Managing Chronic Pain in Patients with Hemophilia
Integrating Clinical Research Into The Product Development Cycle
Originally Published MDDI May 2001
Product Development
A systematic approach that views the clinical research department as an integral part of the development team can enhance the likelihood of success in the creation of new products.
Nancy J. Stark
Many medical device companies use a project management approach for product development. The project team, comprising a team leader (or project manager) and representatives from various departments, is responsible for planning and implementing the project. When the project is to develop a new device or enhance an existing one, the clinical research department can play an active, contributory role.
The product development cycle can be divided into five phases: concept, prototype, prepilot, pilot, and production. This paradigm is similar to the standard project management model consisting of project definition, project planning, project tracking and maintenance, and project closeout.
The elements of design control—plan, input, review, output, verification, validation, transfer, changes, and history file—are embedded over specific phases of the product development cycle and help characterize the phases. Figure 1 shows the relationship of the product development cycle, design control elements, and clinical research activities.
Clinical trials most often occur during the last four phases of product development, depending on the purpose of the trial. Typically, the way one names a trial—for example, pilot, feasibility, manufacturing, pivotal, postmarket surveillance—reflects the phase in the product development cycle in which the trial is taking place. Device companies that are owned by drug companies, or those whose management previously worked in the pharmaceutical industry, often use a different nomenclature for trials—generally phase I, phase II, phase III, and phase IV. Regardless of the nomenclature, the role of clinical research is separate and distinct in each of the five product development phases.
CONCEPT PHASE
The first step in standard project management models is the concept phase, in which a project team is appointed to design the new device in accordance with design control requirements. The design control steps are to create the project control plan and to obtain design input.
Project team members meet to identify the design requirements of the product, including requirements for product configuration, formulation, processing and manufacture, packaging, labeling, performance, storage, handling, distribution, regulatory status, bench and animal testing, and human clinical trials. This process is called design input. The team also develops a project control plan describing in general terms who will do what by when. The concept phase of product development culminates when a general plan for building, testing, and manufacturing the product is completed.
Clinical Research Activities. The clinical research representative to the team acts as a consultant during the concept phase, providing input for development of claims and advising as to claims that may be necessary, claims that may be difficult to substantiate, or claims that should be avoided. (A claim is an assertion of truth about a product, especially about its safety, efficacy, performance, or regulatory status.) The representative's primary work product is a clinical development plan—that is, a group of one or more clinical trials that are necessary to substantiate the claims for the product.1
PROTOTYPE (FEASIBILITY) PHASE
During the prototype phase—called the feasibility phase by some companies— various departments will begin evaluating the feasibility of the concept. The manufacturing group will look at production issues, whereas the marketing department may conduct focus panels to evaluate design concepts. If test outcomes are unsuccessful, the prototype is redesigned. If test outcomes are successful, the product design is frozen, signifying the culmination of the prototype phase. Hereafter, all design changes are captured through design change control.
Clinical Research Activities. Preclinical tests for safety, efficacy, or performance in in vitro and animal systems are initiated during the prototype phase. These include biocompatibility tests designed to ensure biological safety of the materials and animal efficacy tests designed to evaluate effectiveness of the design in nonhuman systems. In some companies, these tests are coordinated by the clinical research group; in other firms, preclinical testing is assigned to a different department.
Clinical trials in the prototype phase may include pilot studies to aid in design definition. For example, an algorithm might be loaded into a personal computer, measurements from the subject fed into the computer, and a computed result evaluated for its accuracy in representing a physiological event, with the goal of defining the algorithm. Similarly, various configurations of a device might be evaluated in ill subjects to finalize a design, or anatomical measurements taken from a group of subjects to establish size ranges.
One issue for clinical trials of prototype devices is the extent to which the sponsors must comply with good manufacturing practices. In the United States, regulations declare that investigational devices "are exempt...From good manufacturing practice requirements . . . Except for the requirements found in Section 820.30 [Design Controls]..."2 FDA recognizes that prototype devices are unlikely to meet all the requirements of design controls—a prototype device will not be verified and validated. The preamble to the quality system regulations specifies that "the use of prototypes in clinical studies is acceptable. When prototype devices are used on humans, they must be verified as safe to the maximum extent feasible. Final design validation, however, cannot be done on prototypes because the actual devices produced and distributed are seldom the same as the research and development prototypes. The final verification and validation, therefore, must include the testing of actual production devices under actual- or simulated-use conditions."3
In preparation for any clinical trial, the clinical research team will work with the regulatory department to determine the trial's regulatory status. Is the device under investigation also a drug or cosmetic, requiring compliance with additional regulations? Is the trial exempt from the investigational device exemption (IDE) regulation or an approved IDE needed for the trial? Will the trial be multinational, requiring compliance with regulations from other countries?
Clinical research personnel will also work with the project team to develop a risk analysis. It should be noted that the risk analysis developed for the device is much broader than the risk analysis needed for a clinical trial, which focuses on the medical risks to the subject. The latter also includes any risks that may be study-specific—for example, risks associated with experimental procedures that may be used during the trial, but are not part of the device itself.
PREPILOT (DEVELOPMENT) PHASE
In the prepilot phase—sometimes called the development phase—the manufacturing department works to develop the production process, while other departments develop the processes necessary to carry out functions such as packaging, distribution, or marketing. In design control language, this is the phase of design verification—the period of testing and proving the design features of the device. The design is changed if study outcomes are unfavorable, and design changes are captured through the design change control system. The prepilot phase culminates when the manufacturing process has been finalized.
Clinical Research Activities. During the prepilot phase, prototype devices may be evaluated in humans to verify claims that cannot be tested on the benchtop or in animals. Human studies in healthy volunteers may be conducted with dermal-contact devices to verify safety claims regarding nonirritating or hypoallergenic properties. Feasibility studies in ill human subjects may be conducted to develop hypotheses or obtain data for sample-size calculations. Manufacturing studies may be conducted to optimize formulations to verify claims of reagent sensitivity and specificity for IVD tests, for example, or to evaluate manufacturing processes to verify the integrity of a heat seal in actual use.4
Additional activities of the clinical research team during the prepilot phase include assisting with regulatory applications for clinical trials and beginning execution of the clinical development plan for design verification.
PILOT (SCALE-UP) PHASE
Pilot plants are small manufacturing sites in which processes or techniques planned for full-scale production are tested in advance. Scale-up refers to the activity of moving from limited production to full production, and typically takes place during the pilot phase of product development. The pilot or scale-up phase is that in which design and process verification are completed and transferred into device specifications. The pilot phase culminates when the manufacturing process is confirmed and transfer to production facilities begins.
Clinical Research Activities. A clinical trial is simply one more tool in the product developer's test arsenal for verifying or validating a design. This view of a clinical trial fully integrates clinical research into the product development cycle, and is made clear in the preamble to the quality system regulation: "Clinical evaluation is an important aspect of the design verification and validation process during the design and development of the device."5 Pivotal studies—conducted to substantiate claims of safety, efficacy, or performance—are conducted during the pilot phase to verify processes and design. The trials are called pivotal because the success or failure of marketing applications can depend on the outcome of these studies.
Some companies assign the important activity of reviewing label copy to the clinical research group. The purpose of the review is to identify claims for the device and ensure that there are adequate in vitro, animal, or human clinical data to substantiate them.
The design is changed if test outcomes are unfavorable, and changes are captured through the design change control system. The device may proceed to regulatory submission and commercialization if the test outcomes are favorable.
PRODUCTION (COMMERCIALIZATION) PHASE
Production or commercialization is the final phase of product development—the phase in which the fully approved product is made available for marketing. Validation takes place in the very late stages of the pilot phase or the very early stages of the production phase, since validation testing is performed on initial production units.
Clinical Research Activities. Postmarket surveillance studies and marketing studies are typically performed during the production phase. Postmarket surveillance studies are usually required by FDA in exchange for early introduction of a device. The studies are designed to assess the incidence of patient complications.
Marketing studies is a catch-all phrase referring to the many reasons for conducting clinical studies after device commercialization. Some of these reasons are to generate publicity about the device, to introduce the device into a hospital, to gain additional experience with a device, or to verify design changes subsequent to commercialization.
During the production phase the clinical research group also handles medical complaints, supports regulatory submissions, prepares publications and presentations, and assists with customer preference evaluations.
CONCLUSION
An outdated and unfortunate view of the clinical research department sees it merely as the company's watchdog—reviewing the work of others and passing judgment on its validity or value. A new, more productive view considers the department as a full stakeholder in the product development team. With its unique skill set and access to both medical professionals and human subjects, the clinical research department can bring opportunities for design testing and customer feedback that are vital to a successful product development effort.
Glosssary
Clinical Development Plan—A grouping of one or more clinical trials that, taken together, substantiate the claims, intended use, and regulatory requirements of a device.Pilot Study—Small-scale study often conducted in healthy human volunteers to aid in concept definition, especially for dermal-contact devices.
Human Safety Study—Study conducted in healthy human volunteers to assess irritation or sensitization potential of materials, especially for dermal-contact devices.
Feasibility Study—Small-scale study conducted in ill subjects to develop hypotheses, obtain data for sample-size calculations, or investigate other early development issues.
Manufacturing Study—Study conducted in ill subjects or with specimens to optimize formulations or investigate manufacturing processes.
Pivotal Study—Study conducted in ill subjects to determine safety, efficacy, or performance of a medical device. The study is given this name because the success or failure of a marketing application can depend on the outcome of the trial.
Postmarket Surveillance Study—Study of all persons in whom a device is used after the device is commercialized, usually to investigate the occurrence of rare adverse events or complications. Data are reported as number of adverse events per number of devices used. Comparable to drug phase IV study.Phase I Study—A drug term referring to safety studies in humans to determine maximum safe dose. Usually performed in healthy volunteers, with a typical sample size of ~30 subjects.
Phase II Study—A drug term referring to the first studies in ill humans to investigate safety and efficacy. Typical sample size is ~300 subjects.
Phase III Study—A drug term referring to studies in ill humans to verify efficacy. Typical sample size is ~1000 to 3000 subjects. Comparable to a pivotal study.
Phase IV Study—A drug term referring to a postmarket study.
REFERENCES
1.NJ Stark, "Claims," Chap. 3 in Project Management for Clinical Trials (Chicago: Clinical Design Group, 1999), 47–62.
2.21 CFR, Part 812.1, "Investigational Device Exemptions, Scope."
3.61 FR: 52619–52620, October 7, 1996.
4.The names device companies use to describe these studies—pilot, safety, feasibility, manufacturing—vary widely and the actual name is unimportant. The studies are characterized by a small sample size and a specific objective where the data are used to guide subsequent product development decisions.
5.61 FR: 52618, October 7, 1996.
Nancy J. Stark is president of Clinical Design Group Inc., a Chicago-based contract research organization serving the device and diagnostics industry.
Copyright © 2001 Medical Device & Diagnostic Industry
ConcertAI's TeraRecon, Integrates Clinical And Generative AI, Supporting Clinical Research And Advancing Clinical Care Solutions At #RSNA23
New solutions empower clinicians and research teams with AI orchestration, model development, visualization, and multi-modal data management to power clinical research, clinical trials, and patient care strategies.
CAMBRIDGE, Mass., Nov. 20, 2023 /PRNewswire/ -- ConcertAI's TeraRecon, the advanced visualization and clinical AI leader, recently unveiled first-in-category capabilities in advanced visualization, AI, and expansions to its AI partner ecosystem to enhance research capabilities and support complex clinical study workflows. These solutions will provide researchers with enhanced data analysis tools for in-depth study, contributing to more informed care strategies that can improve patient outcomes.
At this year's RSNA 2023, ConcertAI, and its TeraRecon clinical imaging solutions group, are formally launching a multi-modal AI platform aligning clinical, radiological, whole slide images/digital pathology, along with real-world patient data in support of AI model development for clinical research, clinical trials, and deployment of AI models for prospective clinical validation.
As part of this announcement, ConcertAI is engaging in a multi-year strategic agreement with Memorial Sloan Kettering Cancer Center (MSKCC) focused on advancing Clinical AI in oncology, with an emphasis on enhancing clinical trials and improving oncology decision-making. Leveraging ConcertAI's Eureka Life Science AI Platform,
"Over the past two years, we have focused on the importance of multi-modal data AI model development, validation, stability monitoring, and deployment for insights, as part of clinical trials, and ultimately, clinical care," said Jeff Elton, PhD CEO of ConcertAI. "Multi-modal data enable causal inferences and elimination of confounders for interpretations and predictions. Enabling this required rethinking the tools available to biomedical researchers, while leveraging the power of Generative AI. As a ground-up new approach that allows multi-modal data management, AI model development validation, model management, and model release we can bring the power of deep and wide data at scale, our large research network, and latest predictive AI and Gen AI together for the broadest research community use. Having MSKCC as a multi-year strategic collaborator is an additional assurance of meeting our commitments to patients, clinical providers, and biomedical innovators at pace and the highest possible standards of outcomes."
ConcertAI's TeraRecon will also be showcasing new and expanded collaborations within the Eureka Clinical AI Partner Program, including: Avicenna.AI, Bot Image, Cercare Medical, Coreline Soft, GLEAMER, Infervision, Lucida Medical, Optellum, Riverain, and Us2.Ai, adding to its large catalog of AI models, offering solutions that enable clinicians to efficiently interact with AI findings, in one streamlined place by integrating seamlessly to PACS or Advanced Visualization solutions.
ConcertAI's TeraRecon is also announcing the launch of Pulmonology Suite, a collection of the leading, vendor-neutral, Pulmonology AI algorithms that aid in the analysis and interpretation of Chest CT scans to assess, monitor, and provide insights to support clinicians in treatment decisions for pulmonary conditions. Possible applications of Pulmonology Suite are to aid physicians including pneumothorax, lung nodules, and incidental pulmonary embolism. Pulmonology Suite complements Neurology Suite and Cardiology Suite, released earlier this year.
Learn more about these new solutions and collaborations: schedule a meeting or demo at the main TeraRecon booth #8123 (North Hall) or AI Showcase booth #4773 (South Hall).
Beyond meetings and demos, TeraRecon will offer a number of in-booth and off-site opportunities for RSNA attendees to learn from peers, connect with thought leaders, engage with AI partners, and give back to the local community.
TeraRecon is also showcasing expert physicians that are redefining care delivery by leveraging the latest AI and advanced imaging technology in a series of in-booth Doc Talks. In these informal, 15-minute sessions followed by Q&A, doctors will share use cases and best practices around a variety of imaging workflows to support patient care:
Back by popular demand, TeraRecon will again host AI After Dark – an evening event with cocktails, appetizers, and engaging conversation around "AI Empowering Physicians, Clinicians, Scientists, and Investors Across Generations to Improve the Human Experience within Healthcare." We are fortunate to have Dr. Giovanni Lorenz and Dr. Praveen Ranganath lead a group of esteemed panelists in a robust conversation around AI innovation within the healthcare industry. Register to attend AI After Dark on Tuesday, Nov. 28, from 6:00–10:00pm CT.
Join us at the RSNA AI Theater on Tuesday, Nov. 29, 3:30pm for a detailed conversation with our partner Cercare Medical, on the importance of AI partner ecosystems and "How AI Ecosystems Might Boost Deployment for IT, Efficiency for Clinicians, and Better Care for Patients."
TeraRecon will continue the AI conversations in booth #4773, showcasing a handful of its 18 AI partners, with in-booth presentations and demos from:
Finally, in the spirit of the season, TeraRecon and Cercare Medical will host an Angel Tree in booth #8123. Stop by and scan a QR code to donate a gift benefiting patients at the Ann & Robert H. Lurie Children's Hospital of Chicago. Donate now
About TeraRecon: Serving ~1,900 clinical sites globally, TeraRecon, a ConcertAI company, is a Best in KLAS solution provider for AI-empowered radiology, oncology, cardiology, neurology, and vascular surgery. Awarded the 2020, 2021, and 2022 KLAS Category Leader for Advanced Visualization, TeraRecon solutions are independent of any one manufacturer's imaging equipment or PACS system, allowing a single, unified, and simplified clinical workflow that can improve efficiencies and deliver actionable physician-guided insights. For more information, visit us at www.Terarecon.Com
About ConcertAI: ConcertAI is the leader in Real-World Evidence (RWE) and AI technology solutions for life sciences and health care. Our mission is to accelerate insights and outcomes for patients through leading real-world data, AI technologies, and scientific expertise in partnership with the leading biomedical innovators, health care providers, and medical societies. For more information, visit us at www.Concertai.Com
Media Contact:Megan Duero, megan@galestrategies.Com
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SOURCE ConcertAI
Decentralized Clinical Trials Are Opening The Development Pipeline
There is no doubt that the COVID-19 pandemic has had a major impact on life sciences. Not only has it pushed the limits of modern medicine, but it has also created a significant backlog for clinical trials as well. More than 1,000 clinical trials have been put on hold since the pandemic began, with nearly every clinical research site in the United States reporting one or more clinical trial delays.
The primary reason for this backlog is the possibility of virus spread among clinical trial participants, nearby patients and healthcare workers. Staffing shortages, supply chain issues and other restrictions have only added to this. In response, Clinical research organizations (CROs), life sciences companies, and technology providers have teamed up to develop remote processes for operating clinical trials. The result being, a major shift towards decentralized clinical trials.
"The pandemic has created more urgency around the digital transformation of life sciences organizations," said P360 CEO Anupam Nandwana. "This has resulted in greater adoption of innovative, new technologies and has created a boom for tools that enable things like remote collaboration, remote monitoring, automated data collection and analysis, and more. These systems are in turn transforming the traditional clinical trial approach."
Decentralized clinical trials are gaining steamWith the emergence of these new technologies, CROs and life sciences organizations are able to more easily perform decentralized, virtual clinical trials. And industry leaders are on a mission to make the practice of administering decentralized clinical trials the norm. The Decentralized Trials & Research Alliance (DTRA) is working to unite industry stakeholders with a singular mission to make clinical trial participation widely accessible by advancing policies, research practices and new technologies in decentralized clinical research. With over 50 organizations committed to this effort, it is safe to assume that decentralized clinical trials are more than just a fad.
In addition to innovative platforms like IQVIA Virtual Trials, smart devices are also helping researchers and pharmaceutical organizations get clinical trials back on track. Some medical professionals also believe that devices like Swittons are revolutionize the entire clinical trial process.
According to Kenyatta Cosby, MD, "IoT-powered smart devices are perfect for clinical trials in that they enable multi-point, omnichannel workflows. This new approach delivers a consistent, reliable data flow from the patient to the researcher. Given the current COVID-19 business environment, such innovation has improved patient communication within clinical trials."
Technology puts the patient firstPatient-centricity is a priority for research organizations, clinics and hospitals, and more and more patients expect researchers to conduct clinical trials in a virtual environment. That's why CROs and pharmaceutical organizations are taking steps to future-proof their operations by meeting the needs of a diverse, tech-savvy clinical trial participant. Technologies like the Internet of Things (IoT) hold promise for the future of clinical trials and meeting the needs of patients.
With the appropriate implementation of remote patient-facing technologies, virtual trials will bring improved treatments to patients in less time, at a lower cost. They will also offer much-needed help in the effort to retain participants, better monitor them and move the process forward. One of the things that hinder many clinical trials, especially during a pandemic, is the recruitment of participants. This often has to do with location.
The clinical trial location can make it difficult for willing and qualified patients to participate. The location of the clinical trial also presents serious challenges when it comes to the diversity of trial participants. Because of this, FDA now requires organizations to make trial participation less burdensome, and recommends the implementation of advanced mobile tools in lieu of a site visit. Smart devices answer this call by enabling remote, push-button participation by key populations no matter where they might be.
Technology is needed to make the most out of research dataWhen FDA approved the drug Gleevac in the early 2000s, some felt a new era of precision medicine was born. With this, the life sciences industry experienced a major increase in the amount of research data needed for clinical trials.
"The volume of data required for regulatory submissions from genomic-based studies facilitated a new way of managing data acquisition, analysis and sharing," Cosby said. "Because of this, an even greater amount of data is required today for the drug approval process. The good news, however, is new clinical trial technologies are alleviating the problem of data overload."
With smart devices and other related technologies becoming part of the virtual clinical research mix, researchers have the ability to collect data like never before. A clinical study is nothing without data. However, in the past, a lot of heavy lifting was needed to find the value of that data. With today's virtual trial technologies, research data can be collected and sent for analysis much more easily.
Beyond clinical trialsSystems that enable decentralized clinical trials are still evolving, and one day will offer benefits well beyond clinical research.
"Smart devices will one day be able to monitor patients automatically while transmitting results to researchers instantly, without the patient having to do anything," said futurist Brian FitzGerald. "Critical data will go from the patient to the researcher in a simple, streamlined fashion. This will create significant efficiencies, and will improve the development of advanced therapeutics."
Technology is creating a new world for clinical research. Systems that enable decentralized trials are working to free the development pipeline from the backlog created by the COVID-19 pandemic, and future technologies will build upon this to do even more. As technology companies, researchers, scientists and the government work together to further refine and improve the clinical trial process, the possibilities for improving patient outcomes become more exciting.
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