WARNING LETTER

Adolfo Kaplan MARCS-CMS 523832 — April 20, 2017

Recipient:: Adolfo Kaplan; United States

Issuing Office:: Center for Drug Evaluation and Research; United States

U.S. Food & Drug Administration

10903 New Hampshire Avenue

Silver Spring, MD 20993

WARNING LETTER

CERTIFIED MAIL

RETURN RECEIPT REQUESTED

Adolfo E. Kaplan, M.D. Ref.: 17-HFD-45-04-01

Pulmonary and Sleep Center of the Valley
5300 North McColl Road, Suite 100
McAllen, Texas 78504

Dear Dr. Kaplan:

This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection conducted at your clinical site between November 7 and November 10, 2016. Mr. Travis M. Beard, representing FDA, reviewed your conduct of a clinical investigation (Protocol (b)(4) of the investigational drug (b)(4), performed for (b)(4).

This inspection is a part of FDA’s Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of FDA-regulated research to ensure that the data are scientifically valid and accurate, and to help ensure that the rights, safety, and welfare of the human subjects of those studies have been protected.

At the conclusion of the inspection, Mr. Beard presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your November 14, 2016, written response to the Form FDA 483.

From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your written response dated November 14, 2016, we conclude that you did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations and the protection of human subjects. We wish to emphasize the following:

You failed to ensure that the investigation was conducted according to the investigational plan [21 CFR 312.60].

As a clinical investigator, you are required to ensure that your clinical studies are conducted in accordance with the investigational plan. The investigational plan for Protocol (b)(4) required you to ensure that subjects met the protocol eligibility criteria before enrollment and treatment randomization. Protocol (b)(4) states that deviations from inclusion and exclusion criteria are not allowed and that adherence to the eligibility criteria as specified in the protocol is essential. In addition, Protocol (b)(4) required you to perform certain procedures, such as chest X-rays, at specific times. You failed to adhere to these requirements. Specifically:

1. The investigational plan for Protocol (b)(4) required that to be eligible for enrollment, subjects must demonstrate either of the following:

· a post-bronchodilator FEV1 less than 50% of predicted normal and a documented history of at least 1 moderate or severe (b)(4) exacerbation in the previous 12 months

· a post-bronchodilator FEV1 between 50% and 80% of predicted normal and a documented history of at least 2 moderate exacerbations or a documented history of at least 1 severe (b)(4) exacerbation in the previous 12 months

The protocol defined a documented history of a (b)(4) exacerbation as a medical record of worsening (b)(4) symptoms that required systemic/oral corticosteroids and/or antibiotics (for a moderate exacerbation) or hospitalization (for a severe exacerbation). The protocol also specified that subjects’ verbal reports were not acceptable.

Out of four total subjects enrolled at your site, you enrolled three subjects who did not meet this requirement. Specifically, you allowed the enrollment of the following subjects with a post-bronchodilator FEV1 (forced expiratory volume in 1 second) between 50% and 80% of predicted normal, even though they did not have a documented history of at least 2 moderate (b)(4) exacerbations or at least 1 severe (b)(4) exacerbation in the previous 12 months:

a. Subject 11153, who had a post-bronchodilator FEV1 of 68% of predicted normal, was enrolled on June 4, 2015.

b. Subject 11154, who had a post-bronchodilator FEV1 of 62% of predicted normal, was enrolled on June 15, 2015.

c. Subject 11155, who had a post-bronchodilator FEV1 of 63% of predicted normal, was enrolled on June 18, 2015. (Note that the Form FDA 483 identified Subject 11155 incorrectly as “Subject 11555.”)

2. The investigational plan specified that any subject who experienced pneumonia and/or moderate or severe (b)(4) exacerbation during the run-in period would be excluded from the study. The protocol defined moderate (b)(4) exacerbation as worsening symptoms of (b)(4) that require treatment with oral/systemic corticosteroids and/or antibiotics, and severe (b)(4) exacerbation as worsening symptoms of (b)(4) that require treatment and inpatient hospitalization.

Subject 11155 experienced a moderate (b)(4) exacerbation with worsening symptoms of (b)(4) requiring treatment with oral corticosteroids during the run-in period. However, this subject was not excluded from treatment randomization.

3. The investigational plan required a chest X-ray to be performed as soon as possible and preferably within 48 hours of moderate or severe exacerbation, as defined by the protocol and described above.

You failed to perform chest X-rays following moderate (b)(4) exacerbations for the following two subjects:

a. Subject 11152 experienced 2 moderate (b)(4) exacerbations with worsening symptoms of (b)(4) requiring treatment with antibiotics, on July 31, 2015, and on September 25, 2015. However, a chest X-ray was not performed following either (b)(4) exacerbation.

b. Subject 11154 experienced 2 moderate (b)(4) exacerbations with worsening symptoms of (b)(4) requiring treatment with antibiotics, on February 25, 2016, and on June 14, 2016. However, a chest X-ray was not performed following either (b)(4) exacerbation.

In your November 14, 2016, written response to the Form FDA 483, you indicated that you delegated day-to-day research activities to an independent research company. You noted that you held regular meetings with the independent research company, during which you received updates on recruitment and follow-ups, signed required documents, and reviewed tests. You also noted that the independent research company did not bring any of the above-mentioned violations to your attention during these regular encounters.

We wish to emphasize that as the clinical investigator, it was your ultimate responsibility to ensure that clinical studies were conducted properly and in compliance with FDA regulations, both to protect the rights, safety, and welfare of study subjects and to ensure the validity and integrity of study data. However, your response is inadequate because, although you indicate in your response that you “do not plan to get involved in clinical research again,” you did not provide details about how you personally plan to prevent similar violations if this decision should change and you conduct clinical research in the future. Your explanation, when taken into consideration with the violations described above, suggests systemic failures in your conduct of this clinical investigation.

Your lack of supervision and oversight of the clinical study raises significant concerns about the adequacy of your protection of the study subjects enrolled at your site in the above-mentioned study, and raises concerns about the integrity of the data generated at your site.

Enrollment of subjects who do not meet eligibility criteria and failure to perform protocol-required procedures, including chest X-rays, jeopardize subject safety and welfare, and raise concerns about the validity and integrity of the data collected at your site. Of particular concern is the fact that three of the four subjects enrolled on the above-mentioned study at your site were ineligible for enrollment into the protocol.

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 these deficiencies and establish procedures to ensure that any ongoing or future studies will be in compliance with FDA regulations.

Within fifteen (15) working 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 address the violations noted above adequately and promptly may result in regulatory action without further notice. If you believe you have complied with FDA regulations, include your reasoning and any supporting information for our consideration.

If you have any questions, please call Adam Donat, M.S., at 301-796-5316. Your written response and any pertinent documentation should be addressed to:

Adam Donat, 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

Food and Drug Administration

Building 51, Room 5352

10903 New Hampshire Avenue

Silver Spring, MD 20993

Sincerely yours,

{See appended electronic signature page}

David C. Burrow, Pharm.D., J.D.

Acting Director

Office of Scientific Investigations

Office of Compliance

Center for Drug Evaluation and Research

Food and Drug Administration

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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

/s/

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DAVID C BURROW

04/20/2017