March 2020

From Planning a Study to Submission

Standardization of Clinical Data Pursuant to CDISC

Both the US American regulatory authority FDA as well as its Japanese counterpart PMDA require compliance with certain data standards specified by the CDISC (Clinical Data Interchange Standards Consortium) when conducting studies with medicinal products and medical devices. So applying the standards is essential for any approval-related studies. In our capacity as a research institute, we have noticed that the demand for compliance with the CDISC standards is increasing – regardless of whether the product is to be approved for use in the US or Japan – on the part of the SPONSORS, sometimes even for studies related to cosmetics. This is why we would like to provide a general understanding of these standards.

CDISC is a non-profit organization. Its declared objective is to apply established data standards to accelerate the development of pharmaceuticals and to make the process more efficient. The fundamental standards provided by the CDISC are geared towards study planning, data collection, data organization and data assessment. They are supplemented by standards that should be applied to the exchange of data. Standards and requirements specific to certain therapeutic areas as well as standards related to the terminology of the data round off the CDISC requirements for the clinical research process. In the following, we would like to present some information of the standards that we offer:

CDASH, SDTM and ADaM

1. Data acquisition
CDASH (Clinical Data Acquisition Standards Harmonization) is a standard applied to compiling clinical data. It describes how to structure the contents of clinical databases used to collect study subject data gained from the Case Report Forms (CRF). The goal is to create a uniform process, to simplify subsequent transformation of the data in tables as specified by SDTM, and to maximize data transparency for verification purposes and for government agencies – regardless of the study and the SPONSOR.

2. Data organization
Clinical data should be organized as specified by the standard SDTM (Study Data Tabulation Model). SDTM describes the structure of data sets that contain the data from clinical studies documented in the individual CRFs. The strict requirements regarding the format make it much simpler to review the data.

3. Data evaluation
CDISC specifies that data be evaluated pursuant to ADaM. ADaM (Analysis Dataset Model) describes standards for data sets and metadata designed for statistical analysis of the clinical study. The traceability/reproducibility of the result in regard to the data shown pursuant to the SDTM is enhanced by applying ADaM.

Data Exchange Standards

CDISC offers XML-based standards intended explicitly for exchanging structured data from clinical studies. XML (Extensible Markup Language) is a text-based data format made up of so-called tags that can be defined as needed. The standard Define-XML is particularly relevant. Unlike the other standards ODM-XML, SDM-XML, Dataset-XML and CTR-XML, the FDA requires compliance with Define-XML. We will deal in depth with Define-XML and the required approval package (CRT packages) at the end of this article.

Specific Standards

The CDISC has also developed specific standards for certain fields and therapeutic areas. For example, there is an extra standard for medical products. Such a standard is currently being developed for psoriasis. The standards related to specific therapeutic areas contained in Annex 1 exist at present.

Controlled Terminology (CT)

In addition to the described standards, the CDISC provides code lists and values to be applies to the data sets defined by the CDISC. Government agencies and others demand compliance with this terminology. The CT specifies how a collected data element is to be processed in an electronic data set.

FDA and PMDA Requirements

As mentioned at the beginning of this article, both the FDA and the PMDA require compliance with certain CDISC standards. The following table shows what is expected and to what extent we can help you meet these expectations:

Table 1: CDISC standards required by FDA and PMDA and the proDERM Service

FDAPMDAproDERM
ADaMaaa
CDASH--a
Controlled Terminologya-a
Define-XMLaaa
ARM-a-
SDTMaaa

Submission of the NDA (New Drug Application) to the FDA

To have a drug approved for the US market, not only is compliance with the CDISC standards relevant, the correct format of the application is important as well. The application has to be submitted electronically pursuant to the Technical Conformance Guide and includes, among other things, the CRT (Case Report Tabulation) packages SDTM and ADaM. The following illustration shows the elements of the various packages.

Illustration 1: Elements of the CRT packages

Blank CRF / annotated CRF
The annotated CRF (Case Report Form) is an essential document indicating in standardized form the SDTM domain and the SDTM variable to which the respective database fields in the CRF are assigned.

Data Reviewer Guide (SDRG/ADRG)
The Data Reviewer Guide closes the documentation gap between the individual components of the CRT package required for the review. This guide documents mapping decisions, sponsor-specific domains or sponsor-specific Controlled Terminology.

Validation Report
The validity of the SDTM data sets is checked with the aid of the Pinnacle 21 Validator. As a factor of the CDISC standard selected, a series of automated checks is performed to verify compliance with the standards and to detect data errors. Any findings that cannot be remedied are recorded and explained in a Validation Report.

Define-XML
Define-XML transmits metadata structured as a table. In conjunction with the fundamental standards such as SDTM and ADaM, Define-XML provides the metadata from clinical studies required for approval.

Xpt Data sets
These data sets form the core of the CRT packages. The data sets, in SAS Transport File Format (pt), contain all raw data (SDTM) and analysis data (ADaM) as specified by the CDISC data standards and the respective Implementation Guides. They form the basis for the review of data by government agencies.

SAS programs
SAS programs needed to create Tables, Figures and Listings (Tels) are also part of the CRT package, enabling complete and comprehensive review.

ARM
ARM is a standard that ensures traceability of the data flow, from the analysis data sets to the final output (TFL), for the reviewer.

In conclusion, we would like to present our services regarding CRT packages:

Table 2: The CRT packages and the proDERM Service

SDTMADaMproDERM
aCRFa-a
Define-XMLaaa
Xpt-Datasetsaaa
Validation reportaaa
Data Reviewer Guideaaa
SAS programs-aa
ARM-a-
Juliana K.

We would be happy to answer any questions you may have regarding CDISC. Please contact our Innovation Manager Juliana Kramer.

Download this article as a PDF file.

Spotlight on Our Clinical Research Team

Part 1: Architecture of a Clinical Study

The last update introduced you to our Clinical Operations Team – the people actively conducting clinical studies with medicinal products and medical devices. If you compare a clinical study to a house, the Clinical Research Team are the ones who plan the house and design it to be usable. They are the architects of the study, the ones who answer lots of questions beforehand: What is the objective of the clinical study? Which methods can be applied to reliably proving the objective? Which pool of test persons is needed and how many test persons should there be? Which regulatory specifications and guidelines must be complied with to gain approval for a newly developed product? Which recognized tests and methods can be applied? How can methods be created and combined to produce an innovative study design? Is this study feasible (feasibility analysis)? These are just a few examples of typical questions. The most important aspect is to design the study such that it can be conducted successfully to achieve valid results.

The World of Standards and Guidelines

If the objective of a study permits the use and adaptation of recognized study guidelines, our Clinical Research Team researches and creates study designs based on international standards and guidelines. One example of this is the HRIPT (Human Repeat Insult Path Test), a test for which the FDA specifies internationally recognized criteria for planning and performing the test. However, slight modifications can be made to the study design, such as those that consider the method and duration of application (after providing a sound scientific justification) of the pharmaceutical.

Innovative Designs

If a study is to be conducted for which there is no generally recognized procedure, the Clinical Research Team is challenged to be scientifically creative, either developing suitable new methods or relying on past experience.
So research involving scientific literature plays an essential role in developing these innovative study designs. The benefit is that this allows a new design to be tested on a small scale, e.g. as a pilot study. “Innovative spirit” comes into play here, enabling something that at first glance appears impossible to become possible.

Interdisciplinary Collaboration

When it comes to issues related to creating the theoretical study concept, performing the first practical tests and then creating the final design, the Clinical Research Team works closely with other teams. The team works with (bio)statistics to determine the subject number. They agree on potential procedures with the Clinical Operations Team (SEE OUR NEWSLETTER CLINICAL OPERATIONS), and they rely on the input from the physicians for things like inclusion and exclusion criteria, rating scales for a pool of subjects or the assessment of certain side effects in clinical studies. The DaTS Team is always available to help determine the operative feasibility of the planned study. DaTS is the Team for Development and Technical Services – and the focus really is on development and service. This team provides innovative methodical approaches, organizes technical implementation, validates the equipment, and much more.

Medical and Scientific Writing

Once the development of a study design (research, planning and testing) has been completed, the Clinical Research Team produces the documents required, e.g. those needed to conduct the study, for submission to the respective government authority and for later approval of a product.

Overview of our expertise:

  • Medical and scientific consultancy
  • Development of study designs
    • Literature research
    • Development of methods
    • Conducting preliminary tests and pilot studies
    • Implementation of standard study designs
    • Development of experimental study designs
  • Development and creation of a synopsis
  • Creation of study protocol
  • Compiling final report
  • Creation of Lay Summary Reports
  • Management of test samples (Drug Accountability)

Team Clinical Research

Dorothea Wilhelm
Director Clinical Research

For more than 25 years Dorothea plans and manages clinical studies and is currently Director Clinical Research. Her bibliography includes 25 original articles, 2 book chapters, and over 18 abstracts at scientific meetings. She received two government grants to support her research in allergy-incidence at the Department of Immunology of the University of Lübeck. She also received a grant from the University of California to support her research in skin physiology.

Katharina Kapoor

Katharina Kapoor
Project Manager Clinical Research

In the position as Product Development Manager and Study Manager Katharina previously gained experience in pre-clinical topical formulation development. At proDERM she now supports the Clinical Research team as Project Manager and is involved in clinical projects at various stages ranging from early-stage project conceptualization to final reporting. Katharina is a registered pharmacist and holds a Master’s degree in Cosmetic Science.

Brigitte Stephan
Medical Consultant

Dr. Brigitte Stephan, a dermatologist with additional training in allergology, phlebology and naturopathy, has a dual function at proDERM. On the one hand, she is a member of the team of investigators and as such is involved in carrying out the studies. On the other hand, she is a medical expert and scientific advisor for the Clinical Research team.

Mitarbeiter proDERM

Sandra Wipperling
Head Test Sample Manager / Test Coordinator

As Test Sample Manager / Test Coordinator it is Sandras role to care of the test sample logistics and to make sure that everything is in the right place at the right time. She held postions in volunteer recruitment and marketing in a global cosmetic Top-brand manufacturer before joining proDERM in 2006.

Silke Graba
Test Sample Manager

Silke Graba supports in the coordination of the test samples.

Susanne Krönke
Intern Clinical Research

On top of being a doctoral student in chemistry, Susanne Krönke supports us in the areas of data operations and clinical research.

Cedric Noune Tankou
Intern Clinical Research

Cedric is studying Health Sciences at Hamburg University of Applied Sciences. As part of the master’s program, he does a six-month internship in our clinical research department.

Studies in Times of Covid-19

proDERM starts second Phase

Considering the current legal situation and our hygiene and safety precautions, clinical studies can only be carried out to a limited extent. In this respect, in a first phase after the outbreak of the pandemic and the associated impact on our service as a research institute, we were focused on finalizing projects that had already started. We have largely succeeded in doing this. Projects that were planned but had not started at the time of the outbreak were postponed – in close consultation with our customers – until a later date. (Read our official Covid-19-statement here).

A second phase is currently starting for us: While maintaining the strictest safety precautions, we are ready to conduct new projects and corresponding studies clinically. Among others, the following protective measures are to be considered:

  • A safety distance of at least 2 meters and / or the use of physical protection such as B. plexiglass
  • Obligatory wearing of respiratory masks for proDERM employees and study subjects
  • Disinfection of the hands of proDERM employees and study subjects is mandatory; at the same time we regularly carry out surface disinfection e.g. on door handles

The studies that can be carried out under these conditions are characterized by a small number of subjects and a limited number of examinations. In addition, we are currently working on remote trials. These could take into account surveys, self-assessments by the subjects, application controls and dermatological assessments.

Our business development team is happy to provide you with more detailed information on the study types. Please contact the email BD@proDERM.de. Alternatively you may want to check out the recently published list of study types we are currently able to perform.

No Learnings without Learnings

proDERM Academy Postpones Medical Device Seminar

Medical Devices in the EU – Challenges After May 2020 – This was to be the central topic of the event planned for November of this year. The intention was to gather people from the medical device industry for a one-day seminar, giving us all the opportunity to talk about our initial experience after enactment of the new directive. But because of the coronavirus pandemic and the subsequent need to supply medical devices, the EU Commission decided to postpone implementation of the regulation by one year, until May 26, 2021 (See official statement issued by the EU Parliament).

“The postponement makes it impossible to share our experiences after implementation in November of this year. So to be pragmatic, we have decided to postpone the seminar by one year”,

explains Bernd Brormann, who developed the seminar for the proDERM Academy. At this point we cannot provide any specific information on a new date for the event. It will most likely be scheduled during the second half of 2021. Please check www.proderm-academy.com for updates regarding our seminars.

Digital Offers

Even though the MDR will be enacted later and the seminar is consequently postponed, we assume that there is still a need to share information with one another. So the organizing team and Bernd Brormann are currently looking into the feasibility of a webinar on this topic. As of now, we are planning for the webinar to take place November 4, 2020 (the original date of the seminar). Details will be available soon.

Any questions you may have about events of the proDERM Academy can be answered by our conference manager Birte Wehr. Bernd Brormann is available to reply to questions relating to the clinical testing of medical devices.

Measurement Precision in the Field of Sun Protection

proDERM Once Again Shows Very Good Results

We are pleased to inform you that the measurement precision of our sun protection method pursuant to ISO 24444 has repeatedly been confirmed. This was confirmed by the test series, organized and conducted by Bipea in November 2019, in which 18 test labs participated. The ring trial was conducted with a lipstick with a declared sun protection factor (xpt) of 57.5.

The z-value is the parameter used to determine the measurement precision of a lab. It is calculated applying the sun protection factor (x), the average (x*tot) and the standard deviation (s*tot) determined by a lab. The closer the value is to zero, the more precise is the testing method.

Our method showed that the lipstick had a sun protection factor of 58.8. This is a z-value of 0.11 – one of the lowest deviations from the average.

Illustration 1: Z-values of the participating laboratories

The more the z-value approaches 0, the more accurate is the method!

We are able to measure the SPF according to the latest version of the ISO 24444 guideline. Please read here our according article from January 2020.

Quantifying Absolute Active Ingredients Contents in the Skin

proDERM Launches New Research Project Examining Cannabidiol

Knowledge of the bioavailability of active ingredients is essential to the manufacturers of topical products. For example, a formula can only be developed and optimized for a specific purpose if there is enough information available on how the active ingredients penetrate the skin.

We have been using confocal Raman spectroscopy (CRS) to measure penetration for many years now. CRS is actually the only in vivo method on the market that enables you to quickly and precisely answer questions about penetration while maintaining the natural state of the skin. By investing in a second-generation device, we have been able to expand our capacity for measuring with Raman (Read about it in the article on our website).

One of our new research projects going on now examines the bioavailability of active ingredients not only semi-quantitatively, it also has the capacity to measure the absolute contents of the active ingredients in the skin in µg/cm³. By repeatedly measuring the contents in the skin after different exposure times, we can also determine the permeation in µg/cm²*h. This is the quantity that passes through the corneal layer and penetrates deeper skin layers per unit of time.

The first step of quantitative penetration measurement was to determine the Raman-specific “fingerprint” of selected active ingredients and to create calibration curves in suitable solutions. Then we performed initial measurements on the skin. With the substances for which we could determine the unique and distinctive Raman spectrum in the skin in an adequate quality and strength, in addition to all of the other ingredients, we can then perform depth-resolved quantitative measurement of the contents in vivo. Our initial plan is to perform a study of a series of active substances on a small group of test persons, applying a simple formula of the active ingredients to the underarm. We are anticipating intriguing results regarding penetration and permeation of the substances. Once these trials are completed, we intend to expand testing to include questions on penetration acceleration and then publish the results.

In Vivo Penetration of Cannabidiol

With a forecast annual growth rate of more than 30% by the year 2025, the market for cosmetics containing cannabidiol appears to be much more than just a passing trend.¹ Quite a few positive effects can be attributed to the substance. These include skin care and skin soothing properties as well as anti-inflammatory and anti-oxidative effects. Literature describes applications involving skin moisturizing and barrier protection as well as acne and psoriasis. To our knowledge there are no methods currently available to examine in vivo penetration. This is why we have chosen cannabidiol as one of the active ingredients for our in vivo penetration project. We have already successfully completed initial preliminary tests with cannabidiol. The second phase will perform measurements on the skin.

Raman Webinar on May 28, 2020

To learn more about this topic, please join our upcoming Raman webinar. Stephan Bielfeldt, Vice President and Director Science & Innovation, will present findings on the opportunities available in anti-aging research using confocal Rama spectroscopy (CRS). Sign up here.

Stephan Bielfeldt would be happy to answer any questions you might have regarding our research project. Contact him at:

Stephan Bielfeldt
SBielfeldt@proDERM.de

References

¹ PRNewswire

Local Tolerance of Topical Products

The proDERM Webinar About Skin Compatibility – May 14, 3 pm cet

Local Tolerance of Topical Products

The proDERM Webinar About Skin Compatibility on May 14, 3 pm cet

In her lecture on the subject of skin tolerance testing, Sandra Bleckwenn, Business Development Manager at proDERM, addresses various questions related to the topic: Why are skin tolerance tests necessary? Which exams are available and how do you go about it? Which test fits which product? What are the possibilities for claims related to skin tolerance?
The duration of the webinar is approximately one hour. Participation is free of charge.

Presenter:
Sandra Bleckwenn
Business Development Manager

Registrations can not be accepted anymore.

Anti-Aging-Studies using CRS

The proDERM Webinar on May 28, 2020

Delegates of this webinar will be introduced into the fascinating technology of anti-aging research with confocal Raman spectroscopy, a method to non-invasively quantify the chemical composition of living skin in vivo. As a delegate, you will be provided with our latest research findings on aging and photoaging-parameters as quantified by use of the advanced Raman technology. The webinar will be presented by Stephan Bielfeldt, Vice President and Director Science & Innovation of proDERM. In the end of the presentation, you will have the chance to submit your questions using the webinar chat.

Mitarbeiter proDERM

Presenter:
Stephan Bielfeldt
Vice President and Director Science and Innovation

Register now




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