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2010 Directory & Buyers Guide  Services & Products  Company Index

Applied Clinical Trials Digital Edition - August 2010, Supplement

CRO/SPONSOR : The Nuances of Medical Device Trials  A Triggered Approach to Site Monitoring  INFORMATION TECHNOLOGY : Automating the Phase I Trial  Also in this issue : FDA Addresses Concerns Over Foreign Studies, The Cost Factor in EU Drug Authorization, Baseball?s Ties to Comparative Effectiveness Research, Key Updates to the Form FDA 1572

Applied Clinical Trials Digital Edition - August 2010

 Working in the clinical trials industry for more than 25 years,

 (Baltimore, MD) as a Senior Statistician.  

 Previously President of Chiltern International, 

PhD, has been named U.S. Office President at 

 to Vice President of Operations, where she will lead the growth and expansion of Praxis' international recruitment operations.

 has been promoted to President and Chief Operating Officer of 

 (Cary ,NC), a global CRO and functional service provider organization, has promoted 

 to the role of General Manager, Europe, where he will lead the continued expansion of Ockham's European operations. 

 Director of Automation for the Bioanalytical Group and 

 as Senior Director of Business Development in Generics.

 European Personalized Medicine Association 

, PhD, as Executive Director and Board Member. 

 In her new position as Director of Global Small Animal Development and Reproductive Toxicology (DART) at 

, PhD, will lead the small animal DART teams in North America and Europe.

, PhD, as Executive Vice President and Chief Information Officer, and 

 as Executive Vice President of Global Clinical Development.

, Chief Executive of the Irish Medicines Board, as chair for a second three-year mandate.

, PhD, President and Chief Executive Officer of the CRO 

(Glasgow, Scotland), has won the Ernst & Young, Scottish Entrepreneur of the Year Award.

 (Basking Ridge, NJ) strategic regulatory services group, was honored with the 2010 Canadian Society for Pharmaceutical Sciences Leadership Award at a gala reception during the CSPS 13th Annual Symposium in Richmond, BC. This annual award is bestowed upon a scientist who has demonstrated leadership in advancing the cause of pharmaceutical research and development in Canada.			

(New York, NY) ASPire to Win channel partner program, allowing Novotech to offer sponsors a full range of services around the Medidata Rave electronic data capture and clinical data management solution. 

 (Worcester, MA), a U.S.-based bio-pharmaceutical company, entered into a joint research agreement to explore the benefits of combining proprietary technologies from both companies for the targeted delivery of experimental therapeutics based on RNA interference.

(London, UK) has formed a partnership with 

(Dundee, UK)—a joint venture between UK's NHS Tayside and the University of Dundee—to conduct and support proof of concept and translational medicine studies.			

launched the Safety Reporting Portal Web site, which features increased accessibility to submit reports concerning FDA-regulated products and allows the public to submit a safety report related to foods, drugs, and veterinary products.

Medicines and Healthcare Products Regulatory Agency 

 (Surrey, UK) at the University of Surrey standard accreditation for conducting clinical pharmacology Phase I trials.

Association for the Accreditation of Human Research Protection Programs 

(Washington, DC) has published a performance study on human research protection programs that is available in AAHRPP Advance and at 

(London, UK) has announced that Chiltern Early Phase Limited, based in Ninewells Hospital and Medical School in Dundee, Scotland, has achieved Supplementary Accreditation from the MHRA.

 (Research Triangle Park, NC) has received ISO 9001:2008 certification, affirming that the company's quality management system meets the strict qualifications for the globally accepted ISO standard.

European Network of Centers for Pharmacoepidemiology and Pharmacovigilance 

(London, UK) launched "ENCePP studies," a seal for EU-based, benefit/risk or risk studies that are carried out in compliance with the ENCePP code of conduct for independence and transparency and its methodological research standards and are entered into a publicly available electronic register before their start.			

(Northbrook, IL) has launched Blue Chip Patient Recruitment, a division dedicated to serving pharmaceutical and biotech clients with clinical trial recruitment marketing. 

Official groundbreaking ceremony for a new Ravensburg facility Vetter West with (from right to left): Wolfgang Kerkhoff, Bianca Vetter, Udo J. Vetter, PhD, Daniel Rapp, Thomas Otto, Peter Soelkner, Max Horn, and Gunther Strothe.			

(Concord, OH) has been granted a U.S. Drug Enforcement Administration license, allowing them to handle multiple kilos of agency-controlled Schedule II-V substances for research and development projects at its Concord facility. In addition, its Ricerca France, Lyon, facility has obtained the ISO 9001:2008 certification for all activities performed at the site. 

(Rochelle Park, NJ ) a U.S.-based CRO that focuses on enrollment-driven Phase I-IV clinical trials, has expanded its presence in Europe by taking an equity position in

• Expanding for the first time outside of Europe, 

(Bucks, UK) has opened an office in Carlsbad, CA.

• To allow the company to optimize both its control and logistical processes, which will enable safe and expeditious product delivery to customers, 

 (Ravensburg, Germany) plans to open a new warehouse for cold-storage and room-temperature goods.

(Cambridgeshire, UK) has opened a new facility in Cardiff, UK, where all staff have successfully transferred from the former site operated by Amersham Radiolabelling Services.

• Pharmaceutical outsourcing specialist

has opened its new headquarters in North Wales, UK, to bring together its services that were previously housed in two separate facilities.

(Craigavon, Northern Ireland) has launched XCEL array, a biomarker discovery platform that enables the identification of biomarkers within multiple disease areas, as well as its IXRS 2.0 integrated, interactive voice and Web response technology that features enhanced Web function, such as smart menus and intuitive task management.

 (New York, NY) has released an enhanced version of its SaaS-based Safety Document Exchange that includes configurable rules-based automated workflow, intuitive organization and user-based views, and detailed compliance reporting.  

 (Boston, MA) has introduced its Patient Recruitment Franchise Program and flagship product, FRANCHISE e-BINDER, a flexible communication platform that uses the Apple iPad for processes related to subject recruitment and management.

 (Newton, PA) has introduced its eClinical technology suite as well as its integrated operations platform that uses Microsoft Office and SharePoint platforms for clinical operations.

Providing mobile access to patient data in clinical trial and health care settings, 

(San Ramon, CA) launched an Apple iPad application for its clinical trial data management platform, Prism. 

Business News

Industry news focusing on the people and organizations who work in the clinical trials profession.

Business and News Update August 2010

The automation of Phase I trials takes on many shapes and sizes. While electronic data capture (EDC) remains the most familiar type in Phase I, many other areas in early phase clinical research can be automated. For example, the typically mobile staffers need to know precisely where, when, and how they must execute each step in the protocol process. Samples, especially pharmacokinetics (PK) samples, must be processed accurately. And recruiting full groups is critical to the success and profitability of a unit. Automated solutions can help in each of these areas. 

To ensure the smooth implementation of automation technologies in Phase I, it's important to develop a tailored implementation plan. Only through a managed introduction of new technologies into this highly pressurized environment can the entrance hurdles be overcome. 

While an automated clinical environment is intuitively appealing, the reality is that the shift from a paper-based world does not happen without considerable planning and resources.

  While the best solutions will harmonize easily with current clinical procedures, the need to validate, test, and train in areas that form the heart of a 24/7 enterprise provide a significant hurdle to clear. Two primary benefits drive companies to clear these hurdles: safety and financial. 

A discussion with those employed in the Phase I space will quickly lead to safety— either the need to assess the safety of a new drug or the need to keep the volunteers safe. Focusing on those solutions that can increase the quality, visibility, and speed of data collection (not just EDC but those that improve the quality of the operational process) allows drug assessments (dose escalation decisions and other ongoing safety reviews) to be made quickly and more accurately, while also enabling rapid intervention if the safety of the subject is impacted. Having this higher quality data available online makes it readily available to all global partners—sponsors, CROs, the clinical unit—and facilitates the involvement of those best placed to make assessments. 

The financial benefits can be more subtle but still provide a critical driver toward automation. From a day-to-day perspective, the reduction of errors and the earlier identification of problems when they do occur both reduces or removes the cost of query resolution, which was estimated to be as high as $60 to $100 per query as long ago as 2001,

  and, in more serious cases, the need to repeat procedures from a single subject's blood pressure to an entire study. 

The more operational solutions reduce staff costs, as employees are moved away from the scheduling of studies, recruiting of volunteers, and general paper trail that drives your average unit. This frees the staff to return to clinical activities. Collecting data in electronic format  (eSource) at bedside reduces the resources required compared to traditional paper collection. 

From a practical perspective, the ability to make more efficient use of staffers time is key. Phase I trials are becoming more complex; at the same time, the drive to run a strong business operation is requiring that units take on more trials. Automation can boost productivity so that Phase I units can efficiently run more trials, which translates to more revenue per unit capacity. In addition, an automated unit with this increased level of safety and lower financial cost base starts to differentiate companies from their competitors, enhancing the firm's reputation and delivering a financial impact of its own. 

To inform and drive an implementation plan, it is important to identify and document those benefits that are sought, or if easier, the challenges that the clinical unit seek to overcome. These targets can then drive the selection of solutions and, as importantly, help identify the order in which they are implemented. For the purposes of this article we will look at automated solutions that aid the information flow that drives operational processes and those that facilitate the capture and processing of clinical data. The challenges that fall under this broad definition include: 

. Trials generally require processing six to 12 volunteers as a group. The failure to recruit full subject groups can delay a trial but, more importantly for the clinical unit, have a significant adverse effect on the financial side as all activities are repeated for those volunteers required to complete the group. 

. In Phase I, data is collected at a rapid pace and in a highly structured manner, however, each trial is different. Time is of the essence, and the highly mobile staffers are typically multitasking within the unit, as they are usually handling more than one study. 

. Key to accommodating a new trial is the availability of beds and staff to conduct the trial. In fact, the similarities with a hotel are marked, with the exception that you cannot move volunteers to a neighboring establishment if you overbook. Once started, trials often stop and restart, and trial designs change. This complex picture requires solutions that can model this flexibility and the ability to make real-time changes. 

. In the maelstrom of activity that typifies a Phase I unit, it's important that clinical samples (such as blood) be processed accurately. If these samples are mixed up or improperly stored, or if collection times are missed, the volunteer's data cannot be used and his or her participation in the study can be invalidated. 

. While a strong set of standard operating procedures integrated with evidence of training can support claims of good practice, the ability to present an auditor with contemporaneous data—of freezer temperatures, for example—can provide the definitive picture that attracts both sponsors and regulatory bodies. 

. Missing or erroneous data can invalidate results and necessitate a partial or complete repetition. 

Historically, these challenges have been addressed with increasingly intricate paper processes. These studies are, however, becoming more complex. The unit must accommodate the requirement that early phase trials deliver a first look at efficacy and stakeholders' desire to share data rapidly. Meanwhile, the units aim to take on larger numbers of studies. All of these factors are leading to the simple conclusion that paper processes are no longer practical. 

Once the priorities for automation are identified, the team can select appropriate solutions to meet those challenges. Early in the days of Phase I clinic automation, organizations attempted to modify solutions originally developed for later phases for use in Phase I. Today, however, there are many new solutions available built around Phase I requirements. 

The mobile behavior of staff and wide variety of clinical settings requires portable solutions. These have become possible as the variety of hardware available has increased—touch screen tablet PCs, bacteria and drop resistant laptops, and smaller devices like the PDA and mobile phones—ensuring a tailored solution can be available at the required location. 

Importantly, in parallel with these advances has come the acceptance of processing operational data directly in electronic format. Many homes now have their own wireless networks, and Internet use consumes a large part of the working and recreational day. Historical problems with network speeds are being overcome as high-level broadband becomes widely available. In areas where it is not as available, network accelerator companies provide the required boost. In short, the idea of pushing operational data directly via device and onto a remote database via wireless network is easily accepted by most. 

A natural extension sees the collection of clinical data directly into electronic format. To do this topic justice would require a paper in its own right. Positively, regulatory and industry bodies are starting to provide some guidelines toward such use of eSource, and issues previously seen as barriers are now seen as clearable hurdles.

Key areas where solutions have been developed to support the operational and process management challenges highlighted earlier include:

. To fully automate a Phase I trial, it is important to codify the trial design framework. How many subjects, time of dosing, what clinical samples and data will be collected, and at what time relative to dosing? While the protocol and related documents typically convey this information, it can be captured electronically in just a few hours. This electronic schedule can then drive key operations. The schedule can be sent to the clinical staff via wireless devices, using alerts with the "who, what, when" info that's critical to running the trial. An update to the master schedule (e.g., a one-hour delay to dosing when the pharmacy encounters a delay with the drug) can be cascaded to the team, updating all subsequent activity times. As adaptive trials become more common, the use of an electronic schedule will allow the clinical staffers to accommodate planned and ad hoc trial design changes. 

Information can flow in both directions, with staffers reporting that steps have been completed. A Web-based dashboard can present comparisons of scheduled and actual times, allowing immediate remedial action when needed and preventing protocol deviations. 

A simple extension of this single-study framework allows the management of resources across studies. With the addition of a graphical interface, rapid assessments can be made on how to optimally schedule a new study—ensuring that sufficient beds, appropriately trained staff, and equipment are all available. 

. The basic technology of barcode scanning is familiar to everyone from a trip to the supermarket. It also addresses one of the most fundamental issues in Phase I research: proper identification of subjects' PK (and other) samples. Barcodes can be printed on labels attached to the volunteer, the nurse, and the sample tubes. A three-way scan at the bedside can instantly verify that the right tube is being used for the right subject at the right time, while recording who carried out the procedure. 

An extension to this model allows the samples to be tracked throughout the entire sample processing. For example, when the sample goes into and comes out of a centrifuge, the barcode can be read along with the equipment ID. The transfer of the sample into other tubes can be recorded. The location of a sample can be tracked down to the specific shelf within a freezer. If samples are shipped to an external lab, the information can also be tracked by barcodes. Ultimately, to provide a snapshot of sample processing and location and to identify problems in real time, all the information can be loaded into a master database and monitored via dashboard. 

. One of the most significant benefits of clinic automation in Phase I is the ability to review, monitor, and query the data in real-time. Given the wide range of data being collected, the benefits here extend from those commonly seen from EDC (including simple CRF representation in electronic form, with standard and ad hoc summary reports) to comprehensive dashboards to present operational data (as discussed). Taken together, these options provide data that can be reviewed in great detail or at a high level by the various global players who have an interest in a trial's progress and results. 

Sophisticated tools for volunteer recruitment

. Recruiting full groups, as noted earlier, is important to satisfying the requirements of the trial, which is in turn critical to the financial viability of the unit. A clinical unit's volunteer database is considered one of its prized assets.

More sophisticated systems built for this precise function can drive recruitment campaigns, improving success rates and allowing staff to be deployed to more billable tasks. The basic details tracked (contact info, volunteer history at the unit, and exclusion parameters) can be expanded into a full subject profile. Such a system makes it possible to query the database using selection criteria to identify eligible volunteers for a new trial. Those selected can then automatically be sent an email notification. As potential subjects call in, the recruiting officer can see all relevant data supported by confirmation of the date and trial type of the last trial the subject completed. When the subject is accepted for a trial, their details and history can instantly be loaded into the database. Appointments can be set up based on clinic openings, and automated reminders can be sent out to subjects. 

. For most, the rapid and accurate capture of clinical data is the most familiar component of the automation picture. The benefits of EDC technology for automating the clinical trial process are now widely understood.

  And EDC fits as well if not better in the Phase I space. Key to success, however, is the adoption of processes appropriate to this phase—applying a Phase III EDC approach to Phase I trials would hamper success, much as applying paper-based Phase III data management processes to Phase I trials is not effective. 

Beyond replacing paper CRFs with eCRFs, other techniques can be used to automate data capture. For example, with ports on new generations of medical equipment, such as sphygmomanometers for measuring blood pressure, data can be captured directly into the electronic database with no staff interaction other than the push of a button. Barcode scanners can rapidly scan standardized answers from a wide variety of data collection activities, such as categorical responses associated with the severity of an adverse event. 

When considering how to automate Phase I trials, there are a number of preliminary steps that can ensure a smooth implementation. Here are some key issues to consider. 

Agreement on the primary benefits and goals

. While the many benefits discussed in this article can easily justify an automation project, certain issues may be particularly critical to your organization. Getting agreement across the team up front may influence precisely how you implement automation technology and how rapidly you do it. 

Work with your vendor to gain in-house experiences

. Before committing to a major implementation exercise, you can work with your vendor to run sample projects. Setting up mock studies can be helpful to ensure that all team members understand the implications of the new solutions and that they are right for you. 

. Create a project team with representatives from each area of the operation—not just IT and data management. These representatives can serve as ambassadors for the system, and are essential to "buy-in" from the clinical teams. They can provide invaluable details to ensure the implementation matches your environment. Don't rely on vendors to provide subject matter expert (SME) support. Nominate staffers to get inside the system from the start and get them to act as local SMEs. 

. Has your team thought through the steps that will be required to transition to an automated unit? It's important that the team be progressive in its thinking regarding eSource, for example. Many staffers still feel nervous about moving away from paper, and worry about fallback plans if a device breaks or the wireless infrastructure goes down. Staff must be open to learning new technologies and processes for this type of initiative to succeed. And even with the flexibility afforded by newer systems, adapting to new processes will still be required.  

. Clinical units are 24/7 environments. Many clinical units adopt a phased approach, automating one area at a time rather than all at once. For example, it may make sense to start with just one trial, automating the PK sample processing lab, and then moving to the recruiting process and the clinic floor. It is important to also allow sufficient time to work in partnership with your vendor as they mentor you through the initial trials. 

. In transitioning to a software-based environment, putting the right technology infrastructure in place is a key ingredient for success. Working in conjunction with your software vendor, you can determine the best barcode readers, laptops, and handheld devices for optimal interoperability. Upfront costs for new hardware must be part of your budget. If there are concerns about the use of new technologies—for example, using a wireless network to facilitate direct capture of data at bedside—get this on the table early. Work with your regulatory department to assess concerns and conduct a risk analysis. 

. Depending on the nature of your team, it may work best to train staffers operation-by-operation and then bring the team together to provide an overview of the entire process. It's also important to cultivate a resident expert who can help train other staffers as new professionals come on board. While people often prefer the work procedures they're accustomed to, most clinical staffers understand the importance of keeping current with technology in terms of their professional development. 

Several factors have come together to make Phase I automation practical and viable. Wireless approaches are now well proven and when combined with improved Internet access, new hardware, and the wide range of new solutions, the technological infrastructure is now ready. Clinical units are increasingly aware of the opportunities open to them through these new solutions. With the ability to improve the quality of safety data while reducing costs, these units are focusing on overcoming the challenges inherent in new technology adoption and moving to an automated future. 

 is Director, Commercial Development, at Phase Forward, Waltham, MA, email: 

Feature Article

How to make the leap beyond paper and EDC to create an automated clinical environment that thrives.

Automating Phase I Trials

The Form FDA 1572, Statement of the Investigator, is a basic contract between a clinical investigator and the FDA. It is required in allclinical trials conducted under an Investigational New Drug application. It has also been the source of numerous discussions about exactly who belongs inSection 6 as a subinvestigator. Now, FDA is making it clear. 

FDA has made some big changes in the final version of the 

Information Sheet Guidance for Sponsors, Clinical Investigators, andIRBs—Frequently Asked Questions

—Statement of the Investigator (Form FDA 1572), released in May. The FAQ states that study coordinators should"usually be listed in Section #6 of the 1572." This is a significant change from the July 2008 draft FAQ. Many sites do not list studycoordinators on the FDA 1572, which means that most coordinators will need to file financial disclosure information. It will be a significant change inthe way FDA inspects sites.

Specifically, the FAQ document states: "Generally, a research coordinator has a greater role in performing critical study functions andmaking direct and significant contributions to the study data. For example, a research coordinator often recruits subjects, collects and evaluates studydata, and maintains study records. Therefore, the research coordinator should usually be listed in Section #6 of the 1572." 

This is a big change from the draft FAQ that says: "If a research coordinator is performing critical study functions and collecting andevaluating study data, the coordinator should be listed on Block #6." This is also a very significant difference, and not just because they changedBlock #6 to Section #6. 

FDA is saying that a study coordinator "generally" performs critical functions, and that recruiting subjects is one of them.Obtaining informed consent, although not stated in the FAQ, is also regarded as a critical function. FDA made that clear in a Warning Letter issued byCDER to an investigator in October 2008: "Study coordinators who administered the informed consent, determined subject eligibility, and dispensedstudy drugs were not listed on the Form FDA 1572, Statement of Investigator, for protocols (b)(4) and (b)(4). By performing these significant studyactivities, the study coordinators should have been listed on the Form FDA 1572s as subinvestigators." 

There are other helpful pieces of information in the FAQ. For example, it asks in Section 24: "Are CVs required to be signed anddated?" The answer: "No...The investigator's dated signature on the 1572 is sufficient to attest to the accuracy of the CV or otherstatement of qualifications submitted with the 1572." This should reduce tensions between sites and CRAs who sometimes think that a signed CV isnecessary every year. 

In Section 34 it asks: "Is a statement of qualifications (CV) required for subinvestigators?" The answer? "No. The regulationsat 21 CFR 312.53(c)(1)(viii) require only that subinvestigators' names be listed in Section #6 of the 1572." This lessens the burden ofcollecting additional CVs from subinvestigators that you may be adding to the FDA 1572. However, you will still want to document their qualifications.And FDA states in Section 35 that they want financial disclosure from subinvestigators listed in Section #6 of the 1572. 

A final important note: If a study coordinator is performing critical study functions and is listed on the 1572, they need to understand theregulatory responsibilities listed on the 1572 that they are now assuming. 

 Regulatory Compliance Consultant Carl A. Anderson, LLC

A Closing Thought

FDA is saying that a study coordinator "generally" performs critical functions, such as subject recruitment.

Key Updates to the 1572

The Critical Path Initiative Meets Medical Devices

 What do bandages, drug-eluting stents, dental floss, infusion pumps, and medicinal leeches have in common? To the vast majority of people, the answer to that would be an emphatic "absolutely nothing." But to many of the readers of 

, the answer is obvious—they're all medical devices of one kind or another.

Medical devices, an extremely heterogeneous group of health care products, can use any combination of mechanical, electronic or chemical biochemical action(s) to achieve their purpose.1  Although a medical device doesn't achieve its primary intended effect by pharmacological, immunological or metabolic means, it can be assisted by such means. Two examples of this include drug-eluting stents and bone cements containing antibiotics; both are classified as medical devices based on their primary intended effects: holding open narrowed arteries and attachment of a prosthesis. These are also two examples of combination products that include a drug component that assists in achieving the primary intended effect of the device by pharmacological means. 

Medical devices and drugs can both be developed for the purpose of treating the same disease. For example, electroconvulsive therapy devices and serotonin-reuptake inhibitors have both been approved for the treatment of depression. However, the regulatory pathway to approval for each would be quite different. Not unexpectedly, these differences in regulatory requirements trickle down to the clinical studies that are conducted. It is vital to understand the unique aspects of medical device development before planning a clinical study of a new device. 

The purpose of this article is to highlight the operational and regulatory differences between medical device development and drug development, identify the unique aspects of clinical studies involving medical devices, and highlight best practices for planning and tracking the progress of these studies. 

Unlike the situation for new drugs, it is not necessary to conduct clinical studies for every new medical device before it is approved and marketed. The first step in determining whether or not clinical studies will be necessary is to determine to which category of device your product belongs. Regulatory authorities (in the United States, the EU, and elsewhere) recognize different categories of medical devices based on design complexity, device use characteristics, potential for harm, and other factors. Although each country or region defines these categories in somewhat different ways, they each include an evaluation of risk. For example, the categories of medical devices recognized in the United States are as follows:   

Class 1: These noninvasive devices are usually exempt from the FDA requirement for premarket notification or approval, and will be subject only to the "general controls," specified in the regulations, which are requirements pertaining to manufacturer registration, branding and labeling of the device, and reporting procedures.

Class 2: These are higher risk devices, and the general controls required for Class 1 devices alone are insufficient to assure safety and effectiveness. Additional controls will be required, which may include special labeling requirements, mandatory performance standards, and postmarket surveillance. Clinical data (although not necessarily a study) may be required for some Class 2 devices.

Class 3: These devices are the highest risk devices, and they require premarket approval (PMA; a scientific review to ensure the device's safety and effectiveness). Class 3 includes most devices that support or sustain human life, are of substantial importance in preventing impairment of human health or present a potential unreasonable risk of illness or injury.

In the United States, the FDA has published the categorization of medical devices at 

. Risk categories are similar in other countries, although some differences do exist. Importantly, in 2010 all medical devices marketed in the EU (regardless of classification) must have a clinical evaluation on file with the regulatory authorities. Without this clinical evaluation, which may include information from clinical studies, the device may not be marketed or sold. 

In the United States, the next step in determining whether or not a clinical study is necessary is to determine whether or not the device is "substantially equivalent" to already on the market. Substantial equivalence means that a device has: the same intended use and the same technological characteristics as a marketed device, or the same intended use and different technological characteristics but is as safe and effective as the marketed device and does not raise different questions of safety and effectiveness. If a Class 2 or Class 3 product is not deemed substantially equivalent to another approved product, the submission of clinical data showing safety and effectiveness, although not necessarily efficacy, will be required. 2

For those steeped in drug terminology, medical devices that are "substantially equivalent" to an already approved device are almost never the device equivalent of a generic drug (which must be chemically identical to the innovator drug). Substantially equivalent devices often include fairly significant design changes, but as long as these technological differences don't raise questions about safety or effectiveness, the device will be considered substantially equivalent. In contrast, similar changes made to a generic drug would mean it was no longer a generic product, but a new chemical entity (NCE) subject to the regulations governing NCEs. The terminology varies, but there is a similar determination of equivalence (or not) to already marketed products in other countries as well.

A new drug cannot be marketed in the United States without an approved New Drug Application (NDA). In EU member states, either a Community Authorization or a National Authorization must be obtained. A full discussion of the process to obtain regulatory approval for a new medical device is outside the scope of this article, but as stated previously, due to the heterogeneity of the types of medical devices, there are multiple pathways to obtaining clearance or approval to market a device.

In the United States, the FDA Center for Devices and Radiological Health is responsible for medical device market clearance or approval. Most Class 2 medical devices require the submission of a 510(k) premarket notification to FDA. The FDA will review the information included in the notification, and if it's acceptable, will clear the product for marketing. Most of the information submitted in a 510(k) premarket notification is of a nonclinical nature, and currently only 10% to 15% of 510(k) submissions are submitted with clinical data to demonstrate substantial equivalence.

High-risk medical devices or Class 3 and Class 2 medical devices that are not substantially equivalent to another approved product require premarket approval (PMA) prior to marketing. All PMA submissions contain clinical data, but the volume of data included is generally much smaller than that included in a similar application for a new drug. A recent review of the summaries of safety and effectiveness data for 78 PMAs for high-risk cardiovascular devices showed that 65% of the FDA approvals were based on a single study that included an average of 300 patients.

Although the regulatory approval process is quite different in the EU, the same high-level principle applies: Before a device can be marketed, the developers must demonstrate the new product is safe and effective. As in the United States, the type and amount of data required for review varies by type of device as well as risk; however, every medical device sold in the EU (regardless of classification) must have a clinical evaluation report in its technical file. 

In the EU, unlike the United States, organizations called Notified Bodies are responsible for assessing conformity of medical devices with the relevant directives. Notified Bodies are not governmental agencies but are appointed by EU Member States to undertake specific tasks identified within EU directives. They will inspect and audit manufacturers to ensure that all requirements are met. In the United States, these activities are performed by the FDA. 

Obtaining regulatory approval for a medical device can take anywhere from months for many substantially equivalent devices to 10 years (or more) for a high-risk, innovative device. Not surprisingly, it is difficult to determine a single average cost for development of a medical device.
   

Accurately planning for any clinical study requires a thorough understanding of the operational work required and the level of effort that will be necessary. In many ways, planning and conducting a study of a medical device is very similar to planning and conducting a study of a drug.  

Activity-based planning, which is sometimes referred to as a "project-management approach" or a "bottom-up approach," is an effective method for estimating the budgetary and headcount needs for medical device studies. This approach—a thorough discussion of which is outside the scope of this article—starts with determining the level of effort for a specific resource (person) to perform a given activity, which is typically calculated using an algorithm derived from experience and analysis of the cost and time drivers that affect each activity. After calculating the effort (in work hours), the cost for that specific activity can be derived by factoring in the hourly cost of the person(s) who perform that task. The compilation of costs for all tasks in the project is the total project cost. 

Most of the activities performed for a medical device study are virtually identical to those performed for a drug study. For example, both types require a study protocol (which is also called an investigational plan), informed consent forms, case report forms, qualified study sites, appropriate site and vendor contracts, IRB review and approval, monitoring and drug/device accountability, collection and cleaning of data, and analysis and summarization of study results. Both require the input of statistics, data management, clinical operations, project management, and medical, quality, and regulatory staff to successfully complete. 

However, as highlighted in the rest of this article, there are important differences between drug and medical device studies that must be taken into consideration. 

In the United States, the conduct of medical device studies is regulated under the Investigational Device Exemption (IDE) regulations (21 CFR Part 812). For studies that meet the definition of "significant risk," which means it has the potential for serious risk to the health, safety or welfare of a subject, an IDE must be submitted to and approved by FDA before the study can begin. The FDA has 30 days in which to review and respond to an IDE application. Unlike an IND, an IDE application must be submitted for every applicable device study, not just the first study of a particular version of a device, and it must be formally approved prior to the study. The safety and effectiveness data collected during a study conducted under an IDE can be used to support a PMA or Premarket Notification 510(k) submission to FDA.

Clinical studies with devices of significant risk must be approved by both the FDA and an IRB before the study can begin, and many IRBs will require that FDA approval be obtained prior to their review. Studies with devices of nonsignificant risk don't require FDA approval but must be approved by the IRB before the study can begin. 

In the EU, manufacturers must notify the relevant Competent Authorities prior to the conduct of a proposed study, who have 60 days to review and authorize studies of higher-risk devices. For lower-risk devices, the Competent Authority may immediately issue a letter of no objection as long as ethics committee approval has been obtained. A standard application form for notifying the Competent Authorities that a study is planned has not yet been developed, so the appropriate application form(s) must be obtained from each relevant Competent Authority. 

There is no standard form equivalent to a Form FDA 1572 that an investigator participating in a medical device study must sign, either in the United States or the EU. However, for studies conducted in the United States, 21 CFR 812.43(c) outlines the elements that must be included in an investigator agreement that must be signed by each investigator prior to participating in the medical device study. 

The vast majority of the time, sponsors do not charge the participants in a study, their physicians, or insurance companies for the cost of an investigational drug (Treatment INDs are an exception to this; sponsors are allowed to recoup the cost of the drug but are not allowed to make a profit). For most pharmaceutical companies, the cost of manufacturing the investigational product is usually not so high as to represent a barrier to conduct of a study.

For an investigational medical device, the situation can be completely different. Many medical devices being tested under an IDE are complex and expensive to manufacture, yet represent only incremental improvements over approved devices that have already been demonstrated to be safe and effective. There is very little reason to think that these improved devices are not safe and effective, and the expense of providing the new-generation device free-of-charge could be a significant barrier to the development and evaluation of incremental improvements. 

To lower this barrier and ensure that their patients have access to improved products, the U.S. Centers for Medicare and Medicaid Services (CMS) will reimburse for the cost of investigational medical devices that meet certain criteria—although they'll only reimburse up to the cost of a currently marketed, similar product. These medical devices are "Category B Investigational Devices," and must be studied under an IDE. The investigator (with the sponsor's assistance) is responsible for submitting a Medicare Request for Reimbursement Letter to verify that the device is reimbursable before conducting the study. Although private insurers are not required to follow Medicare guidelines, they tend to institute coverage policies that are similar to Medicare. 

This means that for some investigational medical devices, the sponsor company could charge the investigator for the device, and the investigator would then obtain reimbursement from Medicare or other insurer. The extra time and effort that will be required to obtain these reimbursement decisions must be built into the timeline and budget for the clinical study. 

However, the current version of ISO 14155 does not address all of FDA's specific requirements for the conduct of clinical studies (e.g., the presence of written SOPs, minimum data retention period, access to source data, definitions of reportable adverse events). For studies that will be conducted under an IDE and used to support a 510(k) or PMA in the United States, it is important to ensure that all of the study will be considered acceptable to the FDA. It is important to make sure that FDA GCP requirements will be met. 

ISO 14155 is currently in the process of being updated, and the Draft International Standard (DIS) is currently available. It's very likely that the next approved version will more closely mirror ICH GCP. To obtain a full copy of the currently approved ISO 14155, or ISO/DIS 14155, or any other of the approximately 18,000 ISO standards, visit the ISO Web site at 

 Quick—what's ISO 14155, and what does it have to do with clinical trials? Many clinical research practitioners are surprised to learn that ICH guidance documents, including ICH GCP, were developed for medicinal products only, and do not formally apply to medical devices. If you've worked on medical device studies before, particularly in the EU, you're probably already aware that the GCP requirements in the EU Medical Device directives can be met by following ISO 14155: Standards for the Clinical Investigation of Medical Devices. This standard is one of many published by the International Standards Organization (ISO). 

Adverse events reporting requirements for medical devices are different from those for drugs, and this can cause a fair amount of confusion for both sponsors and investigators.

 In a study of a drug, all adverse events, regardless of cause, are reportable. There are good reasons for this: Drugs are distributed systemically in most situations, may or may not be metabolized or affect the metabolism or availability of other drugs, and may or may not affect multiple organs. Many of the side effects of drugs occur at a background level in the general population, and it is often necessary to analyze data from large groups of patients to determine whether or not an adverse event is related to a drug. 

Medical devices, on the other hand, usually act locally and have a transparent method of action, and it is often easy to determine if an adverse event is caused by the device (e.g., a faulty device that delivers an electric shock to the patient). Most medical device side effects don't occur at a baseline rate in the population, so statistical analyses involving large groups of treated and control patients are often not necessary to attribute a particular adverse event to a device.

In the United States, the FDA requires that investigators prepare and submit a report of any Unexpected Adverse Device Effect (UADE) occurring during a medical device study to the sponsor and their IRB within 10 working days of learning of the event. The sponsor is then required to conduct an immediate evaluation of the UADE and submit a report to the FDA, all reviewing IRBs, and all participating investigators within 10 working days after they were notified that the UADE had occurred. Although the acronym UADE used by the FDA to define what reports have to be expedited doesn't include a reference to the seriousness of the effect, the FDA defines a UADE as a serious adverse effect on health or safety (21 CFR 812.3). 

The relationships of each category of medical device adverse events are shown in Figure 1. Depending on the type of medical device, it might be advisable to include additional requirements for adverse event reporting in your protocol. Of interest, the current draft of the ISO 14155 standard that is circulating for comment includes a requirement that all adverse events be recorded on CRFs (regardless of their relationship to the device). 

It is important to ensure that your investigators understand how to categorize adverse events so that they can record and report them appropriately. It can be useful to provide a tool that will assist them with this—one example seen online recently is an "Adverse Event Wheel," which the user spins until all of the attributes of a particular event are visible on the wheel and the event categorization is provided. The protocol or investigational plan for the study must identify reporting time frames, as well. 

In the EU, adverse event reporting requirements are defined on a by-country basis, so the sponsor will need to ensure that they understand the requirements and have implemented appropriate methods to meet them. 

The CRFs designed for the study must enable the investigator to record the appropriate information about an adverse event. Medical device adverse event reports will usually include information about what happened to the device as well as what happened to the subject. 

Finally, it is important to determine what tool will be used for coding of adverse events that occur during a medical device study. Unfortunately, although the MedDRA coding system is used by most sponsors to code adverse events in drug studies, no such standardization has been accomplished in the device world.6 

It is virtually never necessary to involve an engineer in the training of a site participating in a drug study, and in most cases, the training involved does not involve hands-on preparation or administration of the drug itself. However, in studies of complex medical devices, it may be necessary to spend a good portion of a day training the site staff on the appropriate use of the device (e.g., an updated infusion pump). In some cases, the CRA, who may also be a nurse, will be able to provide the training without assistance; however, in others it is necessary to have someone from the engineering team conduct portions or all of the training.

On time and on budget are always necessary for a clinical trial, but medical devices offer nuances.

Considerations for Medical Device Trials

Risk-Based Monitoring – Part Two In Depth Review

Increasing Intensity of On-Site Monitoring a Troubling Trend

Industry Metric Indicates Low ROI with Full Source Document Verification

Has FDA Guidance on Risk-based Monitoring Impacted SDV Coverage Yet?

Faced with the near-perfect storm of an increase in drug development costs, a reduction in the number of drug approvals, and an increased level of drug safety scrutiny, biopharmaceutical manufacturers are under enormous pressure to make their operations leaner and more efficient. Among the many clinical development processes that need to be conducted in a smarter, more cost-effective manner, clinical data monitoring stands out as a promising area in which operational efficiencies can not only reduce costs but also improve research quality and patient safety. 

Although the U.S. FDA guidance and the International Conference on Harmonization (ICH) guidelines for Good Clinical Practice propose an "adequate" level of clinical monitoring to ensure subject protection and data quality—and acknowledge that there is generally a need for on-site monitoring throughout a clinical trial—these regulations fall short in dictating the frequency of on-site visits. As such, in a historically conservative practice, trial sponsors and CROs traditionally monitor every site in a study every four to eight weeks. Given the volume and size of studies, in addition to the ever-growing cost of bringing a new compound to market, a new practice of risk-based clinical monitoring using triggering techniques can be adopted that enables organizations to focus resources on high-priority sites without compromising safety or quality of research. 

Risk-based monitoring is a program of risk assessment for clinical conduct and data collection that applies available monitoring resources according to the identified risks—and reassesses those risks on a regular basis throughout the study. Under risk-based monitoring using triggering techniques, the fundamental premise is that monitoring sites where there's little or nothing to monitor is not a useful proposition. 

In a typical study, for example, one-third or more of the sites do not enroll a single patient. Yet the standard industry practice is to visit these nonenrolling sites as frequently, as if they were  enrolling the same amount of subjects, and sometimes even more frequently under the need and guise of boosting subject enrollment. If a trial sponsor is not using risk-based monitoring techniques—and they're simply deploying clinical research associates (CRAs) to every site based on "usual practice"—they limit the resources that could be deployed to high enrollment sites where monitoring is needed. In addition, the attention of limited and costly resources are dissipated and focused away from problem areas instead of toward them. Likewise, the average clinical trial site only enrolls three to four patients, but every site is treated equally from a monitoring perspective. This practice is an enormous waste of resources and energy that could instead be focused on where the needs are. 

To ensure that valuable resources are allocated in the most efficient manner, risk-based monitoring promotes the use of data to initiate a site visit only when justified by on-site workload or other quality triggers. The method involves the identification of risks and then links each risk with appropriate triggers that will initiate source data verification. Study risks may include past site performance; the number of subjects and rate of site recruitment; staff feedback on protocol compliance, site contact, and record keeping; information received from data management, such as missing case report forms (CRFs), query rates, and CRF completion delays; inaccurate or repetitive data; and safety issues. It's important to emphasize that risk-based clinical monitoring using triggering techniques doesn't compromise quality, but rather improves it. 

One way to manage risk and use data as a trigger for on-site visits is to monitor the workload at each site. Predictive algorithms and historical data can be used at the beginning of a study to predict patient visits, establish a schedule of events, and to estimate the amount of source data verification work expected. These calculations can then be used to establish work volume thresholds to justify a monitoring visit. Once pre-established volume accumulates at a site, the system triggers a monitoring visit. The time-and-events schedule established at the study's outset adjusts on a daily basis as new information is collected about each site, and is used to instruct the deployment of CRAs. 

What if an adverse event occurs at a research site before enough work has accumulated to set off a volume-based trigger? Protocol-based monitoring can be used in tandem with volume monitoring conditions. A site scheduled for a visit in one month's time will trigger an immediate visit in the event that a death occurs, for example. Under current standard industry practice, that same site would have gone without a visit for an additional month. 

To ensure quality, time thresholds can also be built into risk-based monitoring systems so that in the event a visit has not been triggered within a certain time frame because of volume, protocol or other risk-based measures, a site visit will occur regardless. Data quality issues, and unacceptable lags between patient visits and data entered in the system are additional examples of risk-based triggers utilized to initiate a monitoring site visit. 

Triggered monitoring reduces risk because site visits are initiated in reaction to what's happening at the site, rather than as a result of arbitrarily applied time intervals. Subject protection as well as data collection and oversight are still very much the priority—and can be done more intelligently and more efficiently. 

This concept of using triggering techniques to identify risk isn't a radical idea in the pharmaceutical industry. FDA's Division of Scientific Investigations (DSI) is discussing the same approach. They also need to make data-driven decisions on whom to inspect. 

As such, DSI staff would apply triggering techniques to develop systems that answer the questions "What are the risks?" and "What triggers can we establish that would permit the inspection of sites and, by implication, the certification of data?" By using a triggered-based system for detecting signals, DSI would be able to deploy personnel only to facilities that require a physical inspection—thus saving time, energy, and valuable resources. 

At the ACRP Global Conference in April 2009, Dr. Leslie Ball, DSI Director, succinctly stated that the current system of clinical monitoring "encourages an approach similar to old-fashioned manufacturing systems: Produce the product, catch the defective ones, and throw them out after the fact." Furthermore, this type of system does little, if anything, to ensure the end goal of obtaining quality data that could be used to establish confidence in the safety and efficacy of the compound in question. 

Although the FDA and other regulatory agencies are actively encouraging the use of risk-based clinical monitoring, there's still considerable uncertainty among biopharmaceutical manufacturers regarding its implementation. Part of the issue is the concern that regulators may not be as willing to accept data from studies using risk-based clinical management plans that incorporate these ideas because of the lack of consistent applications. Due to the potential risk to future market potential of its product, it's often difficult for pharmaceutical companies to promote unproven practices without more guidance from regulators and other stakeholders. This translates into the field as a continuation of business as usual, and the standard practice of regular visits to every site in a study at the traditional intervals. 

From a risk-based perspective, the best way to attack risk is to identify the risk—and then try to mitigate it. In the present industry model for clinical monitoring, the risk is usually not well characterized. As such, we're not able to focus our resources on precisely where the risk is, and essentially, we end up fighting the war on multiple fronts. 

With risk-based monitoring using triggering techniques, enormous cost-savings can be realized by a more thoughtful, coordinated approach to identifying risk. As previously discussed, triggered monitoring replaces time intervals as the basis for monitoring frequency and substitutes a combination of metrics (e.g., data quantity, subject enrollment, safety signals) to predict risk and trigger site visits. Similarly, instead of all sites being treated equally in a traditional model, a triggered model identifies sites by metrics such as workload and quality, safety issues, as well as subject enrollment and retention. Most significantly for subject safety, all safety events are treated equally in a traditional monitoring model, whereas a triggered model catches safety signals as they happen, which then triggers a site visit. Quite simply, triggered monitoring enables focused attention of high risk and/or high benefit, while promoting efficient utilization of time and resources. 

A recent Quintiles pilot exercise comparing a traditional monitoring model to a triggered monitoring model produced some encouraging results. Using triggering techniques, a 25% reduction in the number of site visits was achieved, and on-site CRA utilization increased from 10% in a traditional model to 75% in the triggered model (see Figure 1). These results show that trial sponsors and clinical research organizations not only can work less and save resources, but also obtain better output. 

Other studies lend support to the value of this model as well. A postmarketing study for a cardiovascular drug conducted in 2008 by a large pharmaceutical company demonstrated quality improvement with the use of a hybrid on-site, centralized monitoring method, as compared with sites monitored exclusively by CRAs. The hybrid method produced significantly fewer data clarification forms (DCFs) as compared to the traditional on-site CRA method. In addition, the hybrid approach reached 100% DCF resolution six days earlier than the traditional approach. 

Eisenstein demonstrated significant cost savings with the use of EDC and modified site management practices, with as much as 20% of a trial's total cost saved with the use of a more centralized approach to monitoring, as compared with traditional on-site evaluation methodologies.1 

In a review of study design and acceptable monitoring practices, Baigent suggests that central statistical monitoring should guide the frequency and content of on-site visits.2 

In fact, the ICH-GCP guidelines acknowledge the potential for central statistical monitoring to play a prominent role in any monitoring plan, stating: ''In general there is a need for on-site monitoring, before, during, and after the trial; however, in exceptional circumstances, the sponsor may determine that central monitoring in conjunction with procedures, such as investigators' training and meetings, and extensive written guidance, can assure appropriate conduct of the trial in accordance with GCP. Statistically controlled sampling may be an acceptable method for selecting the data to be verified.'' 

To apply a trigger monitoring algorithm, there are three primary tools required. First, it's necessary to have a robust predictive modeling tool using sophisticated statistical algorithms that take into account variables such as historical data and the statistical distribution of patients. This enables sponsors to predict enrollment and an accurate time-and-event schedule. Without this capability, there is a high degree of risk that fundamental assumptions made will be inaccurate. 

Second, an electronic system is needed to essentially function as a bridge between scheduling systems and EDC. This tool must be capable of extracting data from multiple sources (EDC, IVR, etc.) and feeding them into the CRF scheduling mechanism. For example, if a death occurs at one of the study sites and was noted in an EDC/CRF system, this program must be able to translate the event into a trigger that initiates a monitoring visit. 

Finally, a scheduling tool is necessary. Once the study's time-and-event schedule has been built, there must be a program capable of performing the scheduling and making adjustments to that schedule as new data are incorporated. 

With pressure on industry to control costs and do more with less, sponsors can institute smarter processes at every step of the development continuum. Simply put, given the benefits and potential efficiencies triggered monitoring provides, industry should continue supporting triggered monitoring projects and initiatives to define the value of this method and criteria for implementation. Only through these efforts can industry determine how triggered monitoring can improve clinical research while also promoting quality and safety. 

 is Executive Director, Product Management, email: 

, PhD, is Vice President, Enterprise Transformation Unit, at Quintiles, Durham, NC.

1. E. Eisenstein, R. Collins, B. Cracknell et al., "Sensible Approaches to Reducing Clinical Trial Costs," 

2. C. Baigent, F. Harrell, M. Buyse, J. Emberson, G. Altman, "Ensuring Trial Validity by Data Quality Assurance and Diversification of Monitoring Methods," 

Among the many clinical development processes that need to be conducted in a smarter, more cost-effective manner, clinical data monitoring stands out as a promising area in which operational efficiencies can not only reduce costs but also improve research quality and patient safety.

Applied Clinical Trials-08-01-2010

Applied Clinical Trials Digital Edition - August 2010, Supplement

Applied Clinical Trials Digital Edition - August 2010

Business and News Update August 2010

Automating Phase I Trials

Key Updates to the 1572

Considerations for Medical Device Trials

Triggered Monitoring

Foreign Clinical Trials Under Scrutiny

Deconstructing Relative Effectiveness Efforts

Diabetes Drug Update

Effective Comparisons: Baseball and CER

Act cover

EMA Reveals Online Plans

What Factors Influence a Site to Say "Yes" to a Trial