Descriptive statistics present a good first overview of the data. The frequency of occurrence, as part of descriptive statistics, provides information that is easy to extract and to understand. There are three different types of frequencies, the absolute, the relative and the cumulative frequency.

The absolute frequency of occurrence is the number of times a value occurs or is recorded. Absolute frequencies can be shown for ordinal or interval data and are often presented graphically in histograms, where the height of the bars represents the number of patients within the defined category. The intervals are usually specified as consecutive categories of a variable. They must be adjacent and are often chosen to be of the same size.

Relative frequency, or also called empirical probability, is obtained from absolute frequencies divided by the overall number of subjects included in the trial or a certain subgroup being investigated. It is referred to as percentage, proportion, ratio, rate, or fraction dependent on overall number of patients. The sum of all relative frequencies is equal to 1 or 100%.

Relative frequency is more informative than absolute frequency because it puts the absolute frequency in relation to the size of the sample being looked at. Observing twenty adverse events in a trial of twenty-five patients may be concerning. On the other hand, 250 adverse events in a sample of 25000 patients, meaning a relative frequency of 1%, is likely to be a very good outcome. What matters is the perspective that is provided by the relative frequency!

The cumulative frequency is the sum of frequencies (either absolute or relative) of all the values equal to or less than a considered cut off point. The relative cumulative frequency is the result of dividing the absolute cumulative frequency by the total number of patients or just summing up all relative frequencies up to that threshold.

If you are interested in a visual presentation of this topic, please feel free to follow us on our GCP Mindset YouTube channel! If you would like to know more about how we could implement statistics in your clinical trial, send us a mail at statistics@gcp-service.com.

Descriptive statistics summarize a sample, for example the group of patients included in a clinical trial. They have to be distinguished from inductive and explorative statistics, which aim to provide results for interpretation or to support the (main) analysis, respectively. Clinical characteristics, such as the distribution of age or gender, or the proportion of subjects with related co-morbidities can be presented for the sample.

What does summarize mean? In general, the reporting of descriptive statistics of single variables can include scatter parameters, such as the mean, the median, and the mode; and dispersion parameters, which are the range, quartiles, the variance, and the standard deviation. For quantitative data, this usually includes the overall number of patients, and the number and percent of patients within the respective subgroup. For qualitative data the mean, median, standard deviation, quartiles, and extreme values are reported.

Descriptive statistics can additionally be presented in graphs, of which there are many possibilities, depending on what should or needs to be shown; the most common one being the histogram.

Apart from the above-described univariate descriptive statistics, that present one variable only, there are also bi- or multivariate descriptive statistics, which describe the relation between pairs of variables. These include, amongst others, cross-tabulations, or graphical presentations, for example by scatterplots. These are not plainly descriptive statistics anymore but shall still be mentioned here since they don´t aim to provide inductive or exploratory results.

Descriptive statistics are usually reported for the total sample, for the treatment groups that are being investigated in the study, and for predefined subgroups; for example, by grouping patients according to their country of residence or study site.

If you are interested in a visual presentation of this topic, please feel free to follow us on our GCP Mindset YouTube channel!
If you have any statistical questions, feel free to contact us at: statistics@gcp-service.com

What do statisticians mean when they talk about parameters or variables? In the frame of a clinical study, a variable is something that can be measured – like the blood pressure for example. Let us assume as the main objective of our study, we are interested if the investigational product is decreasing the blood pressure over time. What we can do to answer our question easily, is to measure the blood pressure once in the beginning of the trial and then again, after the patient used the product, after three months. We can compare these values or variables directly. So, variables in general are quantities which vary between distinct individuals, in this case patients. Sometimes it is not possible or too costly to obtain the variable of interest directly. This is when so called surrogate variables come into play. These are variables that are directly connected to the variable of interest but can be assessed easier, faster, or cheaper. Therefore, they are used to measure the actual variable of interest indirectly. In clinical trials, surrogate variables must fulfill certain criteria before they should be used as such: There should be a scientific reason behind assuming that there is a connection between the surrogate and the actual variable of interest, there should be studies of the prognostic value of the surrogate in the general population, and there should be prior clinical trials that have investigated the direct outcome as well as the surrogate. Having only a correlation is not sufficient to serve as a surrogate variable. Now that we know what a variable is, how does it differ from a parameter? Parameters are what biostatisticians use for the statistical analysis. They do not relate to actual measurements but to quantities defining a theoretical model. If we look at our example with the blood pressure, here we would calculate the change in blood pressure from the beginning to the end of our trial, for the two treatments. What we compare now between the two treatments are parameters. They cannot be measured directly and were computed from measured variables. If you are interested in a visual presentation of this topic, please feel free to follow us on our GCP Mindset YouTube channel! If you have any statistical questions, feel free to contact us at: statistics@gcp-service.com
It is a widely spread view that biostatisticians should be involved only after data has been collected. But involving a biostatistician already in the planning phase can efficiently save time and money throughout the whole duration of the trial. In the planning phase, a biostatistician has an important impact on the structure and type of the study. The definition of the objective of the trial is done by considering scientific and logistical aspects, to determine which objective is most likely to result in a successful and meaningful trial. Here, the biostatistician advises on endpoints for the trial, which should be objectively measurable and clearly defined. It has to be defined if the trial is of confirmatory nature or solely exploratory, as well as the number of treatment arms and how they are embedded in the trial design. Only then the sample size can be calculated by the biostatistician, which has a large influence on the costs, logistics and duration of the clinical trial. Further aspects in this phase of the trial, that involve biostatisticians, are decisions regarding the use and type of randomization, whether interim analyses can and should be conducted and how exactly the primary endpoint of the trial will be analyzed. All of this will be formalized in a Clinical Study Protocol or Clinical Investigation Plan. As such, involving a biostatistician during the planning phase of the trial can not only optimize the use of resources but also maximize the success probability of a clinical trial. During the active phase of the trial, biostatisticians monitor the ongoing trial and provide support for making decisions that may impact the analysis at the end of the trial. They may further be involved in identifying issues with data quality and integrity, and conducting any interim analyses foreseen for the trial. The biostatistician will also set up a Statistical Analysis Plan, which prospectively describes the technical details of the entire trial analysis in greater (and more technical) detail. Finally, in the close-out phase a final check of the data and any preconditions for the analysis will usually be performed and the database locked. Only after that, all data will be provided to the biostatistician and analyzed according to the planned analysis. Once the results are available, a Clinical Study Report or Clinical Investigation Report must be written, which is generally also reviewed or co-authored by the biostatistician to confirm that all results were interpreted correctly. At the very end, the biostatistician must also ensure that everything is documented and archived correctly. If you are interested in a visual presentation of this topic, please feel free to follow us on our GCP Mindset YouTube channel! If you would like to know more about how we could implement statistics in your clinical trial, send us a mail at: statistics@gcp-service.com

A medical writer is responsible for producing well-structured documents presenting scientific, clinical, educational, or promotional information clearly and concisely. In clinical trials, delivery of these documents requires input from areas such as data management, biostatistics, and regulatory affairs. Data managers supply clinical data to be used by biostatisticians who process them to derive conclusions regarding safety and efficacy of the treatment or device under investigation.

Regulatory affairs managers make sure that a clinical trial is conducted according to regulations and are in charge with communicating with regulatory authorities and ethics committees. Therefore, a medical writer is in constant communication with all these parties to ensure satisfactory generation of clinical trial documents. The interaction with the sponsor/client is also important, especially in the beginning and final stages of document creation. Typically, there are several daily calls with team members and clients to coordinate and clarify different tasks.
Throughout the day, medical writers usually work on several projects in parallel, for example in relation to clinical trials of drugs in different stages of development. They may exist solely as the only writer on a project, or they may be a part of a medical writing team, as in the case of large global phase III trials.

A day usually starts with a review of the work schedule, meetings, and timelines regarding different projects. An indispensable aspect is literature search and review, as medical writers need to be familiar and up- to- date with current research on medical conditions and the evolution of their therapies. This also serves to gather material to be incorporated into introduction and discussion sections of documents such as clinical study protocols and reports.
In addition, local translations and country-specific regulatory adaptations of documents need to be tended to. Close cooperation with biostatisticians is a must, as the interpretation of statistical analysis is crucial for the results and impact of clinical trials.
Usually, not all of the above will happen every single day, but it is nevertheless always a dynamic and gratifying work environment. Lastly, some medical writers also spend a significant portion of their time travelling, for example to congresses where they are involved in producing posters and presentations for expert speakers.

Medical writers communicate clinical data and various findings in medicine to a wide range of audiences and within the scope of a number of different documents. These audiences may include physicians, patients, regulatory authorities, scientific community, and the general public. A medical writer needs to be thoroughly familiar with each of these audiences, considering their level of understanding and their different interests. For example, the wording and format of an Investigator’s Brochure, which aims to explain the background and properties of a drug to a Physician has very different style and requirements from an Informed Consent Form, which must present information to a prospective patient in layman’s terms.

The focus of Regulatory Writing is the development of novel drugs and medical devices with the end goal of obtaining marketing authorization for them. This encompasses documents of formulaic format such as Clinical Trial Protocols, Reports, Investigator’s Brochures and Informed Consent Forms. They are produced at different stages of drug development and need to be approved by bodies such as Ethics Committees and Regulatory Authorities. Besides regulatory and ethics bodies, their designated audience comprises doctors who will administer an experimental treatment, and patients who will receive it.

On the other hand, Medical Communication may provide educational content to the general public on the developments in health and different medical conditions, for example in health magazines. In addition, it may also be more narrowly targeted, and done for promotional purposes focusing on single pharmaceutical companies and their products with the target audience being health care professionals and consumers.
Medical writing offers an opportunity to learn about various health fields, medical conditions, as well as drugs, medical devices and treatments. There is a wide variety of places where medical writers work. Some are employed in Contract Research Organizations (CROs) and handle a large portion of regulatory writing for pharma companies and the biotech sector.

Pharma companies themselves also have their own internal teams of specialized medical writers. Typically, when regulations change, job opportunities are created for medical writers and regulatory affairs staff. Other medical writers work as editors in medical and science journals or in marketing. It is also possible to work in institutions such as research centers and larger hospitals, thereby handling their public relations.

Interestingly, medical writing also offers ample opportunity for remote or freelance work, with many writers switching from in-house to freelance and the other way around. Pursuing a medical writing career path in a CRO combines high responsibility with excitement. Here medical writers pose a crucial asset to the team, handling a variety of documents involved in the drug development and its reporting.
Their day-to-day work is an adventure of juggling multiple projects, and specializing in health areas of highest interest. Interestingly, this is also a recession-proof professional journey since it is tied to the pharmaceutical industry; medical writers will continue to be in demand with the increase of the global drug development.

An essential, and often overlooked part of the work on clinical trials is medical writing. It is involved at the start and end of the study, as well as for all changes to regulatory documents throughout the trial. In this first part of a series on medical writing, we highlight the skill set needed for anyone pursuing this exciting and rewarding career path.

Medical writing combines scientific rigor with writing creativity. In addition to mastering writing and editorial skills, medical writers are highly analytical and able to organize ideas and infer conclusions. They have good communication skills as they are constantly interacting with people such as statisticians, regulatory affairs managers, and clients. They are able to efficiently organize their work, participate in multiple projects in parallel, and cope with strict deadlines. On the technical side, they are highly proficient in interpretation of clinical and scientific data, have excellent English skills and are able to produce writing material in various formats depending on the target audience. They are familiar with medical terminology and conditions, and often have a high understanding of statistics as well as the regulatory environment. They welcome criticism about their writing, improving their output by incorporating suggestions and comments from clients and coworkers alike.

Most medical writers come with a degree in life sciences such as medicine, biology or pharmacy. More than 50% of medical writers have doctoral degrees, as scientists commonly switch to medical writing after doing a PhD or later during their postdoc career. Sometimes, it is also possible for people to go into medical writing from non-scientific fields, for example, from being a translator; a lot of clinical trial documents often need to be translated into individual languages of different countries where trials are conducted. In this case, they come with good writing skills and need to learn medical terminology.

The new MDR requires small to midsize medical device companies to take over sponsor responsibilities for their clinical trials. Some companies find they cannot take over this responsibility due to their need for:

• scientific and regulatory knowledge in clinical trials
• QM system compliant with MDR and ISO14155
• manpower to keep sponsor oversight
• other tools to manage clinical trials
• experience in selecting the best investigational study sites for their clinical trials
• training in the clinical trial requirements of their people, vendors, and study sites
• etc.

GCP-Service wants to make sure that this situation does not lead to market exclusion of excellent medical devices. Therefore we offer to take over sponsor responsibilities for companies for their clinical trials. With this responsibility we work hard to prove the performance, safety, and benefit of such products to make market approval possible.

With more than 16 years of clinical trial experience GCP-Service loves to take over the responsibilities many organizations feel they are unable to do. The safety and rights of patients as well as the regulatory environment no longer allows a trial and error approach anymore. Therefore our approach is to do it the right way the first time!

E-Mail: info@gcp-service.com

ICH GCP and ISO14155 defines the term monitoring as “The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).” Furthermore, the quality standards state “The sponsor should ensure that the trials are adequately monitored.”

It is clear, standards and technology used 20 years ago are no longer adequate today. However most clinical trials are still monitored as if it were the year 2000. This includes outdated monitoring practices.

Internet, electronic software tools, and a better understanding of risk management overall are combined to implement the powerful oversight processes that are on site and remote clinical monitoring. We work with eCRFs, ePro, eISF, eTMF, CTMS, eICF, IRT and many other online tools to help our clients oversee 97% of study data remotely. This remote technology reduces the need for resources that traditional on site monitoring and study site visits significantly demand. COVID19 has forced a change in overall mindset and shown the world the need to incorporate new remote working processes. Remote monitoring it is more than a just possibility… it’s a necessity!

We use the technology of today to bring your study to its highest potential.

E-Mail: info@gcp-service.com

“Is it equivalent?”

As a medical device manufacturer, you are very aware of MEDDEV 2.7/1 rev. 4. from 2016. Following this document when planning and executing your Clinical Evaluations is crucial in helping you meet the MDR requirements that will be implemented May 26th 2021.

The most critical requirements of MEDDEV include: Clinical Evaluations must be linked to safety, performance and risk-benefit endpoints; the frequency of updates, qualification of Clinical Evaluation Report author(s), etc. Furthermore, there are requirements concerning the scientific and statistical validity of data, the specifications when the Clinical Investigation is to be performed, and the strict requirements for demonstrating the equivalence.

We are here to help.

Our team has experience in searching literature resources, biostatistics, medical writing of study protocols and/or study reports, appraising scientific and methodological quality of clinical data, and performing clinical investigations according to ISO 14155. With this experience our team delivers a successful Clinical Evaluations. Our team has experience in searching literature resources, biostatistics, medical writing of study protocols and/or study reports, appraising scientific and methodological quality of clinical data, and performing clinical investigations according to ISO 14155. With this experience our team delivers a successful Clinical Evaluations.

Given that the gap analysis doesn’t show any missing clinical data we assist you with compilation of a Clinical Evaluation Report. Our Reports not only meet all current requirements, like the MEDDEV and the MDR, but also MDCG and IMDRF guidelines.

If you are interested in more details, please feel free to contact me at jpaseka@gcp-service.com or +420774735206. Please follow us on as we continuously give you helpful hints for successful Clinical Investigations. There are many ways of cost-effective data collection, and the most important is to start as soon as possible.

Looking forward to hearing from you soon!

Jiri Paseka

ICH GCP and ISO14155 defines the term monitoring as “The act of overseeing the progress of a clinical trial, and of ensuring that it is conducted, recorded, and reported in accordance with the protocol, Standard Operating Procedures (SOPs), Good Clinical Practice (GCP), and the applicable regulatory requirement(s).” Furthermore, the quality standards state “The sponsor should ensure that the trials are adequately monitored.”

It is clear, standards and technology used 20 years ago are no longer adequate today. However most clinical trials are still monitored as if it were the year 2000. This includes outdated monitoring practices.

Our team believes that the monitoring 20 years ago matched perfect with the requirements of the time. However, monitoring nowadays is significantly different. Internet, electronic tools, and a better understanding of risk management have brought to light the powerful process that is clinical monitoring. We work with eCRFs, ePro, eISF, eTMF, CTMS, eICF, IRT and many additional modern tools. These tools help us and our clients to oversee 97% of study data remotely. This reduces the need for resources that traditional on site monitoring and study site visits significantly increase. COVID19 has shown us that we must change our mindset to incorporate new remote working processes. Remote monitoring it is more than a possibility it is a necessity.

If you want to change your clinical monitoring to meet higher standards and keep up with today’s technology boom, contact us today!

E-Mail: info@gcp-service.com

René Pulles, Lead Regional Operations Manager in Nijmegen

Why open a new branch office in the Netherlands?

The answer is clear. The Benelux area is home to nearly 30 million people. The Netherlands alone has a population of around 17.5 million and a high population density of 416 inhabitants/km², making it the fifth most densely populated country in Europe.

Benelux is known for its strong economy and many key opinion leaders declare this region as an important region for clinical trials. The Netherlands has a great deal of knowledge and expertise in the field of drug development. More than 400 drug companies, 7 academic hospitals and 14 universities are located within a circle of 200 kilometers. The excellent infrastructure, but certainly also the arrival of the European Medicines Agency EMA in Amsterdam, make the Netherlands an attractive location for pharmaceutical companies. In the Netherlands, more than 65,000 people are directly and indirectly employed in the pharmaceutical sector. There are an estimated 550 new clinical studies per year in the Netherlands, clients could be some of the 2,900 innovative R&D life science companies and 420 biopharmaceutical companies that call the Netherlands their home.

Straightforward communication is valued in the Netherlands as well as Germany, which helps in resolving issues quickly and efficiently. If you are not used to hearing opinions that are direct, then working in the Netherlands or Germany may take some getting used to.

At GCP-Service we use our international team to speak openly about issues in a respective manner. For example, it does not make sense to describe excellent study data if the study data is overall bad just for the sake of politeness. We will not waste time or resources. Let`s speak openly about issues and openly about their resolution!

E-Mail: info@gcp-service.com

There are approximately 1,300 new studies registered annually in the Central and Eastern Europe (CEE) region. Poland, Hungary, and the Czech Republic take the largest share, each with 300 – 400 clinical trial registrations annually. However, it is important to consider the two of the most crucial success factors: start-up timelines and clinical trial quality overall.

# START-UP TIMELINES IN THE CEE REGION

The study start-up is a very complex process. At times this phase seems to be bottlenecked especially because many start-up tasks are performed by multiple people, in different locations, and various sites. Delays in the start-up phase are now considered the norm but does this really have to be the case? The answer is no, it doesn’t have to be this way in the CEE Region!

In the CEE Region the Investigators and study teams are motivated to participate in studies. Not only for the therapeutic benefits, but for the scientific opportunities that studies bring, like networking with the international medical community.

At GCP-Service we have a defined start-up team. Our Leaders – top managers from all affected departments – are able to manage all the country and site-specific aspects and work in a very targeted manner to start enrolment in the agreed timelines. For feasibility processes we work with PI-Select, an e-tool that shorten the average time of an investigator’s response from weeks to days. During the start-up process itself we use our own unique tools like a database with individual sites requirements for investigator’s agreements.

Here‘s the team! At GCPS you can easily get in
touch with our team of experienced leaders who
can accelerate the demanding start-up phase.

# QUALITY

Based on the FDA’s publicly accessible Clinical Investigator Inspection List, the analysis of findings and outcome classifications from FDA inspections during Investigational New Drug (IND) studies was published.

Over 230 FDA inspections were conducted within CEE countries. The results indicated that the number of studies where “no deficiencies” were noted were double the number when compared to the findings in Western Europe, and in the USA. Of note, there were 15-26% less Voluntary Action Indications compared to results in developed countries.

Quality is never an accident; it is always the
result of high intention, sincere effort, intelligent
direction and skillful execution. Will A.Foster

# CONCLUSIONS

Clinical studies in the countries of Central and Eastern Europe have a long history of study experience. The main reasons to CEE sites are the availability of patients with certain health problems that meet the inclusion/exclusion criteria and patients are willing to participate in studies.

At GCP-Service, we connect Western Europe and Central and Eastern Europe and expand the potential for your clinical trial population. By providing a wider population group this helps accelerate recruitment and reach the required number of participants needed. The CEE Region should be considered when options might otherwise be insufficient or more costly if limited to US or Western European sites only.

Ing. Kristýna Paseková

Phone: +420 776 805 805
E-Mail: kpasekova@gcp-service.com

#### THE CEE REGION IS THE RIGHT PLACE FOR YOUR NEXT STUDY.

Core benefits when working within the Central and Eastern European Region include:

• Coverage of the Czech Republic, Slovakia, Hungary, and Poland
• 64 million CEE Region inhabitants
• Legislation fully harmonized with the EU
• Well-equipped and high-quality healthcare facilities
• Qualified staff, supportive environments, and recognized motivational factors that actively support study development

Clinical research has a long tradition in the Czech Republic, Slovakia, Hungary, and Poland. These countries have great recruitment potential, transparent regulatory process, and predictable start-up timelines. The CEE countries are fully compliant with the EU directives and are ready to implement the new upcoming regulations.

Investigators are well educated, regularly trained on ICH GCP standards, highly motivated, and deliver both recruitment targets and high-quality data for your study. Many sites also have Clinical Trial Coordinators on staff to support, facilitate, and organize your daily clinical trial activities and needs.

### Frequently asked questions about working in the Central and Eastern European Region:

Is the site staff fluent in English?

o Yes. Investigators and Clinical Trial Coordinators are always fluent in English. General working communication in English at sites amongst
site staff in the CEE is expected and delivered.

Is working in the CEE region affordable?

o Yes. Extremely low costs are not to be expected but, the CEE Region offers the best cost to benefit ratio worldwide. Currently Central and
Eastern Europe shows excellent recruitment rates and produces high-quality data. This may not be the lowest price worldwide but cheaper countries don’t produce the quality output like the CEE Region does.

Are studies for Medical Devices also applicable to receive these CEE Region benefits?

o Yes. There are slight differences in regulatory and ethical approval processes but, the environment for these studies is very
favorable in CEE Region. CEE Clinical Investigations are also an emerging market.

➜ Rest assured, CEE countries are well prepared for the new MDR and ISO 14155:2020 updates!

### Why choose the CEE region as the place to conduct your clinical trial?

• High density of quality sites
• Fully trained site staff
• Up to date medical equipment
• Sites frequently staffed with Clinical Trial Coordinators
• Transparent and professional regulatory environments
• Excellent cost benefit ratio

Ing. Kristýna Paseková
Phone: +420 776 805 805
E-Mail: kpasekova@gcp-service.com

The protection of personal data in clinical trials is a major concern considering for instance the health data of patients. In the European Union this was strongly enforced on 25th May 2018 as the General Data Protection Regulation (GDPR) came into effect. Consequently, this affects Non-EU sponsors since they equally need to ensure full compliance with this regulation when conducting clinical trials in the EU. To ensure the enforcement of the GDPR, sponsors are therefore required to appoint an EU Data Protection Representative. We at GCP-Service, can offer you this representation ensuring your full compliance contributing to a smooth study conduct.

The GDPR affects your clinical trial in many ways, such as proper handling & reporting of data breaches, secure data transfer to 3rd countries, dealing with sensitive data processors, appropriate training of your study team and much more. Failing to meet this regulation often leads to unnecessary study delays. We for example often observe that submission procedures are prolonged as informed consent forms lack to meet the GDPR leading to a delayed study kick off.

However, our experienced Representative team can support you in meeting the various challenges set out by the GDPR. Our experts aim to increase your transparency and ensure that all regulatory requirements are met.  We further resolve any uprising data protection issues throughout the study conduct. Among other things our service therefore includes the following:

• effective consultancy
• coverage of the entire European Union
• main contact point to supervisory authorities
• effective handling of data breaches
• preparation and review of GDPR compliant study documentation / submission dossiers

Our EU Data Protection Representative service can further be offered in combination with our Legal Representative for drug studies (acc. EU Regulation 536/2014) and Authorized Representative for medical device studies (EU Regulation 2017/745).

If you are in need of representation services or require some advice, we are happy to support you.

Benjamin Tsiflidis (btsiflidis@gcp-service.com)
Phone: +49 (0)421 89 67 66 15

Selecting the most suitable countries and sites for your clinical trial is a major step towards getting your study started off right. It also ensures a smooth study conduct. This becomes even more evident in view of the COVID-19 pandemic and its implications.

When considering running your study in the EU keep in mind this brings along many benefits. Generally, the EU has great social, cultural, ethnical & economic diversity. This means the incidences of different diseases and their prevalence rates are as equally diverse. From a sponsor perspective, this offers unique benefits in terms of finding the right study population and finding an acceptable risk-cost profile for your study.

Our Representative Services are designed to support you in finding the right European countries for your study. We provide you with the required expertise to ensure your study meets full regulatory compliance. We offer our regulatory expertise for both drug studies as a Legal Representative (acc. EU Regulation 536/2014) and medical device studies as an Authorized Representative (EU Regulation 2017/745). Additionally, we can represent you in the Non-EU countries of Switzerland and The United Kingdom.

To our understanding, legal Representative is an added value to your study and not seem as another mere financial burden. Legal Representative services should ensure:

• A smooth study conduct
• Regulatory compliance
• Cost-efficient rates
• Review of essential study data/documents,
• Effective communication with regulatory authorities
• Oversight to international sponsors (via eTMF/eISF)
• Review of the TMF and evaluate its inspection readiness, etc.
If you are in need of representation services, we are happy to support you.

Benjamin Tsiflidis (btsiflidis@gcp-service.com)
Phone: +49 (0)421 89 67 66 15

We use our smartphones daily, but the adoption of ePRO in the pharmaceutical industry surprising still meets resistance. This opposition is still present even considering the increasing shift to ePRO in recent years. In my opinion, ePRO should be the gold standard for PRO data capture in clinical trials.

Currently there is has been an increase in reconsidering traditional data collection strategies in clinical trials. Due to the complications COVID-19 created worldwide, paper data collection strategies became even more difficult than previously. As a consequence the benefits of ePRO became obvious, proving the underestimated power ePRO has to offer. The higher demand for ePRO from companies not using electronic capture systems came as they saw patient compliance rates fall drastically. Companies who did not want to use ePRO before COVID-19 suddenly found themselves trying to quickly obtain this service to stabilize patient reported outcomes. It is important to mention many times the quality of the paper documents collected fell short of basic standards, adding yet another barrier to data collection.

The advantages over paper-based PROs include:

Accuracy – By using direct validation methods

Integrity – Electronic time stamps and audit trails help avoid “parking lot syndrome” (filing out the PRO just before the visit)

Security – ePRO data is stored on secured servers with backup safeguards. Thus, can never be lost.

Compliance – Use of automated notifications raises patient awareness and provides valuable feedback. In addition, the patient can integrate these important, but sometimes inconvenient, tasks better in their daily life.

Speed – Data can directly be assessed, is available for remote review, and can be integrated in other systems.

Most importantly the FDA has officially stated ePROs are preferred over paper PROs. The increase in implementation of ePRO in clinical trials indicates electronic systems are effective in increasing the data capture benefits in clinical trials.

It is obvious that the advantages of ePRO will remain long after COVID-19 has passed, but the memories and outcome results during a pandemic when an electronic system was desperately needed and not used will remain much longer.

For more information please click here to contact me. Another information resource worthy of review is the European Medical Agency (EMA) reflection paper on expectations for electronic source data and the FDA’s  guidance for industry on patient-reported outcomes. ).

I look forward to supporting you with your ePRO goals.

Thomas Kissner (tkissner@gcp-service.com)
Phone: +49 (0)421 89 67 66 12

Choosing the appropriate data collection strategy has always been a key to success in clinical trials.This is even more important considering COVID-19 and its effects on clinical trials this year.

An internal survey of our current projects during this pandemic showed that those trials using ePRO (or other eCOA measures) had less delays when compared with studies using EDC alone. Unfortunately the worst case scenario occurred for paper-based or hybrid studies had to put on hold or even postponed entirely due to the consequences of the COVID-19 pandemic.

Fortunately we consistently receive positive feedback from our clients that patients using our ePRO system are more willing to participate in electronic data collection. This is part because our ePro resource allows study patients to submit their responses remotely. This eliminates a potential risk of exposure to COVID-19 as the result of being physically present for a site visit.

ePRO uses a patient focused approach to increase patient recruitment, retention, and engagement within a clinical trial. Patient compliance is increased by using flexible notifications and reminders that easily integrate into a patient’s daily schedule.

Using ePRO as BYOD makes the data entry process easier for the patient. It empowers patients to report data using their mobile phone on their own time and in the comfort and safety of their own home.

For those reconsidering their data collection strategy the Risk Assessment and Mitigation Strategies for PRO Data Collection regarding COVID-19 issued by the ePRO consortium is an excellent resource.

It is my pleasure to support you in finding the data collection strategy, whether planned or current, that’s right for you and your clinical trial.

Please click here to contact me today and don’t forget ask for a demo of our a free PRO solution software.

I look forward to hearing from you!

Thomas Kissner (tkissner@gcp-service.com)
Phone: +49 (0)421 89 67 66 12

We take great pleasure in announcing the expansion of our company with the opening of the new office in Potsdam. The metropolitan region of Berlin and Potsdam is one of the most attractive locations in Europe with excellent universities, research facilities, hospitals, and a flourishing startup scene.
Managing Director is Judith Huellebrand. She has extensive experience in clinical research for almost 15 years in the field of medical devices and drugs.
We are excited about the new opportunities the office in Potsdam brings in terms of collaboration and innovation for our new and existing partners, clients and vendors.

We proudly like to announce, that we opened our first German subsidiary on the first of April 2020 in the western part of Germany. The new office is located in Siegburg (between Cologne and Bonn), which has an ideally infrastructure for travelling (ICE railway station nearby). Our Managing Director Petra Löhmer, has more than 25 years of clinical research experience. The new subsidiary enables small to midsize biotech and medical device companies of the western and southern part of Germany to have a closer contact to our clinical research experts. Petra is happy to discuss your potential new projects and collaboration interests.

The time in which the European Medicines Agency did not care about medical devices is over.

EMA has published the first of a series of guidance documents to help applicants prepare for obligations stemming from the new EU regulations on medical devices.

The new regulations introduce new roles and responsibilities for EMA and national competent authorities (NCAs) in relation to certain types of medical devices and IVDs. The Agency is working closely with the EU regulatory network and with stakeholders from the pharmaceutical and medical device industries, including notified bodies, to ensure a smooth transition to the new regulatory framework.

The biggest challenge is currently “to ensure we have the appropriate expertise and resources to adequately carry out these new tasks,” said Guido Rasi, Executive Director of Agency.

This first document developed jointly by EMA and the Co-ordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) in close collaboration with the European Commission, focuses on the  stipulation that marketing authorisation applications for medicines with an integral medical device must include the results of the device’s assessment of conformity by a notified body. Approximately 25% centrally authorized medicines include a medical device component, and the majority of these involve an integral device.

EMA will publish further updates to the Q&A document addressing other requirements for various categories of devices, including those made of substances that are systemically absorbed, products which are not clearly defined as medicinal products, known as ‘borderline products’, and in vitro diagnostic tests used to determine patients’ eligibility for a specific medical treatment.

The complexity of regulations correlates with the complexity of products we develop nowadays. The increasing influence of the EMA in the medical device world is a logical consequence. Medical Device manufacturers should learn to understand their notified bodies as well as the EMA better, because EMA is watching them!

Source: https://www.ema.europa.eu

Since 06 December 2018 the guideline on the content, management and archiving of the TMF is final and will be effective from 06 May 2019 onwards. All enthusiasts of paper TMFs should review the guideline carefully and honestly question their way of approaching TMF management over the last 20 years.  Sponsors of multinational studies should consider the following requirements:

• The sponsor may choose to outsource duties and functions of the sponsor to a CRO. The sponsor remains responsible for the trial and will need to maintain oversight. Therefore, access to the CRO maintained part of the sponsor TMF or at least regular access to relevant documents from it will be necessary to fulfil these responsibilities effectively.
Do you spend the manpower, time and money to visit your CRO and their local facilities on a regular basis to maintain TMF oversight?
• The timelines for submission and filing of all documents to the TMF in procedural documents or TMF plans should be defined. This is particularly important for more complex TMF arrangements with multiple parties involved.
Where timelines are defined, timelines need to be controlled. Do you control the TMF management timelines in your TMF?
• The TMF should be managed securely at all times to ensure completeness and to prevent accidental or premature loss, unauthorized alteration or destruction of documents. Access to the TMF should be based on a role and permission description that is defined by the sponsor and/or investigator/institution.
Do you know every storage location of the essential documents throughout the course of your studies? Have you visited the home offices of freelancers and homebased staff? Do you control whether the role-based permissions of accessing the TMF are kept?
• As per Article 58 of the Clinical Trials Regulation (EU) No 536/2014 “unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical TMF for at least 25 years after the end of the clinical trial.
Do you have the capabilities to archive your documentation for the prolonged period, which requires more space, more manpower and little staff turnover?

After many years of experience in conducting and auditing multinational studies including TMF auditing, we have seen a large number of paper-based TMFs, stored at different locations and facilities, maintained by a large variety of people according to different cultures, rules and timelines. At least 90% of those paper TMFs did not match with the new EMA guideline on TMF management.

Most likely, if a TMF of a multination trial is to be established and managed on paper, the required resources for the TMF will let the study costs explode. Comparing costs for storage, control and manpower of an electronic TMF with a paper TMF, is similar to comparing the costs for doing a job with a computer versus using a typewriter.

The main difference is that the typewriter has been removed from most offices 30-40 years ago. It seems that the only reason for using a paper-based TMF is a nostalgic one. Without any doubt, the transition from paper to digital systems requires resources. Nevertheless, postponing this transition will cause even greater economical disadvantages for sponsors and may significantly risk the success of clinical trials and organizations.

The bad news is “time flies”, the good news is “you are the pilot”. Regulation (EU) 2017/745 (MDR) will apply after a transitional period. Namely, 3 years after entry into force for the Regulation on medical devices, which means spring 2020. The last year to fly into the right direction started!

For the future development of medical devices, the new MDR requires:

– more clinical data;

– more robust data;

– more transparency;

– minimization of patient risks;

– better control of entire life-cycle of the medical devices.

Even though the MDR will not make the medical device world in Europe perfect, it is useless to complain. The system will be changed, and it will become more like the US system, where medical devices fall under the US drug law (CFR). Consequently, some medical devices will be removed from the market, while others will move into another risk-class. Manufacturers will need to conduct 10 times more clinical trials with their new products to receive a CE mark, which will make the medical device development more expensive. In the past many manufacturers made rough estimations on sample sizes for their trials based on the nonvalid statements of notified bodies. In future a powered sample size calculation will be required. Nevertheless, if biostatisticians qualified in  medical devices trials will be involved, we do not expect dramatic  increase in the size of the medical device trials. However, the results of these future trials should be much more powerful compared to the past.

We can see also a lot of cost saving potential for the medical device companies such as:

– moving their trials from the high cost regions to central and eastern Europe, a region that is which more cost-effective for clinical trials;

– involvement of new, highly motivated clinical sites which are much more effective compared to “old professors” (key opinion leaders serving as key opinion leaders for all, even competing companies anyway);

– changing from paper to electronic documentation as nowadays eCRFs are less expensive compared to paper CRFs;

– change from onsite monitoring to remote monitoring, especially for low or medium risk devices;

– change from manual monitoring to statistical monitoring as software can check data better than people;

– planning and designing trials more professionally, having in mind that clinical product development is no academic research.

Yes, the costs of clinical development of medical devices will increase, but as pilots should not choose the way through the thunder storm, you should not choose the expensive way into the unknown. Clinical development of medical devices might be new for many medical device companies however thousands of clinical device trials have been already performed and experienced people and companies exist. Hence do not think you need to reinvent the wheel.

Why do so many companies run their clinical studies like driving with the car through the fog?

In no other industry can you find so many extremely smart people with excellent ideas to help patients, but when the clinical trial phase starts, many of those intelligent people start playing roulette. Millions of Dollars are spent to see at the end of the trial, if the results are positive in terms of efficacy and safety. If not, all money is gone. And errors during measuring or recording efficacy or safety can quickly turn a study heading the right way into one unable to show the desired outcome.

In most studies it is quite simple to get a better view into the data fog. Nowadays, statistical monitoring can show how our data look like during the whole course of the study and quickly identify spurious data or systematic errors before it is too late. Sponsor who use the foggy way of driving a clinical trial should not complain about the high risk of clinical research but think about more intelligent ways of conducting it. It is not enough to have smart people, people need to do smart things.