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Released by FDA:  12/19/05.  Posted by FDA:  1/11/06

Raymond E. Tidman, M.D.
101 Riverstone Vista
Suite 206
Blue Ridge, Georgia 30513

Dear Dr. Tidman:

Between April 21 and 29, 2003, Ms, Stephanie E. Hubbard, representing the Food and Drug Administration. (FDA), conducted an investigation and met with you to review your conduct of a clinical investigation (protocol #L [deleted by FDA] entitled: "A Multicenter, Investigator-Blinded,  Randomized Study to Compare the Safety and Efficacy of IV Daptornycin with That of Vancomycin or a Semi-Synthetic Penicillin in the Treatment of Complicated Bacterial Skin and Soft Tissue Infections Due to Gram-Positive Bacteria") of the investigational drug [deleted] now known as Cubicin (daptomycin for injection), performed for Cubist Pharmaceuticals , Inc.  This inspection was a part of FDA's Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to ensure that the rights, safety, and welfare of the human subjects in the study have been protected.

At the conclusion of the inspection, Ms. Hubbard presented and discussed with you the items listed on the Form FDA 483, Inspectional Observations.  Based on our evaluation of the information obtained by the agency and your April 30, 2003, written response to the inspectional observations, we conclude that you violated the Federal, Food, Drug, and Cosmetic Act (the Act) and FDA regulations governing the use of investigational new drugs, by your Failure to protect the rights, safety, and welfare of human subjects and failure to adhere to the investigational plan.  We wish to emphasize the following:

1.  You failed to protect the rights, safety, and welfare of subjects under your care [21 CFR 312.60].

a.  For monitoring the safety of subjects, the protocol required that hematology, serum chemistries (including creatinine phosphokinase (CPK)), and urinalysis be obtained at study admission (Day 1) and at the end-of-therapy (EOT) visit, and that serum CPK be monitored throughout the study (Day3,.Day 5, Day 7, and daily thereafter, if drug therapy was continued beyond 7 days).

In addition, the protocol provided detailed instructions about what to do if subjects experienced elevated CPI levels:

"If CPK levels exceed the upper limit of normal by twofold at any time of the central laboratory will automatically evaluate CPK isoenzymes to determine if the elevated fraction is M/M.  Venous blood samples will then be obtained on a daily basis and sent to central laboratory for CPK monitoring (i.e., CPK will be determined each day, with other serum chemistries determined every other day).  If CPK levels subsequently decline to within the normal range, then venous blood samples be obtained according to the original schedule.  If CPK levels exceed [deleted] U/mL, the unblinded investigator will call the medical monitor.  A decision to discontinue or continue the subject will be jointly made and will be based on the risk/benefit of continued therapy for the subject.  If the subject continues in the trial and CPK levels increase another twofold, the subject must be withdrawn from the study and CPK isoenzymes, serum myoglobin, and urinary myoglobin will be evaluated at the termination visit." (emphasis in original)

Despite the importance for subject safety of monitoring CPK levels, and the protocol's explicit requirements to do so, you did not obtain all required CPK levels, or other required laboratory results for any subject you enrolled (see table below).  For some subjects, you failed to obtain most of the required CPK levels.  Elevations in scrum CPK activity provide an early indication of muscle toxicity and rhabdomyolysis, a disease resulting from skeletal muscle injury with release of muscle fiber contents into the systemic circulation that may lead to kidney failure.  Failure to obtain required laboratory results may have exposed your subjects to an increased and unnecessary risk of serious toxicity.

* EOT = End-of-Therapy
** See violation 2.e below

b.  The protocol excluded subjects who mere caking HMG Coenzyme A reductase inhibitors (statins).  There is an established association between statins and incidence (albeit rare) of rhabdomyolysis, and a possible association with the study drug.  Subjects168145 was taking Lipitor (a statue) at the time she was enrolled in the study and continued to take it throughout her participation in the study.  Exposing this subject to two drugs with the potential to cause this condition may have increased this subject's risk of serious toxicity.

2.  You failed to adhere to the protocol [21 CFR 31,160].

h.  The protocol inclusion criteria required that specimens for a Gram stain be obtained from subjects < 48 hours prior to initialing study drug.  For subject 168147, the Gram stain was obtained one day after starting the study drug.   In addition, for subject 168153, the Gram stain was obtained three days after starting the study drug.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug.  Your written response to the 483 dated April 30, 2003 attributed most of the deficiencies to the study coordinator or the hospital laboratory, and you stated that you planned to ensure more strict compliance in the future; we do not find your explanations acceptable in addressing the matters under complaint.  It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations.  You must address these deficiencies and establish procedures to ensure that any on-going or future studies will be in compliance with FDA regulations,

Within fifteen (15) working days of your receipt of this letter, please notify this office in writing of the actions you have taken or will be taking to prevent similar violations in the future.  Failure to adequately acid promptly explain the violations noted above may result in regulatory action without further notice.

If you have any questions, please contact Leslie K. Ball, M.D., at (301) 927-5455, FAX (301) 827-5290.  Your written response and any pertinent documentation should be addressed to:

Leslie K. Ball, M.D.
Branch Chief
Good Clinical Practice Branch 11, HFD-47
Division Of Scientific Investigations
Office of Medical Policy
Center for Drug Evaluation and Research
7520 Standish Place
Rockville, MD 20855

Sincerely yours,

Joanne L. Rhoads, M.D., MPH
Director
Division of Scientific Investigations, HFD-45
Office of Medical Policy
Center for Drug Evaluation and Research