FDA Medical Device Reviews: Evaluation is Needed to Assure Requests for Additional Information Follow a Least Burdensome Approach

Determining that a new medical device is safe and effective is a substantial investment of time and resources for the sponsor and FDA, the agency that regulates medical devices. FDA relies on the device sponsor to provide supporting data at the time of its original submission, and the agency can request additional information during the review. The Federal Food, Drug, and Cosmetic Act, as amended, requires that when FDA requests additional information from sponsors, the agency consider the least burdensome means of evaluating a medical device.

GAO was asked to provide information on FDA's implementation of the least burdensome requirements in its medical device review process. This report (1) describes FDA's requests for additional information and sponsor disagreements, (2) describes its least burdensome training efforts, and (3) describes FDA actions to improve its requests for additional information and examines the extent to which it has evaluated its implementation of the least burdensome requirements. GAO reviewed FDA documents and guidance and interviewed agency officials. GAO also interviewed officials from four relevant medical device manufacturing associations.

Since 1997, the Food and Drug Administration (FDA) has been required to consider the least burdensome means of evaluating certain types of medical devices for marketing, including when requesting that sponsors—generally manufacturers—seeking to market their medical devices provide information in addition to what was provided in their submissions. GAO found that, from 2001 through 2016, FDA issued letters asking sponsors to provide such information for a majority of the more than 62,000 medical device submissions that it reviewed. Sponsors may formally disagree with the request on the grounds that it is not the least burdensome method needed for FDA to review the submission. For example, sponsors appealed FDA decisions internally to agency management 63 times from 2013 through 2016, and of these, FDA identified 33 such appeals in which the sponsor raised an issue related to least burdensome requirements. FDA agreed or partially agreed with the sponsors in 11 of these appeals. Medical device industry representatives noted that these appeals may not fully represent the number of such disagreements, because applicants are generally concerned that an appeal would damage their relationship with FDA and potentially negatively affect future device applications.

FDA provided staff training that was specifically dedicated to addressing the least burdensome requirements from 1997 through 1999. Since 1999, FDA has not offered a course dedicated to the least burdensome requirements, but has incorporated related concepts into other training programs, such as in a training mandatory for most new reviewers. In response to the 21st Century Cures Act, enacted in 2016, FDA is providing new least burdensome training to all relevant employees, and said that 80 percent had received the training as of October 2, 2017. Although FDA did not specifically evaluate the effectiveness of past training on least burdensome requirements, it is implementing an evaluation of all device-related training, including the new least burdensome training. It also plans to complete a required audit of training on least burdensome requirements by June 2018.

FDA has not specifically evaluated implementation of the least burdensome requirements. However, in response to broader evaluations, such as an independent assessment of its medical device review process, the agency is in the early stages of developing processes that may improve its requests for additional information. For example, FDA plans to conduct an audit of letters requesting additional information. FDA is developing the audit's methodology and expects it will assess whether the agency's process was followed. However, due to their early stage, the extent to which these efforts will allow FDA to assess implementation of the least burdensome requirements is unclear. In 2002, FDA stated that it planned to periodically assess the implementation of the least burdensome principles, and federal internal control standards identify the importance of performance metrics for such assessments. However, the agency has yet to develop performance metrics to do so. Until such measures are developed and used, FDA will not be able to evaluate whether it effectively and consistently applies a least burdensome approach in its medical device reviews.

GAO is making one recommendation that FDA develop and use performance metrics to evaluate the implementation of the least burdensome requirements. The Department of Health and Human Services agreed with GAO's recommendation.

The Food and Drug Administration (FDA), within the Department of  Health and Human Services (HHS), is responsible for ensuring that  medical devices sold in the United States provide reasonable assurance  of safety and effectiveness and do not pose a threat to public health.  Making this determination represents a substantial investment of time and  resources for both FDA and the device sponsor, generally the  manufacturer. For example, in 2014, FDA reviewed about 4,100  submissions from sponsors seeking to market their medical devices, and  each review ranged from an average of 125 days for lower-risk devices to  an average of 330 days for higher-risk devices. In making its  assessment, FDA relies on the sponsor to provide supporting data at the  time of its initial premarket submission and may thereafter request  additional data in the course of the review to obtain sufficient evidence  supporting the safety and effectiveness of the medical device. However,  any request for additional information has the potential to impose undue  burden on the sponsor and delay the review of the device, and sponsors  may opt to formally disagree with the necessity of the requested  information.

Given the resource investment involved in getting a medical device to  market, as well as the public health need, efforts have been made to  streamline the decision-making process without compromising scientific  integrity or FDA’s ability to protect the public health. For example,  Congress has already taken several steps to reduce unnecessary  burdens associated with the medical device review process. For certain  types of premarket submissions, federal law requires FDA to utilize the  “least burdensome” means possible in certain elements of the review  processes of medical devices. FDA has laid out broad principles in  guidance interpreting how those statutory provisions apply throughout its  reviews. In 2016, Congress required FDA to provide training for  appropriate staff on the meaning and implementation of the statutory least  burdensome requirements and conduct periodic assessments of  implementation to ensure that the least burdensome requirements are  fully and consistently applied.

You asked us to provide information on FDA’s implementation of the least  burdensome requirements, as well as any training FDA has done to  ensure staff are aware of the statutory requirements. This report  1.  describes FDA requests for additional information to support medical  device reviews and how least burdensome requirements were related  to sponsor disagreements about these requests,  2.  describes FDA efforts to ensure that its employees are trained on the  least burdensome requirements, and  3.  describes the steps FDA has taken to improve its requests for  additional information and examines the extent to which it has  evaluated its implementation of the least burdensome requirements.

To describe FDA requests for additional information to support medical  device reviews and how least burdensome requirements were related to  sponsor disagreements about these requests, we analyzed agency  documents, such as FDA’s guidance for industry and staff on the least  burdensome provisions and FDA’s annual performance reports. For fiscal  year 2001 through fiscal year 2016, the years for which FDA had reliable  data, we analyzed counts of medical device submissions received and  reviewed by FDA, as well as FDA’s requests for additional information  from medical device sponsors. We also reviewed internal appeals and  disputes of FDA decisions submitted by sponsors that FDA identified as  being related to the least burdensome requirements. Information on  internal appeals was limited to the period from May 2013 through fiscal  year 2016. To assess the reliability of data FDA provided, we interviewed  knowledgeable agency officials, conducted quality checks to identify any  obvious errors, and compared the detailed data FDA provided to us with  summary data that FDA had publicly reported on its website. We  determined these data were sufficiently reliable for the purposes of our  reporting objective. We also reviewed a non-generalizable sample of  requests for additional information FDA issued to sponsors during the  medical device review process. We interviewed FDA officials from the  Center for Devices and Radiological Health (CDRH) responsible for  reviewing medical devices. We also interviewed representatives of the  medical device industry to obtain the industry’s perspectives on how the  least burdensome provisions have been involved in FDA’s requests for  additional information.

To describe FDA efforts to ensure that its employees are trained on the  least burdensome requirements, we asked FDA to identify any training  activities for medical device review staff that related to the least  burdensome requirements since they were first established with the  enactment of the Food and Drug Administration Modernization Act of  1997 (FDAMA). For certain of those activities, we examined the specific  course materials so we could further illustrate how these materials  referred to the least burdensome requirements. We also reviewed  documentation describing FDA evaluations of this training, as well as  planned evaluations. We interviewed FDA officials about how training on  the least burdensome requirements had changed and about the planned  changes to least burdensome training and training evaluations.

To describe the steps FDA has taken to improve its requests for  additional information and examine the extent to which it has evaluated its  implementation of the least burdensome requirements, we reviewed  relevant statutes and guidance that set out relevant requirements for both  reviewers and sponsors outlining FDA’s implementation of the least  burdensome requirements and its plans for evaluation of that  implementation. We also reviewed documentation describing, and spoke  with relevant FDA officials about, performance metrics that the agency  uses to monitor its implementation of the least burdensome requirements  and evaluations the agency had conducted or planned to conduct. We  compared the extent to which FDA has evaluated its implementation of  the least burdensome requirements with federal standards for internal  control.

We conducted this performance audit from November 2016 to December  2017 in accordance with generally accepted government auditing  standards. Those standards require that we plan and perform the audit to  obtain sufficient, appropriate evidence to provide a reasonable basis for  our findings and conclusions based on our audit objectives. We believe  that the evidence obtained provides a reasonable basis for our findings  and conclusions based on our audit objectives.

FDA classifies each medical device type intended for human use into one  of three classes based on the level of risk it poses to the patient or the  user and the controls necessary to reasonably ensure its safety and  effectiveness. Examples of types of devices in each class include the  following:

Class I: tongue depressors, elastic bandages, reading glasses, and

Class II: electrocardiographs, powered bone drills, and mercury

Class III: pacemakers and replacement heart valves.

Before medical devices may be legally marketed in the United States,  they are generally subject to one of two types of FDA premarket review  processes.

Premarket approval (PMA) process: Class III device types are  typically required to obtain FDA approval through the PMA process.  Under this process, the medical device sponsor must submit an  application that includes—among other things—full reports of  investigations, typically including clinical data, providing reasonable  assurance that the new device is safe and effective. The PMA  process is the most stringent type of premarket review. A successful  application results in FDA’s approval to market the device. From 2001  through 2016, medical device sponsors submitted 651 PMA  applications, and FDA approved for marketing 506 of those  submissions. (See fig. 1.)

Premarket notification, or 510(k), process: Most medical devices  requiring premarket review are subject to FDA’s premarket notification  or 510(k) process. This includes class I and II device types that are  not specifically exempted from the 510(k) notification requirement.  Under this process, the medical device sponsor must notify FDA at  least 90 days before it intends to market a new device and  demonstrate to FDA that the new device is substantially equivalent to  a predicate device, and therefore does not require a PMA. For most  510(k) notifications, clinical data are not required and substantial  equivalence will normally be determined based on comparative  descriptions of intended device uses and technological  characteristics, and may include performance data. A successful  510(k) submission results in FDA’s clearance to market the device.  From 2001 through 2016, medical device sponsors submitted 61,439  premarket notifications and FDA cleared 51,028 devices for market.  (See fig. 2.)

During premarket review under both the PMA and 510(k) processes, FDA  and the medical device sponsor may engage in an interactive process. To  start, there may be a pre-submission meeting between FDA and the  sponsor, during which the parties discuss the upcoming review and try to  resolve potential obstacles for approval or clearance. Then, FDA receives  the premarket submission, makes a determination to accept or not accept  the submission, and assigns a reviewer. In making its assessment  whether to approve, or clear, a submission, FDA relies on the sponsor to  provide supporting data as part of the submission. However, the agency  can request additional information in the course of the review in order to  make a determination of reasonable assurance of safety and  effectiveness, or of substantial equivalence. This additional information  can be obtained through informal interactions, such as a phone call or  email. Alternatively, for more significant issues, FDA may make a more  formal request for additional information, known as a deficiency letter in  the case of a PMA application and additional information (AI) letter for a  510(k) notification. FDA will issue such requests if the submission lacks  significant information necessary for FDA to complete its review, and the  agency will request the sponsor amend the submission to provide the  necessary information regarding the device.

If a sponsor disagrees with an FDA regulatory decision concerning a  medical device submission, including a CDRH employee’s decision to  request additional information or a significant decision regarding approval  or clearance of a medical device, it can take multiple actions.  Specifically, a sponsor can, among other things, (1) contact the CDRH  Ombudsman for assistance, (2) file an internal appeal of an FDA  decision, or (3) request that the disagreement be resolved through  CDRH’s Medical Device Dispute Resolution Panel, as described below.

Ombudsman: According to FDA’s guidance, prior to the agency  reaching a regulatory decision, the most effective means of resolving  a dispute between CDRH and an external stakeholder is through  discussion and agreement. The CDRH Ombudsman is available to  assist in clarifying issues, mediate meetings and teleconferences, and  conduct discussions with the parties in an effort to resolve  disagreements short of a formal review or internal appeal.

Internal Appeal: Once FDA makes a regulatory decision, a sponsor  can request a supervisory review of that decision, which we refer to as  an internal appeal. For this process, the supervisor of an FDA  employee will, at the request of a medical device sponsor, review a  decision or action of the employee and issue a decision. The decision  rendered by the supervisor, acting as the review authority, customarily  takes one of the following forms: overturning the decision of the  employee; upholding the employee decision; or, in some  circumstances, referring the matter back to the employee for  reconsideration under defined conditions.

Medical Device Dispute Resolution Panel: If the dispute remains  unresolved, the sponsor may request that FDA convene the Medical  Device Dispute Resolution Panel. The panel is intended to provide a  means for independent review of a scientific controversy or dispute  between a sponsor and FDA, and make a recommendation to the  Center director. According to FDA’s guidance, the panel is primarily  intended to address scientific controversies rather than other issues  such as regulatory, legal, or statutory authority disputes.

As part of its commitments associated with the Medical Device User Fee  Amendments of 2012 (MDUFA III), FDA agreed to participate in an  independent, comprehensive assessment of the medical device  submission review process. Acting on recommendations from the  contractor that conducted the assessment, FDA established working  groups for each submission type, including PMAs and 510(k)s, which  studied existing review processes and made recommendations. In  August 2017, the Medical Device User Fee Amendments of 2017  (MDUFA IV) reauthorized FDA’s medical device user fee program, and  FDA committed to another independent assessment. FDA has  committed to hiring a contractor to conduct this assessment by the end of  December 2017 with a second phase to begin in 2020.

In 1997, FDAMA added a requirement that the agency use the least  burdensome approach during certain parts of PMA and 510(k) reviews.  These requirements were intended to reduce unnecessary burdens  associated with the premarket approval and clearance processes;  however, they did not lower the statutory criteria for demonstrating a  reasonable assurance of safety and effectiveness or substantial  equivalence. While the language in FDAMA differs slightly for the PMA  and 510(k) processes, in both instances FDA was directed to consider the  “least burdensome” means of requesting information needed for its  review. Specifically, FDAMA requires that when the agency specifies data  that must be submitted as part of a PMA application, the agency must  consider the least burdensome appropriate means of evaluating device  effectiveness that would have a reasonable likelihood of resulting in  approval. The agency must similarly consider the least burdensome  appropriate means of demonstrating substantial equivalence when  requesting information under the 510(k) notification process. In both  cases, FDA is statutorily required to request only information that is  necessary to support the determination that there is reasonable  assurance of effectiveness or substantial equivalence, respectively.

Subsequent laws have clarified the least burdensome requirements. In  2012, the Food and Drug Administration Safety and Innovation Act clarified that the term “necessary” means the minimum required  information that would support either a determination that a PMA  application provides reasonable assurance of the effectiveness of the  device or a determination, for a 510(k) notification, of substantial  equivalence between a new device and a predicate device. In 2016, the  21st Century Cures Act added a provision applying the least burdensome  concept to FDA’s requests for additional information in the PMA  process. The law also applied the least burdensome concept to  significant decisions, such as denials of PMA applications, requiring such  decisions to include a brief statement regarding how least burdensome  requirements were considered and applied. Additionally, the law  mandated each FDA employee involved in premarket submission  reviews, including supervisors, to receive training on the least  burdensome provisions, and required the agency to conduct an audit of  the training, among other things, no later than June 2018.

Although FDA officials have noted that the least burdensome principles  are broad and could apply to all activities within the PMA and 510(k)  premarket review process, they noted that the requests for additional  information represent a key juncture for the application of least  burdensome requirements. According to agency officials and industry  representatives, the requests for additional information—deficiency letters  in the case of PMAs and AI letters for its 510(k) reviews—are when FDA  and the sponsor could disagree on whether the requested information is  necessary for the agency to reach a final decision on the medical device  under review.

FDA Implementation of the Least Burdensome Requirements

Following the enactment of FDAMA in 1997, FDA went through a process  in collaboration with the medical device industry to define the least  burdensome concept and develop an approach to implement the  provisions. Based on this, FDA released multiple guidance documents  related to least burdensome requirements from 2000 through 2002.

In November 2000 guidance, FDA outlined a four-part approach— referred to as “four-part-harmony” by FDA staff—for communicating  deficiencies to medical device sponsors in accordance with the least  burdensome requirements. The guidance helps reviewers describe  deficiencies identified in submissions in ways that are direct, concise,  and complete, thus ensuring a more effective use of reviewers’ and  sponsors’ time, effort, and resources. It also provides a suggested  format for sponsors to respond to FDA. FDA updated this guidance in  September 2017.

In 2002 guidance, FDA described its principles for implementing the  least burdensome requirements and its activities to assess  implementation. The guidance outlines FDA’s interpretation of the  least burdensome concept as described in FDAMA, and explains its  application to activities associated with PMA and 510(k) reviews. The  guidance also states that FDA was in the process of developing tools  to be used by both agency staff and its stakeholders to periodically  assess the implementation of the least burdensome principles. It  noted some measurement tools had already been developed and that  additional tools were also needed to assess the impact of the least  burdensome approach on expediting the development of new medical  technologies.

In addition, FDA has included language about those requirements in other  guidance documents. For example, in 2014, FDA issued guidance on the  510(k) program that describes how the least burdensome principles may  affect the type of information necessary to demonstrate substantial  equivalence at different decision points in the review of a 510(k).

FDA Frequently Requested Additional Information to Support Medical Device Reviews, and Sponsor Disagreements Often Related to Least Burdensome Requirements

FDA Issued Deficiency and Additional Information Letters for a Significant Proportion of PMAs and 510(k)s

FDA requested sponsors provide additional information for a majority of  the PMAs and 510(k)s it reviewed. For the period 2001 through 2016,  FDA issued a large number of deficiency and AI letters relative to the  number of submissions, although there was variation annually. For  PMAs, the number of deficiency letters as a percentage of new PMA  applications submitted ranged from about 54 percent to 113 percent  annually, or 82 percent on average, from 2001 through 2016. For the  years 2006 through 2010, this percentage, as well as the total number of  letters was higher, and FDA issued more deficiency letters than there  were PMA applications submitted. Similarly, AI letters as a percentage of  total 510(k) notifications received ranged from about 58 percent to more than 174 percent annually, or about 106 percent on average, from 2001  through 2016. While the number of 510(k) notifications remained similar  across the time period we examined, from 2009 through 2012, the  number of AI letters issued each year was, on average, nearly double the  number in other years. During this period, FDA issued more AI letters  than there were 510(k) notifications submitted. Since 2014, these  percentages have been lower for both PMAs and 510(k)s.

FDA officials acknowledged the historical increase in the number of  deficiency and AI letters and noted the more recent decrease. The  officials attributed this decrease to a number of changes the agency  agreed to in MDUFA III. For example, FDA implemented a policy to  review submissions for administrative completeness prior to accepting the  submission. They said this allowed the agency to limit deficiency and AI  letters to issues related to the quality of the data provided and the studies  conducted in support of the submission rather than to administrative  issues. Also as a result of MDUFA III, the agency implemented an  interactive review process to increase informal interaction between FDA  and applicants and to minimize the number of review questions  communicated through deficiency and AI letters. (See table 1.)

We identified changes in how the deficiency letters and AI letters  referenced the least burdensome requirements. Based on our sample of  73 letters from 1997 through 2016, FDA included an explicit  acknowledgment of the least burdensome requirements in the letters  issued from 2001 through 2009. However, based on our review, this  practice ended in 2010, and later letters did not include this standard  language. Representatives from the medical device industry told us that  including the least burdensome language in the deficiency letters was a  good practice because it raised awareness of the least burdensome  principles. In September 2017, FDA released updated deficiencies  guidance that, according to FDA officials, instructs staff how to better  articulate the reason that the information is needed in accordance with  the least burdensome requirements. This guidance does not set forth  boilerplate language regarding the least burdensome requirements for  use in deficiency letters, but does include examples of well-constructed  deficiencies, definitions for major and minor deficiencies, and a statement  that FDA will attempt to resolve minor deficiencies interactively.

Though Data are Limited, Least Burdensome Requirements were a Significant Contributing Factor in Disagreements Raised by Medical Device Sponsors

The least burdensome requirements were often a significant contributing  factor in disagreements raised by medical device sponsors, according to  FDA officials and available FDA data. According to FDA, the most  effective means of resolving disagreements is through discussion and  mediation, and to that end, the Ombudsman’s office is routinely involved  in discussions between firms and medical device reviewers during the  review process. For example, in 2016, the CDRH Ombudsman was  involved with PMA and 510(k) medical device reviews 360 times out of  3,444 submissions. Although the agency was unable to identify which of  these interactions were related to least burdensome requirements,  agency officials told us that a substantial number likely resulted from a  difference of opinion between the applicant and FDA on the appropriate  level of scientific evidence, a portion of which likely have a least  burdensome component.

The least burdensome provisions were also frequently related to issues  that applicants raised during internal agency appeals of FDA decisions of  PMA and 510(k) reviews. Although FDA did not have readily available  data on appeals that occurred prior to 2013, the agency was able to  provide information about the 63 appeals of significant decisions that  occurred from 2013 through 2016. Of these 63 appeals, FDA identified  33 appeals—2 related to PMAs and 31 related to 510(k)s—in which the  issue identified by the sponsor was related to least burdensome  principles. According to medical device industry representatives,  sponsors may not always pursue an appeal, so the number of official  appeals may not represent the extent of least burdensome-related issues  that sponsors experience. They said the sponsor may determine it is best  to avoid conflict that could complicate future device submissions and  comply with the request for additional information, even if it disagrees.

Of these 33 appeals, FDA agreed, or partially agreed with the sponsor for  11 appeals, which resulted in FDA overturning the decision or reopening  the file and continuing the review. For the remaining 22 appeals, the  agency upheld the initial reviewer decision. The following presents  examples of appeals where the issue identified by the sponsor was  related to the least burdensome requirements.

In one appeal related to a 510(k) review, the sponsor objected to the  reviewer’s finding that the device was not substantially equivalent to a  device already on the market. The sponsor stated that it had provided  sufficient data for a substantial equivalence determination, and the  FDA reviewer’s request for additional risk mitigation measures and  supplemental testing was unwarranted and inappropriate. The review  authority determined that, while the information provided in the 510(k)  premarket submission was not sufficient to establish substantial  equivalence, some of FDA’s requests were unwarranted. As a result  of the appeal, FDA reopened the file and provided the sponsor an  opportunity to respond to a new set of requests for additional  information.

In an appeal related to a PMA review, the sponsor contended that  FDA’s not approvable decision reflected an inconsistent and  erroneous interpretation of the clinical data supporting the safety and  effectiveness of the subject device, and that the data it had provided  was sufficient for FDA to reach an approved decision. The sponsor  further contended that the review staff failed to utilize the principles  outlined in FDA guidance. The review authority upheld FDA’s initial  decision and determined there was not sufficient valid scientific  evidence to demonstrate a reasonable assurance that the subject  device was safe and effective under the proposed conditions of use.

The Medical Device Dispute Resolution Panel, which provides another  avenue to resolve disagreements between sponsors and the agency, has  also addressed issues related to the least burdensome requirements.  Since the panel was created following FDAMA in 1997, medical device  sponsors have requested that FDA resolve three disagreements through  this avenue, each related to PMAs. Although not tracked by FDA, at our  request, officials reviewed the records and found that one of the three  disputes was related to the least burdensome requirements. Specifically,  for a September 2001 dispute, FDA officials said the sponsor requested  the panel after FDA initially found that the data from the clinical study  submitted by the sponsor did not sufficiently support effectiveness. After  reviewing evidence from the applicant and from FDA, the dispute  resolution panel determined that the sponsor had provided sufficient  evidence to prove effectiveness, and the device was ultimately approved.

FDA Offered Some Training on the Least Burdensome Requirements, and Evaluates its Training for Effectiveness

FDA Offered Some Early Least Burdensome Training at Limited Times, and Has Incorporated Related Information in Broader Training

FDA officials indicated that training specific to the least burdensome  requirements was held in the years following the enactment of FDAMA in  1997. FDA was unable to provide records of that training, including its  content. However, officials told us that the training was specific to the  least burdensome requirements and offered from 1997 through 1999.  FDA officials said the agency offered other presentations in subsequent  years that they said covered similar least burdensome topics. For  example, the agency provided slides from a presentation created in 2000  that provided an overview of FDA’s implementation of the requirements.

Although FDA officials told us this least burdensome specific training was  not offered after 1999, they identified various other trainings that they said  incorporated the least burdensome concept. For example, a 2005  presentation on clinical trial design has multiple slides on least  burdensome requirements, and specifically states that a course objective  is to “understand how least burdensome principles apply.” Least  burdensome requirements are also mentioned in other training materials  where they may not be the focus—for example one slide of a presentation  on biomarkers included a mention of least burdensome requirements.  Officials also identified the training program for new reviewers that FDA  implemented in 2011 as a source of training on least burdensome  principles. Specifically, the Reviewer Certification Program is a training  curriculum that FDA has required most new device reviewers to complete  since 2011. The training curriculum covers a wide variety of courses on  topics related to a reviewer’s responsibilities. While none of these  courses is specific to the least burdensome requirements, there are  courses covering related topics. For example, there is one course on  technical writing that includes FDA’s guidance on developing deficiencies  with least burdensome principles. Five other courses on different topics  mention either the least burdensome requirements or related principles,  such as a course on FDA’s legislative history that included a slide  identifying the least burdensome statutory provisions as an element of  FDAMA, though the slide did not explain the least burdensome  requirements or provide additional context. Of the 490 staff assigned to  review PMAs and 510(k)s, FDA indicated that as of the end of calendar  year 2016, 335 had completed the Reviewer Certification Program, 150  started working on premarket submissions prior to the beginning of 2011,  and the remaining 5 individuals did not complete the training for varying  reasons.

In response to the 21st Century Cures Act, enacted in December 2016,  FDA is providing mandatory online training specific to the least  burdensome requirements. FDA indicated that the training focuses on key  behaviors that reflect the least burdensome approaches as documented  in updated guidance that FDA issued in September 2017. FDA officials  told us that, as of October 31, 2017, 91 percent of CDRH staff had  received the new least burdensome specific training. In addition to the  online training, FDA plans other activities, such as follow-up office-level  briefings to address questions or concerns and an introductory podcast  from the CDRH director. In addition to providing this training to current  employees, FDA plans to incorporate least burdensome requirement  training into new employee orientation and the Reviewer Certification  Program, and plans to include ongoing support and promotion of least  burdensome principles through a center working group on the least  burdensome requirements. In addition to course-based training, FDA  officials told us that least burdensome concepts are conveyed to  reviewers through mentoring. Officials explained that much of the training  on the least burdensome requirements occurs through mentoring and  conversations with supervisors, and that those encounters are not  documented.

FDA Is Implementing Evaluations of All Training Courses for Medical Device Review Staff, including Courses that Address the Least Burdensome Requirements

While FDA has not had processes in place to evaluate its medical device  training, it is implementing such processes for all training, including  courses related to the least burdensome requirements. In its June 2014  report, the contractor performing the independent evaluation noted that  CDRH did not have mechanisms in place to measure the quality and  effectiveness of its training programs. The report noted that FDA should  identify metrics and incorporate methods to better assess review process  training satisfaction, learning, and staff behavior changes. FDA officials  explained that while they had customer reaction evaluations for trainings  for at least 24 years, they started evaluating training participant learning  with the Reviewer Certification Program starting in 2010.

FDA is in the process of implementing a training evaluation model, which  includes various levels of evaluation, from assessing participant response  to the training to evaluating its impact on the agency. As of 2017, FDA  reported it was evaluating training programs to determine participant  learning and preparing to evaluate whether that learning changed  participant behavior. Officials told us they anticipate beginning to conduct  evaluations that assess agency impact in fiscal year 2018, and they plan  to have the model completely implemented for all trainings by fiscal year  2020. FDA currently evaluates its Reviewer Certification Program to  determine participant learning, and though the least burdensome  requirements are not specifically addressed in the Reviewer Certification  Program evaluation materials FDA provided to us, they did include  questions on topics related to least burdensome requirements.

In addition to its current training evaluation plan, FDA is also required by  the 21st Century Cures Act to conduct an audit of the training and its  effectiveness in implementing the least burdensome requirements.  Specifically, the training audit is to be conducted by the ombudsman  responsible for premarket reviews, identified by FDA as the CDRH  Ombudsman. According to a draft plan, FDA plans to conduct training  evaluations, a process review of 510(k) and PMA documentation to  assess reviewer compliance with FDA procedures, and seek feedback  from industry on its experience with the premarket review process and  how the least burdensome requirements are applied. Officials indicated  that criteria are still under development and that they hoped to have them  further developed in the first quarter of 2018, with the authorizing  legislation requiring completion of the audit by June 2018, 18 months  after enactment of the law.

FDA is Taking Steps that May Improve Its Requests for Additional Information Overall, but Has Not Fully Evaluated Its Implementation of the Least Burdensome Requirements

FDA Is Implementing Processes to Improve the Consistency and Clarity of Its Requests for Additional Information during Medical Device Reviews

Some stakeholders and others have raised concerns about the  consistency and clarity of FDA’s requests for additional information during  medical device reviews. For the past 17 years, FDA has required  reviewers to only request information that is necessary to make a PMA  determination of “reasonable assurance of safety and effectiveness” or a  510(k) determination of “substantial equivalence” in their review of a  submission. Representatives of one of the organizations representing  the medical device industry noted the high percentages of medical device  submissions that involve a letter, and some of their member companies  have said that FDA reviewers may request additional information as a  result of intellectual curiosity rather than a “need to know.” In addition, the  independent assessment’s 2014 report, funded by FDA as part of  MDUFA III, found inconsistent decision-making among FDA review staff  throughout various stages of the review process, including additional  information requests. While the 2014 report did not address least  burdensome requirements explicitly, it examined related processes. For  example, according to the report, there was inconsistent decision-making  among FDA review staff throughout various stages of the review process,  including a lack of clarity regarding FDA reviewer thresholds for triggering  deficiency letters. The report recommended that FDA develop criteria and  establish mechanisms to improve consistency in decision-making  throughout the review process.

To address problems identified during the independent assessment, FDA  is implementing several initiatives to improve center processes. FDA  officials told us that, in anticipation of MDUFA IV, they recognized a need  for a dedicated quality management infrastructure. In 2014, FDA  established a Quality Management Unit to improve center processes,  which they said would include those related to the least burdensome  requirements. The unit completed a framework that outlined its vision and  mission and established organizational objectives, such as developing a  document control system, providing training, and conducting quality  assessments, audits, and management reviews.

In addition, FDA officials told us that starting in October 2017, FDA  planned to fulfill its MDUFA IV commitments to improve the clarity and  consistency of its deficiency letters and AI letters after releasing updated  guidance.

In September 2017, FDA published guidance reflecting the  commitments under MDUFA IV that all deficiency letters and AI letters  include a statement indicating the specific basis for any cited  deficiencies. According to FDA officials, this new approach will help  ensure that the letters more consistently ground requests for  information in the specific reason that FDA is requesting the  information from the sponsor. For example, FDA may cite a law, final  rule, or specific scientific issue as the basis for its request, rather than  providing a more general statement of the request’s relevance.  According to industry representatives, in the past, FDA reviewers  have, at times, asked for additional information without including  justification, and may have requested additional information as a  result of intellectual curiosity rather than a “need to know.” The  representatives stated that this new policy may better ensure the  reviewers apply the least burdensome approach to their review.

The updated guidance also explains that all deficiency letters and AI  letters will undergo supervisory review prior to issuance to ensure that  the information requested is relevant to a marketing authorization  decision, all four elements of the deficiency are included, deficiencies  are prioritized from most to least significant, and each deficiency is  appropriate to include in light of the totality of all deficiencies. Officials  told us that while supervisory concurrence was previously needed,  under the new guidance, supervisors are now expected to review for  certain criteria. For example, in the past, supervisors may have  considered whether four-part harmony was addressed in each  deficiency letter, but under the updated guidance this is now an  expected practice. Officials said this will increase the extent to which  deficiency letters are consistently constructed.

In the MDUFA IV commitment letter, FDA agreed to base all  deficiency letters and AI letters on a complete review of the  submission and include all deficiencies. Therefore, FDA officials told  us that any deficiencies identified following that letter would generally  be limited to issues raised as a result of new information. For  example, if FDA asked for information on bio-compatibility testing,  FDA will first review that information, and based on that review may  ask for new information. In that instance, the information responding  to the initial deficiency is new information. FDA officials said that past  letters should also have included all deficiencies, but this may have  been done inconsistently.

To further standardize its process for reviewing medical device  submissions and developing requests for additional information, FDA is  developing and implementing smart templates. FDA officials told us that  these templates guide device reviewers through a standardized process  for each submission. For example, they help reviewers identify the types  of information necessary and include prewritten deficiency letters that  have been approved by internal experts. FDA has had a smart template  in place for the 510(k) process since 2013, according to FDA reports.  FDA indicated that the template is already required for certain offices and  divisions within CDRH, and plans for full adoption in the future. FDA  officials told us that the agency also developed templates for de novo  premarket submissions, which are currently available for voluntary use  and will likely be mandatory in fiscal year 2018. Officials told us they  plan to hire a person to develop a template to guide PMA reviews, which  will likely take most of 2018. They told us the use of the smart template  for PMAS will likely become mandatory for use by all reviewers in 2019.  In addition to improving the consistency of deficiency letters, FDA officials  said the information generated from the templates could be used to track  deficiencies and requests for additional information, as well as provide  information on the number and type of deficiencies in the letters. FDA  officials told us that the plans for database and back-end analytical  capabilities using information from the smart templates were less certain  and dependent on available resources, and they pointed out that the  information technology infrastructure can present unforeseen challenges.

FDA Has Not Developed Metrics to Evaluate Implementation of the Least Burdensome Requirements, and While a New Audit Process Could Aid Oversight, Its Scope Is Still Unclear

FDA has not established performance metrics that would allow it to  evaluate its implementation of the least burdensome provisions. FDA  officials told us that the agency does not track concerns related to the  least burdensome requirements, such as by examining dispute data to  identify those that may be related. According to FDA’s 2002 guidance, the  agency was in the process of developing tools to be used by both agency  staff and its stakeholders to periodically assess the implementation of the  least burdensome requirements. The FDA guidance identified a need  for additional tools to accurately assess the agency’s incorporation of the  least burdensome principles into its various regulatory activities and to  assess the impact of the least burdensome approach on expediting the  development of new medical technologies. Agency officials told us FDA  had not developed these tools, but was now in the process of making  other tools available. For example, they cited the development of the  smart templates that will guide reviewers as they evaluate medical device  submissions and generate deficiency letters. Officials noted that, given  the scientific nature of the inquiry, and because least burdensome is a  general principle, developing a metric specific to the least burdensome  requirements is a challenge. While this can be a challenge, FDA officials  have noted that they are attempting to identify surrogate measures that  can provide an indication that the reviewer considered the least  burdensome requirements when making a request. According to federal  standards for internal control, performance metrics are important for  management to have relevant, reliable, and timely information available  for management decision–making and external reporting purposes.  Without such a metric, FDA may be asking medical device sponsors to  provide information unnecessarily or in less efficient ways that are not in  compliance with the requirement to use the least burdensome approach  to medical device reviews.

FDA is in the process of developing an audit program that could provide it  with information on its implementation of the least burdensome  requirements. FDA has committed to conducting annual quality audits,  which will be led by CDRH’s Quality Management Unit. Accordingly, FDA  plans to identify, with industry input, areas to audit at least once per year.  Initially, the agency has agreed to complete an audit of deficiency letters  and pre-submissions by the end of fiscal year 2020. As of August 2017,  FDA was still planning the deficiency letters audit, and developing its  methodology and identifying audit outcomes. FDA officials told us the  agency plans to finalize a deficiency letters audit plan by the spring of  2018 and begin data collection by early summer of 2018. Officials  explained that the audit will focus on processes—for example, the audit  will not examine the scientific content of deficiency letters but will instead  focus on whether CDRH has followed existing policies and procedures  surrounding deficiency letters. In addition, the Quality Management Unit  was still in the process of hiring most of its staff. As of August 2017, FDA  officials told us the unit had 6 staff reporting to an Associate Director, and  CDRH plans to gradually hire 20 more staff by 2020, starting once  MDUFA IV funds are available beginning in October 2017.

In addition to these more specific efforts, FDA also plans to continue its  overall evaluation of the medical device review process. The 2016  independent assessment resulting from MDUFA III broadly evaluated  FDA’s device review process, and although it mentioned least  burdensome requirements only briefly, it addressed a number of related  elements, including the quality of the review process and staff training.  Under MDUFA IV, FDA committed to another independent assessment in  two phases: (1) an evaluation of FDA’s implementation of the corrective  action plan FDA developed in response to the MDUFA III assessment  and (2) an evaluation of FDA’s premarket device review program to  identify efficiencies that should be realized as a result of the process  improvements and investments under MDUFA III and IV, among other  things. As with the prior assessment, the new assessment will likely  examine processes related to the least burdensome requirements, though  the extent to which it will address the requirements is not yet known.  Agency officials told us that FDA has committed to hiring a contractor by  the end of December 2017.

FDA must balance the need to obtain sufficient data to determine the  safety and effectiveness of medical devices under review, with the  potential for undue burden and approval delays if unnecessary data is  requested. Assuring that the agency uses the least burdensome method  to complete its review helps to ensure it is able to make decisions about  medical device approval in a timely way. While FDA implemented  guidance and training related to the least burdensome requirements  following the passage of FDAMA in 1997, it has taken few steps to  develop performance metrics to evaluate the extent to which reviewers  are using a least burdensome approach when reviewing medical device  submissions. Recently, FDA implemented several changes that have the  potential to improve its oversight of the least burdensome requirements  and the clarity with which reviewers communicate the need for additional  information. While planned audits of FDA’s medical device review  process have the potential to provide the agency with evaluation tools  through which to assess performance, these audits are still early in their  development and the extent to which they will allow FDA to assess  implementation of the least burdensome requirements is unclear. A  complete and thorough assessment will be important for the agency to  assure itself and external stakeholders that its reviews adhere to the least  burdensome principles and requirements and thus are appropriately  balanced.

We are making the following recommendation to FDA:  The Commissioner of FDA should develop performance metrics and use  them to evaluate the implementation of the least burdensome  requirements, such as during its planned audits of medical device  deficiency letters. (Recommendation 1)

We provided a draft of this report to HHS. HHS concurred with our  recommendation and provided written comments, which are reprinted in  appendix I. In its written comments, HHS agreed that appropriate  implementation of the least burdensome requirements is essential to  FDA’s evaluation of its PMA and 510(k) medical device submissions, and  agreed that it is important for FDA to evaluate how successfully it is  implementing the requirements. HHS also reiterated FDA’s commitment  to the least burdensome principles and provided an overview of its related  efforts, several of which were noted in our draft report. HHS noted its  concern that our draft report did not sufficiently capture all of FDA’s  efforts. While HHS cited FDA’s efforts related to improving the science  underlying its regulatory decisions, which could reduce burden on medical  device sponsors, our review focused on the steps involved in FDA’s  review process. In this regard, HHS concurred with our recommendation  that it develop performance metrics and use them to evaluate the  implementation of the least burdensome requirements, such as during its  planned audits of medical device deficiency letters. In response to this  recommendation, HHS indicated that FDA intends to assess how it  follows least burdensome requirements as part of these audits. We  continue to encourage FDA to develop the evaluation tools necessary to  ensure it conducts a complete and thorough assessment of its  implementation of the least burdensome requirements. In addition to  these general comments, HHS provided technical comments, which we  incorporated as appropriate.

As agreed with your office, unless you publicly announce the contents of  this report earlier, we plan no further distribution until 30 days from the  report date. At that time, we will send copies of this report to the  Secretary of Health and Human Services and other interested parties. In  addition, the report will be available at no charge on the GAO website at  http://www.gao.gov.

If you or your staff have any questions about this report, please contact  me at (202) 512-7114 or crossem@gao.gov. Contact points for our  Offices of Congressional Relations and Public Affairs may be found on  the last page of this report. GAO staff who made major contributions to  this report are listed in appendix II.

Appendix I: Comments from the Department of Health and Human Services

In addition to the contact above, William Hadley (Assistant Director),  Matthew Byer (Analyst-in-Charge), Luke Baron, and William Garrard  made key contributions to this report. Also contributing were Sam  Amrhein and Jennifer Rudisill.

FDA regulates medical devices to ensure they are safe and effective, and relies on the organization sponsoring the device (usually the manufacturer) to provide the relevant information when the device is submitted for review. FDA is required to use a “least burdensome” approach in its review of medical devices, including when it requests additional information from sponsors.

We looked at FDA’s implementation of the least burdensome requirements, and found the agency hasn't developed performance metrics to evaluate them. We recommended that FDA develop metrics to evaluate whether it consistently applies a least burdensome approach in reviews.