat business, staff turnover, quality objectives, visibility of leadership, and accessibility to staff during an audit.
  • Assess vendor continuity. In other words, are you sure that the vendor still exists in a few years? Are there any signs of potential acquisitions or mergers, which could potentially influence the commitment of the vendor to your company?
  • Invite a subject matter expert to accompany the auditor. The assigned auditor may not have the in-depth knowledge to assess certain aspects of the considered services. If necessary, involve the Information Technology department or consider to hire a GxP IT auditor.

Consider the potential risks in the combination of vendor activities and systems.

Don’t only consider the potential risks at the level of individual vendors, but also ensure adequate oversight of and assess potential risks in the entire chain of processes and data, from vendor to vendor, from vendor to sponsor. A systematic quality (risk) management approach will finally ensure the integrity of the entire clinical study.

 

Conclusion

When activities are outsourced, the most important task of a Sponsor is to keep good oversight, both by overseeing the individual vendors and by looking in a more systematic way at the use of different vendors in one study. Adequate vendor oversight could avoid issues, which may have any impact on the integrity of the entire study.

Blog by: Henrieke de Bie - Senior Consultant at Xendo

Brexit Life Sciences Highlights
12-12-2017

#Brexit Life Sciences Highlights

Below you'll find the highlights that we have selected for you regarding regulatory, pharmacovigilance and quality related matters in the Life Sciences industry in a chronological order


Brexit preparedness: EMA to further temporarily scale back and suspend activities, EMA, 01-08-2018 - General

Following the implementation of phase 1 and 2 of the business continuity plan, in phase 3 EMA will start to temporarily scale back or suspend additional activities through to 2019. This contributes to protecting EMA’s essential public health activities and allows for training of EMA staff who will be re-assigned to new duties ahead of the peak relocation time which will start in early 2019. 

Activities initially impacted by phase 3 include (a.o.) collaboration at international level, development and revision of guidelines, holding of non-product related working parties, and clinical data publication.

Read more. 


Practical guidance for procedures related to Brexit for medicinal products for human and veterinary use within the framework of the centralised procedure, EMA, 19-06-2018 - General

The below Practical Guidance has been developed taking into consideration that as of 30 March 2019 the United Kingdom will become a third country. As a result, MAHs and applicants of centrally authorised products for human or veterinary use need to ensure that the necessary changes are made by the 30 March 2019, unless indicated otherwise in the guidance below. This document complements the EC-EMA Q&A to provide procedural and practical guidance regarding submission of changes and related fees.

Read more. 


Questions and Answers related to the United Kingdom's withdrawal from the European Union with regard to national authorised medicinal products for human use, EMA, 19-06-2018 - General

This list of Q&As has been drafted by the CMDh taking into account the European Commission's and EMA's Questions and Answers on the same issues within the framework of the centralised procedure. This version is an update of the initial list of Q&As as subsequently amended and it replaces all previous versions of Q&As. The new text introduced in this version of Q&As is indicated by the word "NEW". The Q&As may be further updated and complemented in the future.

Read more. 


The European Medicines Agency and Netherlands agree on Seat Agreement, EMA, 24-04-2018 - General

The agreement describes how the Agency, its bodies, and its employees will be treated by the Dutch government after the transition and are operational in the Netherlands. Negotiations between EMA and the Dutch government were wrapped up earlier then expected, which is has a positive affect on EMA staff and their families because they will have clarity sooner and can focus on settlement in the Netherlands. The agreement will come into force once both parties have signed the document.

Read more. 


Completion of redistribution of the UK Centrally Authorised Product portfolio, EMA, 11-04-2018 - General

The methodology for the redistribution of the UK product portfolio for CHMP/CVMP/CAT/PRAC (Co)-Rapporteurships for human and veterinary products was endorsed by the Management Board at its December 2017 meeting. The methodology is flexible, easy to explain and implement, and can be applied equally to human and veterinary medicines. It involves a multifaceted approach for allocation of the UK product portfolio within the Network, which takes into consideration the results of the surveys, the expertise within the Network and workload for each medicinal product. The proposal ensures an optimised and robust allocation of the workload across the Network and guarantees efficiency within the Network, making it sustainable. In addition, it allows NCAs to participate in EMA activities, as per the capacity of each NCA.

Read more. 


MPA Brexit info meeting, Läkemedelsverket, 5-2-2018 - GENERAL

Slide deck from the Swedish Medicinal Products Agency with a brief Brexit introduction and insighto into Brexit from a pharmaceutical perspective, practical aspects, variations, change of RMS – Reference product from UK and a Q&A session.

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Notice to marketing authorisation holders of centrally authorised medicinal products for human and veterinary use, EC & EMA, 29-1-2018

Subject to any transitional arrangement that may be contained in a possible withdrawal agreement, as of the withdrawal date, the EU rules in the field of medicinal products for human and veterinary use no longer apply to the United Kingdom. This has, in particular, the following consequences in the different areas of EU law on medicinal products:

  • EU law requires that marketing authorisation holders are established in the EU (or EEA);
  • Some activities must be performed in the EU (or EEA), related for example to pharmacovigilance, batch release etc.

Read more.


EMA surveys pharma companies on their preparedness for Brexit, EMA, 23-1-2018 - GENERAL

The European Medicines Agency (EMA) is launching a survey to gather information from companies on their Brexit preparedness plans and identify any particular concerns with regard to medicines supply that may impact public or animal health.

Read more.


MHRA update to pharmaceutical companies on exit preparations, MHRA, 16-1-2018 - REGULATORY AFFAIRS

More clarified information on the positioning of the MHRA in its current environment and future Brexit changes to ensure continuity.

Read more.


Guidance from the Irish authorities on Brexit, HPRA, 20-12-2017 - REGULATORY AFFAIRS

According to the HPRA, there are many areas to consider regarding Brexit - but these also all subject to change depending on the Brexit government discussions. This is explained clearly is this guidance for areas like Reference Member States, MS, generic, Clinical Trials, PhV, import & export. It also reaches out to the Irish HA and stakeholders to be pro-active.

Read more.


EMA Management Board: highlights of December 2017 meeting: Brexit update and adoption of work programme and budget for 2018, EMA, 15-12-2017 - GENERAL

The Management Board of the European Medicines Agency (EMA) heard from Executive Director Guido Rasi and Deputy Executive Director Noël Wathion how the Agency is preparing for relocation to Amsterdam in the Netherlands, and operationally for the United Kingdom’s (UK) withdrawal from the European Union (EU). This is the first meeting of the Board since the General Affairs Council (Art.50) of 20 November and the decision of the EU 27 Member States to relocate the Agency to Amsterdam. EMA now has just over 15 months to prepare for the move and take up its new seat in Amsterdam by 30 March 2019 at the latest.

Read more.


EMA management Board meeting, EMA, 15-12-2017 - REGULATORY AFFAIRS

EMA and the Dutch authorities are currently working on a Memorandum of Understanding (MoU). The Board was also informed that EMA’s Brexit preparedness business continuity plan will enter Phase 2 in January 2018.

Read more.


Brexit related manufacturing and supply, European QP Association, 12-12-2017 - QUALITY MANAGEMENT / QP

This Q&A document explains from the manufacturing, release and distribution perspective and recommends that Life Sciences companies should be pro-active to ensure compliance and efficiency during Brexit.

Read more.


Questions and Answers related to the United Kingdom's withdrawal from the European Union with regard to national authorised medicinal products for human use, CMDh, 1-12-2017 - REGULATORY AFFAIRS

On 2 May 2017, the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) published a Notice to marketing authorisation holders of national authorised medicines products for human use. In this regard, marketing authorisation holders of national authorised medicinal products for human use are reminded of certain legal consequences that need to be considered in a timely manner. Preparing for the consequences of the UK’s withdrawal from the Union is not just a matter for European and National administrations, but also for private parties. 

Read more.


Is Brexit a positive for the UK’s pharma sector? Here are seven factors in favour of this, EPM Magazine, 29-11-2017 - GENERAL

Article which shows more intel about how the Brexit will positively influence the UK's pharmaceutical industry.

Read more.


Procedural guidance to help pharmaceutical companies prepare for Brexit, EMA, 28-11-2017 - GENERAL

The guidance document outlines the practical and simplified requirements that companies should follow when they apply for changes to their marketing authorisationto allow for the continued marketing of their medicine in the European Economic Area after the UK withdraws from the EU. The guidance has been prepared on the basis that the UK will become a third country as of 30 March 2019. It should be read in conjunction with the Questions and answers related to the United Kingdom's withdrawal from the European Union with regard to the medicinal products for human and veterinary use within the framework of the centralised procedure published in May 2017.

Read more.


The Netherlands welcome EMA, 20-11-2017 - GENERAL

Rembrandt and van Gogh, tulips, clogs and windmills, a sample of what we’re famous for. We might be small, but we’re a great country. And it’s our pleasure to welcome the European Medicines Agency to The Netherlands.

The Netherlands will prove itself to be a true home to the internationally oriented EMA community and its staff thanks to its excellent accessibility, high-quality of living, and a population consisting of over 180 nationalities.

Read more.


The Dutch Bid for EMA, CGB-MEB - GENERAL

The Dutch Health Authority has promoted its offer to attract the EMA in a nice looking website.

Have a look!


EFPIA Brexit Survey results, EFPIA, 8-11-2017 - GENERAL

A slide deck with the insightful results of a survey performed by the European Association of Pharmaceutical Industries and Associations surrounding the impact that Brexixt will have on the Life Sciences Sector.

Read more.


END

 

SERIALISATION AND UDI: 4 REASONS TO START TODAY
05-12-2017

#SERIALISATION AND UDI: 4 REASONS TO START TODAY

In recent years, new European legislation on traceability of medicinal products and medical devices was introduced to guarantee patients’ safety and to avoid fraud. Depending on the industry in which you work, you might have heard more of either Serialisation or UDI (Unique Device Identification). Below we will mention the difference between them. Although the terminology is somewhat different for medicinal Products and for medical devices, in both cases, this is about traceability. And to be precise, it is about track (where the product is now) and trace (where the product came from).

In this blog, we will explain why we advise you - as a medical devices supplier, a medicines supplier or as a logistics service provider - not to wait much longer and start implementing unique identification to take advantage of traceability.


The benefits of traceability

Legislation is not the only reason to implement unique device identification. Traceability has a significant impact on the efficiency of your own and your customers’ operational processes. Traceability is actually nothing new. In many other industries, logistical efficiency is crucial and for years, organisations have been ‘tracking and tracing’ their products with unique identifiers.

For healthcare institutions and pharmaceutical wholesalers, working ‘lean’ is becoming the new standard. For example, if your products do not have machine-readable barcodes, institutions might not purchase your products, as being able to scan all products, benefits them in many respects. Think of: having all relevant data available as soon as a product arrives, having insight of your stock levels, constantly knowing where it is or getting an alert when the expiration date is within e.g. a year. With traceable products, you are better prepared for your customers’ requirements and, of course, for your own efficiency improvements.


4 reasons to start today

As the legislation applies as of February 2019 (for medicines) and May 2020 (for medical devices1), you might think you still have time. But consider to start yet for the following reasons:

  1. Efficiency. Just because of the fact that efficiency is of increasing importance to you and your customers, traceability is recommended.
  2. Implementing traceability might require some significant organisational adjustments, think of:
    • Redesign of packaging and labeling
    • Adjustments to packaging lines and automation systems
    • Documentation of adjusted packaging specifications and procedures including getting approval for them
    • Validation of new or modified packaging processes, equipment, and IT systems.
  3. It is better to avoid rushing into (flawed) decisions. In case you need advice or support to design a new or modified process, the farther the deadline, the more time you have to consider your options.
  4. Practice in the United States has shown, that even with a segmented implementation and with a wealth of experience with UDI, manufacturers have difficulty meeting the deadlines.

The difference between Serialisation and UDI

The European Medical Device Regulation (MDR) 2017/745 published in 2017 elaborates on prior traceability regulations and introduces UDI for medical devices, which you should apply as of May 5th, 2020. UDI stands for ‘Unique Device Identification’ and consists of a device identifier (for manufacturer and model) and a product identifier (for packaging unit, batch, production date or expiration date). So, as it is prescribed now, ‘unique’ does not imply traceability of the smallest saleable unit.2

When reviewing Serialisation regulations for medicines, you will find that the identifier prescribed should be unique for every saleable unit, enabling traceability throughout the entire sequence from manufacturer to the last part of the supply chain, in particular cases even up to the individual patient. The Delegated Regulation (EU) 2016/161 published in 2016 introduces two safety features - a unique identifier (two-dimensional barcode) and an anti-tampering device - to be placed on the packaging of medicinal products as of February 9th, 2019. Although this level of identification for medicines is not yet required for medical devices, it is expected that future ‘Implementing Acts’ for the new MDR will include traceability of the smallest saleable unit, up to the patient as well.


Getting started

So, what now? Start orientating and ask yourself questions like: What is your organisation’s situation at this moment? What is your knowledge of the legal requirements and of the efficiency opportunities? What should be your next step? What do you need for that? How much time will it take? 

It’s well-advised to raise your knowledge level, provide a clear overview of your situation, do a gap analysis and provide solutions, explore different options, share best practices with others in the field, and start drafting an action plan. If you are uncertain about some aspects, don’t hesitate to contact us, we will be happy to talk to you about it.

Blog by: Louis Habets - Sr. Consultant & Trainer at Xendo

 


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Footnote 1

If the European Medical Device Database Eudamed not fully functional is on May 26 2020, numerous requirements listed in the MDR and relating to where any information needs to be stored in Eudamed, will apply six months from when the Commission has published a notice declaring that Eudamed has achieved full functionality. While waiting for Eudamed to become fully functional, the corresponding provision regarding the exchange of information in the MDD and AIMDD will continue to apply. This regards particularly Vigilance Reporting, Clinical Investigations, the Registration of Devices and Economic Operators, as well as Certificate Notifications.

Footnote 2

When will UDI carriers really need to be placed on the label of devices and all higher levels of packaging as described in Article 123,3f, depends on the Risk Level of the product:

  • May 26, 2021 for Implantable and Class III devices;
  • May 26, 2023 for Class IIa and IIb devices;
  • May 26, 2025 for Class I devices.
  • How soon the UDI carrier need to be placed on re-usable devices is determined in Article 123,3g as:
  • May 26, 2023 for re-use Implantable and Class III devices;
  • May 26, 2025 for Class IIa and IIb re-usable devices;
  • May 26, 2027 for Class I re-usable devices.

Slide Deck: Changes in the Medical Device Legislation; the day after.
24-11-2017

#Slide Deck: Changes in the Medical Device Legislation; the day after.

Feel free to download the slide deck of one of our recent talks on the new Medical Device Regulation which was presented by Jan Bart Hak at the autumn meeting of the Pharmacovigilance  Platform Netherlands on November 21st, 2017.


The European Medical Device Regulation 2017/745 (MDR) is published on May 5, 2017, in order to replace the current Medical Device Directive 93/42; it will apply 3 years after this date. Requirements related to the technical file and procedures will be significantly reinforced, without the possibility of grandfathering.

These new requirements will affect the entire medical device (MD) industry with products in the EU. This implies that companies with products on the market within the European Union will need to come up with a transition plan to comply with these new rules and they have until May 25th, 2020 to do so.

A short calculation tells us that the countdown is at two and a half years at this point. As an example, in case the clinical evidence needs to be updated, one must start now. Clinical evidence can be collected in a clinical investigation or via post-marketing surveillance, which includes vigilance and post-marketing clinical follow-up studies. If a medical device company does not start now, it can be too late risking the CE mark and so market access.

Click here for the PDf of the full slide deck.


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MDR: Why you should start now or lose money!
21-11-2017

#MDR: Why you should start now or lose money!

Although the new Medical Device Regulation (MDR) is now officially effective (in co-existence with the Medical Device Directive, MDD) we’ve noticed that some companies are well on their way with the transition (mostly EU companies) but there seems to be only a small percentage of US companies that has actually started to transition from MDD to the MDR. Especially for Regulatory Affairs (RA) managers this might be frustrating because they are well aware that from short-term perspective sticking your head in the sand, in the long run, might cost you serious money. Here’s why.



MDD TO MDR


For those who haven’t yet had the time to investigate what (mandatory) changes the future holds in the Medical Device field, we can summarize it as follows: requirements regarding your product are increasing and becoming stricter. Examples are requirements regarding, risk classification, clinical evidence, Economic Operators, and Post-Marketing Surveillance. All currently certified Medical Devices (MDs) must be re-certified in accordance with these new requirements.
First of all, companies are well-advised to perform a GAP-analysis to see how they want to proceed with their product. Three likely outcomes could be:

  1. You find no go GAPs which means ‘no worries’.
  2. Major GAPs meaning there’s a lot of work and you should start rather sooner than later.
  3. So many GAPs that you might consider discontinuing your product and withdraw it.


This implies that companies with products on the market within the European Union who find themselves in the second category will need to come up with a transition plan to be compliant with these new rules and they have until May 25th, 2020 to do so. A short calculation tells us that the countdown is at two and a half years at this point.


To assist RA managers eager to start a possible transition we’ve lined up some situations that might motivate all their colleagues to set things in motion. We suggest exploring the three most likely options that could be considered.



1. WHAT IF I DON’T?


Definitely a bad idea. The new MDR does not allow for grandfathering meaning that products that are currently on the market will not automatically be approved to stay on the market. So, if you choose not to transition to the MDR your product will no longer be allowed on the European market and consequently, you will lose income in other countries where turnover is dependent on a valid CE-mark.



2. I’LL DO IT LATER


Tempting, but not a good idea either. To explain this, let’s have a look at the math. To be compliant with the new MDR there are activities that have certain throughput times.
For example, let us assume that your clinical evaluation gap analysis shows that you need to upgrade your clinical data with data from a Post-Marketing Clinical Follow-up study (PMCF). If we pivot these numbers against the time left until you lose your CE-mark, we come to the following:

Activities that would have to be performed against the time it would take and the time that is left in months.

All these activities alone leave you with ‘0‘ months left until your CE mark (read: market approval) expires if you aren’t compliant with the new requirements. So actually, we can say that every moment that companies are delaying the transition to the MDR they will be facing a loss of revenue from the marketed product.



3. START NOW


Yes, we agree. This does not mean that you will be overwhelmed by additional work that can’t be handled.
For instance, your strategy on extending clinical data can be considered via Post Marketing Surveillance while still under the MDD using a PMCF study to gather this data. Under the new MDR, this collection of clinical data without a CE-mark will be considered a clinical investigation, which is subject to far stricter requirements. In that case, you’ll have to set up, for instance, a new randomized controlled clinical study with a 100 patients, a 6-month patient follow-up, and at 10 different sites which is a very costly process with patient insurance, submittal to the Competent Authorities and longer timelines than a PMCF. And also for other issues, a pragmatic approach can often be chosen so that your product’s certification remains valid and continuity of sales is not hampered by regulatory issues.


ARGUMENTS & BUY-IN


We can assure you that securing buy-in from the decision makers and different stakeholders in your company is essential in situations like these. So to pave the way we’ve lined up some arguments to use in persuading that you need to start today.
Since it all usually comes down to commercial considerations, this is likely to be your strongest argument. Here are some examples to paraphrase the money issue:

  • Loss of revenue in all countries where turnover depends on a valid CE-mark
  • Correct expected projections beyond 2020
  • Losing business will eventually result in a loss of qualified staff
  • Increased investments will be required to make up to regain lost market share
  • Investors are very aware of the MDR and usually require a transition plan
  • The company’s reputation is at stake

TRANSITIONING


The implementation of the MDR or the transition, if you will, is most likely an extensive project. And this actual transition is something we’ll get back to in another blog. To put it shortly, all companies are strongly advised to come up with a comprehensive transition plan including:

  • Relevant Differences
  • Risk Class Determination
  • Conformity Assessment Procedure
  • Top Management Awareness and Commitment
  • Implementation Plan
  • Assessment Partner
  • Product Documentation
  • Quality Management System
  • Post Market Activities and Reporting

In conclusion, although the deadline of May 2020 seems far away, it really is false security. To ensure continuous compliance of medical device products to the new legislation, i.e. the MDR, a swift start and a solid plan are necessary. This will bring peace of mind to any Medical Device company because business continuity is assured.


So instead of waiting around to see what the future holds, get started and find out where you’re at. And if you’d like some more specific information don’t hesitate to leave us a message.

Blog by: Nick Veringmeier


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EMA: Welcome to the Netherlands
20-11-2017

#EMA: Welcome to the Netherlands

Rembrandt and van Gogh, tulips, clogs and windmills, a sample of what we’re famous for. We might be small, but we’re a great country. And it’s our pleasure to welcome the European Medicines Agency to The Netherlands.

The Netherlands will prove itself to be a true home to the internationally oriented EMA community and its staff thanks to its excellent accessibility, high-quality of living, and a population consisting of over 180 nationalities.

As a fast-growing company, we are ready to support all life sciences companies during the transition of the EMA from London to Amsterdam. With over 240 efficiently cooperating consultants (including QPs, QPPVs, and Auditors) in different fields of expertise, we’re able to offer our customers a complete palette of services. Especially our familiarity with The Netherlands’ Health Authority, the MEB-CBG, will prove to be an asset for all companies that require expertise regarding their upcoming Regulatory Affairs changes that this transition will bring about.

Please contact us to find out more.

Xendo awarded for the third time in a row as FD Gazelle
14-11-2017

#Xendo awarded for the third time in a row as FD Gazelle

Xendo was named an FD Gazelle 2017 again, meaning we belong to the fastest growing companies in the Netherlands for the third time in a row. The Gazelle Awards, an initiative of the ‘Financieele Dagblad’ (Dutch Financial Times), are awarded annually to the fastest growing enterprises, where the main criterion is a turnover growth of at least 20% per year during a three-year period.

André van de Sande (CEO, Xendo) says:

Our clients increasingly know how to find us for our expertise and support in all phases of product development and we are very grateful for the trust they place in Xendo.

Based on this trust, we have been able to grow our organization from 60 to over 240 employees. We plan to further expand in the Netherlands as well as internationally and as such we are always open to getting into contact with new potential colleagues. Please visit our website to see an overview of our most recent vacancies.