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French GVP: 7 major changes for the pharmaceutical industry
29-11-2018

#French GVP: 7 major changes for the pharmaceutical industry

 On February 5, 2018, the French National Security Agency for Medicines and Health Products (ANSM) updated their Good Pharmacovigilance Practices (FR-GVP)[1] with the aim of bringing the French particularities in line with EU pharmacovigilance requirements (EU-GVP)[2]. Initially, the FR-GVP were published in 2005 and last updated in 2011. This new version introduces substantial modifications in order to adapt to today’s drug safety challenges and the new version of EudraVigilance (EV) system which was launched on November 22, 2017.

So, what are the major modifications and how do you deal with these changes? Our before and after comparative analysis helps to clarify these questions by identifying the seven major changes.


1. A first time for the ANSM

Before, the FR-GVP would have been submitted by ANSM to the French government and validated by the French Minister for Solidarity and Health. However, with the aim of simplifying the procedure, the power of approval for such matters has been transferred to the General Director of ANSM, currently Dr. Dominique MARTIN, according to the Code of Public Health[3]. This responsibility gives the ANSM a full control on the FR-GVP and this new version is the first one that has been published since this decision.


2. A new tool for reporting AEs

In line with the ANSM program of continuous improvement and modernization, a web portal[4] for reporting adverse events (AEs) has been established in March 2017. This permits both patients and healthcare professionals to access the different reporting systems of AEs. Information collected through this online platform is automatically sent to the adequate regional pharmacovigilance center among the Centres Régionaux de Pharmacovigilance. In the new version of the FR-GVP, the chapter relating to the declaration of AEs describes this new tool as the preferable method to declare AEs. Furthermore, a chapter is specifically dedicated to the role of the patients in PV and explains the procedure to declare AEs through this new platform. 


3. Description of EUQPPV & LPPV roles

The FR-GVP also details the role of the EU-QPPV (Qualified Person responsible for Pharmacovigilance in EU) and of the LPPV (Local Person for Pharmacovigilance). Indeed, pharmaceutical companies need an efficient PV system by appointing an EUQPPV, responsible for all related PV activities, and an LPPV, in charge of all PV activities on a national level.

Moreover, an EU-QPPV can also handle the position of LPPV if he/she:

  • Is a medical doctor or a pharmacist
  • Is located and executes his/her activities in France
  • Has proven expertise in PV

4. Modifications of MAH and ‘’Exploitant’’ responsibilities

The ANSM published an FAQ in June 2018 which:  

  • Explains the differences between Exploitant and MAH, as the Exploitant is a local particularity. An Exploitant is a company which commercializes the pharmaceutical product without necessarily being the MAH. An Exploitant can be responsible for PV activities but in this case, the respective roles between Exploitant and MAH must be defined.
  • Clarifies the AEs declaration to the ANSM. There is no more obligation for Exploitant/MAH to report Medication Errors without AE to the “ANSM Medication Error Desk’’ or to submit reports of abuse or dependence to medicines containing psychoactive substances to the Dependence Evaluation and Information Center (CEIP).

5. Definition of the scope of audits

The new FR-GVP specifies that the Exploitant must monitor the PV system, its performance, and efficacy by conducting audits in accordance with GVP Guidelines.

The scope of the audit can vary according to the status of the Exploitant.

Indeed. if the Exploitant is also the MAH, the audit program should be based on PV audit procedures and cover at least:

  • Internal PV procedures and their correlation with the regional PV system in place at HQ level
  • Audits of affiliates where appropriate
  • Audits of vendors providing PV-related services
  • Audits of distributors, etc.

On the other hand, if the Exploitant is not the MAH (e.g a French affiliate), the scope of the audit concerns:

  • PV procedures (internal and in the interface with MAH), reference can be made to audits performed by the MAH
  • Contracted vendors
  • PV partners (local contract)

If the audit is performed by the MAH, the Exploitant (responsible Pharmacist and LPPV) must get a copy of the audit report including CAPAs.


6. Harmonization with European-GVP

France contributes to the European Medicines Agency’s Eudravigilance database. Due to Eudravigilance new functionalities from November 22, 2017, new procedures for the exchange of electronic transmission of Individual Case Safety Reports (ICSRs) have also been implemented in the FR-GVP. The ANSM no longer sends ICSRs to pharmaceutical companies by regular post but uses Eudravigilance. For ICSRs from literature, pharmaceutical companies are no longer required to forward the corresponding articles to the ANSM since 10 July 2017.


7. Clarification on the PSMF

Like the MAH, the Exploitant must have an up-to-date copy of the Pharmacovigilance System Master File (PMSF). In addition to the global PSMF, a local PSMF is also required and should include:

  • The identity, qualification and contact details of the LPPV/EUQPPV
  • The organizational chart of the local PV services and the management system
  • The description of the organization of the PV system and the management of PV related activities
  • The list of current procedures concerning PV
  • The description of all PV tools used in the company
  • The list of all the contracts between the Exploitant and the MAH
  • The description of PV training
  • The description of the archiving process

 


What’s next?

From now on, the ANSM has stated that the FR-GVP will be updated on a regular basis to give clearer guidelines on the National level, ensure a better concordance with the EU Guidelines and improve communication with pharmaceuticals companies.

Blog by: Juliette Bayle

[1] Bonnes Pratiques de Pharmacovigilance, 05-02-2018, https://ansm.sante.fr/content/download/115483/1461439/version/1/file/BPPV-fevrier_2018.pdf
[2] Good Pharmacovigilance Practices (EMA),
https://www.ema.europa.eu/en/human-regulatory/post-authorisation/pharmacovigilance/good-pharmacovigilance-practices
[3] Article 2 of the ordinance n.2016-966 (5 July 2016), Code of Public Health
[4] www.signalement.social-sante.gouv.fr
Get the most out of your GMP effectiveness checks
22-11-2018

#Get the most out of your GMP effectiveness checks

The effectiveness check; a requirement after the close out of your investigation, following a deviation, suspected product defect or other problem (EU GMP Chapter 1.4.xiv).

But what exactly is the effectiveness check, and how do you apply it adequately?

The effectiveness check is the verification that the root cause was remediated. It is performed as the final act but can be defined as soon as the root cause is known.

When performing an effectiveness check, it usually belongs to one of three different categories:

  • Check for recurrence of the root cause
  • Check process data
  • Use audits and spot checks

Recurrence of the root cause

Trending for recurrence is the most common approach used. However, there are some challenges when using recurrence as an effectiveness check. The problem that was resolved should be a recurring issue, with a known rate of occurrence. This rate of occurrence should be sufficiently high, and consistent. The effectiveness check is aimed at waiting a set amount of time to ensure the issue doesn’t happen again. This only works if there is ample opportunity for it to happen, in case the root cause was not remediated adequately.

Talking about the time frame, this should not be an arbitrary period (3 months, 6 months), but should be based on the rate of occurrence. As a general guidance, the time required is three times the number of batches needed for 1 occurrence (e.g. if an issue occurs 1 in 20 batches, then the time frame should be approximately 60 batches).


Process Data

Process data is used when the corrective actions are aimed at adjustment or improvement of systems, which are regularly or continuously monitored. This can be continuous process monitoring, like conductivity or temperature, or data that is obtained on a regular basis, like IPC measurements or QC (release) tests. In both cases, it must be possible to obtain a sufficient amount of data from before and after the implementation of CAPA to trend the data. Furthermore, the adjustment or improvement should introduce a significant shift in the process monitored. The shift or difference observed should be statistically relevant.


Audits and Spot Checks

Whereas the two methods described above are data-driven and provide objective evidence for the effectiveness check, these methods are not always useable. For example, when a corrective action intends to obtain a behavioral change, there is generally no data generated by a system that can be used to verify if the intended change was achieved. In this circumstance, the only method is to go and observe the behavior as a process witness. Although there are drawbacks to this approach, it might be the only one available. As with the other methods, the conditions and requirements for the effectiveness check must be well defined, taking into account the risks associated with the type of effectiveness check performed.


Completion of the effectiveness check

When the effectiveness check is performed, and the CAPA remediated the root cause, the evidence is added to the record, and the file is closed. But what would you do when the effectiveness check fails? In that case, you have to assess where it failed. Generally, there are three possibilities.

  • Firstly, the true root cause was not found. In that case, you have to redo the root cause analysis, redefine CAPA, and set up a new effectiveness check.
  • Secondly, the CAPA did not adequately remediate the root cause. When that happened, the CAPA plan needs to be redefined. The original effectiveness check is likely still applicable, as the root cause didn’t change.
  • Lastly, the effectiveness check was not set up correctly. In that circumstance, the effectiveness check can be redefined and redone.

Another point to consider is that, in a well-developed quality management system, effectiveness checks are, to a certain extent, inherently part of your system. For example, when the deviation management system includes a check on recurrence for each new event, this could replace the effectiveness check for a recurring issue. Or, when the remediation of the root cause includes a validation, and the validation includes the verification of the desired functioning of the system, this can be used as an alternative to the effectiveness check.

At the moment, the effectiveness check is still a topic that leads to a lot of worries and is not structurally implemented in many companies. It is not always applied correctly, or occasionally, not applied at all. Even though it is the closing out, and confirmation that you adequately remediation your problem. And a regulatory requirement.

Also struggling with the effectiveness check? Don’t hesitate to contact us!

Blog by: Onno Kaandorp

A Day in the Life of: Ton de Ridder
14-11-2018

#A Day in the Life of: Ton de Ridder

FACTS

Age: 47

Studied: Laboratory techniques

Experience: Computer systems Validation, Performing validation studies, Preparation Clinical Trials, GLP QA auditor, performing analyses on analytical laboratory

Goals: Taking on more responsibility as a consultant and buying a yacht to cross the atlantic


PERSONAL DESCRIPTION

I studied Laboratory techniques and subsequently achieved my Bachelor of Applied Science in Chemistry in Leiden. I worked for Astellas for 15 years first as a technician in clinical trials (preparing all clinical materials such as capsules, labelling, packaging, etc) and then as a GLP QA Associate (performing audits). In 2015, I started working at Xendo in the computer system validation team, and I am currently an associate consultant.  

As a person, I can describe myself as an honest and open-minded person who is always willing to learn and has a keen eye for quality.


MORNING

How do you get ready to start your day?

Living in Leiden, I take my bike to work permitting me to get some fresh air and energy, and I also use this time to switch my mind from family to work matters.

What is something you look forward to every day?

Regardless of the subject I feel well when I achieve the tasks I’ve planned for myself on a typical day.

So, what do you do every morning?

Working on various projects and making sure all prerequisites (GMP qualified laptops for instance) for us to do our work are available and if they’re not, coming up with solutions to get results. I also like to plan ahead to make sure I have a good overview of all the tasks and deadlines we have concerning the different projects.


LUNCH

How do you spend your lunchtime?

Depending of the workload, I preferably have lunch in the canteen with colleagues talk about just about everything, work related or not.


AFTERNOON

What is something you do every day?

Our team, as the name implies, is mostly involved in projects within pharmaceutical companies to make sure their computerized systems are compliant. So this means we write protocols, execute and report the actual validation, and we also perform project management.

Besides this, communication is key for me, so I try to keep an open channel with my colleagues so we can support each other whenever it’s needed.

What is the most challenging part of your job or day?

The most challenging part of my work is to find a balance between priorities and deadlines: because being involved in multiple projects at the same time shouldn’t mean less quality work.

What makes you happy during your day?

It’s always nice to hear that your work is being appreciated: getting a compliment gives me energy, makes me feel understood motivated. In general, I believe positive feedback works better than an overload of criticism.

And how does this company define and measure your success?

It is mostly based on facts (number of hours, daily activities,…), regular meetings with the project manager and project members who provide feedback.


CAREER

Why did you pick this job?

I enjoy the fact that I get to work in various companies of different sizes and cultures and collaborate on different levels within these companies. Besides, I also love a good challenge!

How does it fit into your career plan?

Moving forward in my career, I would like to be promoted to consultant.The reason is that I want to manage and take responsibility for my own projects and be successful in that position.  I’d get to set up my own team I’d like to focus on blockchain technology and its implications for the pharmaceutical industry. And, of course, working my way to a big yacht in the atlantic eventually.

To whom would you recommend this line of work?

I guess to people who have a common interest in IT and/or automation and regulated environments. The work covers the full lifecycle of a computerized system so you need to be able to maintain a good helicopter view and overcome obstacles as you move forward in your projects. In other words; who wants to be consultant needs to enjoy a fun rollercoaster ride!


Send us a message if you'd like to find out what your day could look like!

The new Medical Device Regulation 2017-745: Safety by design and by vigilance
13-11-2018

#The new Medical Device Regulation 2017-745: Safety by design and by vigilance

As an essential aspect of compliance to the new Medical Device Regulation 2017-745, this blog intends to shed some light on safety and performance requirements for medical devices and the way to monitor this, or better: vigilance in general. Of course, the scope of this blog also encompasses the In Vitro Diagnostic Regulation 2017-746, because vigilance is applicable to both.

Naturally, vigilance as part post-production activities, as well as post-market surveillance (PMS) are deployed to guard the safety and improve the performance of medical devices. Procedures for vigilance and PMS should be set up carefully, planned for, elaborated and where needed optimized and adjusted. Even so, PMS plans should be recorded within the technical documentation prior to CE marking and should be executed subsequent to its availability to the market. Several aspects of these processes have been intensified in the new MDR as compared to the Medical Device Directive (MDD). For instance, safety & performance, the supply chain and the Quality Management System (QMS) are affected significantly and we’ll discuss those in this blog. Potential issues can be identified by performing an audit on vigilance and PMS plans, so that identified gaps can be addressed appropriately and result in an MDR-ready system.

So who should be reading this? Basically, every economic operator in the EU who’s involved in the medical device industry and especially the manufacturer.

Or as defined in the MDR:

‘economic operator’ means a manufacturer, an authorised representative, an importer, a distributor or the person referred to in Article 22(1) and 22(3)

Note: article 22(1) and 22(3) deal with the person who combines devices bearing a CE mark into a system or a procedure pack.


Product Safety & Performance

Implementation of the mandatory vigilance is to guard the two integral focuses of any economic operator involved with medical devices: safety and product performance. In the fourth pre-amble of the MDR, vigilance is stressed as a key element of the regulatory approach and chapter VII is devoted almost entirely to describing the requirements and obligations regarding PMS and vigilance.

Over the course of development, the manufacturer is supposed to map a medical device’s safety and performance and both require accurate monitoring and where applicable adjustment.

The identification and estimation of the significance of incidents in the commercial lifecycle of a medical device and (adverse) events in the developmental (clinical) phase require in-depth research, root cause analysis and Periodic Safety Update report (PSUR). Subsequent to the results of this analysis, recurrent patterns in complaints, (adverse) events and incidents have to be precluded. Accordingly, the establishment of the Corrective and Preventive Action (CAPA) pinpoints the necessary adjustments and mitigating handlings. Consequently, the results of the analysis determine the magnitude of required adjustments for the design of the medical device and the QMS if needed.


Quality management system

In order to comply with the MDR, economic operators should invest in an efficient roadmap leading to an MDR-proof QMS for their product(s), that much is clear.

According to the MDR, this means making sure that:

  1. Emphasis on clinical data/evidence, PMS and vigilance will play a much more extensive role in addition to the clinical evaluation process.
  2. The roles and responsibilities of the economic operators, the supply chain from manufacturer to distributor (to the patient) have been outlined also regarding the handling of feedback from users, patients, healthcare providers, and other stakeholders, e.g. vigilance).
  3. The chain must be controlled.

 


Supply chain

The supply chain is the path a medical device travels from the manufacturer to the final destination of use. The parties involved are defined by the MDR as economic operators, which include manufacturer, authorised representative, importer and/or distributor, depending on what is necessary.

Depending on the organisation and the location of the manufacturer one, or more economic operators are involved/required for the supply chain. E.g., manufacturers located outside the European Union must have an authorised representative residing in the European Union.

For the supply chain of the medical devices, agreements describing the roles and responsibilities must be in place. This becomes more important in case the manufacturer and the distributor do not belong to the same organisation. Quality agreements then become essential, not only for the distribution of the devices but also for the vigilance obligations.


Set up of the QMS

A manufacturer, whose situation is matching with abovementioned concerns, might by now be interested in taking actions to set-up or insure of an MDR compliant QMS system. Manufacturers and other economic operators must keep in mind that there is not much of time left since MDR will officially be applicable from May 2020. Taking into account Brexit and the limited number of Notified Bodies that will be approved for the MDR, this limited amount of time becomes a constraint for manufacturers to:

  • Set-up an ISO13485:2016 and MDR compliant Quality System in order to get the medical device CE marked
  • Upgrade the QMS and CE marking of devices that are already compliant to the MDD on the European Market
  • Ensure that specific elements are also MDR compliant, e.g. Clinical Evaluation, Risk Management and Unique Device Identification (UDI)

Since the manufacturer is responsible for vigilance, the QMS must cover the feedback activities as well as trending and vigilance, from manufacturer to user. In case the distributors/importer are different legal entities, a quality agreement must be in place to take care of the vigilance responsibilities.


Room for improvement: pharmaceutical companies

It is a trend that pharmaceutical companies are more and more directly involved with medical devices, not only as a simple means to administer medicinal products. For example, they are involved in the development of novel combination products, where a drug is combined into a single unit with a device; also software as a medical device, better known as apps, is a new field where they are active in. Pharmaceutical companies are already familiar with pharmacovigilance, where the adverse events of a drug can be recorded and investigated. Vigilance for medical devices is at first sight similar, but it is not the same as pharmacovigilance. Therefore, pharmaceutical companies also handling medical devices must bring their systems in line with the MDD and/or the MDR to ensure that the requirements are met; to help them meet this goal, several Medical Device Guidance Documents (MEDDEVs) are available.

Within the medical device industry, the vigilance system gives input to the manufacturer to improve the safety and performance of their medical device (-s). Also, other means can be used for this, e.g. post-production information, feedback, and complaints from users, patients, healthcare providers, and other stakeholders

From a business efficiency perspective, it’s interesting for companies to investigate how to integrate their Pharmacovigilance and (material- or medical device) vigilance systems. Instead of having two separate systems with their own upkeep, a well-combined system can be both compliant and cost-effective.


Checks and balances: auditing

So, how exactly do you make sure that all is well and you’ve got yourself covered? The answer is: as a manufacturer (or any economic operator), you should perform a system audit to verify that your supply chain does not only supply to your end users but also ensures that events are reported accordingly, vigilance and that proper feedback from the market is obtained, post-market surveillance.

It’s recommended to make use of an (external) medical device vigilance auditor who evaluates and reviews your QMS throughout the chain and assesses its compliance to the MDR requirements. Additionally, an MDVA assesses also any non-conformities. Hereby the manufacturer is insured of a compliant Quality System throughout the supply chain and is primed and prepared for the audits of authorities and/or Notified Bodies.

Manufacturers of certain categories of medical devices might benefit specifically from such an audit because they are so-called ‘out of the ordinary’. Such devices are:

  • Self-certified medical devices; the classification criteria of medical devices are stricter whereby numerous Class I (self-certified) devices would be classified as Class IIa/b according to the MDR
  • Drug-device combination products; are classified as Class III whereby the safety and compatibility of the device, medicinal product and the combination of these two must be substantiated
  • Software as a medical device; is classified as Class IIa/b contingent to its (remote) options, configurational abilities, and risks with respect to the critical parameters

Naturally, for you as a manufacturer of Class II and/or higher Classes of medical devices, an audit will contribute to ensuring that the setup and maintenance of vigilance and post-market surveillance plan/method are performed appropriately. Of note, besides the benefits of an audit for medical device manufacturers, the MDR obliges the manufacturers to audit their critical subcontractors and suppliers as well. This aims to warrant accurate monitoring of the medical device’s integrity until it reaches the user/patient.

If you’d like to do your own pre-audit, you might want to start out with a free checklist for Medical Device Vigilance: request here.


In conclusion

The new MDR has been around for some time now and one of its focal points is the safety and performance of medical devices. To achieve this a manufacturer of medical devices, and even all economic operators, are legally obliged to set-up, implement and maintain an effective system for both vigilance and post-market surveillance. To check if the system is working properly, it should be subject of an internal audit. In this way, any third-party inspection will have a fully compliant outcome and, most important, the safety and performance are warranted for the patients.

Often we encounter situations within the medical device supply chain that an economic operator, manufacturer or not, is assuming its vigilance and PMS system to be compliant. Nevetherless, by asking right questions the contrary is proven. Thus, how do YOU ensure that the vigilance and post-market surveillance of YOUR product are fully compliant?

Blog by: Nadia Vazirpanah & Marc Klinkhamer

Infographic - ATMP Development
19-10-2018

#Infographic - ATMP Development

Thanks to the popular reactions we've had on our approach to ATMP development we'd like to share this infographic.


As the face of modern medicine is changing, so should the development strategies of new medicines, including advanced therapy medicinal products (ATMPs). In the infographic, we present essential steps in ATMP development; how to design a valuable project plan, set critical milestones, and the identification of development gaps that can be intercepted without compromising on safety and efficacy, all to smoothen and speed up the process from ATMP development to marketing authorization.

Academia and startups are usually more focused on getting the science right but are often less experienced regarding the development of a medicinal product. As a guide through the development maze, it is of utmost importance to create a development plan and identifying all the interdependencies between non-clinical, CMC, and clinical development, from an early stage on. Furthermore, a tailor-made regulatory strategy should be developed. This regulatory strategy should provide guidance and focus, especially in early development where engagement with regulatory agencies supports to align development milestones and assure regulatory compliance in the end.

Although each ATMP is unique and needs a tailored development and regulatory strategy, critical steps can mostly be identified and anticipated on beforehand.

Check it out here!

Proactive Pharmacovigilance And Its Importance: Benefits And Challenges
11-10-2018

#Proactive Pharmacovigilance And Its Importance: Benefits And Challenges

Feel free to download the slide deck of one of our recent talks on the proactive pharmacovigilance which was presented by Sonia Mangnoesing at the PhV Day on October 10th, 2018.


With the changes in Pharmacovigilance regulations over the last years, a shift has been seen in how we conduct Pharmacovigilance. Moving from a more reactive approach to a proactive approach. Maybe also moving from the ‘person’s approach’ to the ‘human factors’ approach. But why is this important, what are the benefits? That is a question many of us can answer in a fairly good way. Some may have had the opportunity to experience its benefits more than others, but since the changes in regulation, most will agree that this is the way forward.

Yet, when we look at how Pharmacovigilance is executed in practice, we too often see that different challenges cause a less than optimal Pharmacovigilance system. The challenges that we all can face in pharmacovigilance are not unique, but rather universal and their solutions hopefully applicable to different settings.

Download presentation here.

Brexit & QPPV: Time to Prepare
09-10-2018

#Brexit & QPPV: Time to Prepare

Time is progressing, towards the official transition date in the Brexit process 30 March 2019 (actually as this is a Saturday, the implementation should be effective as of 29 March), as per notice from EMA in May of last year:

When the United Kingdom will have become a ‘third country’ all regulatory and practical consequences will become applicable. Although deeply affecting all business sectors, EU regulatory authorities, and individual citizens, the prospect of this transition, is specifically important for the pharmaceutical industry.

The English Health Authority published at 6th of August 2018 that the UK and EU agreed upon the terms of an implementation period to the end of December 2020, once finalised as part of the Withdrawal Agreement. It states amongst other things that marketing authorisation holders and qualified persons for pharmacovigilance will continue to be able to be based in the UK and access EU markets during the transition period. The Withdrawal Agreement as a whole still has to be finalised, aimed for October 2018.

QPPV

One example of where the impact will be particularly highly felt is the role of the Qualified Person for Pharmacovigilance (QPPV) with European responsibility.

EU law stipulates that companies marketing medicinal products in the EU are not just authorized in the EU/EEA, but they even enforce specifically that some activities must be performed in the EU (or EEA). For example, the execution of the QPPV role and its pertaining activities such as oversight of the pharmacovigilance system and safety of the medicinal products marketed by the EU MAH. This aspect is also directly important for patient safety in the EU and even globally. Hence, the consequences of the UK becoming a third country are therefore significant and preparatory activities need to be started in a timely fashion.

QPPVs fulfill a complex and difficult role as central pivot of the MAHs pharmacovigilance system and are uniquely responsible for the PV QMS as well as its outcomes, such as the benefit-risk balance of all the MAH’s medicinal products in the EU Market. The QPPV role requires therefore highly qualified, trained and scientifically and medically aware persons. QPPV are scarce resources and especially with so many currently established in the UK there will be a resounding impact when these QPPV drop out of the EU system more or less at the same time. According to the Article 57 database, there are about 150 UK-based QPPVs. In fact, this will be challenging to cope with for all MAH with products in the EU, since simultaneously with a move of MAH’s from the UK, the need for QPPVs will increase in the remaining EU countries. This will lessen the average available QPPV resources thereby putting the MAH already residing in the EU under additional pressure to find suitable personnel to occupy the QPPV role.

GUIDANCE

To help clarify where and how changes may be required, an extensive and very practical Guidance Document has been published on 19 June 2018 (EMA/478309/2017 Rev. 2). This document complements the Questions and Answers (Rev 03 from 19 June 2018 ) prepared jointly by the European Commission and EMA related to the United Kingdom's withdrawal from the European Union and is drafted to provide procedural and practical guidance to marketing authorisation holders (see also Notice to Applicants, updated on 23 January 2018). These documents and many more are available on the EMA website to support the MAH in their transition and it is advisable to use them.

EVALUATE AND SET UP A STRATEGY

BREXIT consequences will also enforce MAHs with their EU headquarter in the UK  to consider relocation to a remaining EU country, change the EU QPPV location accordingly as well as the location of the Pharmacovigilance System Master File (PSMF). This pivotal pharmacovigilance document, likewise, needs to be located in an EU country. Each MAH that will need to transfer the QPPV/PSMF responsibility must be aware that continued compliance with the regulations surrounding the QPPV role needs to be guaranteed throughout the change process and change control should cover all processes. This is at the same time fully under the responsibility of the QPPV incumbent at that moment, making the controlled change processes extra challenging. And at the end, the QPPV and PSMF details need to be updated in the Article 57 database.

PREPARE

It may be prudent for all MAHs affected by Brexit to evaluate carefully where in the post-Brexit EU they want to establish the QPPV and PSMF. Aspects to use for this assessment may be qualification and numbers of potential QPPV resources and reflect this e.g. against (co)rapporteurs, language as well as footprints of their company and medicinal products market to ensure a more evenly spread distribution of QPPVs. As a spin-off effect, this may even cause a more even distribution of regulatory burden for Health Authorities. 

7 Things to Consider in Medicinal Cannabis Development
27-09-2018

#7 Things to Consider in Medicinal Cannabis Development

Mention the word cannabis and the confusion starts; legal or illegal, nutraceutical or medicinal product, psychoactive or non-psycho-active, clinically significant or not. At the same time, the cannabis industry is booming and attracting many investors. Currently mainly focused on the growing of the plant and exploiting the benefits of medicinal cannabis but more and more the focus shifts to the use of purified cannabinoids into medical products. In this blog, you will find out more about the regulations regarding medicinal cannabis and what to expect of it in the near future.


1. Cannabis

The first thing to set straight is the name cannabis. This is not a specific type of plant or product but more an all-encompassing term of a number of plants, materials, and products. The two common active substances (cannabinoids are called THC and CBD and are representative for the majority of endeavors in cannabinoid product development. THC and CBD are quite different from one another and in the table below you can see a comparison. Next to these two, there are over a hundred other known cannabinoids with slightly different chemical structures.

 

 

THC

CBD

Psychoactive

Yes

No

Legal status

Listed in narcotic laws, exemption needed1

Not listed in most countries (except US, UK, and some others)1

Origin

Weed plant

Hemp (grown for fiber)2,3

Growing location

Hot and humid climate/greenhouses

Moderate climate2

Products

Medicinal/recreational

Nutraceutical/medicinal

Appearance in pure form

Sticky oil/resin

Crystalline material

Stability

Unstable towards oxygen and light

Stable

Receptor activity

CB1/CB2 partial-agonist

CB1/CB2 antagonist

Proven clinical effects

Relieving chronic pain, muscle spasms, nausea

Epilepsy

Products

Marinol, Sativex (in combination with CBD)

Epidiolex (Lennox-Gastaut and Dravet Syndrome)

  1. please check the legal status if you embark on a cannabis project
  2. specially bred CBD-containing plants are grown in greenhouses. These are mainly intended for medicinal products
  3. if hemp is grown to isolate CBD, an exemption from the narcotics law is required in most countries

2. Regulations

So how is medicinal cannabis regulated? Currently, there are 27 countries, mainly in Europe and the Americas, where medicinal cannabis is permitted. It is usually prescribed by GPs and provided by pharmacies. Pharmacies obtain their packaged product from wholesalers and those from growers of cannabis plants. Both the growers and the distributors require licenses from local governments to be allowed to work with this plant material. To obtain such a license you’ll need to demonstrate aspects such as:

  • protective measures to prevent cannabis material from going missing
  • the exact handling of the material
  • growing,
  • importing,
  • re-packing,
  • storage,
  • distribution,
  • R&D-activities,

Currently more than 100 producers have been successful in obtaining the license, mainly in Canada. Having said that, it’s complicated to work in several countries at the same time because each country has its own set of regulations.


3. Quality Standards

When producing medicinal cannabis, Health Authorities may require a product to comply with the standards described in the Good Manufacturing Practice guidelines (GMP), e.g EU countries. This is managed by clearly defining specifications for possible quality risk factors like:

  • content
  • moisture
  • foreign matter
  • microbiology

Information on GMPs can be found in EU GMP “Eudralex 4” or the United States FDA 21CFR part 210 and 211

Interestingly, the GMP isn’t required for planting or seeding of cannabis plants. Instead, this typically requires Good Agricultural Practice (GAP which secures a constant quality of the plant material and is often done in a secured greenhouse).  GMP usually starts at harvest of plant buds.


4. Extract or purified substance?

Currently, the cannabis industry’s focus is still on plant material possibly because the terpenes exert a beneficial effect and dried buds are easy to get by and use. Besides this, the actual use of plant material ranges from tea made from the leaves to smoking it. It comes as no surprise that standardizing the use of cannabis to secure constant dosing for patients is key and it’s certainly worthwhile to investigate more advanced ways of delivering cannabinoids.  For instance, by presenting an extract or purified THC / CBD to patients you increase your control over the contents and dosing becomes more accurate, opening possibilities to investigate treatment efficacy in clinical trials. A number of companies are already using purified THC and CBD (essentially pure active substances) in clinical studies aimed at obtaining marketing authorization.

Example:  Sativex. By extracting the active materials from the plant and formulating it as a spray, GW Pharma obtained a marketing authorization in the EU and Australia. They did the same to register CBD in the US for treatment of rare epilepsy syndromes.

This is remarkable because the extracts used for Sativex still contain a large number of other cannabinoids as well as terpenes. Although we assume it’s because of the THC and CBD, it is not clear which components are actually responsible for the efficacy in pain reduction or reduction of seizures.


5. Formulation

Whether extracts or purified cannabinoids are used, there is a number of possibilities to administer these active substances to patients; each with their own pros and cons. Therefore, when embarking on a cannabis project (or any project in fact) it is useful to start with the patient in mind and define requirements that will treat a patient in the most comfortable way possible.

Some of the formulations:
 

 

Pros

Cons

Oral tablet

Easy to use

High first pass effect (extensive metabolism by the liver)

Cumbersome manufacturing

Inhalation

Demonstrated way of delivery (recreational use)

High plasma level leading to psycho-active effects

Patch

Easy to use

Only low doses can be given

Mouth spray

Immediate delivery

Only low doses can be given

Chewing gum/pastilles/lozenges

Easy to use

Cumbersome manufacturing


6. Stability

One aspect that needs to be considered when extracting and purifying THC is its stability, or rather its instability. Unlike CBD, THC is vulnerable to oxygen, light, and possibly moisture and it is readily decomposed by radical oxidation. This means standard formulation techniques aren’t sufficient to provide a stable drug product and instead requires encapsulation techniques. Methods have been developed to protect the THC by encapsulation into a polymeric or a liposome matrix. Surprisingly, the dissolution in aqueous ethanol mixture also exerts a stabilizing effect as demonstrated by the Sativex spray developed by GW Pharma.


7. Clinical studies

As previously stated, a number of treatments have been approved by Health Authorities. These are mainly in the area of pain reduction, emesis, nausea and symptom reduction in MS-patients. It is known that cannabinoids act on a multitude of different receptors in the body, either as agonists or antagonists, and could potentially interfere with disease mechanisms. Therefore, cannabinoids are thought to have the potential to treat or cure also diseases such as cancer (see e.g. the excellent review paper of Massi et al.)


Future

So, why haven’t we found more cures to date? Is it possible that the multi-compound containing plant material has hampered the progression of cannabinoids in approved treatments? As indicated before, these are ill-defined materials of a number of cannabinoids and terpenes and with a multitude of administration routes. So, claims using medicinal cannabis can’t be substantiated with clinical evidence. With THC and CBD now readily available as GMP-material, the scientific community is more suitably equipped to perform clinical studies. Hopefully resulting in approved drug products that treat patients safely and effectively.

Blog by: Jan Zorgdrager & Marc Stegeman

How to manage the risk of Elemental Impurities (ICHQ3D)
12-09-2018

#How to manage the risk of Elemental Impurities (ICHQ3D)

ICH Q3D

The mission of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) is to ensure safe, effective and high-quality medicines through worldwide harmonisation. Harmonisation achievements in the Quality area include pivotal milestones such as the conduct of stability studies, defining relevant thresholds for impurities testing and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP) risk management. In addition, the guideline ICH Q3D for Elemental Impurities has been implemented at the beginning of this year. This guideline provides a platform to develop a risk-based strategy to control and limit elemental impurities. As a consequence, this can have a major impact on drug development and more specifically on the quality of your drug. This blog will bring you up to date on the implementation of the Guideline for Elemental Impurities.

In every step of the drug development process, impurities can arise. Impurities are substances that are added or formed during the development process and have a non-intentional (potentially toxic) effect on the drug. They can be organic molecules, residual solvents or inorganic compounds. Elemental impurities are commonly called heavy metals and most of them are toxic to humans. Therefore, the levels of Elemental Impurities must be managed within acceptable limits in order not to harm the patient.


Development of ICH Q3D guideline

While initially used to control metals like lead, copper and other heavy metals that constitute a health hazard, the assessment of Elemental Impurities (EIs) has gained considerable attention over the last years.

ICH Q3D arose out of a need to develop a globally harmonized guideline and is the culmination of several initiatives intended to modernize the control of EIs in pharmaceutical products. The U.S. Pharmacopeia (USP) had been discussing the modernization of its heavy metals monograph for several years prior to the initiation of the Q3D Expert Working Group. The European Medicines Agency, after many years of discussion, had implemented a safety and risk-based approach to control residual catalysts in pharmaceutical products approved to be marketed in the EU. The ICH Q3D now replaces these earlier initiatives.


ICH Q3D Guideline

The ICH Q3D Guideline represents a list of 24 elements, classified in 4 categories according to the toxicity and probability of occurrence.
It promotes a risk-based approach to assess the presence of EIs in drug products. Since the new guideline relates to the relevant route of administration of your drug product, a more specific assessment of actual toxicological risk to the patient can be given. A safety-based Permitted Daily Exposure (PDE) has been developed for the oral, inhalation, and parenteral routes of administration for 24 elements that are classified based on safety and relative abundance in nature.

Click here for enlarged image.

ICH Q3D presents major challenges to testing and risk assessments related to meeting current stringent limits for specific elements to assess patient risk. The likelihood that certain impurities in a medicinal product are present, should be determined through a valid risk assessment. An important detail is to ensure whether the controls built into the process are acceptable to limit the level of EIs in the medicinal product. The risk assessment should also clarify whether the proposed control strategies are sufficient or if additional control strategies are needed. When the risk assessment indicates that the level of an EI may exceed the control threshold, additional measures need to be implemented to ensure that the level does not exceed the PDE.

These additional measures can include, but are not limited to:

  • Reduction of EIs to levels that do not exceed the control threshold through purification steps or implementing in-process or upstream controls
  • Selection of components of improved quality
  • Establishment of specification limits for the drug substance, excipient or drug product
  • Selection of an appropriate container closure system

Based on the outcome of the risk assessment, a clear control strategy needs to be provided.

As EIs can be present in every step of the development of your drug product, the control of EIs should be considered across the entire product lifecycle. Whenever changes are implemented, the risk assessment on EIs should be reviewed and updated because every change possibly impacts the EI content of your drug product. For instance, changes in synthetic routes, excipient suppliers, materials, processes, equipment, container closure systems or facilities on the original risk assessment should all be evaluated. Also, the regulatory implications of modifications to the risk assessment and control strategy should be considered, and, when needed, appropriate variations need to be submitted.

EI data for some components may be limited during drug development, which could direct the applicant to a particular control strategy. For example, the applicant may choose to carry out end product testing as the initial strategy. As additional experience and knowledge are obtained with time, the applicant may determine that a change in the calculation option, risk assessment and/or control strategy may be warranted to ensure the levels of EIs.


Risk assessment on Elemental Impurities

Since the implementation of the ICH Q3D guideline on EIs, drug product manufacturers are obliged to carry out a thorough risk assessment to identify and control EIs. As EIs can occur in drug substance as well as in the final drug product, all potential sources should be considered in the risk assessment. The risk of any elemental impurity occurring in the product at a level > 30% of its PDE should result in a control strategy for that particular EI:

Elemental impurities (EI) level

Actions and/or control strategy

Elements that are not likely to be present in the risk assessment

Risk assessment (RA), validated test method(s) used during the RA and results should be available during inspection and review.

No further action required.


Elements < 30 % of PDE
(below control threshold)

No further action required, i.e. existing controls to be considered as adequate.

Potential consideration for periodic testing.


Elements from 30 % - 100 % of PDE

Define additional controls:

Specification on DP or components.

Define upstream control and impact on EI level.


Elements > PDE

Evaluate safety assessment and rational to support levels higher than the PDE for specific elements.

Define upstream control and impact on EI level.

Because of all the implemented changes, the ICH Steering Committee decided that the development of a comprehensive training program and supporting documentation was necessary. They have developed a training program to ensure the proper interpretation and effective utilization by industry and regulators. Ten training modules are provided to assist industry with the implementation and include examples, you can find them here.

Get your knowledge on EIs up to date now!

Blog by: Bertine Vorstenbosch

Orphan Drugs: Product Similarity & Market Exclusivity
02-08-2018

#Orphan Drugs: Product Similarity & Market Exclusivity

The effects of the EU orphan legislation are substantial: over 1,950 orphan designations have been issued by the European Commission since the year 2000, of which 142 have resulted in authorised medicinal products so far (EMA Annual report 2017). The EU orphan incentives stimulate the development of medicinal products to make sure patients suffering from rare diseases have access to the same quality of treatment as other patients. For many start-ups and small pharmaceutical companies, developing a drug without the benefits of the orphan incentives is unthinkable and the orphan drug designation (ODD) is an absolute condition for investments.  

However, with more and more drugs getting approved while maintaining the designated orphan status, developers of drugs within the same orphan drug condition see themselves faced with a higher raised bar. Questions like “what are the options for a product to enter the market in case of an already approved drug for the same therapeutic indication” are frequently asked? The situation is complex as two different set of criteria of the orphan drug regulation apply, each with its own conditions and consequences:

  1. Market exclusivity of the competitor
  2. Maintaining the orphan drug designation status by showing significant benefit.

The criteria and options for entering the market in case of another orphan drug approved for the same therapeutic indication with market exclusivity period are summarized in the scheme below:

MA: Marketing Authorisation; ODD: Orphan Drug Designation

*Similar being defined as an identical active substance, or an active substance with the same principal molecular structural features (but not necessarily all of the same molecular structural features) and which acts via the same mechanism (EC 847/2000 Art 3.3(c), amended by EC 2018/781).

**Clinical superiority being defined as a medicinal product is shown to provide a significant therapeutic or diagnostic advantage over and above that provided by an authorised orphan medicinal product (EC 847/2000, Art 3.3(d)).

***Significant benefit means a clinically relevant advantage or a major contribution to patient care (EC 847/2000, Art 3.2)

 


1. SIMILAR PRODUCTS: MARKET EXCLUSIVITY

The first criterium in getting your product registered relates to the presence of a 10-year market exclusivity for another designated orphan drug being granted a marketing authorisation. I.e. another similar medicinal product can in principle not be placed on the market in the EU for the same therapeutic indication (Art 8(1) EC 141/2000). In this concept, a similar medicinal product is defined as an identical active substance, or an active substance with the same principal molecular structural features (but not necessarily all of the same molecular structural features) and which acts via the same mechanism (for detailed explanation, refer to EC 847/2000 Art 3.3(c), C(2008)4077, and EC 2018/781). The market exclusivity period can be extended by two additional years when the results of studies in the paediatric population are presented in accordance with a Paediatric Investigation Plan. The market exclusivity incentive prevents other companies to easily place a generic product on the market, irrespective of the legal basis of the original application and of the patent situation.

Marketing authorisation for similar products

If the active substance is indeed similar, your product can only be placed on the market for the same therapeutic indication when

  1. consent of the original marketing authorisation holder is obtained,
  2. the original marketing authorisation holder is unable to supply sufficient quantities or
  3. the medicinal product is safer, more effective or otherwise clinically superior despite having a similar active substance (for a detailed explanation see: C(2008)4077).

In these cases, marketing authorisation will be granted and the product can be launched but without the orphan drug status and the rights of market exclusivity.

If the situation and clinical program of your similar product allow, the planned indication might be adjusted to target a patient group not protected by the market exclusivity. Alternative indications might already be explored during the development of your product in case of the expected competition of a similar product. The adapted indication can but might not necessarily have an orphan drug status.

Marketing authorisation for non-similar products

If your product contains a non-similar active substance while the intended indication is similar, marketing authorisation can be granted by the EMA or national authorities without further provisions or restrictions related to marketing exclusivity of the registered competitive product. The usual positive benefit/risk requirement for your product applies for a marketing authorisation without ODD status and without benefits from incentives related to ODD status. In case the marketing authorisation of your product is granted via a full or full-mixed application, i.e. based on own clinical studies, the usual data exclusivity (8 years) and market protection periods for this type of application apply, protecting you from generic products for the same indication entering the market. Also, the patent protection period applies as usual.


2. MAINTAINING ODD AFTER MA FOR NON-SIMILAR PRODUCTS: SIGNIFICANT BENEFIT

In case ODD status is wished additional to the marketing authorisation, for either the protection period of market exclusivity or to increase market value, the second criterium of significant benefit has to be complied with. To maintain ODD status after marketing authorisation of your product, clinically relevant advantage or major contribution to patient care, compared to all authorised orphan drug product and other products and treatments for that orphan condition needs to be demonstrated.

This concept of significant benefit can be based on improved efficacy, improved safety or a major contribution to patient care and there has to be a high probability for patients to actually experience this benefit when using your product. At the time of marketing authorisation application, the demonstration has to be based on clinical comparison data. Depending on the situation either a direct or an indirect comparison between your product and the competitive product(s) can be made. Likewise, comparison with other treatments which the patients diagnosed with the orphan disease may receive needs to be provided. If benefits to patients are expected to be similar or if the investments to gather comparison data via clinical studies will be too high or time-consuming, your product can still obtain a marketing authorisation without the ODD status as explained above in this blog.

The concept and requirements for the significant benefit are further explained in Recommendations from the Committee for Orphan Medicinal Products (EMA/COMP/15893/2009), Guideline on the format and content of applications for designation as orphan medicinal products (ENTR/6283/00) and Commission notice 2016/C 424/03.


3. WHAT STEPS CAN YOU TAKE?

The approval of a competitor orphan drug product with rights of market exclusivity in the target indication of your product will raise the bar, but options still remain to register and market your product. If not similar in active substance, market authorisation with and without maintaining ODD status is possible. If you have an EU orphan drug status for your product, this is what you can do:

  • Continuously follow-up on programs of competitor products, similar or non-similar, in the orphan drug condition not to be surprised by granting of approval of another orphan drug in your target indication.
  • Even though competitor products have not been granted marketing authorisation, evaluate similarity and significant benefit criteria explained in this blog and the pros and cons for each option.
  • Anticipate if you need to prepare for alternative routes in your development program.
  • In case extra investments in the clinical program are needed to maintain the ODD status at the time of marketing authorisation, assess whether the investments balance the expected profits on the market.

4. RECOMMENDED READING

 

Blog by: Patricia Baede, Liesbeth Hof

6 Ways to increase the value of your ATMP development
10-07-2018

#6 Ways to increase the value of your ATMP development

As the field of modern medicine is changing, so should the development strategies of new medicines, including advanced therapy medicinal products (ATMPs). Many ATMPs are being developed for rare/orphan diseases with an unmet medical need. The inherent complexity of ATMPs poses several challenges to the translation of these products to the clinic, like not being able to follow standardized CMC, non-clinical and clinical development strategies. Instead, comprehensive and product-specific development programs may be required prior to marketing approval. Altogether, a bumpy road to market authorization lies ahead.

In general, in the translation of an ATMP from research to market authorization, it’s worthwhile to pay careful attention to the following aspects:

  1. Business strategy and investors
  2. Product Definition
  3. Chemistry, Manufacturing, and Controls (CMC)
  4. Nonclinical development
  5. Clinical development
  6. Regulatory strategy

In this blog, we will briefly touch upon these areas.


1: Business strategy and investors

Building a solid business case early is a strong prerequisite for being successful in partnering with investors and co-developers. And as such it is likely to be considered a solid proposition for investment if you’re planning both for development of your product into clinical stages as well as market approval in the end.

You need to address essentials like:

  • Company organization
  • Partnerships & collaborations
  • Roles and responsibilities of the management team and board
  • IP and freedom to operate
  • Competitor analysis

In this way, you cover a major investment requirement to position your ATMP development from a broader perspective and to provide a clear market assessment of your ATMP.


2: Product definition

A target product profile (TPP) is an important tool to facilitate the interactions with health agencies to align your development with regulatory expectations. In addition, the TPP is also a valuable instrument to facilitate both internal and external communication and can be translated into a Quality TPP (QTPP). Both are dynamic documents that facilitate the integration of all development disciplines into a predefined and suitable process.


3: CMC development

ATMPs are usually manufactured using complex biological and technological processes for which many protocols are to be developed. . Various cell lines, tissues, or vectors are needed as starting materials and multiple steps are required to select, modify and expand cells and/or produce your vector. Culturing, modification, harvesting, purification and formulation of the product all give rise to challenges regarding product quality characteristics like purity, potency, and safety. Furthermore, manufacturing processes often demonstrate an inherent variability causing significant heterogeneity between batches, which also relates to the challenges in testing, characterization and control.

Some things to keep in mind:

  • Changes to an ATMP design to obtain improved product characteristics pose a challenge to the evaluation of the impact on the safety and efficacy profile of the product. It is beneficial to design a solid TPP and a project development plan that properly defines the required product and process characteristics. In conjunction, major milestones and related criteria for the anticipated go-no-go reviews should be defined beforehand. Such a work plan may help to reduce a need for later bridging studies or guide the design of these bridging studies in case they would be required to link early to mid and late-stage development.
  • To create more value you can investigate how to expand your development platform or processes to other indications or products. For example, a change in transgene could possibly treat a different indication with the same vector backbone and promoter.
  • To save time and resources, it is important to perform a solid process development to minimize the gap between non-GMP and GMP manufacturing.
  • Also, the tech-transfer between these should start in an early phase to assure alignment of the development and manufacturing of the ATMP.

Overall, it’s crucial to engage early with regulatory agencies to align your pharmaceutical development, your manufacturing strategy and your comparability plans and discuss the impact on the performed and planned non-clinical and clinical development activities.  This not only speeds up the marketing process but also builds confidence in your company and current product for potential investors.


4: Non-Clinical development

Prior to the clinical administration of an ATMP, adequate non-clinical information should be provided using a relevant animal model. Due to the specific characteristics of ATMPs and differences in regulatory requirements, non-clinical development may not follow a “standardized” approach. Products used in non-clinical studies should be representative of the product that will be administered to humans in clinical studies.  In addition, the animal models used should have a predictive value to the clinical use of the product in humans bearing the disease indication in mind.

The final product should be based on the right data. This might sound like a no-brainer, but in reality, products are being developed that aren’t. For instance, during development imposed differences in isolation of cell sources, other vector backbone or differences in matrix preparation can induce a huge discrepancy in outcome parameters and present the risk of not being able to connect your non-clinical development to a product that can be used in clinical trials.

Non-clinical studies should be performed using the most relevant in vitro and in vivo models available, the rationale for the selection of these models needs a solid justification. The animal model needs to be suited to allow for translation to the clinical use of the product. In case a single animal model isn’t sufficient to bridge non-clinical study outcomes to a clinical prediction, various different animal models may need to be employed. Very important notice on this is that early interaction with regulatory authorities has proven beneficial in convincing on the justification of the proposed animal models.

Dosing is always a difficult issue. As ATMPs are being developed in animal models that for example are different in size, metabolism, immunological status compared to humans, the administered dose cannot be translated on a one to one basis for human use. The best you can do is to make an educated estimate on the dose and stay on the safe side. Also, take into consideration the method of administration, as different routes of administration can have different tolerability and efficacy outcomes.

In gene therapies, the risk of viral spreading into the environment should be addressed in non-clinical studies. Non-clinical studies are required to estimate the potential shedding of the viral vector. A challenge in the design of meaningful shedding studies relates to the fact that many viral vectors used in gene therapies do not infect and rarely replicate in nonhuman species. One way to address this is to take advantage of the fact that many vector types have been used clinically with different indications and publically available shedding data may be applied in the environmental risk assessment.


5: Clinical development

Many ATMPs are first in man clinical trials and/or first in class medicinal products. Consequently, the clinical trial design harbours specific challenges like:

  • The mode of delivery that should be described in an extensive TPP at an early stage of development
  • Setting your inclusion and exclusion criteria right
  • Selection of a starting dose and a staggered approach for patient enrolment

These clinical trial design aspects are important considerations as the safety profile of ATMPs can be evaluated only limitedly in non-clinical studies. In some cases, an estimated risk can be accepted when the potential clinical benefit outweighs the potential risk within a specific population. Clinical study design should be able to detect clinically meaningful endpoints but surrogate endpoints can be accepted for example in the context of rare disease indications.

Potential safety issues may relate to inflammatory responses, immunogenicity, disturbed gene control and off-target effects and there is a potential risk of transmission to third parties. Also, for gene therapies, other concerns relate to the persistence of viral vectors and genomic integration into the host's genome. For cell therapies and tissue-engineered products, specific risks may relate to graft failure, oncogenicity and unwanted immune responses.

Given the unique character of ATMPs specific requirements for long-term follow up are demanded. The design of the long-term follow-up regimen needs to be determined on a case-by-case basis depending on the product and the trial population.  


6: Regulatory strategy

A scattered regulatory landscape poses inherent challenges for the development of a globally acceptable development strategy. In many cases, not only the large agencies as EMA and FDA are involved but also different national agencies. So, transitioning from preclinical development to market authorization requires a carefully considered regulatory strategy and close collaboration with Health Authorities (global and local) to support the development of your ATMP.

It’s advised to apply a risk-based development approach as described by EMA in their risk-based approach guideline to ATMPs.

As indicated by EMA in this guideline: “The risk-based approach is based on the identification of various risks associated with the clinical use of an ATMP and risk factors inherent to the ATMP with respect to quality, safety and efficacy”. This statement in itself suggests that the design of an integrated development strategy would require a multidisciplinary integration of CMC, non-clinical and clinical development and should be strongly connected to a regulatory strategy that accounts for the product as well as the regulatory challenges.

A solid regulatory strategy will not only expose any regulatory challenges but also create regulatory opportunities. It will allow you to:

  • Set milestones and deliverables
  • Identify risks and mitigation strategies
  • Set up a strategy for communication with Health Authorities

This will all be beneficial in guiding your ATMP through the regulatory maze and make sure opportunities turn into reality.


Considerations

To date, only a few ATMPs obtained marketing authorization and most academia and startups are usually more focused on the science and technology than the actual development of these innovative and often complex products. Wrapping up, we stress the importance of creating a development plan that identifies all the interdependencies between non-clinical, CMC and clinical development early on.

Although each ATMP is unique and needs a tailored development and regulatory strategy, critical steps can actually be identified and anticipated on beforehand and a tailor-made regulatory strategy can provide you with the guidance and focus required for successful development. Especially in the early stage of development, engagement with regulatory agencies supports to align development milestones and assure regulatory compliance in the end.

When you realize that all the different aspects of ATMP development are intertwined and changing one might have a huge impact on another, you are on the right track. So get ready to save time and get your development plan and regulatory strategy straight!

Blog by: Harm Hermsen & Merel Stok

 

 

 

 

Medical Device Regulation: 4 Steps to prepare your clinical evidence
19-06-2018

#Medical Device Regulation: 4 Steps to prepare your clinical evidence

It’s been looming for a while now: the new MDR. There’s been a lot of talk about how it will affect companies in different ways. For instance, we wrote this blog on “why it’s a good plan to start preparing because otherwise, it’ll probably cost you money in the end”. From this point onwards, we will be sharing blogs on specific topics to help you prepare.

In this one, we will provide you with some strategies to prepare for the increased need for clinical data & evidence to CE mark your device. So let’s get started:

Initiation of the increased requirements for clinical evidence was actually already initiated with the last revisions of the MEDDEV guidance documents with the MDD still being in place. The further increase in the number of articles referring to clinical evidence in the MDR illustrates this huge increase of focus:

  • the MDD mentions clinical investigations in 1 article
  • the MDR has 12 articles on pre CE marking activities and 10 on post-CE-marking activities regarding clinical evidence.

Medical Device Regulation (MDR)

Medical Device Directive (MDD)

CHAPTER VI: CLINICAL EVALUATION AND CLINICAL INVESTIGATIONS: Article 61 to article 82

 

CHAPTER VII: POST-MARKET SURVEILLANCE, VIGILANCE AND MARKET SURVEILLANCE: Article 83 to article 92

 

And associated annexes XIV, XV

Article 15 with reference to Annex X: clinical evaluation requirements

WHO SHOULD BE WORRIED?

The increase in requirements for clinical evidence is also visible in the behavior of the Notified bodies. When manufacturers currently submit their technical files for obtaining the CE mark, they already experience that the need for more robust clinical evidence is requested. More importantly, manufacturers also experience the increased need for clinical evidence during re-certification of their device. Examples are already available about manufacturers that aren’t granted prolongation of the CE mark on their device with the result that it has to be withdrawn from the market. These examples are not limited to small start-up companies or to high-risk class devices: there are also established companies that were faced with no prolongation of certification until they were able to provide the necessary clinical evidence. Moreover, there are examples of low-risk class devices that lost their CE mark too.

It can even be that manufacturers with low-risk devices are more at risk regarding the extension of the CE mark because the gap been new requirements and the available clinical evidence might be bigger than for high-risk, class III, devices.

WAITING IS NOT AN OPTION

All currently certified Medical Devices must be re-certified in accordance with these new requirements. Because certification might be for a period of 3 years, the result is that a device that is CE marked just before May 2020 under the MDD may bear the CE mark for the next 3 years up to 2023. However, the MDR implies that PMS activities (Chapter VII) apply in full force as of May 2020. That means that when the PMS activities show that the clinical data is not sufficient your medical device needs a design change (or change in Instructions For Use) or is at risk for losing its CE mark. Also, 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 what steps do MD companies need to undertake?

1. ASSESSMENT OF CLINICAL EVIDENCE

First, companies are well advised to perform an analysis of their current clinical evidence (Clinical Evaluation Report) in reference to the MDR. Three likely outcomes could be:

  • All is fine, ‘no worries’.
  • Major issues meaning there’s a lot of work and you should start rather sooner than later
  • So many issues that you 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. In a previous blog, we already explained the options and respective consequences (MDD -> MDR) suggesting that action should be taken in a timely fashion.

2. CLINICAL STRATEGY

Based on the assessment outcome, a clinical strategy proves to be very useful. The clinical evaluation plays a central role in this process. The MDR describes that the process is started with a clinical evaluation plan during the development process of the product. During this phase of the products life cycle, the clinical evaluation used to be finalized and included in the submission package to the NB, under the MDD. Under the MDR, the process of clinical evaluation continues during the life cycle of the product, and depending on the risk class of the product, needs to be updated regularly. E.g. for class IIB and III, this needs to be done annually, even when your device is CE marked under the MDD as described above.

We could identify several main options depending on the extent of the necessary upgrade. The clinical evaluation report needs updating:

  • An update of literature data (together with vigilance) seems to be sufficient
  • An update of literature data alone is insufficient:
    • Clinical data needs to be collected via a clinical investigation
    • Clinical data needs to be collected via Medical Device Vigilance (article 87 and 88) and PMCF (Annex III - 1.1 - b)

3. CLINICAL STUDIES

To extend the clinical data or evidence, you can perform an investigation or post-market follow up study (PMCF). In case you are considering to extend the intended use, this might be the best moment to start a clinical investigation. It will help you to increase the clinical evidence but also broaden the intended use at the same time. If you only need to increase the clinical data, a PMCF might be more applicable and cost-effective.

4. PLANNING

As a manufacturer of CE marked products, you should carefully plan to ensure that the most efficient solution for meeting the requirements for clinical evidence is found and implemented in time. You do not want to lose your CE certificate and thereby access to the marked and your revenue. A timely upgrade of your clinical evaluation to meeting the MDR requirements will lead to the highest chances for success. It will also help you to identify if additional actions are required to collect the clinical evidence.

CONSIDERATIONS

Wrapping up we’d like to emphasize that it all boils down to timing from this points onwards, Beware that the deadline of May 2020 is less than two years away. Being aware of the upgrade requirements for your medical device assures business continuity.

So:

  1. Assess your current clinical evidence
  2. Set up a clinical strategy accordingly
  3. Perform additional clinical studies if needed
  4. Plan your improvements

If you would like some more specific information on the clinical strategy in line with the regulatory requirements, do not hesitate to leave us a message.

Blog by: Jan Bart Hak