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Recipient Name
Roy S. Rubinfeld, M.D.

3131 Connecticut Ave., Apt. 2809
Washington, 20008
United States

Issuing Office:
Center for Drug Evaluation and Research

United States


Department of Health and Human Services logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
  Silver Spring, MD  20993 


Ref: 15-HFD-45-04-01 
Roy S. Rubinfeld, M.D.                                                                     
President, CXL-USA, LLC
11200 Rockville Pike, Suite 150
Rockville, MD  20852
Dear Dr. Rubinfeld:
This Warning Letter informs you of objectionable conditions observed during the U.S. Food and Drug Administration (FDA) inspection at CXL-USA, LLC, conducted August 18 and 19, 2014. Ms. Cynthia Harris, representing the FDA, conducted an investigation and met with you to review CXL-USA’s role as the sponsor of a clinical investigation (Protocol (b)(4). 
This inspection is a part of the 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 the human subjects of those studies have been protected.
At the conclusion of the inspection, Ms. Cynthia Harris presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your September 19, 2014, written response to the Form FDA 483. 
From our review of the Establishment Inspection Report, the documents submitted with that report, and your September 19, 2014, written response to the Form FDA 483, we conclude that CXL-USA did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations. We wish to emphasize the following:
1.      Failure to submit an IND for the conduct of clinical investigations with an investigational new drug that is subject to 21 CFR 312.2(a) [21 CFR 312.20(a), (b) and 312.40(a), (b)].  
In relevant part, the Federal Food, Drug, and Cosmetic Act (FD&C Act) defines the term drug as “articles intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease” and “articles (other than food) intended to affect the structure or any function of the body of man or other animals” [21 U.S.C. 321(g)]. CXL-USA studied the efficacy of (b)(4). As a result, because the (b)(4) was intended for the treatment of (b)(4) meets the definition of a drug under the FD&C Act. 
To market a new drug lawfully, a sponsor must obtain approval of a new drug application or abbreviated new drug application under Section 505 of the FD&C Act [21 U.S.C. 355]. An Investigational New Drug (IND) application allows a sponsor to obtain an exemption from this requirement to distribute an investigational drug [21 U.S.C 355(i)]. FDA regulations require a sponsor to submit an IND application before conducting a clinical investigation of a drug in human subjects, unless the clinical investigation qualifies for an IND exemption.
A marketed drug product is exempt from the IND requirements if all of the following exemption criteria are met:
  • The drug product is lawfully marketed in the United States;
  • 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;
  • 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;
  • 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;
  • The investigation is conducted in compliance with the requirements for institutional review set forth in 21 CFR 56 and with the requirements for informed consent set forth in 21 CFR 50; and
  • The investigation is conducted in compliance with the requirements of 21 CFR 312.7 regarding promotion of investigational drugs.
A person planning to conduct an in vivo bioavailability or bioequivalence study is not required to submit an IND when certain criteria under 21 CFR 320.31 are met.
(b)(4)’s investigational drug, (b)(4), is not a lawfully marketed drug product in the United States, nor is it exempt from the IND requirements.  As a result, before using (b)(4) in a clinical investigation, (b)(4) was required to submit an IND for the drug to FDA, and to have an IND in effect under 21 CFR 312.40.
FDA records indicate that (b)(4) did not submit an IND before conducting the investigation under Protocol (b)(4), a clinical investigation of (b)(4).  We note that human subjects were enrolled at 15 different sites to participate in clinical investigations (initiated in 2009) with the(b)(4). During FDA’s inspection, you stated that (b)(4) is the sponsor for approximately (b)(4) clinical investigations with this unapproved product. 
We acknowledge that in your September 19, 2014, written response, you indicated that (b)(4) submitted an IND to the FDA on September 12, 2014. However, your response is inadequate because as a sponsor, (b)(4) should have obtained an IND before initiating Protocol (b)(4) and enrolling human subjects into Protocol (b)(4).
2.      Failure to ensure proper monitoring of the clinical investigations [21 CFR 312.50; 312.56(a)].
FDA regulations require that sponsors ensure proper monitoring of clinical investigations and ensure that their clinical investigators conduct those investigations in accordance with the general investigational plan and protocols contained in the IND. Our investigation found that CXL-USA failed to ensure proper monitoring of Protocol (b)(4). Specifically, during the inspection you indicated that CXL-USA (1) did not review investigation-related data or records, (2) did not perform any site monitoring, and (3) relied on clinical site “self-monitoring.”
In your September 19, 2014, written response, you indicated that clinical sites conducted self-monitoring “for informed consent signatures, data collection and other similar study tasks.” As a corrective action, you indicated that formal self-monitoring protocols and formal sponsor-monitoring protocols are being developed.
Your written response is inadequate because you did not include a copy of your proposed monitoring plans. As a result, we are unable to determine whether your plans appear sufficient to prevent similar violations in the future. In addition, please note that a sponsor may transfer its obligation to monitor to a contract research organization only, and any such transfer of obligations must be described in writing [21 CFR 312.52].   
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 or will take 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 contact Chrissy J. Cochran, Ph.D., at 301-796-5633; FAX 301-847-8748. Your written response and any pertinent documentation should be addressed to: 
Chrissy J. Cochran, Ph.D.
Branch Chief (Acting)
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 5364
10903 New Hampshire Avenue
Silver Spring, MD 20993
Sincerely yours,
{See appended electronic signature page}
Sean Y. Kassim, Ph.D.
Office Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.

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