WARNING LETTER
Richard J. Obiso, PhD dba Avila Herbals, LLC
MARCS-CMS 622821 —
February 04, 2022
Delivery Method:
VIA UPS and Electronic Mail
Product:
Drugs
Recipient:
Recipient Name
Richard J. Obiso, Ph.D.
Recipient Title
Owner/Clinical Investigator
Richard J. Obiso, PhD dba Avila Herbals, LLC
4025 Childress Road
Christiansburg
,
VA
24073-5968
United States
(b)(6)
Issuing Office:
Center for Drug Evaluation and Research | CDER
United States
WARNING LETTER
Ref. No.: 22-HFD-45-01-01
Dear Dr. Obiso:
This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your clinical site from July 12 to July 26, 2021. Investigator Melanie N. Daniels, representing FDA, reviewed the role of Avila Herbals, LLC (hereafter referred to as Avila Herbals) as the sponsor of the following clinical investigation of the investigational drug
(b)(4)
(also referred to as
(b)(4)
(hereafter referred to as
(b)(4)
:
• Protocol
(b)(4)
During the inspection, FDA also reviewed your conduct as the clinical investigator of the clinical investigation referenced above.
This inspection was conducted as a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of human subjects have been protected.
At the conclusion of the inspection, Investigator Daniels presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge our receipt of Avila Herbals’ August 6, 2021, written response to the Form FDA 483.
From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and Avila Herbals’ August 6, 2021, written response to the Form FDA 483, it appears that Avila Herbals, as the sponsor, and you, as the clinical investigator, did not adhere to the applicable statutory requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and applicable regulations contained in Title 21 of the Code of Federal Regulations, part 312 (21 CFR 312) governing the conduct of clinical investigations and the protection of human subjects. We wish to emphasize the following:
1. Failure to submit an Investigational New Drug application (IND) for the conduct of a clinical investigation with an investigational new drug that is subject to 21 CFR 312.2(a) [21 CFR 312.20(a), 312.20(b), and 312.40(a)].
Section 201(g) of the FD&C Act defines the term
drug
in part as “articles recognized in the . . . official
(b)(4)
. . . ,” and as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man or other animals” [21 U.S.C. 321(g)].
(b)(4)
is recognized in the official
(b)(4)
.
1
As described in the protocol for the clinical trial listed above, the investigational article,
(b)(4)
, “is a well characterized
(b)(4)
. . . manufactured using a standardized protocol with defined quality control acceptance criteria that include the determination of the specific chemical content of the
(b)(4)
, which follows the official
(b)(4)
.” For these reasons, we conclude that
(b)(4)
is a drug as defined in section 201(g)(1)(A) of the FD&C Act because it is an article recognized in the official
(b)(4)
.
Further, the
(b)(4)
as used in the clinical trial listed above was investigated for use to cure, mitigate, treat, or prevent disease. For example, the protocol and its appendices state the following:
• “[T]he active pharmaceutical ingredient (API)
(b)(4)
, has an important and novel
(b)(4)
effect”; “
(b)(4)
is proposed as a potential treatment for
(b)(4)
”; and you “plan observational studies to assess the effectiveness and safety of
(b)(4)
in healthy volunteers” (referring to the
(b)(4)
effect and treatment of
(b)(4)
outlined in the study synopsis).
• The
(b)(4)
in
(b)(4)
“contains different constituent compounds such as
(b)(4)
that may contribute to
(b)(4)
activity, improving the
(b)(4)
. In addition, and more importantly, the API
(b)(4)
, may have an important and novel
(b)(4)
effect.”
• “We present below both published and unpublished research demonstrating the ability of
(b)(4)
and
(b)(4)
(containing
(b)(4)
) that demonstrate [sic]
(b)(4)
activity.”
• “
(b)(4)
is indicated for
(b)(4)
: Drug:
(b)(4)
”; “Primary Purpose:
(b)(4)
.”
• “Investigators at Avila Herbals would like to assess the benefit of a
(b)(4)
.”
• “There is no direct medical/health benefit to you by participating in this study other than a potential treatment for the infection.”
• You “have every expectation that COVID-19 will also be susceptible to
(b)(4)
. . . . Initial results demonstrate a very significant
(b)(4)
activity against COVID-19.”
• “This large real-world cohort . . . provides a unique opportunity to study this medicine during the current emergency situation.”
• “Volunteers will also be asked to assist in completing a Clinical Assessment Questionnaire of their clinical signs and symptoms of infection, exposure to SARS-CoV-2, and their vaccination history and treatment.”
For these reasons, the
(b)(4)
as used in your clinical study is also a drug as defined in section 201(g)(1)(B) of the FD&C Act because it was intended to cure, mitigate, treat, or prevent disease, including COVID-19.
Moreover, this product is a “new drug” as defined by section 201(p) of the FD&C Act, 21 U.S.C. 321(p), because it is not generally recognized among qualified experts as safe and effective for use under the conditions prescribed, recommended, or suggested in its labeling, and/or because it has not been used to a material extent or for a material time under such conditions.
To market a new drug lawfully (with certain exceptions not applicable here), a sponsor must obtain FDA approval of either a new drug application or an abbreviated new drug application under section 505 of the FD&C Act [21 U.S.C. 355]. An IND allows a sponsor to obtain an exemption from this requirement in order to distribute an investigational drug [21 U.S.C. 355(i)]. FDA regulations require a sponsor to submit, and to have in effect, an IND before initiating a clinical investigation of a drug subject to 21 CFR 312.2(a) in human subjects, unless the clinical investigation qualifies for an IND exemption under 21 CFR 312.2 (see 21 CFR 312.20 and 312.40(a)). Section 312.2(b)(1) provides an exemption from the requirement to obtain an IND before initiating a clinical investigation of a lawfully marketed prescription drug if all five of the exemption criteria set forth in that regulation are met.
(b)(4)
drug products like
(b)(4)
, which are not the subject of a new drug or abbreviated new drug application approved under section 505 of the FD&C Act, are not lawfully marketed. In addition, one criterion for this exemption is that the investigation is conducted in compliance with the requirements for institutional review set forth in 21 CFR part 56, and with the requirements for informed consent set forth in 21 CFR part 50. As discussed further below, this investigation was not conducted in compliance with those requirements. Thus, Avila Herbals did not satisfy the criteria for an exemption from IND regulations.
Because
(b)(4)
is a new drug that is subject to section 505 of the FD&C Act and 21 CFR 312.2(a), and because this clinical investigation did not qualify for an exemption under 21 CFR 312.2 from the requirement to submit an IND, Avila Herbals was required to submit and to have in effect an IND for this clinical investigation before initiating the study and before enrolling human subjects. There are no FDA records to indicate that Avila Herbals submitted an IND before initiating this clinical investigation of
(b)(4)
, in which
(b)(4)
human subjects were enrolled at one clinical site.
(b)(4)
or
(b)(4)
was administered in
(b)(4)
doses to healthy human subjects
(b)(4)
or
(b)(4)
times a day for 7 days to evaluate clinical safety, or in 1, 2, or
(b)(4)
doses of
(b)(4)
of
(b)(4)
or
(b)(4)
administered all at once to evaluate pharmacokinetics.
In its August 6, 2021, written response to the Form FDA 483, Avila Herbals stated that it failed to submit an IND to the FDA prior to conducting this study because of incorrect information received from a “
(b)(4)
field professional.” Avila Herbals indicated that although it followed the
(b)(4)
in developing this product, it now understands that “FDA treats
(b)(4)
products as a drug” and will make all corrections to reach compliance in the future.
Avila Herbals explained that it will submit an IND to FDA when conducting a clinical investigation in human subjects. In addition, it stated that all members of the clinical trial team will receive “certified” training completed internally or externally prior to starting a clinical investigation. Moreover, Avila Herbals indicated that it instituted a new policy that gives basic instructions and references in performing a clinical study.
We are unable to determine if Avila Herbals’ corrective action plans are adequate to prevent similar violations in the future because they do not provide sufficient details about how it will determine whether future clinical investigations in human subjects fall under the requirements of 21 CFR part 312. For example, Avila Herbals has not provided details on the “certified” training completed internally or externally that clinical trial team members will receive before starting a clinical investigation, or on the policy being drafted that gives basic instructions and references in performing a clinical study.
2. You failed to assure that an Institutional Review Board (IRB) that complies with the requirements set forth in 21 CFR part 56 was responsible for the initial and continuing review and approval of the proposed clinical study [21 CFR 312.66].
As a clinical investigator, you are required to assure that an IRB that complies with the requirements set forth in 21 CFR part 56 is responsible for the initial and continuing review and approval of a proposed clinical investigation. You failed to assure that an IRB that complies with 21 CFR part 56 reviewed and approved your conduct of Protocol
(b)(4)
. Specifically, you failed to use an IRB for the initial or continuing review or approval of Protocol
(b)(4)
.
In Avila Herbals’ August 6, 2021, written response to the Form FDA 483, it stated that it attempted to hire a third-party IRB but was informed that they do not review
(b)(4)
products. Avila Herbals explained that it therefore created its own IRB to review the protocol for errors, ethics issues, and the protection of human subjects, and that this IRB informally reviewed and approved the protocol. Avila Herbals acknowledged that there was no documented third-party IRB review. It explained that this also occurred because of incorrect information obtained from both the
(b)(4)
website and a
(b)(4)
field professional.
Avila Herbals stated that it will ensure documented third-party IRB review and approval of a proposed clinical investigation prior to conducting a clinical investigation in human subjects and prior to submission to FDA. It stated that all members of the clinical trial team will receive “certified” training completed internally or externally prior to starting a clinical investigational study, and it indicated that it instituted a new policy that gives basic instructions and references in performing a clinical study.
We are unable to determine if Avila Herbals’ corrective action plans are adequate to prevent similar violations in the future because they do not provide sufficient details about how you, as the clinical investigator, will ensure that review of a study by an IRB that complies with 21 CFR part 56 is conducted and documented, nor do they provide sufficient details about the policies being drafted for basic instructions and references in performing a clinical study. For example, we did not receive details on the “certified” training that clinical trial team members will receive before starting a clinical investigation.
As a clinical investigator, your failure to ensure the initial and continuing review and approval of your clinical investigation by an IRB that complies with 21 CFR part 56 raises significant concerns about your protection of the study subjects enrolled at your site and jeopardizes subject safety and welfare. IRB review serves an important role in the protection of the rights and welfare of human research subjects. The purpose of IRB review is to ensure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in the research. As the clinical investigator, it is your responsibility to ensure that clinical investigations are conducted properly and in compliance with FDA regulations in order to protect the rights, safety, and welfare of study subjects.
3. You failed to obtain informed consent in accordance with the provisions of 21 CFR part 50 [21 CFR 312.60 and 21 CFR 50.27(a)].
As a clinical investigator, you are required to obtain informed consent in accordance with 21 CFR part 50. Except as provided in 21 CFR 56.109(c), informed consent shall be documented 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)). You failed to document informed consent properly because you did not use a written consent form approved by the IRB for Protocol
(b)(4)
.
2
In Avila Herbals’ August 6, 2021, written response to the Form FDA 483, it stated that the written consent form was not approved by an IRB prior to conducting the clinical investigation because of the issues described in its response regarding your failure to ensure the review and approval of the clinical study by an IRB that complies with 21 CFR part 56, and because of the incorrect information you received from both the
(b)(4)
website and a “
(b)(4)
field professional.” Avila Herbals stated that it will ensure the documented IRB review and approval of a written consent form prior to conducting a clinical investigation in human subjects and prior to submission to FDA, and indicated that a policy is being drafted for proper IRB review of a written consent form. It also stated that all members of the clinical trial team will receive “certified” training completed internally or externally prior to starting a clinical investigational study.
We are unable to determine if Avila Herbals’ corrective action plans are adequate to prevent similar violations in the future because they do not provide sufficient details about how you, as the clinical investigator, will obtain informed consent in accordance with 21 CFR part 50 by documenting informed consent using a written consent form approved by an IRB. They also do not provide sufficient details about the policy being drafted for proper IRB review of a written consent form. For example, we did not receive details on the “certified” training that clinical trial team members will receive before starting a clinical investigation.
As a clinical investigator, your failure to obtain informed consent in accordance with 21 CFR part 50 raises significant concerns about your protection of the study subjects enrolled at your site and jeopardizes subject safety and welfare. IRB approval of the written consent form used to document informed consent serves an important role in the protection of the rights and welfare of human research subjects. The purpose of IRB review is to ensure, both in advance and by periodic review, that appropriate steps are taken to protect the rights and welfare of humans participating as subjects in the research. As the clinical investigator, it is your responsibility to ensure that clinical investigations are conducted properly and in compliance with FDA regulations in order to protect the rights, safety, and welfare of study subjects.
4. You failed to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects [21 CFR 312.62(a)].
As a clinical investigator, you are required to maintain adequate records of the disposition of the drug, including dates, quantity, and use by subjects. You failed to comply with this requirement. Specifically, you failed to maintain drug disposition records for any of the
(b)(4)
subjects enrolled at your site who received
(b)(4)
.
In its August 6, 2021, written response to the Form FDA 483, Avila Herbals stated that its drug disposition records were not adequate with respect to quantity and use by subjects because the clinical study team did not have complete training and because the protocol allowed for the at-home administration of study drug. Avila Herbals stated that it will ensure the documentation of administered study drug by manually tracking the time, day, amount, subject identification, drug identification, and “any events” on a log. In addition, it stated that all members of the clinical trial team will receive “certified” training completed internally or externally prior to starting a clinical investigational study.
We are unable to determine if Avila Herbals’ corrective action plans are adequate to prevent similar violations in the future because they do not provide sufficient details about the log that will be used to manually capture information documenting the administration of study drug, nor do they provide sufficient details about the “certified” training that clinical study team members will receive before starting a clinical investigation.
Your failure to maintain drug accountability records compromises the validity and integrity of the data at your study site.
This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address any deficiencies and establish procedures to ensure that any ongoing or future studies comply with FDA regulations.
Within 15 business days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to adequately address this matter may lead to regulatory action. If you believe you have complied with the FD&C Act and relevant regulations, please include your reasoning and any supporting information for our consideration.
If you have any questions, please call Miah Jung, Pharm.D., M.S., at 240-402-3728. Alternatively, you may e-mail FDA at CDER-OSI-Communications@fda.hhs.gov.
Your written response and any pertinent documentation should be addressed to:
Miah Jung, Pharm.D., M.S.
Branch Chief
Compliance Enforcement Branch
Division of Enforcement and Postmarketing Safety
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
Building 51, Room 5219
10903 New Hampshire Avenue
Silver Spring, MD 20993
Sincerely yours,
/S/
David C. Burrow, Pharm.D., J.D.
Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
U.S. Food and Drug Administration
____________________________________________
1
(b)(4)
2
In addition, an IRB did not waive the requirement for documentation of informed consent under 21 CFR 56.109(c).
Content current as of:
02/15/2022
Regulated Product(s)
Drugs