FDA Issues Draft Guidance Describing Benefit-Risk Factors Taken Into Account In Post-Market Compliance Decisions

By Allyson B. Mullen – 

It is an open secret that at some point in every device company’s life one or more of its devices will likely be out of compliance with the Federal Food, Drug, and Cosmetic Act. That is because the regulatory scheme is complex and subjective, and any problem in the manufacture or use of the device could result in a violation.

Although there are many “technical” violations, FDA does not take enforcement action to remove violative product from the market in most cases. This seeming lack of action is partly because the agency is not aware of every violation.  But even among those that come to the agency’s attention, it simply does not have the resources to take action every time.  More important, doing so would frequently be more detrimental to patients and doctors than leaving violative product on the market. 

Device companies are not always aware of FDA’s enforcement discretion to not take action or how best to advocate for such discretion. FDA’s recent draft guidance, “Factors to Consider Regarding Benefit-Risk in Medical Device Product Availability, Compliance, and Enforcement Decisions” is intended to clarify “the benefit and risk factors FDA may consider in prioritizing resources for compliance and enforcement efforts to maximize medical device quality and patient safety.”  

FDA often formally considers product availability and benefit-risk evaluation when deciding whether to take enforcement action. For example, in consent decrees, it is not uncommon for FDA to permit continued sale of violative devices that FDA determines are “medically necessary.”  To our knowledge, the draft guidance is the first time FDA has comprehensively listed the factors that underlie these enforcement decisions. However, these factors likely have always been used and will continue to be used even prior to finalization of the guidance.

The factors FDA has called out are quite similar to the factors identified in earlier premarket benefit-risk guidances FDA has issued. The factors are:

Benefits

• Type of benefit;
• Magnitude of benefit;
• Likelihood of patients experiencing one or more benefits;
• Duration of effects;
• Patient preference on benefit;
• Benefit factors for healthcare professionals or caregivers; and
• Medical necessity.

Risks

• Risk severity;
• Likelihood or risk;
• Nonconforming product risks;
• Duration of exposure to population;
• False-positive or false-negative results;
• Patient tolerance of risk; and
• Risk factors for healthcare professionals or caregivers.

The draft guidance acknowledges that the benefits and risks associated with a device and its noncompliance may change over time. FDA notes that, “as the medical device is used, patients may experience significantly longer treatment effects than those described in the device labeling.”  While FDA will not typically permit a device company to make device performance claims beyond the cleared/approved labeling, FDA is expressly using such expanded performance data in a benefit-risk assessment. 

The draft guidance does not explain how FDA will weigh or evaluate these factors to make a final decision as to whether or not to take a contemplated enforcement action. It states that FDA will use the outcome of the benefit-risk analysis to “make informed appropriate decisions” and

Specific benefit-risk analyses will again need to be viewed in context, but generally, if FDA’s benefit-risk assessment indicates high benefit to patients with little risk, FDA may decide to work with the manufacturer to address the underlying issue without initiating a formal compliance or enforcement action. If FDA’s benefit-risk assessment indicates low benefit to patients with high risk, FDA would likely take formal compliance or enforcement action to address the problem.

It is highly unlikely that FDA will decline to take enforcement action in every situation where the benefits of a violative device outweigh the potential risks. How far the benefits must outweigh the risks and how certain FDA must be of the benefits and risks in order to avoid enforcement action is not specified in the draft.

The draft guidance indicates that FDA may use the results of the benefit‑risk analysis to inform decisions such as:

• “When should a firm’s recall strategy appropriately include a correction instead of a removal?
• What actions, if any, may FDA take when continued access to a nonconforming device or a device manufactured by a firm with regulatory compliance issues might be needed during a shortage situation?
• When is it in the best interest of the public health to grant a variance from certain [quality system (QS)] regulation requirements for QS issues identified during a PMA pre-approval inspection?
• When might FDA exercise enforcement discretion and not take immediate action against a company for marketing a device with a significant change or modification prior to obtaining clearance, as required by 21 CFR 807.81(a)(3)?
• Is a manufacturer’s proposed correction strategy adequate given the benefit-risk assessments and mitigation activities?
• Upon observing a violation, when might FDA send a Warning Letter or Untitled Letter and when would it be appropriate to take an alternative, more informal approach?”

These questions are not only relevant to situations in which a product shortage could occur if FDA were to take action (e.g., medical necessity). The draft guidance states that the factors in the guidance apply not only “to compliance and enforcement decisions that potentially have a direct effect on product availability, when appropriate, [but] FDA may use the outcome of a benefit-risk assessment to inform other decisions related to compliance and enforcement.”  It states that when making decisions that will not potentially impact product availability, FDA may also consider “whether regulatory non-compliance increases risk of harm to patients, whether taking (or not taking) a contemplated compliance or enforcement action would impact patients, the manufacturer’s regulatory history, and steps taken by the manufacturer to address the situation.”

Because this guidance applies to all potential compliance and enforcement actions, device companies should be aware of the factors FDA will use to analyze these situations and when applicable, use these factors to urge FDA to exercise enforcement discretion and permit important devices to remain on the market while the company comes into compliance.

The draft guidance states that its purpose is to “improve the consistency and transparency of” FDA’s decision making regarding compliance and enforcement actions. Outlining specific factors could certainly help consistency.  To truly increase transparency as to FDA’s decisions, industry needs to know both when FDA has taken action (typically is available through warning letters and other enforcement actions) and also when it has not. The draft guidance helps somewhat with the latter by providing two examples of cases in which enforcement discretion would be exercised.

We commend FDA for attempting to give some insight into its decision making. However, it would be helpful to have many more examples, with as much insight as possible into FDA’s reasoning and weighing of benefit‑risk.  We would hope the final guidance expands the number of examples, especially as to situations in which enforcement discretion applies.

Procedurally, the draft guidance does not say whether FDA will formally document its benefit-risk analyses and decisions. We wonder if it will because if these analyses are formally documented they may be able to be obtained through a Freedom of Information Act request.  If industry could obtain such analyses, they would likely be heavily redacted, but could provide some additional insight into instances in which FDA chose not to take action. 

One area where this guidance may have a significant affect on current industry practice is off-label promotion. As noted above, FDA indicates it has discretion to perform a benefit‑risk analysis to assess whether or not to issue a warning or untitled letter to a device manufacturer that has made a major change in its device’s intended use without obtaining a new 510(k) clearance (i.e., promoting a device for a new intended use).  Many off-label uses may provide significant benefits to patients and/or doctors while posing low risks. 

It is not clear whether the draft guidance will have an effect on current FDA or industry practice. FDA publishes annual statistics regarding, among other things, the number of warning letters issued and recalls undertaken by industry.  We will certainly be watching to see if there is any significant change in these numbers to assess the potential impact of the guidance.