Inspections, Compliance, Enforcement, and Criminal Investigations

Thomas S. Tooma, M.D. 11/2/15

  

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

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

 

WARNING LETTER
 
 
 
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
 
 
November 2, 2015                                                                                   
                                                                                                      
Thomas S. Tooma, M.D.                                                               Ref: 16-HFD-45-10-02
NVISION Laser Eye Centers
3501 Jamboree Road, Suite 1100
Newport Beach, California  92660-2956
 
Dear Dr. Tooma:
 
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 June 29 and July 17, 2015. Ms. Diane C. Van Leeuwen and Ms. Vickie L. Anderson, representing FDA, reviewed your conduct as the sponsor- investigator of a clinical investigation (“Study of the Safety and Effectiveness of Photochemically Induced Collagen Cross-Linking at an Irradiance of 18 mW/cm2 in Eyes with Keratoconus or Ectasia”) for the investigational drug riboflavin ophthalmic solution (0.1% and 0.25%). 
 
This inspection is a part of the 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, Ms. Van Leeuwen and Ms. Anderson presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your August 4, 2015, written response to the Form FDA 483.
 
From our review of the FDA Establishment Inspection Report, the documents submitted with that report, and your August 4, 2015, written response, we conclude that you did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations. We wish to emphasize the following:
 
1.    You failed to submit an 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), (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 function of the body of man or other animals” [21 U.S.C. 321(g)].    
 
You studied the efficacy of 0.1% and 0.25% riboflavin ophthalmic solutions, in combination with ultraviolet-A (UVA)-induced cross-linking of corneal collagen, for the treatment of keratoconus or ectasia. As a result, because the ophthalmic solution was intended for the treatment of keratoconus or ectasia, riboflavin ophthalmic solution 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 an abbreviated new drug application under Section 505 of the FD&C Act [21 U.S.C. 355]. An Investigational New Drug application (IND) is the means by which a sponsor obtains 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 part 56 and with the requirements for informed consent set forth in 21 CFR part 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.
 
Your investigational drug, riboflavin ophthalmic solution, is not a lawfully marketed drug product in the United States, nor is it exempt from IND requirements. As a result, before using riboflavin ophthalmic solution in a clinical investigation, you were required to submit an IND for the drug to FDA, and to have an IND that had gone into effect under 21 CFR 312.40.
 
FDA records indicate that you failed to submit an IND before conducting the investigation under the inspected study, a clinical investigation of riboflavin ophthalmic solution. We note that your records show human subjects were enrolled at a minimum of seven different sites, to participate in a clinical investigation (initiated in September 2012) with the UVA light device plus riboflavin ophthalmic solution 0.1% or 0.25%.
 
In the August 4, 2015, written response to the Form FDA 483, you indicated that you offered the surgical procedure for humanitarian/compassionate-use purposes, and that you submitted protocols and informed consent documents to an IRB. You stated that the IRB, the distributor of the riboflavin ophthalmic solution, and other ophthalmologists with whom you spoke did not inform you that an IND was required to conduct this study. You acknowledged, however, that you should have contacted FDA about whether an IND was required.  You stated that in the future, you will never conduct a clinical study without adequate due diligence, including discussion with FDA.
 
Your response is inadequate because you have not yet submitted an IND application to FDA for the inspected study. In addition, as the sponsor of the inspected study, you were required to submit an IND and to have an IND that had gone into effect before initiating and enrolling human subjects into this study. 
 
2.    You failed to ensure proper monitoring of the clinical investigations [21 CFR 312.50 and 312.56(a)].
 
FDA regulations require that sponsors ensure proper monitoring of clinical investigations, and ensure that their clinical investigators conduct the investigations in accordance with the general investigational plan and protocols contained in the IND. Our investigation found that you failed to ensure proper monitoring of the inspected study.  The records associated with the inspected study do not indicate that proper monitoring was performed.
 
In your August 4, 2015, written response to the Form FDA 483, you acknowledged  that you depended on the surgeons to conduct the trial according to protocol, and that you did not have a monitor for this study. In addition, you acknowledged that you were not aware of all that was required of you as a sponsor. 
 
You stated that for the current study, you will hire an experienced monitor to ensure that “all the procedures/protocol in all sites are adequately monitored, all data collected, all consent procedures are followed, etc.” You also stated that in the future, you will hire an experienced monitor to ensure that all study procedures are precisely followed. 
 
Your written response is inadequate because you did not provide your proposed monitoring plan, including a timeline for when the experienced monitor would be hired. As a result, we are unable to determine whether your proposed plan appears sufficient to prevent similar violations in the future. In addition, please note that a sponsor may transfer its obligation to monitor a study to a contract research organization only, and any such transfer of obligations must be described in writing [21 CFR 312.52].
 
3.    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 subjects at the seven study sites who underwent corneal cross-linking and received riboflavin ophthalmic solution in one or both eyes.
 
In the August 4, 2015, written response to the Form FDA 483, you stated that you were not aware that you needed to maintain records of the disposition of the drug. You indicated that in the future, you will maintain drug disposition records for riboflavin ophthalmic solution. 
 
Your written response is inadequate because you did not address how you will maintain drug disposition records for the current study, or for future studies in which you serve as a clinical investigator. As a result, we are unable to determine whether similar violations will be prevented in the future.
 
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 explain the violations noted above adequately and promptly may result in regulatory action without further notice.  If you believe that 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.
Acting Division Director
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,
/S/                                                                       
David C. Burrow, Pharm.D., J.D.
Acting Office Director
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration

Page Last Updated: 11/30/2015
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