Having worked in both startup and large corporate environments myself, I have seen firsthand the similarities and differences. While resources can definitely be different between small and large companies, a focus on streamlining preclinical development is definitely a shared goal. Making the upfront effort to fully understand and characterize the regulatory pathway and evidence requirements pays dividends for a company of any size as it allows them to develop a strategic approach to testing that aligns with regulatory milestones. Anticipating topics and data that FDA is likely to scrutinize allows for prioritization of specific testing and building a scientific justification for where testing can be scaled back to minimize the overall burden. External resources and consultants can also provide subject matter expertise as an extension of product teams and can help identify a least burdensome approach. The drive and agility of startups, with the right support, can position them just as well as large device companies to get their products across the finish line to regulatory approval.

Yes, this certainly does happen although most of the time it is not for lack of effort on the sponsor’s part. Of course there can be situations in which the originally intended regulatory path is no longer viable based on feedback from FDA or following a denial decision such as a Not Substantially Equivalent (NSE) determination on a 510(k). More commonly, however, a new regulatory requirement is discovered because a sponsor has not considered that their clinical intended use includes a specific anatomy, surgical procedure, or patient criteria for which FDA requires specific evidence. In these situations, I encourage sponsors not to panic. There are often ways to leverage testing that has already been conducted or is already planned to satisfy the new requirement. It is ideal to understand the complete regulatory requirement landscape from the beginning of development, but things can change later in the process and the mindset must shift to pivoting.

There are three primary considerations for me when considering a CRO partner: proficiency, communication, and attention to detail. First and foremost, a CRO should be proficient, not just generally competent, in the device type, species and model, surgical techniques, instrumentation, and analyses that are required for your study. Many CROs claim they can do it all, but they should be able to produce ample evidence and case studies that specifically demonstrate their proficiency. Transparent and consistent communication is huge for me. You can usually get a sense within the first few interactions with a CRO, whether they’re going to be a responsive, dedicated one-to-one partner. Frequent, clear communication is important in all phases of the study to keep things on track, but is most critical during the active study phase when things can change quickly and rapid decision making is necessary. Finally, a CRO’s attention to detail from initial quote to final report can make or break a study. The quote itself is a great opportunity to gauge this: having all requested study design elements captured accurately, line item descriptions and individualized costs instead of big buckets, and a clear layout of study deliverables and timelines. I find that a CRO’s attention to detail is directly correlated with the rigor, quality, and integrity of data and the caliber of reporting.

A least burdensome approach to preclinical testing is always the goal, but it can be challenging depending on the specific evidence requirements for your product. First and foremost, start by critically assess your device’s design, intended use, and how it will interact with the body, and trying to anticipate where FDA will place the most scrutiny. As an example, for an endovascular stent FDA will be particularly interested in thrombogenicity and vessel wall response, while for an absorbable orthopedic implant FDA will be most interested in the absorption timeline, tissue ingrowth, and residual strength. Focus on ensuring that your testing plan fully addresses these areas of scrutiny, and then look for opportunities to justify leveraging or scaling back somewhat on other endpoints. A good example of this would be certain biocompatibility endpoints, which may be able to be incorporated into a clinically relevant large animal model to avoid the traditional exhaustive testing under ISO 10993.

In designing studies, the best way to support regulatory strategy is to anticipate how specific study design elements and outcomes may be interpreted by FDA. Study elements like sample size, animal care and evaluation parameters, success criteria, and raw data documentation are the most common areas of FDA scrutiny. For scientists that are routinely designing and executing studies, draw on your historical experience with the types of deficiencies or requests for additional information sponsors have received from FDA and make recommendations to preempt those. For scientists on the sponsor side planning studies, rely on test facility personnel to leverage their expertise with similar devices and study types to understand the relative regulatory risk of each study variable. For anyone designing studies, having a well thought out scientific justification for each study design element will directly support a successful regulatory strategy.

One of the most common deficiencies is that a preclinical study’s design does not account for the full scope of a device’s biological effects with respect to time and tissue interaction. As an example, for a permanent implant, there is an evolution of the device’s interaction with the implanted tissues over time and FDA wants to see evidence that the biological response to the implant has reached a steady state, which requires demonstrating consistency across multiple timepoints. While an acute, non-survival study for the same device may be useful to support its safety and usability during implantation, a single acute timepoint simply cannot demonstrate biological steady state and would be considered insufficient by FDA. It is essential that preclinical studies take into account a device’s biological effects at the time of initial introduction into the body as well as how the response may change over time.

It can be challenging early in development to have fully mapped out regulatory milestones and the data necessary to support them as this information often needs to be derived from a variety of sources. The PMA path requires multiple submissions, such as an Investigational Device Exemption (IDE) to pursue a clinical study, and the evidence requirements for each of those submission milestones is more standardized, easily understood, and able to be strategically prioritized. For the 510(k) path, on the other hand, the only formal milestone is often the 510(k) submission itself. In this situation, I recommend that companies initially focus on proof-of-concept or feasibility testing to build confidence in their device’s safety, functionality, and usability prior to definitive testing (e.g., biocompatibility studies). Pre-submissions can also serve as informal milestones through which companies can prioritize presenting data and obtaining feedback on a specific topic as this can enable a more phased approach to evidence generation.

I believe the single most important thing a company should have before engaging in the pre-submission process is a comprehensive device description that includes the clinical intended use and a description of device design, materials, and manufacturing methods. The goal of a pre-submission is to obtain detailed and substantive feedback from FDA on specific key topics, and the best way to accomplish this is to ensure that FDA fully understands your device. A modest amount of early characterization or feasibility data, such as initial benchtop evaluations of mechanical properties or general functionality, is often helpful to support your device’s technological characteristics and intended use. But there is no expectation of having exhaustive testing completed prior to interacting with FDA through a pre-sub.

FDA guidance documents are a great resource if one happens to exist and is applicable for your device or technology. Unfortunately, that is not always the case. In those situations, I look at prior approvals of similar devices. There are often publicly accessible FDA documents, such as Summary of Safety and Effectiveness Data (SSED) for PMA products, or 510(k) summaries, available for previously approved products that contain information about the types of testing and data that supported those approvals. While there is no guarantee that FDA will request or accept an identical testing strategy for a new product, you can often obtain a helpful framework from the most recent approvals to serve as a starting point.

Many companies understandably hope and believe that they will be able to do more with less in terms of evidence and still have a successful regulatory outcome, so they underestimate the scope of testing they will ultimately need to perform to satisfy FDA. There is a strong desire to shorten timelines by limiting the type and amount of testing performed, such as avoiding animal studies, and leveraging as much as possible from benchtop data. When reviewing submissions, FDA often relies on data that demonstrates a device’s biological effects to make conclusions about device safety and will routinely request such data prior to issuing a clearance or approval. So a common early mistake is that companies will plan their regulatory strategy around insufficient testing without accounting for the need to produce data that supports their device’s biological safety.