CRO Partnerships: Strategies for Successful Postapproval Studies

GUIDE TO OUTSOURCING: CLINICAL RESEARCH

The medical device industry produces approximately 100,000 individual products, and the responsibility for determining the safety and efficacy of those products in the United States lies with FDA. In 2007, global demand for medical devices resulted in sales of $286 billion.¹ Of that amount, about $75.6 billion was generated in the United States. Market growth is estimated to be 8–10% per year, fueled by aging populations in the United States, Europe, and Japan and the ensuing desire for active, healthy lifestyles. Orthopedics, neurology, cardiology, and cosmetics/aesthetics are the fastest-growing medical device market segments in the United States.^2,3

FDA is charged by Congress to seek the “least burdensome means” to evaluate pivotal trial data required to establish safety and efficacy of medical devices. This reality limits the size and duration of trials, often necessitating additional postmarket surveillance data on device performance after FDA approval is obtained.^4,5 The Office of Surveillance and Biometrics (OSB) within CDRH oversees postapproval programs once the Office of Device Evaluation (ODE) has cleared or approved a medical device for marketing.

Although similarities exist in the development processes between drugs, biologics, and devices, there are distinct differences (see Table I). Class III medical devices are evaluated for safety and efficacy. Unlike biologics and pharmaceutical medications, however, few medical devices achieve blockbuster status (>$1 billion in annual sales) after they become widely available. This is beginning to change, however, with cardiovascular drug-eluting stents.

In the United States, different FDA centers review and evaluate devices and drugs. Devices are classified by categories based on perceived risk (Class I, II, or III) and require alternative types of documentation than drugs or biologics for regulatory applications. Drugs and biologics are characterized by FDA as having greater risk, longer development times, and higher expenditures for development through regulatory approval than devices.^5,6
The goals of postmarket medical device programs are to deliver accurate and timely information about adverse events, quickly analyze and assess data, and alert device users of potential risk. The medical device reports (MDRs) submitted by manufacturers to CDRH rely on those manufacturers, importers, and user facilities to comply with mandatory reporting requirements.⁵ Class II or Class III device manufacturers are generally required to conduct postmarket surveillance studies under the following conditions:⁷
When the likelihood of device failure would be reasonably expected to have serious adverse health consequences.When a device is intended to be implanted in the human body for more than a year.When a life-sustaining or life-supporting device is used outside of a device user facility.
CDRH maintains a list of all ongoing required postmarket approval (PMA) studies and their progress.⁸ Currently there are 91 PMA studies in progress. When postmarket studies are required, the device company assesses whether it has the internal resources necessary to conduct postmarketing studies or whether it would be more efficient to outsource that function. Development of postmarketing studies is complex, and thus contract research organizations (CROs) can often provide the necessary expertise. CROs offer economies of scale, and many have experience with hundreds of studies in a variety of therapeutic categories. Such experience means that CROs can help determine the number and types of patients required. Postmarket CRO specialists can identify the optimal geographic distribution of sites for a study, the type of data to collect, how to process and analyze data, and how to see trends across product lines.
The Decision to Outsource: Pros and Cons
Pros. Outsourcing can be strategic or tactical in nature, and it serves as a means to balance the workload for developers. It can enable medical device manufacturers to expand capacity, manage costs, and draw on external expertise.
Strategic outsourcing requires a formalized arrangement and is characterized as competency driven. Tactical outsourcing tends to be more ad hoc and capacity driven. Both types can enable sponsors to convert the fixed costs of personnel and facilities into variable costs.
Over time and within each functional department, CROs develop consistent processes for tasks and establish benchmarks and guidelines to expedite work flow, communication, and economies of scale. Each CRO develops tools, processes, and methodologies unique to that organization that maximize efficiencies. Postmarket CRO specialists offer the device or therapeutic expertise to provide realistic estimates on costs, cost-effective strategies for conducting a study, and insight and wisdom on what has worked and what hasn't from past experience.
Of equal importance for the device company sponsor is for the CRO to anticipate potential problems and employ strategies to avoid them or reduce their effect. CROs that specialize in postmarket studies are structured to process large quantities of information from multiple sites over long periods of time. It is essential that such CROs are compliant with prevailing regulations and understand federal codes, including 21 CFR Part 11 and electronic data systems.
Furthermore, good postmarketing CRO project managers and teams understand the crucial principles of customer service that are necessary to ensure positive experiences. The project managers are experts in the recognition, tracking, and handling of the device in use. CROs should manage complaints and customer feedback and provide triage for inevitable problems.
Cons. One of the primary downsides of working with CROs is that team members can and do change over the course of the study. CROs may hire entry-level people, so it's important to look at the training, mentoring, and development programs that CROs offer their team members. Experience makes a difference, and the reality is that every team member has to start somewhere. Staffing is based on project or contract need, and larger projects may require time to hire or train staff. Turnover varies from CRO to CRO, department to department, and year to year. As an industry, it is not uncommon to see 20% turnover in any given year; however, much of that change may be attributed to promotion or departmental changes as much as employee turnover.
Assessment of CROs

The selection of a CRO for postmarket studies is approached with the same due diligence used for any vendor. There are a number of questions to ask and characteristics to assess for the device maker to ensure that the CRO is a well-matched fit for the project under consideration (see Table II).

Medical device experience is desirable, but if used as the sole criteria for provider selection, it limits utilization of lessons learned and therapeutic experience amortized from nondevice clinical trials. CROs with demonstrable therapeutic and regulatory expertise in postmarket assessments and solid project management experience may be compatible candidates and, therefore, should not be ruled out if specific device experience is limited.
CROs and sponsors need to effectively communicate to maximize the collaboration of the partnership. It is important to ensure that both parties are speaking the same language and to clarify any problems that arise. It is essential to set clear expectations. When CROs are fully engaged and involved in decision-making processes at program genesis and throughout the trial, the experience is likely to be much more favorable. A CRO that is brought in early is much more likely to have a full understanding of the client management and program goals and is able to drive the project with those in mind. When the CRO is brought in late into the study development process and has limited capability to comment on study plans, those impediments may affect the CRO's ability to provide shared experiences and insight.
Developing a Study for a Cardio Medical Device
The following example illustrates what can happen when a company is unprepared and engages a CRO.
Situation: A device company has limited experience working with CROs and has vague expectations of CRO roles and responsibilities.Type of Study: A complete postmarketing study with (PMA)-conditional approval is required. Current study status is “enrollment closed.”CRO Services: Required services include clinical operations, data management, biometrics, safety, and medical writing.Region: The region to be studied is the United States only.Site Selection: Site selection is driven by senior executives and sales and marketing teams from the device company. Selected sites include physicians and experts recognized by peers for excellence in their therapeutic specialty and with the facilities, staff, and experience to conduct clinical trials.
Because the device company has little experience working with CROs, expectations for what makes an effective, strategic client-CRO working relationship are vague. The CRO wants to amortize and maximize its expertise and experience for the sponsor to exceed or at least match expectations. To achieve that goal and ensure high-quality deliverables, the CRO requires a working knowledge of the sponsor's decision processes, an understanding of who delegates what (and when), and a clear understanding of the scope and review of assumptions to prevent translation issues. Translational issues occur when the sponsor and CRO have different understandings of tasks or deliverables. When defining the scope of a program, it is critical to ensure that all details preformed by the CRO are transparent. Study scope definition should avoid the use of “gray area” language. If the CRO will be reviewing queries in an electronic data capture system, queries should be defined as both automatic (generated by edit checks) and manual (generated by a study-team member).
The majority of program challenges center on communication for team coordination. Team members include clinical operations staff, data managers, biostatisticians, medical writers, and safety and quality personnel. Some companies make decisions through groupthink activities whereas others have a clear decision tree and decision makers. At the start of new a study, a CRO's project manager must quickly learn how decisions are made at the sponsor company and build this into his or her planning. Engaging key decision makers in the early development of study planning, development of study plans, and team meetings can assist in smoothing out this bumpy process. If key individuals are only brought into the process toward the end, it can derail planning and lead to timeline delays. For example, to avoid issues that could affect end-of-study reporting, it is critical when developing a monitoring plan to include not only the clinical group but also the data management and biometrics groups.
The communications plan, therefore, becomes vital to establishing a successful working partnership. Initial issues for clarification include clear delegation of the CRO's responsibilities, the sponsor's responsibilities, and the interdependencies between the two. All parties should concur on the study purpose and the data management plan in order for data to be effectively analyzed and used. To facilitate those processes, regularly scheduled reviews between the CRO and the sponsor occur when milestones are met.
Process owners at the sponsor and CRO require an understanding of how their procedures affect other departments. Clear expectations for team members are important because it affects decisions and tasks that guide and affect the rest of the development team. Biannual face-to-face meetings and regularly scheduled teleconferences with clear purpose and goals are an effective means to meet those objectives. Early involvement of the CRO's periapproval services are warranted so that team members can identify the needs of individuals and the interdependencies of what each team member requires.
Sites for this trial are determined by the sponsor. Many of the investigators have well-established relationships with their sales liaisons and have previous experiences with the sponsor. Initially, investigator needs are relayed through the sales force to the CRO, which occasionally creates tension and negatively affects conditions for a smooth, functioning study. To minimize these incidents, the CRO establishes a help desk for sales team inquiries, and responses by the CRO are relayed directly back to the site, which alleviates many of the early concerns between sales liaisons and the CRO.
The CRO develops a study-tracking Web site. The Web site allows the sponsor's sales team to evaluate a site's status and provide feedback to stakeholders at the site. Further, the CRO and the sponsor's legal team work closely to ensure timely negotiations of contract language designed to facilitate rapid study start-up.

Lessons Learned = Best Practices. Every study offers opportunities to assess what worked well and what could have been done better. The benefits of the lessons-learned sessions are to set expectations, calibrate the team, and develop an action-item list to improve processes. This example presented opportunities for both the sponsor and the CRO to share experiences across each aspect of the study: from project management through safety training. To ensure a successful partnership, it is important to understand the tasks that will be completed by both the device company and the CRO (see Table III for a sampling of tasks. For a comprehensive matrix, go to devicelink.com/mddi/CROchecklist).

Conclusion: Strategies for Success
Early collaboration and honest communication are critical for establishing how the sponsor-CRO-study vendor development team works together. A clear understanding of decision making, roles, responsibilities, and interdependencies creates a culture of partnership and empowers team members to work toward problem solving as issues arise.
Device companies need to use planning time to map out project management processes, risk-benefit planning, and study details, including delegation of responsibilities among sponsor, CRO, and other study vendors. It is critical to address any issues or concerns as soon as they arise. Contingency planning often keeps the study on time and on budget, and the earlier it is implemented, the better.
It is incumbent on the device company to provide adequate resources in terms of budget and head count. The CRO must be aware of who holds contracts, who the primary manager is, and who is empowered to make requests. These responsibilities can be enabled with a study-scope matrix that identifies who does what and when, as well as how the CRO and other vendors fit within the interactions. The success of a study ultimately depends on the relationship between the medical device company and the CRO and their ability to jointly resolve problems based on mutual respect and honesty.
Barb Vargas and Yvonne Albright are senior project managers and Anne Santovito is project manager at Covance Periapproval Services (Conshohocken, PA).
References

1.“Critical Trends in $286 Billion Global Medical Devices and Diagnostics Market” analyzed in a new report from Health Research International, PRSafeNewswire; available from Internet: www.digital50.com/news/84894; accessed March 9, 2009.

2.“U.S. Medical Devices Industry Poised for Healthy Growth,” Frost & Sullivan, June 26, 2008; available from Internet: http://engineers.ihs.com/news/2008/frost-medical-devices-growth.htm; accessed March 9, 2009.

3.RR Andrew, “Full-Service Outsourcing Paving the Way in the Medical Device Industry,” (Waltham, MA: Foster-Miller); available from Internet: www.foster-miller.com/literature/documents/Full%20service.pdf.

4.DS Baim et al., “Postmarketing Surveillance for Drug-Eluting Coronary Stents: A Comprehensive Approach,” Circulation 113 (2006): 891–897.

5.The Least Burdensome Provisions of the FDA Modernization Act of 1997: Concept and Principles; Final Guidance for FDA and Industry, FDA, October 4, 2002; available from Internet: www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm085994.htm.

6.MS Rosen, “Yer Biotech Blues,” available from Internet: www.midwestbusiness.com/news/viewnews.asp?newsletterID=19470; accessed March 9, 2009.

7.Guidance for Industry and FDA Staff—Postmarket Surveillance Under Section 522 of the Federal Food, Drug, and Cosmetic Act, FDA, April 25, 2006; available from Internet: www.fda.gov/cdrh/osb/guidance/316.html; accessed March 9, 2009.

8.PMA—Post Approval Studies, FDA; available from Internet: www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma_pas.cfm; accessed July 9, 2009.

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