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Who we are

Xendo, a ProPharma Group company, is a leading consultancy and project management organisation in the fields of (bio)pharmaceutical products, medical devices, and healthcare. Thanks to our multi-disciplinary, knowledge-driven approach, we deliver a broad palette of services to the life sciences industry, applying the right colour to projects we participate in. For over 25 years, we have successfully completed thousands of national and international assignments for start-ups as well as for the largest, established multinational companies and organisations. ProPharma Group combined with Xendo has more than 1,000 professionals worldwide providing an unmatched variety of compliance related services including medical information, pharmacovigilance, clinical safety, regulatory affairs, and a continuously expanding range of compliance, quality assurance, validation, and consulting services; providing a full-colour spectrum.

Our clients

The spectrum of our fields of expertise is as broad as the range of clients we work for, enabling us to cater to the varied needs and wishes of the Life Science industry. By creating an integrated solution, ProPharma Group is your single-source, global independent provider of compliance, regulatory affairs, pharmacovigilance, and medical information solutions providing the insights and services needed to maintain the highest level of value and patient safety.

We bring our palette of services to companies, ranging from start-ups to multi-national organizations, to provide them with robust solutions. Whether they are a (bio)pharmaceutical or medical device company, a hospital or a pharmacy, a manufacturer or a laboratory, we match their colour.

12-09-2018
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#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

10-09-2018
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#A day in the life of: Nadia Vazirpanah

FACTS

Age: 31

Studied: Cardiovascular and immune diseases; Ph.D.

Experience: Ph.D. and Xendo (since January 2018)

Goals: Growth and contribute beyond myself


PERSONAL DESCRIPTION

I’m Nadia Vazirpanah and I joined Xendo’s Young Talent program (Medical devices) in January 2018. I was born and partly raised in Iran but it is in the Netherlands that I completed my bachelor study at the Medical Laboratory Research in Groningen and my two Masters at the Vrije University in Amsterdam. During my Ph.D. position at the UMC Utrecht, I had the privilege to collaborate with multiple national and international experts. Simultaneously while working for Xendo, I am completing my dissertation to defend my thesis by November this year.


MORNING

How do you get ready to start your day?

I live in Utrecht and travel daily to Leiden and use this time to prime my mind and plan strategies on how to tackle daily challenges prior to getting started in the office. However, once I reach Xendo - I first grab a cup of coffee!

What is something you look forward to every day?

Since I plan my day ahead, I am quite prepared for the things that I aim to accomplish throughout the day, hence, what really excites me are opportunities and unplanned events that just happen spontaneously!

Can you name some typical activities?

Selecting and applying appropriate sections of the Medical Device Regulation and standards and customize it specifically for the Medical Device in question. Also, defining and describing a product as adequate as possible is one of the essential activities.


LUNCH

Tell about your colleagues a bit perhaps.

Within Xendo, there are a variety of consultants with diverse ethnical and education background and expertise. Whenever there is a specific question, there is always a colleague willing to communicate and convey his/her knowledge and experiences with a cup of coffee or during lunch.


AFTERNOON

What is something you do every day?

The most amazing part of being a consultant is the variety of projects and challenges that you face. The rules are always the same, but the game changes continuously! And one thing we implement in all projects is to think and act along with clients.

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

You have to imagine and picture a device in your mind completely in order not to leave any part undescribed and unaddressed; so you need a vivid imagination.

What makes you happy during your day?

I feed the monkey of my mind by having debates and discussions with my senior colleagues. This way I try to be challenged to think differently and see opportunities from multiple angles and to try and translate them into tailored solutions for each project.


CAREER

Why did you pick this job?

After finishing my Ph.D., I realized that I enjoy change, different ways of thinking, and delineating a subject over a longer period. Besides this, the contact with a large network of colleagues and clients makes each day of working-life unique and extraordinary.

How does it fit into your career plan?

I learn something by being present in this environment where you’re involved in multiple projects every day. Like Benjamin Franklin said; “Tell me and I forget, Teach me and I remember, Involve me and I learn.” This is how Xendo structures the Young Talent Program.

How does this company define your success?

Parallel to ‘learning on the job’ the success is achieved as a result of preparation, hard work and learning from failure.

To whom would you recommend this line of work?

If you need variety, want to be challenged, think outside of the box, work in a team, and contribute by taking responsibility in projects then you should consider this line of work. Are you gifted with a healthy and bright imagination and do you enjoy divergent projects? Consider working in this line of work within the wonderful world of Medical Devices.


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

02-08-2018
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#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

10-07-2018
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#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

 

 

 

 

06-07-2018
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#RegChange

The daily business of regulatory professionals involves processing of complex information from inside business and authorities. Today’s validated IT solutions are usually not flexible enough to keep pace with the ever-changing regulatory environment and the need for on-the-spot information. We build RA intelligence tools based on our day-to-day work experience. Our RA consultants translate specific tasks e.g. variation classification into flexible and versatile solutions like the mobile App RegChange.

In this tool, the EU classification guideline is broken down into the individual changes, greatly simplifying navigation through the document. Conditions, notes and documentation requirements directly connected to the selected change and Article 5 changes are included.

Note: RegChange has been made publicly available by the BPI (German Pharmaceutical Association) and is used by over one hundred professionals daily. 

Try RegChange!

25-06-2018
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#Biotech-BBQ – What's hot?

Date: 26.09.2018 | 8:00 - 16:15
Venue: Strelitzer Straße 60, 10115 Berlin at CQ Beratung + Bildung
Organizer: bbb Biotechverbund Berlin-Brandenburg Akademie UG (haftungsbeschränkt)
Costs/fee: Regular - 90,- € | Early-Bird - 75,- € if you register by July 31st 2018

It is an exciting time for companies developing new and complex biopharmaceuticals. As we gain more experience in the application of highly advanced technologies, as well as in new production processes for biopharmaceuticals, the regulatory landscape and recent strategies for the development of these products are rapidly evolving. It is not an easy task to keep track of best development practices and regulatory requirements.


This interactive workshop will support you in your efforts to better understand these relevant topics based on the vast experience of our speakers who will present case studies in their respective fields. As a highlight of this workshop, a panel discussion will take place to address and discuss questions and issues that you are facing in your daily business.


Outcomes of this workshop: gaining insights into improving your product development regarding timelines, costs and risk management.


Who should attend: Professionals and Managers in regulatory and development functions and Financial Investors.

Presentations will be in English, the detailed agenda can be found here.

Our presenters are recommending 3 blogs for pre-reading:

  1. #QUALITY BY DESIGN IN THE DEVELOPMENT OF BIOPHARMACEUTICALS – HOW REGULATORY AFFAIRS CAN MITIGATE BOTTLENECKS
  2. #BREXIT: CONSEQUENCES AND PREPARATION TIPS FOR BIOTECH & PHARMA
  3. #ARE YOU PREPARED TO JOIN THE BIOSIMILAR RACE?

Register now!

19-06-2018
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#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