- Entellus Medical
- Issuing Office:
- Center for Devices and Radiological Health
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10903 New Hampshire Avenue
Silver Spring, MD 20993
April 6, 2017
VIA UNITED PARCEL SERVICE
Robert S. White
President and Chief Executive Officer
Entellus Medical, Inc.
3600 Holly Lane N. Suite 40
Plymouth, MN 55447-1286
Dear Mr. White:
This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection conducted at Entellus Medical, Inc., from September 6, 2016, to September 27, 2016, byinvestigators from the FDA Minneapolis District Office. This inspection was conducted to determine whether activities and procedures as sponsor in the significant risk clinical study “Use of XprESS Multi-Sinus Dilation System and Path Assist Confirmation Tools in Pediatric Patients”, Investigational Device Exemption (IDE) G140080, complied with applicable federal regulations. The XprESS Multi-SinusDilation System and the Path Assist Confirmation Tools are devices as that term is defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 321(h), because they are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or to affect the structure or function of the body. This letter also requests prompt corrective action to address the violations citedand discusses your written response dated October 12, 2016 to the noted violations.
The inspection was conducted under a program designed to ensure that data and information contained in requests for IDEs, Premarket Approval (PMA) applications, and Premarket Notification (510(k)) submissions are scientifically valid and accurate. Another objective of the program is to ensure that human subjects are protected from undue hazard or risk during the course of scientific investigations.
Our review of the inspection report prepared by the district office revealed serious violations of Title 21, Code of Federal Regulations (CFR): Part 812 - Investigational Device Exemptions and Part 50 - Protection of Human Subjects, which concerns requirements prescribed under section 520(g) of the Act, 21 U.S.C. § 360j(g). At the close of the inspection, the FDA investigator presented an inspectional observation Form FDA 483 for your review and discussed the observations listed on the form with you. The deviations noted on the Form FDA 483, your written response, and our subsequent review of the inspection report, are discussed below:
1. Failure to secure compliance with investigators who are not complying with the signed agreement or investigational plan and the IRB approved protocol [21 CFR 812.46(a)]
As a sponsor, you are responsible for securing compliance with the signed agreement, investigational plan, FDA regulations, and the IRB’s conditions of approval (21 CFR 812.46(a)). Examples of this failure include but are not limited to the following:
At multiple clinical sites, Entellus Medical clinical personnel were present during procedures that included protocol deviations consisting of use of the device on the frontal and sphenoid sinuses of pediatric subjects under the age of 12. The FDA approved protocol and IRB approved informed consent states that only the maxillary sinuses should be treated for pediatric subjects under the age of 12. Yet, 18 out of 33 pediatric subjects received balloon sinuplasty treatment on the frontal and sphenoid sinuses.
One clinical investigator performed 11 planned protocol deviations, a second clinical investigator performed 6 planned protocol deviations, anda third clinical investigator performed 1 planned protocol deviation. Although your firm requested approval,FDA denied your firm’s request, during a telephone conference with ODE, to treat frontal and sphenoid sinuses in the 2-12 year old cohort on May 13, 2014, which was prior to treatment of the pediatric subjects. Also, FDA notified your firm on June 25, 2015 that data collected as a result of the deviations would not support a future marketing application in children 2-12 years old for treating sphenoid and frontal sinuses. We stated our concerns for higher risks of injury in children 2-12 years old due to absent or incomplete anatomical development.
However, your staff still did not secure investigators’ compliance and pediatric subjects continued to be treated off-protocol after receiving these communications. In addition, the examples below were not reported to FDA (see citation 2 for additional information). Examples include but are not limited to the following:
Subject Age (in years)
Right frontal and right sphenoid
Only reported right frontal
Right frontal added in surgery
Bilateral sphenoid added in surgery
Your lack of securing compliance led to the off-protocol treatment of the frontal and sphenoid sinuses in pediatric subjects under the age of 12. This off-protocol use could have led to serious medical complications in these children including Cerebrospinal Fluid leaks, intracranial complications, and meningitis.
FDA considers children a vulnerable population due to the increased potential for violations of human subject protections and heightened risk to subject safety. By failing to properly secure investigators’ compliance, you did not adequately protect the welfare, rights and safety of pediatric subjects.
2. Failure to obtain approval of a supplemental application and IRB approval prior to implementing a change to the investigational plan [21 CFR 812.35(a)].
A sponsor is required to obtain approval of a supplemental application and IRB approval prior to implementing a change to an investigational plan (21 CFR 812(a) (1)). You failed to obtain FDA approval for use of the XprESS Multi-SinusDilation System and the Path Assist Confirmation Tools in the frontal and sphenoid sinuses in subjects under the age of 12.
Your IDE application for the “Use of XprESS Multi-Sinus Dilation System and Path Assist Confirmation Tools in Pediatric Patients” was approved with conditions by the FDA on May 30, 2014 for the treatment of the maxillary sinuses in children 2 to 12 years of age. One of the conditions mentioned in this approval stated:
“We believe that this stratification is appropriate as long as the procedure for those subjects 12 years and under will be limited to maxillary sinus. The size and accessibility of frontal and sphenoid sinuses in pediatric subjects 12 years and under will likely pose higher risks of injury in this population. Please make this modification to your protocol.”
This approval was granted after ODE verbally denied a request from you to treat frontal and sphenoid sinuses in the 2-12 year old cohort, on May 13, 2014. After receiving the ODE approval you provided a response on June 19, 2014, stating:
“Per your request, we have modified the Investigational Plan Summary (page 5) and section 3.1 Study Population (page 9) as follows:
- Patients 2-12 years old will have treatment limited to the maxillary sinus(es) only
- Patients > 12 through 21 years old will have treatment of the maxillary, sphenoid, and/or frontal sinus (es) based on the treating study Investigator’s medical judgment and patient’s anatomy.”
You were informed on several documented occasions that the FDA had safety concerns and did not approve the use of the device for the treatment of the frontal and sphenoid sinuses on pediatric patients ages 2-12. It is documented that you were aware and encouraged clinical investigators to conduct “Planned Protocol Deviations”, on numerous occasions consisting of this population receiving treatment for the frontal and sphenoid sinuses. You purposefully performed the off-protocol treatment at three clinical sites. Monitoring reports also detailed use of the device as “Planned Protocol Deviations”.
To reiterate, there were 50 subjects enrolled in the study, of which, 33 subjects were under the age of 12. Of these 33 subjects, 18 received treatment for frontal and/or sphenoid sinuses between February 13, 2015 and June 30, 2015. IRB approval was not acquired prior to the implementation of a change to the investigational plan. You did not submit a supplemental application or obtain FDA and IRB approval for this change in the investigation plan.
3. Failure to promptly inform the reviewing IRB and the FDA of significant new information about an investigation [21 CFR 812.40].
As a sponsor, you are responsible for ensuring that any reviewing IRB and FDA are promptly informed of significant new information about an investigation (21 CFR 812.40). You failed to inform the FDA and IRB of the significant protocol deviations. Examples of the protocol deviations include but are not limited to the following:
Date of Treatment
Off-Protocol Sinuses Treated
Reported in Annual Report
Right & left Sphenoids
Bilateral frontal & left sphenoid
Right frontal and right sphenoid
Yes but only frontal was reported
Occurred after Annual Report submission
Bilateral sphenoid added in surgery
Occurred after Annual Report submission and after 6/25/2015 letter from FDA
Specifically, the protocol deviations discussed above occurred between February 13, 2015 and June 30, 2015. It was only on June 1, 2015, that your firm made FDA aware of these protocol deviations through submission of an Annual Report, dated May 29, 2015. Further, the protocol deviations were not reported to the IRB until after FDA’s inspection on September 21, 2016. The deviations are significant as they resulted in additional serious risks to the pediatric study population and should have been reported to the FDA and IRB promptly.
Your failure placed the study subjects at increased risk of harm. Without IRB knowledge of new and significant information concerning changes to the study protocol and FDA approval of the new and significant changes, the study lacked the necessary human subject protection measures and regulatory oversight to ensure that the additional risks from these protocol deviations were minimized and the rights and welfare of the study participants were protected.
4. Failure to have both IRB and FDA approval of an application or supplemental application before beginning an investigation or part of an investigation [21 CFR 812.42].
A sponsor shall not begin an investigation or part of an investigation until an IRB and FDA have both approved the application or supplemental application relating to the investigation or part of the investigation. You failed to submit a supplemental application prior to conducting a study on pediatric patients ages 2-12 for frontal and sphenoid sinuses. The FDA previously stated on several documented occasions that there were safety concerns to treat this population for the frontal and sphenoid sinuses.
Your failure to obtain both FDA and IRB approval placed the study subjects at increased risk of harm. Without these approvals, the study lacked the necessary human subject protection measures and regulatory oversight to ensure that the additional risks from these protocol deviations were minimized and the rights and welfare of the study participants were protected.
We have reviewed your response to the FDA Form 483, dated October 12, 2016, in which you provided corrective and preventative actions for the observations.
Your response acknowledged the following:
- 18 protocol deviations occurred during the study in which subjects were treated for sinuses other than maxillary sinuses in children under the age of 12;
- You did not consider that the protocol deviations should have been reported to the IRB and that the FDA had to approve changes to the protocol;
- You failed to recognize that the protocol deviations could impact subject safety; and
- You did not ensure strict compliance with the study protocol by the clinical investigators.
In your response, you also provided copies of letters notifying the applicable IRBs of the protocol deviations which occurred during the study. Your response states that you provided the parents/guardians of the subjects, who received off-protocol treatment, with the IRB approved informed consent and also a hospital consent which was not approved by the IRB. Finally, you stated that the parents/guardians were aware that the subject would receive treatment of the frontal and sphenoid sinuses.
After review of your October 12, 2016 response, we have determined that it is not adequate. You did not consider the safety concerns stated by the FDA and did not adhere to your statement in your June 19, 2014 response in which you stated that patients 2-12 years old will have treatment limited to the maxillary sinus (es) only. Two subjects, under the age of 12, were enrolled in the study and received treatment of the frontal and sphenoid sinuses after your receipt of the safety concerns from the FDA. Additionally, neither of the informed consents mentioned in your response contained the additional risks associated with the change in treatment resulting from the protocol deviations. The parents/guardians awareness and acceptance of the additional treatment should have been confirmed and documented in a signed consent form that included a description of risks such as Cerebrospinal Fluid leaks, intracranial complications, and meningitis.
Please provide an IRB approved letter notifying the parents/guardians of the subjects under the age of 12 who received treatment of the frontal and sphenoid sinuses, that subjects werenot treated according to the FDA approved protocol and the IRB approved informed consent form. The risks associated with the treatment of the frontal and sphenoid sinuses were not included in the IRB approved informed consent. The letter notifying the parents/guardians should include those risks.
The violations described above are not intended to be an all-inclusive list of problems that may exist with your clinical study. It is your responsibility as a study sponsor to ensure compliance with the Act and applicable regulations.
Within 15 working days of receiving this letter, please provide documentation of your efforts in developing and distributing the letter notifying the parents/guardians of the subjects under the age of 12 who received treatment of the frontal and sphenoid sinuses, that subjects werenot treated according to the FDA approved protocol and the IRB approved informed consent form, in the effort to correct the violations in this letter and to prevent the recurrence of similar violations in current or future studies for which you are the study sponsor. Any submitted corrective action plan should include projected completion dates for each action to be accomplished as well as a plan for monitoring the effectiveness of your corrective actions. Failure to respond to this letter and take appropriate corrective action could result in the FDA taking regulatory action without further notice to you.
Your response should reference “CTS # G140080/E004” and be sent to:
Attention: Sheena A. Green, MS
Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Bioresearch Monitoring
10903 New Hampshire Avenue
Building 66, Room 3520
Silver Spring, Maryland 20993-0002.
A copy of this letter has been sent to FDA’s Minneapolis District Office. Please send a copy of your response to that office.
The Division of Bioresearch Monitoring has developed introductory training modules in FDA-regulated device clinical research practices, which are available on the FDA website. The modules are for persons involved in FDA-regulated device clinical research activities. These modules are located at the following website address: http://www.fda.gov/Training/CDRHLearn/
Robin W. Newman, MSN EdD
Office of Compliance
Center for Devices and