Inspections, Compliance, Enforcement, and Criminal Investigations

Targeted Medical Pharma, Inc. dba Physician Therapeutics 3/29/17

 

  

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10903 New Hampshire Avenue
Silver Spring, MD 20993 

 

WARNING LETTER
 MAR 29, 2017
 
 
CERTIFIED MAIL
RETURN RECEIPT REQUESTED
 
                                                                                                              
ATTN:  Kim Giffoni, Director                                                                Ref: 17-HFD-45-03-02      
Interim Chief Executive Officer
Targeted Medical Pharma, Inc.
2980 Beverly Glen Circle, Suite 100
Los Angeles, California 90077
 
Dear Mr. Giffoni:
 
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 14, 2016, and July 1, 2016. Ms. Diane C. Van Leeuwen, representing FDA, conducted an investigation and met with you to review Targeted Medical Pharma, Inc.’s role as the sponsor of the following clinical investigations of the investigational drug (b)(4):
  • Protocol #(b)(4), (b)(4)
  • Protocol #(b)(4),(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. Van Leeuwen presented and discussed with you Form FDA 483, Inspectional Observations. We acknowledge receipt of your July 18, 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 July 18, 2016, written response to the Form FDA 483, Inspectional Observations, we conclude that Targeted Medical Pharma, Inc., 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 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), 312.20(b), and 312.40(a)].
                                                                                                  
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)]. Targeted Medical Pharma, Inc., studied the (b)(4).  Because the product was intended for the treatment of (b)(4), it meets the definition of a drug under the FD&C Act.
 
To market a new drug lawfully, a sponsor must obtain FDA approval of either 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 (IND) application allows a sponsor to obtain an exemption from this requirement in order 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 under 21 CFR 312.2(b). That regulation provides an exemption from the requirement to obtain an IND before initiating a clinical investigation of a drug 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. 
Targeted Medical Pharma, Inc.’s clinical investigations of (b)(4) failed to meet at least the first criterion.  The investigational drug (b)(4), used to conduct Protocols (b)(4) and (b)(4), was a new, unapproved drug, administered to human subjects twice daily over 28 days to (b)(4)(b)(4) is not a lawfully marketed drug product in the United States and therefore was not exempt from the IND requirements. Before using (b)(4) in a clinical investigation, Targeted Medical Pharma, Inc., was required to submit an IND to FDA, and to have an IND in effect under 21 CFR 312.40. FDA records indicate that Targeted Medical Pharma, Inc., failed to submit an IND before conducting the clinical investigations with (b)(4) under Protocols (b)(4) and (b)(4).
 
In your July 18, 2016, written response to the Form FDA 483, you stated, “(b)(4) is a Medical Food used to treat the nutritional deficiencies associated with pain and inflammation. It is not, nor has ever been our intention to apply for a NDA or market (b)(4) as a drug.”
 
The Orphan Drug Act defines medical food as “a food which is formulated to be consumed or administered enterally under the supervision of a physician and which is intended for the specific dietary management of a disease or condition for which distinctive nutritional requirements, based on recognized scientific principles, are established by medical evaluation” [21 U.S.C. 360ee(b)(3)].    
 
The protocols discussed above were designed to investigate the (b)(4).  There are, however, no distinctive nutritional requirements for individuals with (b)(4). Thus, this product is not a medical food under 21 U.S.C. 360ee(b)(3).[1]
 
Furthermore, the FD&C Act defines the term drug (in relevant part) 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)]. We note that (b)(4) is the study product for Protocols (b)(4) and (b)(4), and that both protocols specify that the clinical endpoint is to examine the “(b)(4)” compared to a nonsteroidal anti-inflammatory drug (NSAID).  
 
Because Targeted Medical Pharma, Inc., was studying the effects of (b)(4) to (b)(4), (b)(4) is an article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease and is intended to affect the structure or any function of the human body, and thus meets the definition of a drug under the FD&C Act. As a result, Targeted Medical Pharma, Inc., was required to submit an IND and not to initiate clinical investigations of (b)(4) in human subjects until the IND was in effect.
 
In your July 18, 2016, written response, you also indicated that a Targeted Medical Pharma, Inc., employee reached out to the FDA before the initiation of the clinical studies and was advised, “although these were Medical Foods and no NDA would be applied for, Targeted Medical Pharma should still apply for an IND.” You stated that a Form FDA 1571 and a Form FDA 1572 were submitted to the Agency for each protocol; however, no response was received by FDA.
 
We are unable to undertake an informed evaluation of your written response because you have not provided documentation to confirm FDA receipt of an IND submission for (b)(4). When FDA receives an IND, FDA assigns an IND number to the application and forwards the application to the appropriate reviewing division within the Office of New Drugs. The review division would have sent a letter to Targeted Medical Pharma, Inc., providing notification of the IND number assigned, date of receipt of the original application, address where future submissions to the IND should be sent, and the name and telephone number of the FDA contact person to whom questions about the application should be directed. 
 
There are no FDA records to indicate that Targeted Medical Pharma, Inc., submitted an IND application before conducting the investigations under Protocols (b)(4) and (b)(4), a clinical investigation of (b)(4). We note that 129 human subjects were enrolled at 11 clinical sites for Protocol (b)(4), and that 122 human subjects were enrolled at 8 clinical sites for Protocol (b)(4). Subjects were treated with (b)(4), an unapproved product, twice daily over 28 days for the (b)(4). As a sponsor, Targeted Medical Pharma, Inc., should have obtained an IND before initiating Protocols (b)(4) and (b)(4) and before enrolling human subjects into both protocols.
 
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 explain the violations noted above adequately and promptly may result in regulatory action without further notice.

 
If you have any questions, please contact Adam Donat at 301-796-5316; FAX 301-847-8748. 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.
Office Director (Acting)
Office of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration


[1]See also 21 CFR 101.9(j)(8) and the guidance for industry Frequently Asked Questions about Medical Foods; Second Edition, May 2016, available at https://www.fda.gov/downloads/Food/GuidanceRegulation/GuidanceDocumentsRegulatoryInformation/UCM500094.pdf.

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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.
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/s/
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DAVID C BURROW
03/29/2017
 

Page Last Updated: 04/17/2017
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