WARNING LETTER
Lauren R. Klein, MD, M.S.
MARCS-CMS 605544 —
May 06, 2021
Delivery Method:
VIA UNITED PARCEL SERVICE AND VIA E-MAIL
Product:
Drugs
Recipient:
Lauren R. Klein, MD, M.S.
Hennepin County Medical Center
701 Park Avenue, #MC-825
Minneapolis
,
MN
55415-1623
United States
Issuing Office:
Center for Drug Evaluation and Research | CDER
United States
WARNING LETTER
Ref.: 21-HFD-45-04-02
Dear Dr. Klein:
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 April 9 and April 23, 2019. Investigator Sharon Matson, representing FDA, reviewed your conduct of the following clinical investigations, which you performed as a sponsor-investigator:
• Protocol HSR 17-4345, “Prospective Observational Investigation of Olanzapine versus Haloperidol versus Ziprasidone versus Midazolam for the Treatment of Acute Undifferentiated Agitation in the Emergency Department,” of the investigational drugs olanzapine, haloperidol, ziprasidone, and midazolam
• Protocol HSR 18-4521, “Prospective Observational Investigation of Olanzapine versus Midazolam for the Treatment of Acute Undifferentiated Agitation in the Emergency Department,” of the investigational drugs olanzapine and midazolam
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 Matson presented and discussed with you the Form FDA 483, Inspectional Observations. We acknowledge receipt of your May 14, 2019, 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 May 14, 2019, it appears 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:
Failure to submit INDs for the conduct of clinical investigations with investigational new drugs subject to 21 CFR 312.2(a) [21 CFR 312.20 and 312.40(a)].
FDA regulations require a sponsor to submit, and to have in effect, an investigational new drug application (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 exemption (see 21 CFR 312.20 and 312.40(a)). You failed to comply with these requirements. Specifically, you initiated and conducted the following clinical investigations of investigational drug products subject to section 505 of the Federal Food, Drug, and Cosmetic Act without submitting and having in effect an IND
1
:
• The clinical investigation of the investigational drugs olanzapine, haloperidol, ziprasidone, and midazolam, conducted under Protocol HSR 17-4345
• The clinical investigation of the investigational drugs olanzapine and midazolam, conducted under Protocol HSR 18-4521
In your May 14, 2019, written response to the Form FDA 483, you stated that an IND was not needed for Protocol HSR 17-4345 or for Protocol HSR 18-4521 because the drugs administered in these clinical investigations were not research interventions. You stated that the Emergency Medicine (EM) physicians were free to use whichever therapy they thought was most appropriate using their professional medical judgment, and could choose not to enroll any particular subject in the investigations. You also stated that all of the drug products are part of the standard of care for sedation treatment.
In the alternative, you argued that if the clinical investigations were subject to FDA jurisdiction, they met the criteria at 21 CFR 312.2(b)(1) for exemption from the requirements of part 312. You argued that the investigations met all five criteria for the exemption. With respect to the third criterion, you stated that the investigation did not involve a route of administration, dosage level, use in patient population, or other factor that significantly increases the risk or decreases the acceptability of the risk to subjects because the drugs were used “essentially in accord with their approved labeling.” You also stated in your response that the EM physicians were well trained to care for these subjects receiving these drugs.
We address both of your arguments below.
1. Protocols HSR 17-435 and HSR 18-4521 were clinical investigations of drugs as defined by 21 CFR 312.3(b).
For the purposes of 21 CFR part 312, a clinical investigation is defined as “any experiment in which a drug is administered or dispensed to, or used involving, one or more human subjects. For the purposes of this part [312], an experiment is any use of a drug except for the use of a marketed drug in the course of medical practice” [21 CFR 312.3(b)].
The clinical investigations conducted under Protocols HSR 17-4345 and HSR 18-4521 involved the administration of olanzapine, haloperidol, ziprasidone, and midazolam, and of olanzapine and midazolam, respectively, to human subjects. Based on the information collected on inspection, Protocols HSR 17-4345 and HSR 18-4521 were designed to study the safety and efficacy of these drug products for the treatment of acute undifferentiated agitation in the Emergency Department (ED).
The use of these drug products was not “in the course of medical practice.” FDA has long held that when an investigator limits his choices, his patients’ choices, and the choices of the people working for him in the treatment of those patients, then he is conducting a clinical investigation. That is different from the practice of medicine, where the primary intent is to treat the individual patient.
2
Both protocols pre-specified the drug intervention to be administered to agitated subjects requiring chemical sedation during specified time periods. This was reinforced by consistent communication from you, the sponsor-investigator, to ED personnel regarding the specific drugs that were to be administered on a given day. As such, the clinical investigations limited the ED physicians’ clinical judgment and limited the interventions available to ED physicians for administration to each subject.
For example:
• Protocol HSR 17-4345 stated: “All patients requiring chemical sedation for [sic] will receive olanzapine as the initial treatment for agitation for 21 days, followed by haloperidol as the initial treatment for agitation for 21 days, followed by ziprasidone as the initial treatment for agitation for 21 days, and finally midazolam as the initial treatment for agitation for 21 days . . . . All patients determined by the physician to require chemical sedation . . . will receive their initial intervention as a pre-specified medication . . . . [T]he clinical protocol will determine which medication the physician must order.” For Protocol HSR 17-4345, on May 30, 2017, you e-mailed Hennepin County Medical Center (HCMC) EM faculty, EM fellows, EM residents, EM physician assistants, and ED nurses, “Starting June 8 . . . [i]f you are planning to give the patient sedation, with this protocol, the
initial
medication given for
ANY
agitated patient in special care
MUST be the “Medication of the Week[”] . . . . Again, this medication of the week MUST be the first medication given to EVERY ED patient in special care for agitation
[emphasis in original].” The medication schedule was described in the e-mail, with haloperidol starting on June 8, ziprasidone starting on June 29, olanzapine starting on July 20, and midazolam starting on August 10. You sent similar e-mails on June 1, 2017; June 6, 2017; June 22, 2017; June 26, 2017; June 28, 2017; and July 19, 2017.
• Protocol HSR 18-4521 stated: “All patients requiring chemical sedation for[sic] will receive olanzapine as the initial treatment for agitation for 6 weeks, followed by midazolam as the initial treatment for agitation for 6 weeks. . . . All patients determined by the physician to require chemical sedation will receive their initial intervention as a pre-specified medication . . . . [T]he clinical protocol will determine which medication the physician must order.” For Protocol HSR 18-4521, on June 22, 2018, you e-mailed HCMC EM residents and EM physician assistants, “If you are planning to give a patient medication in special care, the
initial
medication given for
ANY
agitated patient in special care
MUST be the “Medication of the Week”. [sic] This medication of the week
MUST be the first medication given to EVERY ED patient in special care for agitation
[emphasis in original].” The medication schedule was described in the e-mail, with olanzapine starting on June 18 and midazolam starting on July 18.
Consequently, the investigations conducted under Protocols HSR 17-4345 and HSR 18-4521 were clinical investigations of the investigational drugs olanzapine, haloperidol, ziprasidone, and midazolam, and of olanzapine and midazolam, respectively.
3
Under 21 CFR 312.20 and 312.40, you were required to submit and to have in effect INDs before initiating these clinical investigations.
Your statements that the drugs studied in Protocol HSR 17-4345 and Protocol HSR 18-4521 were not investigational drugs are not persuasive because they are inconsistent with the design and conduct of the clinical investigations. The clinical investigations involved the prospective administration of specific drug products depending on the date of administration, the assessment and documentation of time to sedation, and the comparison of times to sedation among different drugs where the investigational drug was the independent variable of primary interest. Contrary to your assertions, both clinical trials required the EM physicians to administer a specific investigational drug to agitated subjects who were to be sedated chemically. Whether an agitated subject in need of sedation received olanzapine, haloperidol, ziprasidone, or midazolam while Protocol HSR 17-4345 was ongoing, or whether an agitated subject in need of sedation received either olanzapine or midazolam while Protocol 18-4521 was ongoing, depended not on the clinical judgment of the EM physicians but on the date the EM physicians encountered the subject. In addition, the presence of the choice not to enroll any particular subject is common in clinical investigations and does not support your assertion that the drug products were not investigational new drugs with regard to subjects who were enrolled. Finally, the fact that the drugs individually can be part of standard of care does not render then non-interventions in the study setting, as was the case here, where the protocols pre-specified the drug intervention to be administered to agitated subjects requiring chemical sedation, and limited the EM physicians’ clinical judgment and the interventions available to EM physicians for administration to each subject.
2. The clinical investigations conducted under Protocols HSR 17-4345 and HSR 18-4521 are subject to the IND regulations under 21 CFR 312.2 and do not meet the exemption criteria under 21 CFR 312.2(b)(1).
As noted above, FDA regulations require a sponsor to submit an IND before conducting a clinical investigation of a drug in human subjects, unless the clinical investigation qualifies for an IND exemption under 21 CFR 312.2(b). Under 21 CFR 312.2(b)(1), the clinical investigation of a lawfully marketed drug product in the United States is exempt from the IND regulations for a clinical investigation if
all
of the following exemption criteria are met:
1. The investigation is not intended to be reported to FDA as a well-controlled study in support of a new indication for use, and there is no intent to use the investigation to support any other significant change in the labeling of the drug.
2. In the case of a lawfully marketed prescription drug, the investigation is not intended to support a significant change in the advertising for the drug.
3. The investigation does not involve a route of administration, dosage level, use in a patient population, or other factor that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug product.
4. 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.
5. The investigation is conducted in compliance with the requirements of 21 CFR 312.7.
Your use of the investigational drugs (olanzapine, haloperidol, ziprasidone, and midazolam) in the clinical investigations conducted under Protocols HSR 17-4345 and HSR 18-4521 did not qualify for the exemption at 21 CFR 312.2(b)(1). For example, these investigations did not satisfy the third exemption criterion above, found at 21 CFR 312.2(b)(1)(iii). That is to say, the investigations significantly increased the risks (or decreased the acceptability of the risks) associated with the use of the drug products.
Here, the clinical investigations conducted under Protocols HSR 17-4345 and HSR 18-4521 involved the administration of investigational new drugs in populations that significantly increased the risks (or decreased the acceptability of the risks) associated with the use of the drug products.
4
First, neither study excluded subjects taking medications known to have drug-drug interactions with the investigational drugs, such as inhibitors or inducers of CYP450 enzymes. Second, neither study excluded subjects with liver or kidney dysfunction, despite the fact that the investigational drugs are known to be influenced by these impairments. As such, these clinical investigations failed to meet the exemption criteria under 21 CFR 312.2(b)(1)(iii).
We note that on February 16, 2017, you submitted IND 134378 for the investigational drugs olanzapine, haloperidol, ziprasidone, and midazolam in order to conduct a clinical trial that would have been substantially similar to the trial you sponsored and conducted under Protocol HSR 17-4345. In a March 24, 2017, teleconference with you, the Division of Psychiatry Products (DPP) placed IND 134378 on Full Clinical Hold. In addition, DPP issued you a letter dated April 7, 2017, that explained the basis for the hold and detailed recommendations to address the deficiencies with the IND. Among other things, DPP’s letter specifically recommended that subjects with organ (liver or kidney) dysfunction and subjects taking medications with a known interaction with the study drugs be excluded from the study, based on risks of subject safety due to the proposed investigational drugs.
Instead of addressing these deficiencies, you proceeded with a substantially similar clinical investigation of the investigational drugs olanzapine, haloperidol, ziprasidone, and midazolam under Protocol HSR 17-4345, and a follow-up trial of investigational drugs olanzapine and midazolam under Protocol HSR 18-4521, without submitting or having in effect an IND. Moreover, neither Protocol HSR 17-4345 nor HSR 18-4521 addressed the concerns DPP had communicated to you regarding the exclusion of these subjects from the study populations, based on the known risks of the investigational drugs.
Because the administration of the investigational drugs (olanzapine, haloperidol, ziprasidone, and midazolam) in these clinical investigations significantly increased the risks and/or decreased the acceptability of the risks associated with the use of these drug products, the exemption criterion at 21 CFR 312.2(b)(1)(iii) was not met, and you were required to submit and have in effect INDs before initiating these clinical investigations.
In your May 14, 2019, response, you stated that the use of the investigational drugs did not significantly increase the risk or decrease the acceptability of the risk to subjects because the drugs were used “essentially in accord with their approved labeling.” Your statement is factually incorrect, because none of the four drugs used in Protocols HSR 17-4345 and HSR 18-4521 is indicated to treat acute undifferentiated agitation. In any case, your response did not address the fact that study subjects were at significantly increased risk because subjects who should have been excluded from the studies for safety reasons, as DPP had indicated, were not excluded. You also stated in your response that the EM physicians were well trained to care for these subjects receiving these drugs. This, however, does not change the fact that the investigations, by failing to exclude study subjects at significantly increased risk from administration of the investigational drugs, significantly increased the risks or decreased the acceptability of the risks to subjects.
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.
This letter notifies you of our findings and provides you an opportunity to address the deficiencies noted above. 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 address this matter adequately may lead to regulatory action. If you believe that you have complied with the Federal Food, Drug, and Cosmetic Act and FDA regulations, include your reasoning and any supporting information for our consideration.
If you have any questions, please contact Sherry G. Bous, Pharm.D., at 240-402-8176 or CDER-OSI-Communications@fda.hhs.gov. Your written response and any pertinent documentation should be addressed to:
Sherry G. Bous, Pharm.D.
Director
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 5364
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
cc:
Lauren R. Klein, M.D., M.S.
Good Samaritan Hospital Center
Department of Emergency Medicine
1000 Montauk Hwy
West Islip, NY 11795
___________________________
1
Also, neither of these clinical investigations qualified for any of the exemptions listed at 21 CFR 312.2 from the application of 21 CFR part 312. Because you have argued that these clinical investigations were subject to the exemption provided at 21 CFR 312.2(b)(1), we discuss in more detail below the inapplicability of this provision to these clinical investigations.
2
Indeed, FDA has provided guidance on this topic. See FDA’s guidance to industry
Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND
(published in September 2013), at 4, 15 (“For example, a randomized trial evaluating an unapproved use of a lawfully marketed drug is a clinical investigation and may require an IND. In contrast, use of a lawfully marketed drug for an unapproved use in the course of medical practice is not a clinical investigation and does not require an IND because it involves the use in an individual patient where the primary intent is to treat the patient”).
3
We note that, for the same reason, these clinical investigations do not qualify for the exemption from the application of 21 CFR part 312 provided at 21 CFR 312.2(d).
4
See FDA’s guidance to industry
Investigational New Drug Applications (INDs) — Determining Whether Human Research Studies Can Be Conducted Without an IND
(published in September 2013), at 7 (specifically stating that, when considering whether the risk associated with a drug product is significantly increased or the acceptability of the risk is significantly decreased for purposes of 21 CFR 312.2(b)(1)(iii), a population chosen for study could be at increased risk because of decreased renal or hepatic function or because of concomitant therapy).
Content current as of:
10/19/2021
Regulated Product(s)
Drugs