Renowned investor Howard Marks once said “You can’t predict. You can prepare.” It’s a phrase Marks was using to describe the stock market cycle, but it can also be applied to the medical device regulatory pathway. While there will always be unforeseen issues that arise, many risks and obstacles can be mitigated by proper preparation. 

There is a common misconception in the industry that biocompatibility begins with testing. Biocompatibility evaluation starts with risk assessment, as defined in ISO 10993-1—a cornerstone standard referenced in both U.S. Food and Drug Administration (FDA) and European Union (EU) regulatory submissions. ISO 10993-1 establishes a risk-based framework that should be used at the start of a project to determine the appropriate biological evaluation strategy and testing pathway. 

In practice, many regulatory risks and delays arise when this upfront planning step is skipped. As a biocompatibility expert, I see so many companies encountering regulatory risks and obstacles that could have been avoided by taking the time upfront to develop a clear biological evaluation roadmap—before testing begins. This should be done when developing new medical devices for clinical trial or market, or when any significant changes are made to an existing device.

To help medical device companies plan ahead and avoid the hidden costs associated with unplanned or unnecessary biocompatibility testing, it’s important to understand why biocompatibility evaluation plans are essential, which significant aspects to define prior to testing, and practical strategies to avoid over-testing. 

What Is a BEP and Why Do I Need One?

One often overlooked step medical device manufacturers miss during the regulatory process is creating a biological evaluation plan (BEP) to define the overall evaluation strategy, identify relevant endpoints and outline the testing approach—including test type, extraction ratio, duration, and solvents. Without this upfront evaluation, too much is unknown and gaps exist, resulting in unfocused and often inefficient testing. 

While BEPs are the foundation of a compliant and efficient biocompatibility strategy, they are frequently overlooked—even though development of a BEP is consistent with current regulatory expectations. ISO 10993-1 states “appropriate biological evaluation shall be planned, carried out, and documented by knowledgeable and experienced professionals,” underscoring the need to involve those with the appropriate expertise. When looking at the steps that make up the ISO 10993-1 framework, it’s clear why having a BEP should be considered non-negotiable.

Beyond the regulatory expectation that a BEP is prepared ahead of the onset of testing, there are a host of reasons why this step should not be skipped. First is the financial aspect, saving a medical device manufacturer money to create potentially life-saving products. While there is an initial investment that goes into creating a BEP or engaging outside expertise to assist with the task, having a sound regulatory strategy will undoubtedly result in cost savings in the long run. I’ve seen this firsthand, numerous times. When companies engage in proper regulatory planning, they can reap several benefits, which results in faster market access. This ultimately means getting devices to patients who need them as quickly and safely as possible. 

What Goes into Creating a BEP?

The first steps in creating a BEP include gathering a list of the raw materials that will be used in the device’s construction, reviewing what the entire manufacturing process will look like and reviewing any previous testing and clinical data. After those are complete, ask a few strategic questions:

1. Which markets will the device be submitted to? Regulatory expectations vary, and aligning early prevents costly missteps. This should take into account that developing a strategy for the U.S. and EU does not mean the device will meet regulatory expectations for other regions.
2. What is the intended use of the device? 
3. What is the nature and duration of patient or user contact?

Along with baseline information, these three simple questions can garner a lot of information from the start. They help determine the proper product classification, which can be complex and, if mishandled, can result in years of regulatory setbacks. From there, identify which biological effects are relevant and review existing information to see what data support the device’s biocompatibility profile. If gaps remain, targeted testing provides the objective evidence needed to demonstrate risk is controlled.

Next, it’s important to remember the BEP should be treated as a document that can—and should be—updated and revised, when factors warrant doing so. Not only do regulations change on an ongoing basis, other factors like design, intended use, clinical trial findings, etc. should be accounted for appropriately in the BEP to ensure continued alignment with regulatory requirements.

An effective and successful BEP will likely contain the following components:

• An overview or summary that paints the whole picture—or tells the whole story—about the device. This is especially important when a nontraditional testing approach is taken or if the device has unique features. Including a clear summary up front will set the stage for FDA reviewers before moving onto the rest of the document, dramatically improving review outcomes and reducing deficiencies.
• A detailed description of the device that clearly explains its intended use, duration of contact for each part of the device, etc.
• A roadmap for ensuring all biological endpoints will be met and an explanation of why that path forward was chosen.

How Do I Avoid Overtesting?

My top piece of advice is to engage a biocompatibility expert as early as possible to review or establish a BEP. This approach saves valuable time in the long run and can provide peace of mind that the result will be a strategic and efficient roadmap to regulatory approval.

Without a BEP, the company is likely using a “checklist” approach, instead. The biocompatibility regulatory world is always in flux and navigating it can feel burdensome and overwhelming, so it’s understandable why some companies see “checking all the boxes” as the safest path forward. The most common issue resulting from this approach is undertaking a multitude of tests that aren’t needed. Or, it’s difficult to justify why a certain test was done when presenting the data for approval. Related, sometimes animal testing will be among these unnecessary tests that do not generate meaningful or useful data. 

Many companies overcomplicate the process by moving forward without expert input. The simplest way to avoid unnecessary steps is to consult a biocompatibility specialist early. External partners can provide clarity and prevent redundant or irrelevant testing by focusing on the intended use and nature of contact. Your biocompatibility partner will help to understand how to classify a device and components, avoid misclassifying non-contacting components, and will develop a strong battery of objective evidence to support the biocompatibility profile of a device. Working with a biocompatibility consultant early ultimately leads to a smart biocompatibility strategy with targeted testing, an informed regulatory approach, and reduced timelines and resources.

Regulators expect objective evidence that demonstrates a device’s biological safety. They also look for assurance that testing was performed to recognized standards and that the evaluation aligns with the risk-based framework of ISO 10993-1. A strong BEP ensures an optimal testing plan in accordance with the ISO 10993-1 framework, and engaging an outside expert is in direct alignment with the ISO 10993-1 clause stating: “Test data, complete to the extent that an independent analysis could be made, shall be evaluated by competent, informed professionals.”

Expert assessors who have the necessary knowledge and experience shall determine and document:

• the strategy and planned content for the biological evaluation of the medical device
• the criteria for determining the acceptability of the material for the intended purpose, in line with the risk management plan
• the adequacy of the material characterization
• the rationale for selection and/or waiving of tests

The regulatory, financial, and operational risks of not engaging early with a regulatory expert to develop a BEP are too great. Since ISO 10993-1:2025 requires a plan before testing, skipping this step means more chance of delays during the review process. Unplanned testing can waste resources, invalidate results due to poor sample preparation, and delay submissions. In some cases, it prevents market entry altogether. Preparing a BEP takes initial investment, but it streamlines the overall timeline and reduces the likelihood of costly setbacks.

Katie Brinkman leads the development and strategic positioning of Hohenstein Medical’s medical device biocompatibility program, with focus on chemical characterization, ISO 18562 gas pathway testing, and ethical, non-animal assays. Katie has over 15 years of experience in biological sciences, authoring numerous biocompatibility and toxicological risk assessment reports supporting global regulatory submissions. Katie earned a bachelor of science degree in biology from Mississippi University for Women, is an active member of the Society of Toxicology and the Regulatory Affairs Professionals Society. She is also certified as a Biological Safety Specialist by NAMSA.