My Critique of Orac’s: Stanislaw Burzynski versus regulations protecting human research subjects, revisited

Insolent Insolence

Here we go again

Unlike Orac

(David H. Gorski, @gorskon, @oracknows, @ScienceBasedMed, http://www.scienceblogs.com/Insolence, http://www.sciencebasedmedicine.org, #sciencebasedmedicine)

http://scienceblogs.com/insolence/2013/03/26/stanislaw-burzynski-versus-regulations-protecting-human-research-subjects-revisited

let’s compare Burzynski’s IRB to OTHER IRB’s

2/28/2013 – CoreValve

several cases in which site failed to obtain informed consent document (ICD)

2 cases – patients underwent CT angiography as screening procedure for trial without having signed screening ICD

3 cases – patients randomized into trial without having signed procedure ICD

investigator’s failure to notify within 5 days the sponsor or reviewing IRB of significant events

2 deaths
4/28/2011 – 1
5/11/2011 – 1
not reported to IRB until 10/21

2 cases – patients in trial underwent emergency procedures that deviated from trial protocol

1 case – no notification reported
1 case – deviation not reported for 5 weeks

“failure to maintain accurate, complete, and current records relating” to trial

http://www.forbes.com/sites/larryhusten/2013/02/28/fda-issues-warning-letter-to-corevalve-investigator

2/12/2013 – FDA Warning Letters to Institutional Review Boards

http://www.circare.org/FOIA/irblast.htm

11/29/2012 – Salem Hospital IRB

1. IRB failed to prepare and maintain adequate documentation of IRB activities

IRB is required to prepare and maintain adequate documentation of IRB activities including, but not limited to, copies of all research proposals, progress reports submitted by investigators, and all correspondence between IRB and investigators

IRB failed to adhere to requirement

Specifically, the IRB does not retain copies of the following:
a. Original protocols
b. Revised protocols
c. Informed consent documents
d. Protocol amendments
e. Progress report submissions, including all attachments
f. Correspondence between investigators and IRB

2. IRB failed to prepare and maintain adequate documentation of written procedures for IRB

IRB is required to prepare and maintain adequate documentation of written procedures for variety of IRB functions and operations

IRB failed to adhere to requirements

Specifically, IRB policies and procedures do not include written procedures to adequately address following functions and operations:

Conducting initial and continuing review or research;

Ensuring changes in approved research, during period for which IRB approval already given, may not be initiated without IRB review and approval except where necessary to eliminate apparent immediate hazards to human subjects; and

Ensuring prompt reporting to IRB, appropriate institutional officials, and FDA of any serious or continuing noncompliance with regulations or requirements or determinations of IRB, or any suspension or termination of IRB approval

3. IRB failed to prepare and maintain list of IRB members identified by name; earned degrees; representative capacity; indications of experience sufficient to describe each member’s chief anticipated contributions to IRB deliberations; any employment or other relationship between each member and institution

IRB is required to maintain list of IRB members

IRB failed to adhere to requirement

IRB didn’t update roster when membership changed between 12/3/2008 and 3/21/2011
Specifically:

a. IRB meeting minutes 1/21/2009, indicate (b)(6) is present as IRB member

IRB meeting minutes 7/22/2009 announce (b)(6)’s resignation from IRB

IRB roster 12/3/2008 – 3/21/2011 doesn’t list (b)(6) as member of IRB

b. IRB meeting minutes 10/21/2009 indicate (b)(6) approved to become IRB member

IRB meeting minutes 1/20/2010 list (b)(6) as IRB member and show her voting on IRB activities

IRB roster 12/3/2008 – 3/21/2011, doesn’t list (b)(6) as member of IRB

IRB membership rosters aren’t updated as changes in membership occur

Therefore, FDA may not be able to determine that IRB is duly constituted as required

4. IRB failed to review proposed research at convened meetings at which majority of members of IRB are present, including at least one member whose primary concerns are nonscientific areas

Except when expedited review procedure used, IRB may only review proposed research at convened meetings at which majority of IRB members present, including at least one member whose primary concerns are nonscientific areas

IRB failed to adhere to requirements
Specifically:

a. IRB minutes 3/18/2009 indicate 6 of 8 IRB members present

2 IRB members recused themselves during initial review and vote for Study

study approved with less than majority of members present

b. IRB minutes 4/21/2010 indicate 5 of 8 IRB members present

One IRB member recused himself during initial review and vote for Study

study approved with less than majority of members present

c. IRB minutes 10/20/2010 indicate 5 of 8 IRB members present

One IRB member recused himself during review and vote for protocol and informed consent document changes for Study

changes approved with less than majority of members present

maintenance of IRB rosters is important part of IRB activities in that it provides documentation of current membership

appropriate roster maintenance helps ensure proper # of members present at IRB meetings when approving research activities

5. IRB failed to follow FDA regulations regarding expedited review procedures

FDA regulations require under expedited review procedure, review may be carried out by IRB chairperson or one or more experienced reviewers designated by IRB chairperson from among members of IRB; and IRB may use expedited review procedure to review either or both of the following:

(1) Some or all of research appearing on Federal Register list of categories of research eligible for expedited review and found by reviewer(s) to involve no more than minimal risk; or

(2) minor changes in previously approved research during period for which approval authorized.

as stated in Federal Register notice, expedited review procedure may be used for continuing review as follows:

a. Where

(i) research is permanently closed to enrollment of new subjects;

(ii) all subjects have completed all research-related interventions; and

(iii) c research remains active only for long-term follow-up of subjects; or

b. Where no subjects enrolled and no additional risks identified; or

c. Where remaining research activities are limited to data analysis

IRB failed to comply when used expedited continuing review for research not eligible for approval through expedited review procedure

IRB meeting minutes 1/21/2009 indicate continuing review for Study was conducted by expedited review

memorandum from Clinical Investigator, 12/23/2008, requesting annual review for study indicates study was open to enrollment and 4 subjects were currently enrolled

continuing review of Study wasn’t eligible for expedited review

IRB’s written response 7/11/2012 acknowledges validity of each of the violations listed

response states that IRB will develop new written procedures to address each violation

However, draft procedures weren’t submitted with response and will not be available until 2/28/2013

IRB’s response inadequate because it doesn’t describe process that IRB will use to train and educate IRB members, staff, and clinical investigators with respect to new written procedures

Without information, FDA cannot conduct informed evaluation of proposed corrective and preventive action’s potential ability to prevent recurrence of these or similar violations in future

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm330799.htm

9/24/2012 – Texas Applied Biomedical Services IRB

determined that IRB significantly violated applicable federal regulations governing operation and responsibilities of IRBs (available at

http://www.gpoaccess.gov/cfr/index.html)

This letter requests prompt corrective action to address the violations cited and discusses your IRB’s written response to noted violations

applicable provisions are cited for each violation

1. IRB failed to ensure no member participated in initial or continuing review of project in which member had conflicting interest

TABS RRC procedures manual, RRC Membership, states no member of Committee shall be involved in either initial or continuing review of activity in which he or she has conflicting interest, except to provide information requested by reviewing body

meeting minutes 1/26/2012 show 2 committee members, including you as Chairperson, participated in initial review and approval of clinical studies sponsored by (b)(4) (hereafter, (b)(4)) in which members had conflict of interest

Both you and (b)(6) voted to approve protocols sponsored by (b)(4) even though you both provided consulting services to (b)(4), assisting with writing protocols and informed consent documents, for which payment was requested

In your letter, you disagree with observation that TABS IRB members had conflict of interest with review of clinical studies

You explain that one of IRB committee members assisted in initial drafting of clinical study protocols and consulting services provided to (b)(4) by Texas Applied Biomedical Services and/or J Heinrich Consulting are not conflicts of interest

You further explain that consulting services provided “were maintained separate and apart from any TABS Research Review Committee functions and actions.”

We disagree with explanations

2 members in question had conflicting interest when they participated in initial review and approval of protocols and informed consent documents, which they assisted in drafting

Conflicting loyalties, whether conscious or not, may influence IRB’s deliberations

2. IRB failed to prepare, maintain and follow written procedures for conducting initial and continuing review of research

IRB doesn’t have written procedure regarding IRB’s method of reviewing protocols and consent forms to ensure safeguards in place for children who participate in clinical study

meeting minutes 1/8/2012 show IRB approved investigational (b)(4) study involving children (b)(4) years old

In your letter, you acknowledge that TABS RRC hadn’t previously reviewed clinical investigational research studies involving pediatric subjects

You also state that SOP (standard operating procedure) will be written addressing pediatric clinical studies

3. IRB failed to fulfill membership requirements

IRB didn’t possess professional competence necessary to provide complete and adequate review of specific research activities
For example:

A. 1/8/2012 IRB reviewed and approved investigational (b)(4) study involving pediatric and adult subjects with disorders of (b)(4)

Review of IRB’s records indicates IRB lacked professional competence necessary to review study and determine whether it met criteria for approval, including whether risks to subjects were “reasonable in relation to anticipated benefits, if any, to subjects, and importance of knowledge that may be expected to result.”

IRB didn’t include individual with professional competence in treatment of (b)(4) disorders (e.g., a physician), nor is there any documentation to show that IRB invited individuals with competence in this area to assist in review of this study

B. 1/26/2012 IRB reviewed and approved 2 studies involving subjects

IRB did not include individual with professional competence (e.g. a physician) in treatment of (b)(4), nor is there documentation to indicate IRB invited individuals with competence in this area to assist in review of study

In your letter, you disagree with this observation

You explain that TABS IRB doesn’t have medical doctor as active, regular voting member of committee, but committee has access to core group of medical advisors that provide expertise and input for any and all clinical research studies committee encounters

Your letter states independent consultant with extensive experience in (b)(4) research was consulted when IRB reviewed and approved 2 studies involving subjects

meeting minutes 1/26/2012 failed to include documentation of any consult with specialist that was taken into account by IRB committee in decision to approve studies

4. IRB failed to determine that pediatric study is in compliance

Under Additional Safeguards for Children in Clinical Investigations, IRBs are required to review clinical investigations involving children as subjects and approve only those clinical investigations that satisfy criteria within certain risk categories

A. meeting minutes 1/8/2012 show IRB reviewed and approved investigational study involving children

meeting minutes don’t document IRB’s determination of level of risk involved, potential for direct benefit, likelihood of yielding generalizable knowledge about subjects’ disorder or condition, and opportunity to understand, prevent, or alleviate serious problem affecting health or welfare of children

B. meeting minutes 1/8/2012 don’t document IRB discussed and/or determined adequate provisions made for soliciting assent of children involved in investigational study

In your letter you state that all future studies involving pediatric subjects will be more closely scrutinized

Also in your letter you reference FDA Guidance for IRBs and Clinical Investigators – Informed Consent Document Content which provides FDA doesn’t require informed consent document to contain space for assent by children

We don’t accept your explanation

observation on Form FDA 483 doesn’t speak to whether FDA requires Informed Consent document to contain space for assent by children

Instead, FDA investigator observed IRB failed to determine at time of initial review that research study was in compliance

requires IRBs to find and document clinical investigations involving children as subjects meets requirements

meeting minutes 1/8/2012 fail to document additional requirements for review of study involving pediatric subjects

5. IRB failed to prepare and maintain adequate documentation of IRB activities

A. IRB didn’t maintain meeting minutes for 2011

During inspection you told FDA investigator IRB met twice in 2011

According to study list, protocol was modified and approved 8/24/2011 but no meeting minutes were available for review documenting IRB’s activities

In your letter, you confirm there are no meeting minutes for 2011 during which 2 meetings were held

You explain that due to computer crash all minutes and data for time frame were lost

You stated you would “re-create” meeting minutes and provide at later date

It is inappropriate and unacceptable record keeping practice for IRB to re-create minutes for 2011

B. IRB failed to maintain meeting minutes with sufficient detail to show actions taken by IRB and vote on actions

meeting minutes 1/8/2012 fail to show which IRB members present at meeting voted for, against or abstained

IRB reviewed and approved investigational study during 1/8/2012 meeting however meeting minutes don’t document that IRB reviewed and agreed with sponsor’s determination of risk status of investigational to be used in study

In your letter, you stated there was oversight in transcription for 1/8/2012 meeting minutes in recording each member’s vote

Your letter also states you will ensure more complete minutes in future meetings by assigning clerical person to act as recording secretary for IRB meeting

IRB’s failure to maintain meeting minutes is repeat violation identified in last 2 FDA inspections conducted 2007 and 2000

C. IRB failed to maintain IRB membership rosters for 2008 – 2012

IRB membership rosters don’t identify members by representative capacity and employment or other relationship between each member and institution

This is repeat violation identified during FDA inspection in 2000

In your letter, you submitted a revised membership roster 5/11/2012

revised roster fails to comply with regulations because it doesn’t indicate you are affiliated member though you are president of TABS, Inc. and Chairperson of TABS RRC

In addition, (b)(6) is listed as non affiliated member, but immediate family members of employee of institution can’t be deemed nonaffiliated

Based on repeated deficiencies found during last 3 inspections, we have no assurance IRB procedures are adequately protecting rights and welfare of human subjects of research

For this reason, and effective immediately,

· FDA will withhold approval of all new studies and reviewed by IRB; and

· No new subjects are to be enrolled in any ongoing studies and approved by IRB

restrictions will remain in effect until such time as FDA has evidence of adequate corrective actions and notifies you in writing that IRB’s corrective actions are satisfactory.

restrictions don’t relieve IRB of responsibility for receiving and reacting to reports of unexpected and serious reactions and routine progress reports from ongoing studies

http://www.fda.gov/iceci/enforcementactions/warningletters/UCM323868

FDA Warns Stem Cell Company Over Violations

Last April, the FDA inspected

Celltex Therapeutics

9 pages:

http://www.pharmalive.com/fda-warns-stem-cell-company-over-violations

Control procedures are not established which validate the performance of those manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product
Specifically,

You’ve manufactured (mesenchymal stem cells) MSC’s which you’ve released for distribution at least X times between 7/1/11 – present, however:

A. You haven’t performed a process validation for manufacturing MSC’s to assure batch uniformity and integrity as related to each of the following finished product characteristics: viability of cells, the specified cell count, cell type, and appearance of cells
B. You haven’t performed analyses on the final product to assure (b)(4) of the (b)(4) (b)(4) the final MSC’s
C. You haven’t verified the final product to assure the identity of the cell type in the final MSC’s
D. You haven’t performed assay to verify the MSC’s
E. you haven’t performed installation qualification, operational qualification, and performance qualification on the biological safety cabinets, the incubators, and the centrifuges
F. You haven’t performed a validation of your banking and thawing process to assure viability of MSC’s
G. You have no requirement for pressure differential between the clean rooms and the exterior rooms to assure that non-controlled air dose does not flow in the cleanrooms
H. You haven’t monitored the temperature or humidity of the processing rooms where you manufactured MSC’s

manufacturer’s manual for biological safety cabinets states they should be operated in environmental conditions of a (b)(4)

Procedures designed to prevent microbiological contamination of drug products purporting to be sterile aren’t established, written, and followed
Specifically,

You’ve manufactured MSC’s which you released for distribution at least X times between 7/1/11 – present

MSC’s are intended to be administered to patients either intravenously or injected intra-articularly and must be sterile

The inspection revealed:

A. You’ve failed to validate aseptic MSC’s manufacturing process in order to prevent microbiological contamination

Sterility test failures have occurred of the following MSC’s: (b)(4), (b)(4), and (b)(4)
B. You’ve not validated your aseptic gowning process in order to prevent microbiological contamination

there’s no data to support validation/qualification of autoclave cycle

autoclave is used to sterilize gowning wardrobe (lab coat) and parts of incubators

C. You’ve not performed environmental swabbing of biological safety cabinets as part of environmental monitoring program

study hasn’t been performed to assure adequate air flow pattern underneath biological safety cabinet

biological safety cabinets used to aseptically manufacture MSC’s

D. Environmental test results of clean room, biosafety cabinets, and gowning area show isolation of microorganisms as result of use of settling plates

Some microbiological counts documented are beyond established specifications

There’s no data to show microorganism isolated have been identified or investigated

Written records are not made of investigations into the failure of a batch or any of its components to meet specifications

Specifically,

A failure investigation wasn’t performed for the following out of specification results and/or failures to determine the underlying reason or source of the failure

A. Sterility Testing: Sterility test results show the following MSC’s failed initial and repeat testing for sterility: (b)(4) and (b)(4)

The following MSC’s failed initial sterility before testing: (b)(4) and (b)(4)

B. Endotoxin Testing: Endotoxin test results show the following MSC’s units failed initial endotoxin testing on 12-20-11, on 12/7/11, and on 11-10-11

C. Environmental Testing: Bacteria and Fungi tests have been exceeded for the BSC-(Biosafety Cabinet-CleanRoom Gowning Area, (CleanRoom) (CleanRoom and BSC) (Biosafety Cabinet-Clean Room) BSC-M (Biosafety Cabinet-Manufacturing), BSC-Q (Biosafety Cabinet-Quality Control), CleanRoom

In addition there is no written procedure for conducting failure investigations

Drug product production and control records, are not reviewed by the quality control unit to determine compliance with all established, approved written procedures before a batch is released or distributed

Specifically,

You manufactured MSC’s you released for distribution at least X times between 7/1/11- present

you haven’t reviewed all manufacturing records, test records, endotoxin test records, or sterility test records prior to the release for distribution of the MSC’s that you manufactured as evidenced by the following:

A. inspector signature line on manufacturing record 10-20-11 blank

According to outgoing log MSC’s released for intravenous infusion 10-21-11

B. inspector signature line on manufacturing record 7-26-11 blank

According to outgoing log MSC’s released for intravenous (IV) infusion 10-11-11

C. inspector signature line on manufacturing record 10-6-11 blank

According to outgoing log MSC’s released for intravenous (IV) infusion 10-7-11

Batch production and control records don’t include complete information relating to production and control of each batch

Specifically:

A. You don’t document the addition of (b)(4) to your (b)(4) and (b)(4) media used in the manufacture of MSC’s

B. You don’t document the addition of (b)(4) to the (b)(4) media used for banking of MSC’s

C. You don’t document the checks of culture-expansion flasks of MSC’s for evidence of contamination

D. Manufacturing records lack required signatures

http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2012/ucm323853.htm

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4 thoughts on “My Critique of Orac’s: Stanislaw Burzynski versus regulations protecting human research subjects, revisited

  1. Seriously, this has to be one of the worst arguments on the internet. My 8 year-old could do better.

    Didymus, Stan Burzynski has been caught out once again for incorrect practice between his IRB and the clinic. This is a bit more than not following the rules. This is about approving enrollment of patients for treatment without an assessment of the potential harm. Such an exercise is an ethical failure. Scouring the internet for examples where IRB’s from other organisations have broken the rules does not make it OK for Burzynski to break the rules.

    The fact that you seem to think it is, says a fair bit about your moral fibre.

    • ChrisP, thank you for your comments

      I was hoping you we’re going to allow your 8-year old to reply

      Some critics were calling for the clinic to be closed over this

      My attempt was to bring reason to the issue and demonstrate that there are Institutional Review Boards (IRB’s) that have more issues than Burzynski

      So, if one is going to be fair and rational about the issue would require that all the IRB’s that have more issues than Burzynski, be shut down first

      Another issue raised was that the clinical trial should be stopped as was done in the case of another IRB

      However, the FACT is that that IRB had its trial stopped because it had responded to the FDA and the FDA had found the response unacceptable

      At this time we do NOT know Burzynski’s response to the FDA, and what the FDA’s reaction will be

      However, we do know the FDA has been on-site at the Clinic

      The fact that you seem to think that I think it is okay, says a fair bit about your moral fibre.

      • I asked my 8 year old and they responded with “woof woof”.

        The FDA do not have the power to close the clinic. What they should do is what they did with Texas Applied Biomedical Sciences and ban them from running trials. that would make all of Stan’s off-label treatments illegal.

        Simples

        Woof Woof Woof (That was my 8 year old again)

      • I see your reply has “gone to the dawgs”

        And I can see why

        1. The FDA should take the IRB’s reply under consideration before a decision is made, and like the example you refer to, the reply from the IRB should NOT be satisfactory to the FDA as being responsive to the FDA’s points

        2. Exactly WHICH Clinical Trial(s) are you going to stop ? The one(s) that have already been completed by the Clinic ?

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