Subsequent to submitting the above Report on April 16, 2007, pursuant to the Florida Public Records Act, (comma) I obtained minutes and tape recordings of the IRB meetings held on April 24, 2006 and March 26, 2007, when my study was discussed and voted upon. A transcript of the recorded IRB meeting of March 26, 2007 is available at the following site:
Reference:
http://www.rsdfoundation.org/en/IRB_Transcript_3_26_07.htm
The tape recording of the March 26, 2007 IRB meeting reveals that Ms. Epley and Dr. Bercu presented incomplete, false and misleading information to the IRB members. These statements were not mistakes by Ms. Epley or Dr. Bercu. They do not represent confusion or ignorance. What they reflect, in my opinion, is an ingrained policy of covering up the truth. This conclusion is supported by verifiable facts.
On March 14 and March 16, 2007 respectively, Ms. Epley and Dr. Bercu, were made aware of my concern about the misstatements of fact in the February 19, 2007 letter to me written by Ms. Epley on behalf of the IRB. The letter purported to justify their conduct and that of the IRB with regard to their actions concerning my clinical investigation, and it was distributed to university officials and faculty. I advised Ms. Epley and Dr. Bercu that “… it is very important that the misstatements of fact contained in your February 19, 2007 letter be addressed and corrected before the IRB proceeds any further.”
Reference:
http://www.rsdfoundation.org/en/Test_IRB.htm#March14_K
http://www.rsdfoundation.org/en/Test_IRB.htm#March16_K
On March 15, 2007, Dr. Bercu informed me that I had until April 20, 2007 to respond to the February 19 letter, and on March 16, 2007 Dr. Bercu acknowledged:
“Tony: We look forward to your response. Barry”.
Reference:
http://www.rsdfoundation.org/en/Test_IRB.htm#March15
http://www.rsdfoundation.org/en/Addendum_1_IRB_Report.htm#March16_B
Despite Dr. Bercu and Ms. Epley having allowed me until April 20, 2007 to correct the misstatements of fact in the letter so that any IRB action would not be based on erroneous information, the IRB met on March 26, 2007 and some of the same misrepresentations were presented to the IRB as facts by Ms. Epley and Dr. Bercu. In addition, at that IRB meeting they falsely portrayed my request for time to respond to the misstatements in the letter as a request for additional time to address 24 items which, they falsely asserted to the IRB members, had been requested of me but I had supposedly ignored. By letter dated March 27, 2007, emailed to me by Ms. Epley on March 29, 2007, Dr. Bercu advised me that the IRB had met and granted me an extension until April 16, 2007 to address this allegedly missing information regarding my investigation.
On March 30, 2007 I wrote to Ms. Epley in protest, and advised her again there were misstatements of fact in her February 19, 2007 letter which I intended to correct:
"The letter from the IRB which you emailed to me on March 29,2007 has nothing to do with the extension I requested. (Copy of your March 29 letter attached)"
"I requested an extension to reply to your February 19, 2007 letter. Copied below is my March 14, 2007 email to you and Dr. Bercu, in which I state, 'In my opinion, it is very important that the misstatements of fact contained in your February 19, 2007 letter be addressed and corrected before the IRB proceeds any further.”
"Dr. Bercu advised me that he did not see a problem with the extension I requested to reply to your February 19, 2007 letter. Copied below is Dr. Bercu’s March 16, 2007 email to me."
"As agreed, I will respond to the misstatements of fact contained in your February 19, 2007 letter, which I believe the IRB would want to consider before making any decisions in this matter."
“It troubles me that you and Dr. Bercu might allow the IRB to proceed with any decision in this matter without first allowing me to address and correct the misstatement of facts in your February 19 letter --- a letter that you wrote on the behalf of the IRB.”
Reference:
http://www.rsdfoundation.org/en/Addendum_1_IRB_Report.htm#March30
The tape recording of the March 26, 2007 IRB meeting clearly discloses that Ms. Epley and Dr. Bercu made no effort to determine the merits of the matter in a fair and objective manner. IRB Policy 205, Section 5.6, prohibits IRB members from participating in a decision when it is difficult to do so with a “non-biased eye” because of a past or ongoing interaction with the investigator.
IRB Policy 205, Section 5.6:
"Personal Relationship: A past or ongoing interaction with the Investigator which would make it difficult for an IRB Reviewer to review the Investigator’s study with a non-biased eye."
On March 26, 2007, Dr. Bercu and Ms. Epley reported to the IRB members that I had filed a “formal complaint” against them. They proceeded, nonetheless, to present information to IRB that was false and misleading to support the closing of my study. No one on the IRB objected to the IRB proceedings on March 26. Ms. Epley and Dr. Bercu led the IRB discussion aimed at closing my study.
Reference
http://www.rsdfoundation.org/en/IRB_Transcript_3_26_07.htm
¶ During the IRB meeting on March 26, 2007, Ms. Epley represented that there were 24 items the IRB requested that I address, and that I never addressed these items. Such a claim is blatantly false. As noted in my April 16, 2007 Report, there were13 minor items that remained to be addressed following the last meeting of the IRB on April 24, 2006. These items were so trivial that the IRB decided, pursuant to USF policy, that they did not need to be brought back before the IRB for final approval. Moreover, Ms. Epley failed to inform the IRB that my study had been approved pending the submission of these minor revisions. This decision by the IRB to approve the study pending minor revisions to be submitted to Dr. Bercu can be found in the minutes to the IRB meeting of April 24, 2006, at the following site:
Reference:
http://www.rsdfoundation.org/en/IRB_Tapes.htm#min8
The false statement about 24 pending revisions generated a strong negative bias against me by the IRB members at the March 26, 2007 meeting. This fabricated, relatively large number of pending revisions was mentioned at least three times during the 16-minute meeting as a major concern. One committee member stated that 24 pending revisions is a “new protocol altogether” and that my aplication should be closed then and there.
Reference:
http://www.rsdfoundation.org/en/IRB_Transcript_3_26_07.htm
¶ During the IRB meeting of March 26, 2007 Ms. Epley and Dr. Bercu were asked several times why I was asking for a 30-day extension.
Reference:
http://www.rsdfoundation.org/en/IRB_Transcript_3_26_07.htm
Instead of telling the truth -- that I requested the time to correct the record so that the IRB could make an informed decision about my study -- Dr. Bercu and Ms. Epley concealed this information from the IRB.The February 19, 2007 letter written by Ms. Epley on behalf of the IRB, to which I wanted to respond and correct material misstatements of fact, was not even mentioned. Nor did they disclose to the IRB that I felt it to be “very important” that the misstatements of fact contained in the February 19, 2007 letter be addressed and corrected before the IRB proceeded any further.
¶ During the March 26, 2007 meeting of the IRB, Ms. Epley and Dr. Bercu proceeded to undermine my judgment and trivialize my concerns about following FDA regulations and policies. They also suggested to the IRB that I was intending to unfairly harm the IRB as well as undermine its authority.
At the meeting, Ms. Epley accused me of challenging the IRB’s authority. She said, “His point is that the IRB does not have the authority to make him go to the FDA and obtain an IND.”This is one of Ms. Epley’s false statements contained in her February 19, 2007 letter (which I pointed out in the April 16, 2007 Report).
At the meeting, Ms. Epley trivialized my concern about following FDA guidelines and regulations for determining IND exemptions. She gave the IRB false information about how the FDA determines an IND exemption, such as with a simple phone call from the investigator. She told the IRB, “He disagrees that an IND is needed. And all you have to do is call FDA and make that determination.”
¶ At the March 26, 2007 meeting, Dr. Bercu warned the IRB that they should give me an extension of time (to furnish the allegedly missing 24 items of information, with no mention that my request was to respond to the misstatements of fact in the February 19, 2007 letter) because, if they did not, it might give me more “potency” in my complaint against the IRB. He told the IRB that they should give me a 30-day extension because if I “fail”, I could not then say the IRB did not give me a chance.,,,, asserting further to the IRB, “as idiotic as that may seem.”
Reference:
http://www.rsdfoundation.org/en/IRB_Transcript_3_26_07.htm
Clearly, at the March 26, 2007 IRB meeting, neither Dr. Bercu nor Ms. Epley had any interest in allowing the IRB members to know of my communication with them up to that time,. In particular, they did not make the IRB aware of my assertion that the IRB’s failure to determine an IND exemption violates FDA regulations, as does the IRB’s “policy” which requires all investigators to file an IND application with the FDA.
The minutes and tape recordings of the April 24, 2006 IRB meeting corroborate that the IRB is acting in violation of FDA Regulations. At that meeting, Dr. Bercu informed me, for the first time, that I must submit an IND application to the FDA so that the FDA would decide an IND exemption, and not the IRB. He attempted to justify this demand for a decision by the FDA, instead of by the IRB:
To "force" the FDA to interpret its guidelines
To "force" the FDA to take a position
To create an "advantage" for the PI for future research
To "safeguard" the PI
All of these reasons given by Dr. Bercu for requiring that I submit an IND application to the FDA violate the letter and the spirit of the applicable FDA regulations.
The IRB must approve a clinical investigation if all the requirements listed in 21 CFR 56.111 of the FDA regulations are satisfied. 21 CFR 56.111(a)(1) requires that risks to subjects be minimized. 21 CFR 56.111(a)(2) requires that risks to subjects be reasonable in relation to anticipated benefits. My study meets those criteria, and on April 24, 2006 the IRB so acknowledged by granting its approval in accordance with 21 CFR 56.111, pending submission of 13 minor revisions to be submitted to Dr. Bercu, with no additional review by the IRB required. According to IRB Policy 809, Subparagraph 5.9.3, IRB approval should haven been a piece a of cake! I needed to simply “concur” with the IRB’s stipulations in order to have my study approved pursuant to 805 - IRB Review Responsibilities: Federal Criteria for IRB Approval.
IRB Policy 809, Subparagraph 5.9.3
"Approval withheld pending minor changes to be reviewed by the IRB Chairperson, Vice Chairperson or a designated IRB member.
Such minor changes must be clearly delineated by the IRB so the investigator may simply concur with the IRB’s stipulations.
The human research may proceed after the required changes are verified and the protocol approved by the designated reviewer."
21 CFR 312.2(a) of the FDA regulations requires an investigator to submit an IND application to the FDA, unless all the requirements for an exemption as set forth in 21 CFR 312.2(b)(1) of the FDA regulations are met, in which case no IND application is required to be submitted. 21 CFR 312.2(b)(1) identifies five requirements for an IND exemption. Requirements 1, 2, 4, and 5, relate to administrative requirements that are not applicableto my study. However, requirement 3 is applicable, and it provides that an IND exemption is appropriate if: “The investigation does not involve a route of administration or dosage level or 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.”
Having already determined an acceptable and reasonable risk to subjects in the course of approving my study under 21 CFR 56.111 of the FDA regulations, it would have been a straightforward matter for the IRB to then agree an IND exemption under 21 CFR 312.2(b)(1) is appropriate. Instead of evaluating the risk to research subjects and determining an IND exemption is appropriate as set forth in the FDA regulations, the IRB has evaluated the perceived risk to itself if it makes a decision, and has decided its own liability exposure is minimized if the FDA is “forced” to decide an IND exemption in every case. The minutes and recordings of the IRB meetings where my study was considered are totally devoid of any discussion of the criteria for exemption set forth in the FDA regulations.
In fact, the tape recording of the IRB meeting on April 24 demonstrates that I pleaded with the IRB at least three time to consider risk to human subjects pursuant to IND exemption Regulation 21 CFR 312.2(b)(1) as a basis for filing an IND but each time Dr Bercu cut me off in a middle of my sentence and demanded that I go to the FDA for reasons that have noth to do with risk to research subjects.
Instead of considering the interests of the patient population that the study is designed to benefit, the IRB has focused on the interests of the IRB and USF by requiring an IND application to the FDA in every instance. Clearly, this is not what is contemplated by FDA regulations.
The FDA maintains that it does not have authority to limit liability of IRBs or their members. The Agency maintains that "compliance with FDA regulations may help minimize an IRB's exposure to liability."
http://www.fda.gov/oc/ohrt/irbs/faqs.html
Dr. Bercu and the IRB appear to rely on USF Policy No. 404, “Use of Investigational Drugs and Biologics”, as justification for their requirement that the FDA make the decision regarding IND exemption in every case. Paragraph 7 of USF Policy No. 404 does in fact state that the investigator in every study must request an IND or IDE from the FDA, and must further provide an IND Number or letter from FDA exempting approval. The same Policy also states in paragraph 6.4 :
"6.4 IRB Responsibilities: IRB is responsible for applying all federal regulations applicable to the use of investigational drugs and biologics, found in:
6.4.2 21 CFR 56
6.4.3 21 CFR 312
While on the one hand the policy recognizes the legal obligation of the IRB to comply with the FDA regulations governing IND exemption, on the other hand the policy purports to opt out of regulations the IRB apparently does not like.
The IRB’s attempt to abrogate its obligation to comply with FDA regulations by adopting a “policy” is misplaced at best, unlawful at worst. Compliance with the law as embodied in the FDA regulations is mandatory, not optional at the election of the IRB.
Pursuant to 21 CFR 312.2(b)(4) of the FDA regulations, the FDA will not accept an IND for an investigation that is exempt. By not accepting an IND for an exempt investigation, the FDA is clearly relying on the IRB to perform its responsibilities under the law and decide if a study is exempt by properly applying 21 CFR 56.111 and 21 CFR 312.2(b)(1).
On May 11, 2007 I received email correspondence from Mr. Joseph P. Griffin, [ADD HIS TITLE] of the FDA. In response to questions I posed, Mr. Griffin states:
“IRB’s make an independent assessment of the acceptability of the risks and potential benefits of a planned clinical study. However, IRB’s will often want to know whether a drug study is being done under an IND, and if not, whether there is a defensible rationale for doing the study without an IND. If an IRB is uncertain about the need for an IND, it will often direct the sponsor/investigator to ask FDA whether an IND would be needed."
Mr. Griffin clearly asserts the regulatory obligation of every IRB to independently assess the risks/benefits of a planned study. My study is not a case of the IRB being uncertain about an IND exemption after assessing it, and then directing that the FDA be queried. Here, the IRB has violated FDA regulations by adopting a policy that requires every investigator to file an IND application with the FDA, in order to “force” the FDA to make the exemption decision and lift that responsibility off the shoulders of the IRB.
As stated by Mr. Griffin in his letter, FDA can bring an enforcement action against an IRB or otherwise compel compliance with FDA regulations if it determines there has been a violation of the regulations. Rather than file a formal complaint with the FDA seeking FDA enforcement of the regulations breached by the IRB, I met with Dr. Bercu on January 2, 2007 and attempted to point out the violations in the hope that an amicable resolution could be reached. It is unfortunate that he and Ms. Epley have chosen to respond to the concerns I have expressed with untruths, misstatements of fact, and misstatements of law.
Sincerely,
Anthony F. Kirkpatrick, MD, PhD
CC: William Marshall MD, Associate Dean, USF Health
Alan Goldman MD, Chairman, Department of Internal Medicine, USF Health