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Applied Clinical Trials June 2021

MMS Holdings announced that its learning arm, MMS Academy, has expanded its global training portfolio with the launch of new courses in inspection readiness and clinical programming. These new courses will give students and working professionals the opportunity to gain the knowledge that the pharmaceutical, biotechnology, and medical device industries require.

In the 14-week inspection readiness course, students will gain an understanding of global health authority (i.e. FDA, EMA, etc.) inspection processes, targeted industry-specific guidance, and important regulations and guidelines that allow teams to ensure successful regulatory authority inspections.

Mini courses are also available, each lasting three to four hours, and have been prepared with consideration for a variety of specific inspection needs, including: remote inspections, regulatory agency and ISO basics, post inspection management, GMP, Sponsor and CRO inspections, and more.

Intermediate Fundamentals of Clinical Programming, an 8-week course, is designed for intermediate SAS programmers looking to learn more about the CDISC SDTM model. Those taking this course will gain the confidence to model clinical trial data into SDTM domains and a level of expertise to draw upon when engaged in real-world projects.

This course provides an understanding of:

Converting clinical data into SDTM format by understanding the required modeling of the General Observation Class and targeted domains

The components included in define.xml v2.0

The process of third-party validation of the define application

How to resolve and apply corrective measures to ensure modeling is in compliance with SDTM standards

Articles

MMS Adds New Inspection and Programming Courses to MMS Academy

Congressional leaders, as well as regulated industry, want more information from FDA on its strategy for resuming inspections of manufacturing facilities to better assure the quality, safety and efficacy of medical products. The suspension of in-person field inspections in March 2020 has resulted in a huge backlog of delayed site visits, as FDA sent investigators only to those operations deemed “mission critical.”

FDA acting commissioner Janet Woodcock recently confirmed that the agency is returning to normal procedures for domestic inspections, although foreign inspections still will be limited to mission-critical situations. In testimony before the Senate Health, Education, Labor and Pensions (HELP) Committee on July 20, 2021, Woodcock outlined FDA’s plan to “transition to standard operations” for U.S. inspections, which still means focusing on higher-risk establishments and scheduling postponed surveillance inspections based on risk.

Meanwhile, Congressional leaders continue to demand more information on how and when FDA will resume standard operating procedures for inspections, reflecting concerns that postponed oversight may delay the approval of new drugs and biologics. In a lengthy letter to Woodcock dated July 22, 2021, Republicans and Democrats on the House Energy and Commerce Committee requested details on the status of foreign inspections; whether delayed inspections are hindering the approval of applications for new drugs, generics and biosimilars; FDA’s ability to utilize inspection reports from trusted inspectorates; and how FDA’s data modernization initiative will improve its inspection program. The legislators also want to know how much of the $38.3 million provided FDA to help address the pandemic is being used to support the resumption of domestic and foreign inspections, and the impact of FDA’s decision to pre-announce all inspections for the foreseeable future.

FDA normally conducts nearly 1,000 foreign and domestic inspections a year for medical products, but has made less than 100 critical site visits in the U.S. in the last two years, and only a handful overseas. In its “Resiliency Roadmap for FDA Inspectional Oversight” issued May 5, 2021, FDA acknowledged that it had postponed most inspections in 2020 due to the pandemic, focusing primarily on manufacturing operations producing drugs needed to prevent critical shortages and to support the approval of novel drugs or treatments for COVID-19.

 For 2021 the agency has some 15,000 domestic surveillance inspections on its to-do list, most of those involving food and other products, but a third related to drugs.

To better manage this considerable volume of inspection work, FDA is aims to enhance the Office of Regional Affairs (ORA) field inspection program through the agency’s data modernization initiative to provide cross-program interoperability, Woodcock reported to the Senate panel. This includes new technology supporting regulatory assessments to improve the receipt, review and analysis of industry data and records, including a review of inspectional approaches using next-generation assessment technologies.

Furthermore, FDA has established a new agency-wide Inspectional Affairs Council to better coordinate inspection approaches and assessments across product centers. This panel aims to “optimize the inspection process,” explained Judith McMeekin, associate commissioner for regulatory affairs, in a presentation July 14, 2021 to the Alliance for a Stronger FDA. McMeekin, who manages ORA’s 5000 inspectors and other staffers, noted that the Council will provide a forum for the leadership of FDA centers to jointly assess strategies and policy issues across operations to ensure optimal use of resources.

McMeekin reported that ORA has conducted about 30 mission critical foreign inspections during the pandemic, which has involved a tremendous effort to mitigate risks to investigators. ORA also worked to facilitate the emergency approval of vital vaccines to combat the pandemic by devising methods to inspect key vaccine clinical research sites, collaborating with the Center for Biologics Evaluation and Research (CBER) to plan the visits. In just four weeks, a team of more than 50 ORA investigators inspected 26 clinical research facilities to ensure the accuracy and reliability of data to be considered by FDA’s vaccine advisory committee. Here, FDA sent in two inspectors, instead of one, to assess data in the shortest amount of time, supplying them with portable projectors able to review documents from a distance.

McMeekin also highlighted ORA’s need for additional funding, particularly to enhance its operations related to drugs and medical products. Only 10% of its budget is supported by user fees, she explained, and most of its appropriated funds are allotted to food safety and oversight. To expand its drug inspection activities, lab capacity and scrutiny of more imported packages containing drugs, ORA is looking to tap more medical product user fee funds, while also increasing appropriated support to bolster its staff dealing with medical devices and biologics, as well as its cadre of foreign inspectors.

In going forward with scheduling of site visits in the U.S., FDA is utilizing a rating system to assess the number of COVID-19 cases in the local area and risks to personnel, in consultation with state and local authorities. And for now, the agency also is pre-announcing domestic inspections to ensure a facility is available and safe for FDA staffers to visit. But FDA officials recognize that it will take some time to restart its foreign drug inspection program due to the more extensive planning required to arrange for safe travel and site visits.

https://www.help.senate.gov/imo/media/doc/Woodcock%20Testimony.pdf

https://energycommerce.house.gov/sites/democrats.energycommerce.house.gov/files/documents/07.22.21-EC-Letter-to-FDA.pdf

https://www.fda.gov/media/148197/download

FDA acting commissioner Janet Woodcock has outlined FDA’s plan to “transition to standard operations” for U.S. inspections.

FDA Under Pressure to Restore “Normal” Drug Inspections

Mike Rea, CEO and Founder of IDEA Pharma, speaks about how his newly launched sister company—Protodigm—takes lessons learned from IDEA, combined with ideas borrowed from engineering and tech development, to form a new concept in pharma and biotech to innovate drug development with minimized risk and without bias.

Podcasts

Nuance in the CRO World

 addressed the first two elements necessary in 

Figure 1) to help sponsors derive the greatest benefits from eCOA technology: involving all key stakeholders in the earliest stages of designing and implementing eCOA solutions and carefully considering your data NEEDS versus “nice-to-haves.” Part 2 addresses the next four crucial elements: implementing best practices in design, taking advantage of your solution provider’s experience, relying on configurable platforms not customized solutions, and focusing on user experience (UX).

Patient-centric design is the most critical factor in eCOA design. Members of the Transcelerate Biopharma’s Patient Technology Initiative spoke with a diverse group of patients to understand what they would like sponsors to consider when designing studies using patient technology. Among those were patient burden, UX, and patient comprehension

and it is well known within the eCOA industry that best practices should be followed to minimize compromising patients’ comprehension of electronic versions of questionnaires originally developed for paper administration.

Uncomplicated design is crucial in ensuring:

All information can be understood by all end users (sites and patients)

Simplicity of use regardless of technical literacy

One of the easiest ways to ensure simplicity of design is to rely on your solution provider’s previous experience. Typically, they have experience with diverse sponsors, geographic locations, indications, and study parameters. They have spent time extracting lessons learned from post-study discussions with sponsors. Their clinical, scientific, regulatory, project management, and technology expertise is vital in designing and implementing eCOA solutions. Combined with your internal key stakeholders’ project-specific knowledge and their experience with internal processes, systems, and technology, the collaboration will yield a design that makes sense for your study.

Configurable platform vs. customized solutions

Let us first clarify what we mean by “configurable” and “customized.”

 To use existing code from within an application to meet specific requirements.

 To write new software code to meet specific requirements.

In Table 1, we describe the benefits of the configurable platform and potential challenges of customized solutions.

Table 1: Configurable versus Customized Software

Consider configurable solutions that allow you to build your study using a standardized library of assessments to meet study goals. For example, the YPrime StudyBuilder solution offers a range of development settings and outputs a study design that is pre-validated and ready for use. Features of YPrime’s StudyBuilder include:

Thoughtful design requires us to consider the burden this technology may place on patients and sites. It is important that sponsors and solution providers remember to stick to the basics and keep simple the UX design. Some factors to consider:

Amount of time the patient must invest to set up, use, close out, and return the device

Keeping it simple with easy-to-understand user guides, login screen, and other navigation

Amount of disruption to the patient’s daily activities

Level of comfort as patients wear or carry the device throughout their day

Direct patient interaction versus passive data collection and transmission

By investing time and resources upfront on 

 (see Figure 1), sponsors can streamline and gain efficiencies during the study development process, reduce time to first-patient-in, increase site satisfaction, and ensure patient compliance.

TransCelerate Bio Pharma Inc. Patient Considerations: A patient perspective on key considerations for sponsors implementing patient technology in clinical trials. Available from: https://transceleratebiopharmainc.com/patient-technology-implementation-framework/patient-technology-assets/. (Accessed April 19, 2021)

Critical Path Institute ePRO Consortium. Best Practices for Electronic Implementation of Patient-Reported Outcome Response Scale Options. Available from https://c-path.org/wp-content/uploads/2014/05/BestPracticesForElectronicImplementationOfPROResponseScaleOptions.pdf. (Accessed April 19, 2021).

Critical Path institute ePRO Consortium. Best Practices for Migrating Existing Patient-Reported Outcome Instruments to a New Data Collection Mode. Available from: https://c-path.org//wp-content/uploads/2014/05/BestPracticesForMigratingExistingPROInstrumentstoaNewDataCollectionMode.pdf. (Accessed April 19, 2021).

To derive the greatest benefits from eCOA technology, several elements must work together to create a strong foundation for sponsor success.

Thoughtful Design in eCOA Development: Part 2

WCG has announced the acquisition of VeraSci, a global provider of specialty scientific and eClinical software to support the design and execution of clinical trials focused on central nervous system disorders.

VeraSci provides clients with solutions that aim to improve data quality in clinical trials, including endpoint and assessment services, rater training and certification, language and translation support, and eCOA and ePRO technologies. With its Pathway technology platform, VeraSci enables the collection of data that can be used to assess symptoms, cognition, and functional capacity in a wide range of therapeutic indications.

Moving forward, VeraSci will be known as WCG VeraSci. The organization will retain its leadership structure and continue to operate from its headquarters in North Carolina.

WCG Acquires VeraSci

ACM Global Laboratories, Inc. has announced the rebranding of ABS Laboratories to ACM Bioanalytical Services.

Founded over two decades ago by Drs. Colin Feyerabend and Mira Doig, ABS Laboratories was purchased by ACM Global Laboratories in 2018 as it expanded its central laboratory testing offerings for clinical trials to include bioanalytical services. ABS Laboratories, now ACM Bioanalytical Services, specializes in complex assay development and validation for the quantification of drugs, metabolites and biomarkers in biological samples used in pharmaceutical research and development.

ACM Bioanalytical Services will maintain all of its employees, equipment, and location in York, UK.

ABS Laboratories Becomes ACM Bioanalytical Services

Thursday, July 22, from 4:30 to 6:00 p.m. CDT

 – Midwest educational event will cover the Chicago, Columbus, Detroit, Indianapolis, and Minneapolis areas with a specific focus on these therapeutic areas and medical conditions:

https://www.ciscrp.org/event/aware-for-all-midwest-virtual-event/

Events

AWARE for All Midwest — 7/22

Clinical Data Management is a pivotal process in clinical research, capable of impacting the success or failure of any study. During clinical research, data is collected on protocol specifications articulated in Case Report Forms (CRFs), however, there is also a significant value addition provided by external data to the CRF, called ‘Non-CRF data’. The non-CRF data or third-party vendor data is collected through alternative channels. Thus, in collecting data from external sources, data integrity and quality have a critical influence on clinical trial data management and study success. The non-CRF data includes central and core laboratory data, central imaging (any type of medical images.), subject diaries which includes patient-oriented tools such as questionnaires pertaining to the quality of life, pharmacokinetics and pharmacodynamics data, safety laboratory data, genetic data, biomarkers, devices data and randomization data. A big part of this data is generated from services and components that are either outsourced or automated for direct patient interaction (Figure 1).

Figure 1: Common sources of Non-CRF data

While CRF is the major contributor to the collected data, non-CRF data also constitutes a significant portion, thereby contributing to safety and efficacy of the product. The non-CRF data collected during a study is specified in the clinical protocol. To generate this data, Data Transfer Agreements (DTA) are used between sponsor and vendor organizations. However, presently there are no industry-standard formats or procedures to govern this data exchange. For an efficient selection and management of vendors, a critical aspect is to review data transfer agreements for all third-party vendors.

 Hence, the DTA process is extremely critical for the quality of a clinical trial data inference. DTA enables receipt of non-CRF data from vendor to the clinical database. It also defines the structure of the database, data exchange timelines, and data definitions. This time consuming and cumbersome process is critically designed (Figure 2) and includes several challenges, limitations and intricacies requiring multiple review cycles.

The non-CRF data is not configured to EDC and is received as a separate electronic file. After the data has been transferred to a clinical database, there is often a need for manual reconciliation with the existing data. Such manual reconciliations take place between visits across CRF data, and the data stored in third party datasets using listings.

Figure 2 Process of Data Transfer Agreement

The process of non-CRF data reconciliation is fraught with risks of missing out on errors, missing data across datasets, identifying duplicate records etc. resulting in serious consequences on the safety outputs. These risks are compounded due to several additional challenges such as the use of standards, delivery of expected data file formats, uptake of new technology and adherence to timelines.

 For studies that rely heavily on this data, inaccuracies in non-CRF data can be dangerous and provide several underlying risks to patient safety. Despite the largely cumbersome process and careful evaluation of the vendors, there are several challenges (Table 1) in validation and reconciliation of non-CRF data. The challenges result in critical difficulties pertaining to data management, data quality, integrity, and confidentiality. In addition, third party data transfer is required to be handled by the Data Management Group (DMG) during the conduct and closeout phase of the study.

Table 1 Challenges and Limitations in handling non-CRF data

Besides the underlying data issue, there are several reasons for delays in data transfers. Common reasons for the delay include people-oriented challenges (missed data entry, data transfer efforts), technological aspect (e.g., spreadsheets are only limited to include 1 million row

), process errors (missed metadata, poor set up) etc. resulting in rejection and reiteration, consuming efforts, and contributing to delay in database locks in 50% cases.

Figure 3: Third Party data reconciliation Process

The challenges surrounding the DTA, and non-EDC data capture processes help facilitate the collection of such data within the non-CRF data management platform. Such solutions are critical for enabling consistent performance of activities related to vendor operations without jeopardizing the quality and timeliness during the conduct of the trial. Executing operations such as DTA, set-up, validation, reconciliation, queries etc. with minimal human intervention is the need of hour to expedite the process, maintain traceability and avoid delays. The platform should support integration with vendor data management systems to upload and manage the data exchanges provided by vendors. Adopting a platform for such processes will not only make the process validated, traceable and recordable, but would also be instrumental in improving the data quality and turnaround time. Additionally, it would also offer data visibility across different data sets collected from various sources.

Due to an absence of common industry-wide standardized DTA and non-CRF data transfer process, the process of data transfers lack parameter-based metrics that would help determine the efficiency of non-CRF data transfers. Hence, amongst the studies, vendors and sponsors there is a large variation in this process as well as its evaluation. Subsequently, it affects the quality, timeliness, and information standards in non-CRF data in comparison to the CRF data that is well managed, monitored and process-driven. In addition, there exists an opportunity for generation of universal or at least sponsor-level standardization of this process solely by determining the standard metadata structures, defining errors and providing methods for error-elimination at the source. Furthermore, to implement a uniform industry-standard data transfer agreement and corresponding data transfers for all types of non-CRF data, a mix of commitment, participation and continuous efforts towards process development, editing and verification procedures based upon workflow driven approach from all the stakeholders is a priority

Another key route is in deployment of automation-based processes. The process of DTA generation, reconciliation, query generation, integration of non-CRF data into EDC etc. present immediate opportunities for technology to streamline the process for non-CRF data utilization. The principle idea behind this opportunity is to manage all clinical data in a single data repository, providing visibility across all datasets, facilitating automated reconciliations between the current CRF and non-CRF data, generating reconciliation report, error reports, and reject erroneous data before entry into the clinical database. Automation provides a low-risk and efficient technique for reconciliation, without any data loss and saves significant amount of time and cost.

Each study and data type has varied demands. Hence, the success of standard data transfer ecosystem depends upon an effective monitoring of quality, compliance, and efficiencies through metrics. Metrics also contribute to driving delivery governance and enables effective activity management. Periodic analysis of metrics not only reflects partnership maturity but also provides a “

” by representing gaps and quality of deliverables for all processes under purview. Key metrics suggested including:

Key performance indicators for the non-CRF data integration are listed below:

Quality of deliverables should be continuously monitored using key performance indicators from study start up to closeout. The below two quality parameters impacts study timelines, resulting in late submissions of clinical study report to the respective regulatory authorities.

Poor quality in interpretation of results or missing data

It is also important to maintain an efficient and effective communication with vendors to plan schedules and ensure timeliness of data receipt. Hence it is vital to arrive at an agreement prior to the study start up. In addition, vendor data should be reviewed at regular intervals during the study conduct phase to identify generic issues and address them immediately.

Best practices to handle situations such as training, improvement areas or issues with the vendor, include leveraging reference documents, reconciliation checks and transfer of file according to the DTA, standard test names, quality assurance and quality control of vendor data at a nascent stage to avoid any delays.

Clinical laboratory tests influence approximately 70% of the medical decisions. Hence, it is vital that trial results which are critical for safety and efficacy of the treatment, are reported with utmost accuracy. Risk management involves anticipation of errors that might happen, the assessment of errors frequency and the consequences or the severity that might come into play because of it, and finally the decision taken to mitigate the risks to an acceptable threshold.

Service Level Agreement (SLA) as a metric driven approach encompasses the DTA between the sponsor and corresponding vendors. The SLA comprises of a standard flowchart and portrays some of the key roles that are instrumental in delivery of services pertaining to the collection and transfer of Non-CRF data.

Metrics are critical for the reduction of time and effort. Governing SOPs, timely stakeholder involvement, adequate QC procedures and well-defined guidelines are catalysts in ensuring elevated efficiencies.

In addition, unique data identifiers, a structured process for management & reconciliation of non-CRF data, redundancy checks & leveraging the already established standards (CDISC, HL7, etc.) are instrumental for ensuring a high data quality and integrity.

Non-CRF data is critical to various aspects of a clinical study. Despite all the importance that have been identified and laid out, there are no standard processes, quality parameters or automations that can be leveraged to capture the non-CRF data for a clinical study. Standardization and quality metric-based automation of the data transfer agreements will not only enable a seamless validation of the quality pertaining to the available data but also will be instrumental in reducing the overall cycle time. Artificial intelligence as a technology can be seen as the future of this process, that will help unlock capabilities to improvise and transform the three core pillars of the process i.e., data transfer agreement, data capture and data quality along with monitoring by automation-based technologies.

Life Sciences & Healthcare, Clinical Data Management;

is the Head, TCS ADD Data Management; and

of Life Sciences and Clinical Data Management;

https://scdm.org/wp-content/uploads/2020/01/GCDMP-Vendor-Selection-and-Management-2020-Edition.pdf

https://journals.sagepub.com/doi/full/10.1177/2168479016670689

https://support.microsoft.com/en-us/office/excel-specifications-and-limits-1672b34d-7043-467e-8e27-269d656771c3

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3915369/

While Case Report Forms are a main contributor to collected data, non-CRF data such as core laboratory data and central imaging can be critical to any clinical study.

Establishing Metrics and Standardization for Non-CRF Data in EDC

Novartis and the Novartis US Foundation have announced a planned 10-year collaboration with Coursera, the National Medical Association, Thurgood Marshall College Fund, Morehouse School of Medicine and 26 additional Historically Black Colleges, Universities and Medical Schools (HBCUs) to co-create programs that address the root causes of systemic disparities in health outcomes and create greater diversity, equity and inclusion across the research and development ecosystem.

Working together with the communities they aim to impact, the collaboration will focus on increasing clinical trial and clinical trial investigator diversity; addressing inherent bias in the data standards used to diagnose and treat disease; and finding actionable solutions to environmental and climate issues that disproportionately affect health among communities of color.

Over an initial period of ten years, the collaboration will focus on four key areas:

Enable the next generation of Black and African American leaders

 by creating equitable access to high quality education and professional development for future leaders, in health science, technology and business-related fields.

Support the establishment of Digitally Enabled Clinical Trial Centers of Excellence,

 managed and led by clinical researchers of color, to build trust, increase diversity and inclusivity in clinical trials, and contribute to improved health outcomes for people of color.

Research and validate existing data standards 

that drive diagnosis, clinical trial endpoints and population health policy to identify areas for increased inclusivity and ensure accurate data collection and unbiased treatment decisions.

Establish Digitally Enabled Research Centers on the impact of the environment and climate change on health

 to identify solutions to environmental and climate issues that disproportionately affect communities of color.

All parties will spend the next six months co-creating programs with the communities, including establishing the first clinical trial, data standards, and environment, climate, and health research centers at Morehouse School of Medicine. 

Read more about Novartis’ commitment here

Novartis Pledges 10-year Commitment with Morehouse School of Medicine, 26 HBCUs, and More to Create Health Equity Solutions   

Premier Research has announced that it has acquired Health Decisions, a Durham, N.C.-based contract research organization focused on clinical development in all areas of women’s health and diagnostics.

Health Decisions has a dual focus on women’s health research and diagnostics and is supported by a network of 500 women’s health sites. Since 1989 the company has conducted more than 300 clinical trials, including more than 200 studies in women’s health indications such as reproductive and sexual health, menopause, pain management, osteoporosis, osteoarthritis, and gynecologic oncology. It has also delivered multiple PMAs and 510(k)s for IVD-focused sponsors that include successful submissions in high-risk HPV, colorectal cancer, and pre-term birth, amongst others.

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Applied Clinical Trials June 2021