Fix, replace or augment: Key considerations for rescue or transition studies in medical device clinical trials

Clinical trials are demanding, rigorous and time sensitive. This is especially true for medical device development where the protocols, patient selection or surgical interventions may be highly specific. The demands on all parties-the developer, Contract Research Organization (CRO), principal investigator, site staff and participants-are high, so it is little wonder that when a program is not meeting timelines, thoughts of "rescue" or "transition" may need to be considered.

If a CRO is being used to execute the study, replacing an incumbent CRO with another is often an option of last resort for developers. This is due to the time, effort and reputations invested in selecting, commissioning and setting up a CRO to conduct the program or study. Any decision taken around transitioning existing studies should, therefore, be done with caution and pragmatism.

Unquestionably, everyone involved in the execution of a study will be focused on delivering quality outputs and efficient timelines, so that pragmatism is often found in seeking to augment existing relationships with additional third parties contributing to an existing program in order to keep it on track.

There are numerous reasons why even well-qualified, specifically selected CROs sometimes struggle to deliver studies in line with expectations. The complexity of a clinical trial may lead to unexpected pitfalls for CROs who lack specific therapy area or specialized patient setting experience (e.g., neonatal intensive care or post-op), or struggle to recruit the number or diverse mix of patients into clinical trials. Sites, too, invest considerable time, resources and credibility to get to the "green light" ready to enroll participants. Being able to support their success in recruiting is as important to them as other stakeholders in the trial. Slow start-up, lack of resources, difficult or hard to recruit patient populations and escalating costs associated with timeline extensions can all knock a trial off plan and force the need for "rescue" or "transition" to enter the lexicon.

The specialist nature of medical device focused CROs

Biopharmaceutical developers have a wide choice of CROs with a wide range of capabilities: global, regional, niche and/or therapy-area focused. Less so for medical devices. The due diligence of vendor selection will seek to balance qualifications, experience, past performance, geographic coverage, services provided and the ability to meet timelines. Yet while the core requirements are similar between drug and device development, the realities of running studies for medical devices may not be apparent.

Medical device development programs benefit from MedTech-focused CROs that possess the following attributes:

• Dedicated medical device teams with experience in delivering trials both globally and across a wide range of therapeutic areas
• Genuine efficiencies gained through an end-to-end development understanding, capturing and utilizing insights from surgical, interventional and safety/biocompatibility testing to drive protocol and trial design, and ultimately clinical study execution
• Decentralized or partially decentralized trial capabilities where technology can be used to gain additional data points, offset the need for in-person visits, improve patient retention and where proven investigators can be used as the Principal Investigator (PI), with local PIs acting as sub-PIs as needed, based on local regulation. This is particularly important as patient recruitment for clinical trials becomes more specialized and access to PI sites for check-ins, screenings, or sample collection may not be feasible. This is especially true of medical device trials that typically have fewer sites (compared to biopharmaceutical trials) and many more trials being run in community settings.
• Working with a CRO that is already ISO 13485 certified. This important standard, stipulated in EU and many other countries around the world, outlines requirements for quality management systems (QMS) of companies involved in the medical device industry. Working with an ISO 13485 QMS-certified CRO simplifies vendor approval, reduces monitoring and re-evaluation burden, and reduces audit costs and complexity, allowing the developer to proceed with speed and confidence.

Rescuing studies and rescuing relationships: Partnerships vs. transactions

Clinical trials are challenging, and many of these challenges cannot be entirely predicted or anticipated at the outset of a trial. This simple fact establishes four important parameters for selecting a CRO.

1. Experience: selecting a CRO with therapeutic area and medical device specific experience helps because this expertise can help guide the team to anticipate—and mitigate—risk for the program from the outset. The right CRO for your study also understands the patient population and demands associated with your protocol. The CRO should also be able to tap into its own physicians and leverage relationships with Key Opinion Leaders (KOLs) who have experience in the space and can bring their particular insights and protocol considerations from the beginning. Experience also brings an understanding of how studies should be performing, to evaluate performance on an on-going basis, or suggest changes to the protocol, additional training and risk mitigation while the study is underway.
2. Core capabilities: Patient recruitment and site activation will likely remain the most unpredictable variable in any clinical trial, so a CRO with access to data-enabled and targeted recruitment tools as well as access to diverse patients and proven investigators is key.
3. Scale and flexibility: Sometimes, simply applying more resources to a study is what’s needed to get it back on track. A CRO with an agile attitude and the ability to scale to respond to your changing study needs or timelines, can help to keep programs on track.
4. Long-term commitment: Medical device development can take years, so there are significant continuity benefits to be had from working with a CRO as committed to your product as you are. Such attitudes mean proactively working with you to recognize, discuss and mitigate emerging challenges, and typically see the integration of active senior level oversight on programs reflecting a genuine desire to see that relationship mature.

Ultimately, relationships with CROs and other contributors operate as either transactional or by a committed approach. Transactional relationships are more likely to result in frustration as they are based around a set of somewhat inflexible pre-agreed parameters. Actively seeking a partner-like attitude in your CRO, hwere they are committed to your success, is "cheap insurance" for when clinical study challenges (inevitably) emerge. It is important to have mutual verification of program parameters, open dialogue about possible concerns and an active program of risk mitigation. Indeed, the maturity of a partnership approach will include the pragmatism to know when rescue studies should be considered to augment established programs.

When to use the "nuclear" option of trial transition

Ultimately, the decision to transition a trial to another CRO reflects a breakdown in relationship to the point at which confidence is lost. Given the consequences and the threat of yet more delays on a program, critical objective assessment of the existing relationship needs to be carefully thought through, focused on five key areas:

1. Regulatory concerns, including global sensitivities
2. Study conduct concerns, including adequacy of approaches to patient recruitment
3. Data integrity/quality and Trial Master File concerns
4. Team dynamics, including experience
5. Communication issues

Any one of these could be a deal-breaker for an existing relationship, but it is also possible to use this list as a guide to make a decision to augment an existing relationship (with, say, additional regulatory support) or help determine whether a complete reset is appropriate.

When the decision is made to transition your trial to a new CRO, careful consideration should be given to ensure that you understand the following: timing of transition and the potential for increased delays, data transfer and access, funding and investor relations, contract negotiations and regulatory scrutiny.

How to transition a trial, or components of a trial

Of course, if KPIs have been established early and regularly monitored, and relationships carefully maintained by all parties, it will be obvious when a new approach is needed. But if "rescue or transition" is needed:

• Determine if individual components can be outsourced and added to an existing program, or whether wholesale change is needed
• Seek out a provider experienced in conducting transition/rescue studies, and who is able to bring integrated resources forward quickly under the oversight of a senior individual. 
• Revisit other contenders evaluated during the original bidding process.

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