WARNING LETTER
James Findling
MARCS-CMS 598944 —
December 31, 2019
Delivery Method:
VIA UNITED PARCEL SERVICE
Product:
Drugs
Recipient:
Recipient Name
James W. Findling, M.D.
James Findling
9200 W. Wisconsin Avenue
Pavilion IP, Suite 150
Milwaukee
,
WI
53226-3522
United States
Issuing Office:
Center for Drug Evaluation and Research | CDER
10903 New Hampshire Avenue
Silver Spring
,
MD
20993
United States
WARNING LETTER
Ref.: 19-HFD-45-12-01
Dear Dr. Findling:
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 July 11 and August 2, 2019. Investigator Denise L. Burosh, representing FDA, reviewed your conduct of a clinical investigation (Protocol
(b)(4)
, “
(b)(4)
”) of the investigational drug
(b)(4)
, performed for
(b)(4)
.
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 Burosh presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your August 22, 2019, written response to the Form FDA 483. 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)
was a randomized withdrawal design including elements of double-blinded, placebo-controlled therapy for comparison, and randomized assignment either to continue study drug or to change to placebo. The investigational plan for Protocol
(b)(4)
required you to ensure that subjects met the protocol eligibility criteria before randomization onto Study Period 3, the randomized withdrawal period of the study (Weeks 26-34). In addition, Protocol
(b)(4)
required you to discontinue subjects with elevated urine free cortisol (UFC) levels during Study Period 3. You failed to adhere to these requirements. Specifically:
1. The investigational plan for Protocol
(b)(4)
required that to be eligible for randomization, subjects must have completed individual dose titration during Study Period 1 (Weeks 1-12) and subsequently continued
(b)(4)
treatment with no further dose increase during Study Period 2 (Weeks 13-24). Individual dose titration was required because of high intersubject variability in effective dose and a narrow therapeutic window (risk of acute adrenal insufficiency). The protocol further specified that subjects would not be considered complete responders and could not be randomized if, during Study Period 2, their dose was increased above the therapeutic level established at the end of Study Period 1. The steady dose during Study Period 2 was required to demonstrate long-term safety and efficacy with no need for further dose escalation because of therapeutic escape.
Of the three subjects randomized at your site, you randomized two subjects who had dose increases during Study Period 2 above the therapeutic level established for each subject at the end of Study Period 1.
a. Subject
(b)(4)
’s Week 12 dose, on November 18, 2016, was 5 mg twice daily. During the subject’s Week 12 visit, study drug was held because of concerning symptoms of adrenal insufficiency. At Week 13, study drug was restarted on November 24, 2016, at 2 mg twice daily. During Study Period 2, the subject’s dose was increased to 3 mg on December 22, 2016; to 5 mg twice daily on January 18, 2017; and to 7 mg twice daily on February 3, 2017.
Despite these dose increases during Study Period 2 above the dose established for this subject at the end of Study Period 1, this subject was randomized on February 24, 2017, and continued randomized treatment until the end of the randomized withdrawal period on April 20, 2017. This subject subsequently experienced elevated UFC levels > 1.5 times the upper limit of normal (ULN) during the randomized withdrawal period, but was not discontinued from the randomized treatment, as described in Item 2.a. below.
b. Subject
(b)(4)
’s Week 12 dose, on November 23, 2016, was 5 mg twice daily; however, between Weeks 13 and 24, this subject’s dose was increased to 7 mg twice daily on December 5, 2016.
Despite this dose increase during Study Period 2 above the dose established for this subject at the end of Study Period 1, this subject was randomized on March 2, 2017, and continued randomized treatment until the end of the randomized withdrawal period on April 26, 2017.
In your August 22, 2019, written response to the Form FDA 483, you indicated that at the end of Study Period 2, you and your co-investigators realized that Subjects
(b)(4)
and
(b)(4)
were ineligible for randomization because of dose escalations during Study Period 2. You indicated that there was a miscommunication with the study sponsor, and you never received any confirmation from the sponsor that the subjects were randomized. You assumed they were continuing treatment on open-label study drug, until the study sponsor made you aware on July 19, 2019, that both subjects were randomized.
You also noted that both subjects had no clinical changes during the randomized withdrawal period. For Subject
(b)(4)
, you also stated, “in fact, it looks as if her urine cortisol actually normalized while on placebo.”
Your response is inadequate, because study records reflect that you and/or your study staff were aware that both subjects were receiving randomized treatment. In addition, we are unable to determine if your written response provides a corrective action plan that, if properly carried out, would prevent this type of violation in the future. Specifically, you did not provide sufficient details about your plan for implementing additional measures and procedures to address the inspection findings regarding the randomization of ineligible subjects. For example, you did not indicate whether you and your staff underwent retraining activities to prevent future protocol violations. In addition, your written response does not provide sufficient details about how you personally will ensure adequate oversight of study procedures (for example, adherence to eligibility requirements) and protocol training for you and your study staff. Without these details, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future.
We emphasize that randomization eligibility criteria for each clinical investigation are designed both to minimize foreseeable harm to randomized subjects, and to optimize the interpretability of collected data. Randomization of ineligible subjects raises significant concerns about the adequacy of the protection of study subjects enrolled at your site, and also raises concerns about the integrity of the data collected at your site.
2. Protocol
(b)(4)
required you to discontinue subjects from randomized treatment during Study Period 3, the randomized withdrawal period of the study, if (1) the mean of three urine free cortisol samples (mUFC) was > 1.5 times ULN, and (2) at least two individual UFC samples were >1.5 times ULN at a single visit; and to resume open-label treatment of
(b)(4)
at a dose selected by the investigator. This procedure for managing subjects with uncontrolled hypercortisolism during the randomized withdrawal period was required to minimize the duration of exposure to ineffective treatment.
We note that the primary endpoint for this study was the proportion of randomized subjects in each treatment that had an mUFC level < ULN at the end of the randomized withdrawal period, and who were neither discontinued nor had dose increases during Study Period 3, above the level established at Week 26.
Of the three subjects randomized at your site, you failed to discontinue the following two subjects from randomization treatment when mUFC and at least two individual UFC samples were > 1.5 times ULN at a single visit.
a. Subject
(b)(4)
had mUFC and at least two individual UFC values > 1.5 times ULN on March 21, 2017, and again on April 4, 2017, but was not discontinued from the randomized treatment, and continued randomized treatment until the end of the randomized withdrawal period on April 20, 2017.
i. For the March 21, 2017, laboratory results, reported on April 5, 2017, the following laboratory values were > 1.5 times ULN and were marked as “clinically significant” by a subinvestigator on April 6, 2017:
1. mUFC of 105.8 mcg/24 hours (2.1 times ULN)
2. individual UFC value of 118.4 mcg/24 hours (2.4 times ULN)
3. individual UFC value of 87.2 mcg/24 hours (1.7 times ULN)
4. individual UFC value of 111.8 mcg/24 hours (2.2 times ULN)
ii. For the April 4, 2017, laboratory results, reported on April 11, 2017, the following laboratory values were > 1.5 times ULN and were marked as “clinically significant” by a subinvestigator on April 11, 2017:
1. mUFC of 88.3 mcg/24 hours (1.8 times ULN)
2. individual UFC value of 115.1 mcg/24 hours (2.2 times ULN)
3. individual UFC value of 106.4 mcg/24 hours (2.1 times ULN)
Despite elevated individual and mUFC levels during Study Period 3, Subject
(b)(4)
was not discontinued from randomized treatment. As described above, this subject was ineligible for randomization because of an increase above the therapeutic dose established at the end of individual dose titration during Study Period 1, and should not have been randomized onto Study Period 3.
b. Subject
(b)(4)
had mUFC and three individual UFC values > 1.5 times ULN on July 4, 2017, and again on July 17, 2017; however, this subject was not discontinued from the randomized treatment, and continued randomized treatment until the end of the randomized withdrawal period on August 4, 2017.
i. For the July 4, 2017, laboratory results, reported on July 12, 2017, the following laboratory values were > 1.5 times ULN and were marked as “clinically significant” by a subinvestigator on July 12, 2017:
1. mUFC of 108.6 mcg/24 hours (2.2 times ULN)
2. individual UFC value of 105.2 mcg/24 hours (2.1 times ULN)
3. individual UFC value of 124.7 mcg/24 hours (2.5 times ULN)
4. individual UFC value of 96.0 mcg/24 hours (1.9 times ULN)
ii. For the July 17, 2017, laboratory results, reported on July 24, 2017, the following laboratory values were > 1.5 times ULN and were marked as “clinically significant” by a subinvestigator on July 25, 2017:
1. mUFC of 159.3 mcg/24 hours (3.2 times ULN)
2. individual UFC value of 130.8 mcg/24 hours (2.6 times ULN)
3. individual UFC value of 158.4 mcg/24 hours (3.2 times ULN)
4. individual UFC value of 188.6 mcg/24 hours (3.8 times ULN)
Despite elevated individual and mUFC levels during Study Period 3, Subject
(b)(4)
was not discontinued from randomized treatment.
In your August 22, 2019, written response to the Form FDA 483, you acknowledged that neither Subject
(b)(4)
nor Subject
(b)(4)
was withdrawn from randomization when urine cortisol exceeded 1.5 times ULN. As described above, you indicated that you were not aware that Subject
(b)(4)
was randomized.
Concerning Subject
(b)(4)
, you stated that you were certainly aware that Subject
(b)(4)
had been randomized, and that the study sponsor insisted that the subject needed to complete eight weeks in the randomized period, because your study team did not feel this represented a safety risk. You also indicated you thought that for Subject
(b)(4)
, increases in adrenocorticotropic hormone (ACTH) from her
(b)(4)
had broken through her study drug or, less likely, that the subject had been noncompliant with study drug administration. In addition, you noted that four enrolled subjects, including the three randomized subjects, are all doing well.
You noted that you met with your co-investigators and study staff on a monthly basis during the past 11 years, and that you discussed the progress of each of these patients at these monthly meetings.
We are unable to perform an informed evaluation of your response, because you did not provide documentation of any communication with the sponsor to show that the sponsor insisted that Subject
(b)(4)
needed to complete the randomization period despite elevated urine cortisol levels. In addition, as noted above, study records for Subject
(b)(4)
reflect that you and/or your study staff were aware that this subject was receiving randomized treatment.
We are also unable to determine if your written response provides a corrective action plan that, if properly carried out, would prevent this type of violation in the future. Specifically, you did not provide sufficient details about your plan for implementing additional measures and procedures to address the inspection findings concerning your failure to follow protocol procedures. For example, you did not indicate whether you and your staff underwent retraining activities to prevent future protocol violations. In addition, your written response does not provide sufficient details about how you personally will ensure adequate oversight of study procedures (for example, discontinuation of randomized treatment due to safety measures) and protocol training for you and your study staff. Without these details, we are unable to determine whether your corrective action plan is adequate to prevent similar violations in the future.
Failure to perform protocol-required procedures, particularly those related to discontinuation from randomization due to elevated laboratory values, raises significant concerns about the adequacy of your protection of study subjects enrolled at your site in the study mentioned above, and raises concerns about the validity and reliability of the data collected at your site. We are particularly concerned that not only were two of the three randomized subjects ineligible for randomization onto the randomized withdrawal period of the study, but also that two of the three randomized subjects at your site were not discontinued from randomization treatment because of uncontrolled hypercortisolism, as the protocol required.
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 comply 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 Mark S. Miller, Pharm.D., at 301-796-2798. Your written response and any pertinent documentation should be addressed to:
Mark S. Miller, Pharm.D., BCPS, RAC
CAPT, USPHS
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 5352
10903 New Hampshire Avenue
Silver Spring, MD 20993
Sincerely yours,
{See appended electronic signature page}
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
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This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record.
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/s/
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DAVID C BURROW
12/31/2019 07:38:45 AM
Content current as of:
01/14/2020
Regulated Product(s)
Drugs