WARNING LETTER

Steiner Laboratories MARCS-CMS 518625 — June 21, 2017

Delivery Method:: VIA UNITED PARCEL SERVICE

Recipient:: Recipient Name

Gregory G. Steiner, DDS; Recipient Title

Chief Executive Officer; Steiner Laboratories; 1051 Olsen St. Ste. 3611
Henderson, NV 89011
United States

Issuing Office:: Center for Devices and Radiological Health; 10903 New Hampshire Ave
Silver Spring, MD 20993
United States

Dear Dr. Steiner:

This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection conducted at Steiner Biotechnology from December 12, 2016, to December 16, 2016, by an investigator from the FDA San Francisco District Office. This inspection was conducted to determine whether your activities and procedures as sponsor-investigator in the significant risk (SR) clinical studies of (b)(4) and (b)(4) complied with applicable federal regulations. (b)(4) and (b)(4) 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 requests prompt corrective action to address the violations citedand discusses your written response dated January 31, 2017 to the observations on the Form FDA 483.

The inspection was conducted under a program designed to ensure that data and information contained in requests for Investigational Device Exemptions (IDEs), Premarket Approval 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 concern 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 observations 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 submit IDE application to the FDA, and obtain approval of the IDE from FDA and an Institutional Review Board (IRB), before allowing subjects to participate in the investigation. [21 CFR 812.20(a)(1) and (a)(2), 21 CFR 812.40, 21 CFR 812.42, and 21 CFR 812.110(a)]

Neither (b)(4) nor (b)(4) has been approved or cleared by the FDA. Although it appears that these devices are both made up of two previously cleared devices, Socket Graft (K113049) and OsseoConduct (K101718),[1] the combination of these devices constituted a significant change or modification that requires new 510(k)s (see 21 CFR 807.81(a)(3)). The change in materials and chemical composition (i.e., different calcium phosphate minerals and particle sizes), for example, could change the resorption profile of the devices, and thus could significantly affect the devices’ safety or effectiveness (see 21 CFR 807.81(a)(3)(i)). As such, you were correct in submitting a new 510(k) for each of these devices.

It is our determination that your activities constitute investigations, as defined in 21 CFR 812.3(h), because you were conducting research involving one or more subjects to determine the safety or effectiveness of the devices. Moreover, FDA has determined that the investigations are of SR devices because the devices are implants that present a potential for serious risk to the health, safety, or welfare of a subject as defined in 21 CFR 812.3(m)(1).

As a sponsor-investigator, defined in 21 CFR 812.3(o), you have responsibilities of being both the sponsor of the investigation who initiates the investigation and the clinical investigator who conducts and monitors the investigation. A sponsor must submit an IDE application for a SR device to the FDA (21 CFR 812.40), and shall not begin an investigation or part of an investigation until an IRB and FDA both have approved the IDE application or supplemental application relating to the investigation or part of an investigation (21 CFR 812.20(a)(1), 812.20(a)(2), and 812.42). As an investigator, you may determine whether or not potential subjects would be interested in participating in an investigation, but shall not allow any subject to participate before obtaining IRB and FDA approval (21 CFR 812.110(a)).

We note that you should be aware of these requirements based on previous communications from FDA. In an e-mail on December 9, 2011, the Office of Device Evaluation (ODE) in FDA’s Center for Devices and Radiological Health informed you that your investigation of the Socket Graft (K113049) was subject to requirements in 21 CFR Part 812. Also, during a teleconference on December 14, 2011, ODE representatives provided further clarification on these requirements.

As you acknowledged in your signed affidavit dated December 16, 2016, and in your written response to the Form FDA-483, you failed to obtain FDA approval of IDE applications and you also failed to obtain IRB approval prior to beginning these investigations. Specific examples of this failure include but are not limited to the following:

a. In your signed affidavit dated December 16, 2016 and in your written response to the Form FDA-483, you stated that you conducted the clinical research without IRB approval, and collected data later submitted to FDA.

b. (b)(4)

c. (b)(4)

Your failure to (b)(4).

Your written response is inadequate. You assert that you did not conduct an investigation and thus “have done nothing that requires regulatory oversight or an IRB.” FDA disagrees with that assessment. (b)(4).

To conduct investigations on (b)(4) and/or (b)(4) to determine the safety and effectiveness of these devices, we reiterate that approved IDEs are needed.

2. Failure to maintain accurate, complete, and current records relating to your participation in an investigation. [21 CFR 812.140(a)]

As an investigator, it is your responsibility to maintain accurate, complete and current records relating to your participation in an investigation, including various records of each subject’s case history (21 CFR 812.140(a)(3)). You failed to do so. Examples of this failure include, but are not limited to, the following:

a. Failure to maintain any protocols for your investigations; and

b. Failure to maintain accurate, complete and current records for your clinical investigations, such as subject enrollment logs and records, inclusion/exclusion criteria, or signed informed consent documents.

In your written response you stated that you “have done nothing that requires regulatory oversight or an IRB.” For the reasons discussed above, you are the sponsor-investigator of an investigation and are subject to the regulations that include but are not limited to those cited in this letter.

3. Failure to obtain informed consent in accordance with the regulations regarding the protection of human subjects and failure to adhere to informed consent requirements. [21 CFR 50.27(a), 21 CFR 50.25 and 21 CFR 812.100]

An investigator is responsible for ensuring that informed consent is obtained from each subject using an IRB-approved version of the informed consent document prior to involving the subjects in the clinical investigation in accordance with 21 CFR Part 50 and 21 CFR 812.100. No investigator may involve a human subject in research unless the investigator has obtained legally effective informed consent from the subject or the subject’s legally authorized representative (21 CFR 50.20). In addition, an investigator shall document informed consent by the use of a written consent form approved by the IRB and signed and dated by the subject or the subject’s legally authorized representative at the time of consent (21 CFR 50.27(a)).

Additionally, the informed consent document must contain all the basic elements in accordance with 21 CFR 50.25. The basic elements that must be included in an informed consent are:

A statement that the study involves research, an explanation of the purposes of the research and the expected duration of the subject's participation, a description of the procedures to be followed, and identification of any procedures which are experimental.
A description of any reasonably foreseeable risks or discomforts to the subject.
A description of any benefits to the subject or to others which may reasonably be expected from the research.
A disclosure of appropriate alternative procedures or courses of treatment, if any, that might be advantageous to the subject.
A statement describing the extent, if any, to which confidentiality of records identifying the subject will be maintained and that notes the possibility that the Food and Drug Administration may inspect the records.
For research involving more than minimal risk, an explanation as to whether any compensation and an explanation as to whether any medical treatments are available if injury occurs and, if so, what they consist of, or where further information may be obtained.
An explanation of whom to contact for answers to pertinent questions about the research and research subjects' rights, and whom to contact in the event of a research-related injury to the subject.
A statement that participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the subject is otherwise entitled, and that the subject may discontinue participation at any time without penalty or loss of benefits to which the subject is otherwise entitled.

You are an investigator because you are an individual who is conducting a clinical investigation as defined in 21 CFR 812.3(i). Accordingly, you are responsible for ensuring that informed consent is obtained in accordance with 21 CFR Part 50. You failed to ensure that informed consent was obtained from subjects in accordance with the federal regulations. Examples of this failure include but are not limited to the following:

a. The informed consent document that you used for your clinical research did not contain any of the necessary basic elements of informed consent that are required by 21 CFR 50.25.

b. The informed consent document that you used for your clinical research was not approved by an IRB in accordance with 21 CFR 50.27(a).

Your response states that you will no longer submit histological data as evidence of safety and effectiveness for your regulatory marketing applications. This response is not completely clear to the FDA, but we have concerns to the extent that it suggests you intend to continue to conduct investigations without, among other things, obtaining the requisite IDE approval and without ensuring that informed consent is obtained. Regarding this latter concern, we note that a valid informed consent process ensures that research subjects have a clear understanding of the risks of participation in a research protocol and have sufficient opportunity to make an informed decision on whether or not to participate in the study. The informed consent document you used did not include important information such as the risks associated with the investigational device. Study subjects are required to have this information prior to study enrollment. By failing to properly obtain the subjects’ informed consent with the use of a complete, IRB-approved informed consent document before enrolling them in a clinical investigation of your device, you did not adequately protect the rights and safety of those human subjects.

If you intend to conduct FDA-regulated clinical research in the future, proper informed consent must be obtained for all human subjects who participate in the research.

The violations described above are not intended to be an all-inclusive list of problems that may exist with your clinical studies. It is your responsibility as a study sponsor and as a study investigator to ensure compliance with the Act and applicable regulations.

Within 15 working days of receiving this letter, please provide documentation of the corrective and preventative actions that you have taken or will take to correct these violations and to prevent the recurrence of similar violations in current or future studies for which you are the study sponsor and/or clinical investigator. Any submitted corrective action plan must 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 # (b)(4)” and be sent to:

Attention: Sheena 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 San Francisco 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/.

After you respond to this letter in writing, please contact Bill Riemenschneider at 301-796-9682 or via e-mail at Bill.Riemenschneider@fda.hhs.gov to set up a teleconference to discuss the regulatory aspects of your path forward as a clinical investigator and as a sponsor. If you have any questions, please also contact Bill Riemenschneider.

Sincerely yours,

/S/

Robin W. Newman, MSN, EdD

Director

Office of Compliance

Center for Devices and Radiological Health

[1] It is our understanding that the (b)(4) and (b)(4) are identical in terms of design and materials, but differ in their intended uses.