On May 13, 2015, the Food and Drug Administration (FDA or the Agency) released a draft guidance document, Patient Preference Information – Submission, Review in PMAs, HDE Applications, and De Novo  Requests, and Inclusion in Device Labeling (Draft Guidance), discussing the collection and submission of patient preference information that may be used by FDA in decision-making relating to premarket approval applications (PMAs), Humanitarian Device Exemption (HDE) applications, and de novo requests. The draft guidance also outlines considerations for including patient preference information in labeling for patients and healthcare professionals. 

Background

Since 1999, CDRH has included a patient representative as a non-voting member on each of the FDA Medical Devices Advisory Committee meetings to include patient concerns and voices in evaluating device technologies. However, FDA did not have a scientific or formal way to consider patients’ opinions when weighing the benefits and risks of a medical device during the approval process to allow marketing in the U.S.

In recent years, there have been increased efforts to encourage and recognize patient perspectives in medical product regulations and discussions. As part of the Food and Drug Administration Safety and Innovation Act (FDASIA) passed by Congress in 2012, Section 1137 of the Act directed the Agency to “develop and implement strategies to solicit the views of patients during the medical product development process and consider the perspectives of patients during regulatory discussions.” In 2012, FDA finalized its Guidance for Industry and Food and Drug Administration Staff; Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications (March 28, 2012) (Benefit Risk Guidance) to outline key factors that the Agency considers when evaluating the benefit-risk profile of devices in PMA and de novo applications, including patient perspectives, such as patient tolerance for risk and perspectives on benefit. However, the Benefit Risk Guidance document did not specify how or when sponsors should collect or present this type of information. It is important to note that consistent with the Benefit Risk Guidance, the Draft Guidance does not apply to 510(k) premarket notifications.

Prior to the release of the Draft Guidance, FDA also solicited stakeholders’ views through a public workshop held on September 18 and 19, 2013, and a public federal docket (November 2014) to better understand and assess patient perspectives to help inform FDA’s regulatory review of devices.

CDRH also participated in research as a member of the Medical Device Innovation Consortium (MDIC), a non-profit public-private partnership between FDA, National Institutes of Health, Centers for Medicare & Medicaid Services, and several medical device companies, patient groups and other non-profit organizations. On the same day that the Draft Guidance became available, MDIC also released itsframework for incorporating patient preferences into the device development and assessment process, including a catalog of methods for collecting patient preference information that can be used to develop, design, and market devices to meet patient needs.

In this landscape, the Draft Guidance was released as part of FDA’s Patient Preference Initiative to provide more specific guidance to sponsors as to the type of data that FDA would consider in its decision-making process during review of PMAs, de novo requests, and HDE applications for both therapeutic and diagnostic devices. 

Draft Guidance

In the Draft Guidance, FDA acknowledges that patients and caregivers who live with a disease or condition on a daily basis and utilize devices for their care may have developed insights and perspectives on the benefits and risks of devices that can help the Agency evaluate its benefit-risk profile during the regulatory decision-making process. Therefore, the Draft Guidance was released for the following objectives to more formally incorporate patient preference data that may be considered:

  1. to encourage voluntary submission of patient preference information by sponsors or other stakeholders, in certain circumstances;
  2. to outline recommended qualities of patient preference studies, which may result in valid scientific evidence;
  3. to provide recommendations for collecting patient preference information to FDA; and
  4. to provide recommendations for including patient preference information in labeling for patients and healthcare professionals.

FDA defined patient preference information as qualitative or quantitative assessments of the relative desirability or acceptability of attributes that differ among alternative diagnostic or therapeutic strategies. Device attributes include features such as:  effectiveness, safety, means of implantation, duration of effect, duration of use, and other device characteristics that may affect benefit-risk considerations. FDA further distinguished patient preference information from patient-reported outcomes (PRO). PRO measures a patient’s own assessment of health status and/or outcomes at a given point in time (before or after therapy), where patient preference data measure what or how much the patient values one outcome as compared to other potential therapies or attributes. 

In the Draft Guidance, FDA recognized that individual patient preferences may vary, and a patient may not assign the same values to various risks and anticipated benefits as a healthcare professional, family member, or regulator. Evaluations of patient-centric variations in tolerance to risks and perspective on benefits may be considered valid scientific evidence that could inform FDA’s benefit-risk assessment for a device. Notably, FDA clarified that in addition to other factors outlined in the Benefit Risk Guidance, “if this assessment reveals that a significant number of reasonable and well-informed patients would accept the probable benefits despite the probable risks, this may help support a favorable benefit-risk profile.”

FDA listed several study qualities for patient preference studies that the Agency intends to consider when evaluating whether patient preference information constitutes valid scientific evidence:

  • Representativeness of the sample and generalizability of results
  • Capturing heterogeneity of patients’ preferences, accounting for the patient’s own experience of the disease, as well as factors such as:  gender, age, race, socioeconomic/cultural background, disease severity, disease chronicity, and availability of alternatives 
  • Established good research practices by recognized professional organizations
  • Patient centeredness, where the study measures the attitudes and values of well-informed patients
  • Effective communication of benefit, harm, uncertainty, and risk to the patients
  • Minimize potential cognitive bias in study design, e.g., framing as positive (gains) or negative (losses)
  • Logical soundness and consistency in the data
  • Relevance in the preferences measured to be useful in evaluating the evidence
  • Robustness of analysis of results, to ensure appropriate interpretation of the collected evidence
  • Study conduct, to ensure validity and reliability of study results
  • Comprehension by study participants, to ensure that study participants fully understand the risks and other medical information

Additional considerations noted in the Draft Guidance include maintenance of the integrity and validity of the patient preference information submitted for premarket review. In addition, FDA also noted that conditions of approval may be imposed, including limiting approval to an identified subpopulation or requiring collection of postmarket data.

The Draft Guidance also indicated that patient preference information considered in a premarket application can be included in the product labeling, as it could be useful to healthcare providers and patients when making treatment decisions involving benefit-risk tradeoffs or novel treatments. In addition to general labeling recommendations, the Draft Guidance also suggested that the labeling should describe the patient preference study data, including the range of patient preferences, the method used, population studied, attributes and benefits/risks studied, and characteristics of patients who considered the device’s probable benefits to outweigh its probable risks. Overall, labeling recommendations in the Draft Guidance focused on ensuring that patients will be able to understand the patient preference data presented to allow informed decision-making, and will thus be able to form realistic expectations of the benefits and risks that may be conveyed from device use.

FDA also clarified that the proposed framework does not change the review standards for safety or effectiveness for these device submissions. Rather, the Draft Guidance is intended to provide more clarification and guidance on how the Agency considers patient preferences and perspectives in FDA’s benefit-risk determinations. The patient preference data are intended to be considered as part of the totality of evidence with nonclinical and clinical testing, as applicable. FDA further noted that patient preference information may not be relevant or appropriate for all device types, and may be more useful for preference-sensitive products where the patient has multiple treatment options without one that is clearly a superior option. 

As indicated above and as further demonstrated by the PMA example outlined below, patient preference data likely will be important information to be included in PMAs and de novo requests for preference-sensitive devices to further support a risk-benefit analysis of such devices. This is consistent with FDA’s shift on a focus of benefit-risk assessment as a central component of PMAs and de novo requests as outlined in the Benefit Risk Guidance. As further evidence of the importance of patient preference data in de novorequests and PMAs, the Draft Guidance included proposed edits to the worksheet from the 2012 Benefit Risk Guidance document to incorporate patient preference information in the questions to consider in the benefit-risk evaluation. The worksheet from the 2012 Benefit Risk Guidance is used to help frame the benefit risk analysis, which is typically summarized in the decision summary review memos for de novo decisions and in the Summary of Safety and Effectiveness for PMAs. However, CDRH’s review process regarding the device benefits may be somewhat different for HDE submissions, given that the HDE process is limited to evaluation of device safety. Since the key incentive to HDE sponsors is that an HDE is exempt from the effectiveness requirements of a PMA, it remains to be seen whether or how patient preference information will be considered in the HDE process for future products. 

In the Draft Guidance, FDA included several examples of the use of patient preference data in the benefit-risk determination for medical products. In particular, FDA referenced the CDRH Patient Preferences of Weight Loss Devices Study, which was sponsored by CDRH and Research Triangle Institute (RTI) Health Solutions. Study results were recently published in January 20151. The study included obese patients who evaluated trade-offs among effectiveness, safety, and other attributes of weight-loss devices in a scientific survey. Discrete-choice experiments were used to quantify the importance of safety, effectiveness, and other attributes of weight loss devices to the respondents. A substantial portion of these patients indicated they would accept the risks associated with a surgically implanted device if a sufficient amount of weight was lost. The study also allowed development of a tool for CDRH to use to define minimum clinical effectiveness to evaluate new weight loss devices. 

Notably, EnteroMedics MAESTRO obesity device was the first PMA supported by patient preference data, and was PMA approved in January 2015 even though the pivotal study missed its endpoints. In considering the benefits and risks of the device, FDA considered the clinical study data as well as the FDA-sponsored patient preferences survey results regarding obesity devices, which demonstrated a higher tolerance for risk in exchange for weight loss, as noted above. The patient preference information contributed to the Agency’s determination that the probable benefits of the device outweighed its potential risks for PMA approval. 

FDA has emphasized that submission of patient preference information is voluntary and the Draft Guidance is not intended to create extra burden on sponsors of premarket submissions. However, in light of this recent precedent, as well as FDA’s recent actions in this area, sponsors may likely want to consider including this aspect in their study designs to potentially contribute to a favorable benefit-risk determination in support of approval. That said, given that patient preference data have not been typically or consistently collected in device studies as outlined by FDA, it remains to be seen how industry will interpret the guidelines in the Draft Guidance. Further, FDA and MDIC have acknowledged that this is an evolving process as industry, academia, and FDA learn more about the collection and use of patient preference information. The potential for additional costs for sponsors to account for this learning curve or trial and error approach may need to be considered during the device development process. 

CONCLUSION

Given the recent developments in this area, including the Draft Guidance, sponsors should follow FDA’s suggestion to have early interactions with the relevant review division if the sponsor is considering collecting patient preference information for premarket review. FDA suggested that patient preference information may be submitted by sponsors as part of their premarket submissions, or through the pilot program, Medical Device Development Tool (MDDT) qualification process (per FDA’s draft guidance Medical Device Development Tools (November 14, 2013)). In addition, sponsors may wish to engage in pre-submission discussions with FDA early in the process of study design to gain FDA feedback and agreement (see Hogan Lovells July 26, 2012, Medical Device Alert regarding the Pre-Submission Program).

In sum, the Draft Guidance provides more information regarding how to collect patient preference information, how to incorporate such data in premarket device submissions, and how FDA will review that information. The Draft Guidance is in line with CDRH’s continued and increasing efforts to formally leverage patient perspectives and input in the Agency’s benefit-risk regulatory determinations, with the potential to use the data as valid scientific evidence to support device approval.

Although you can comment on any guidance at any time (see 21 CFR 10.115(g)(5)), to ensure that the Agency considers your comment on this Draft Guidance before it begins work on the final version of the guidance, electronic or written comments on the Draft Guidance should be submitted to Docket No. FDA-2015-D-1580 by August 17, 2015.