Documents released by the University of Calgary, Alberta CA, under the Freedom of Information and Protection of Privacy Act. Access Request 01-010, filed 2001-09-12.
Munn Gafuik J-A. University of Calgary Response to Access Request 01-010. 2001-11-07. Available from http://www.circare.org/FOIA/ucati_01-010.pdf
Pages 1 and 2: Documents / disclosures requested.
Pages 3 – 5: Disclosure decisions 1 – 20.
Disclosure request 8:
Disclosure of funding for adult open label study.
Disclosure Decision 8:
No such record exists because there was no funding for these protocols.
Published information contradicts this: Dr. Kaplan lists the following sources of support for the adult open label study:
Supported in part by the Alberta Children's Hospital Foundation and the Alberta Science and Research Authority; and Evince International, Farmington, Utah (who provided E M Power+ supplement free of charge.)
Source: P. 936, in: Kaplan BJ, Simpson JS, Ferre RC, Gorman CP, McMullen DM, Crawford SG. Effective mood stabilization with a chelated mineral supplement: An open-label trial in bipolar disorder. J Clin Psychiatry. 2001;62(12):936-944.
Why does Dr. Kaplan's published statement disagree with information released by the University of Calgary on the funding source? How is it that research funds reserved for pediatric research end up supporting a clinical trial with adult subjects?
Dr. Kaplan mentioned an industry partner
in her re-application for funding to the Alberta Science and Research Authority — Melaleuca Inc. Where did Melaleuca disappear to and why?
Source: Meleuca Inc., p.2, in: Alberta Innovation and Science Disclosure / Bonnie J. Kaplan Ph.D. Re-application for funding for study titled Nutraceutical Treatment of Mental Illness. 1999-03-30. Available from http://www.circare.org/FOIA/asraati_bjkappl2.pdf
Along with the funding award of $500, 000, an industry contribution was announced totaling more than $400,000, according the agency's standard practice of leveraging
research investments. Given that funds were awarded in expectation of this industry contribution, and given that the industry partner mentioned in the funding application is nowhere to be found, some people might reasonably wonder where the industry money might be, and what the provincial government of Alberta understands about this, or whether there isn't a large hole in the province's wallet.
Disclosure request 20:
Name of manufacturer who made the placebo for studies titled
Nutraceutical Treatment of Mental Disorders in Adults: an RCT with Bipolar DisorderandRandomized Controlled Trial of a Nutrient Supplement in the Treatment of Fibromyalgia.
Disclosure response 20:
Cornerstone Nutritional Labs manufactured the placebo.
This is troubling for a number of reasons. The SIC information for Cornerstone, [2099: Food Preparations NEC, and 7389, Business Services NEC; PRI-SIC: 208702 Beverage Powders (Manufacturer), 2ND-SIC: 514914 Health Food Products-Wholesale], give no indication of capacity for pharmaceutical manufacturing — nor does Cornerstone Nutritional Labs make this claim. And this is not to suggest that Cornerstone Nutritional Labs is anything other than a fine manufacturer of food products, under which so-called dietary supplements fall according to FDA regulation. It is, however, to suggest that placebo manufacture is best done by an experienced pharmaceutical provider. Likewise blinding and coding of active and placebo agents for clinical trials is best done by a pharmacist with specialized training or experience, or by a research pharmacologist. When lives are on the line, anything less seems reckless. Given the pungent smell of EmpowerPlus, it's likely making a placebo with the same smell (to maintain the blind) would be extremely difficult.
Unlike Cornerstone Nutritional Labs, Evince International claimed:
Our products are pharmaceutical grade in quality, efficacy and scientific substantiation.
Source: About Evince. 2002-06-27. Available from http://web.archive.org/web/20020205030046/www.evince.org/aboutevince.html
This is misleading at best. Inasmuch as Evince claims to be actively recruiting research subjects, it's indefensible to mislead them about the nature of the investigational product you're hoping to test on them. It's also difficult to understand the basis or motivation of this assertion because Evince International and Cornerstone Nutritional Labs have corporate officers in common [Mssrs Brower and Ballard].
Documents released by the University of Calgary, Alberta CA, under the Freedom of Information and Protection of Privacy Act. Access Request 01-015, filed 2001-11-26.
Munn Gafuik J-A. University of Calgary Response to Access Request 01-015. 2002-02-25. Available from http://www.circare.org/FOIA/ucati_01-015.pdf
Pages 2 – 4: Disclosures requested.
Pages 5 – 7: Disclosure decisions.
Disclosure request 1:
Number of pediatric subjects completing study titled
A double blind case controlled study of the effects of a vitamin and mineral supplement as an adjunctive therapy for Attention Deficit Hyperactivity Disorder,data from which was offered to prospective research participants in the informed consent for the study titledRandomized Controlled Trial of a Nutrient Supplement in the Treatment of Fibromyalgia.
Disclosure response 1:
12 children completed the study.
This conflicts with information entered in the University of Calgary's database of Cumulative Summary of Closed Protocols (prior to 2002), which records a total of 12 children enrolled, 7 of whom dropped out, and only 5 of whom completed the trial.
Source: University of Calgary Cumulative Summary of Closed Protocols. 2002-09-12. Available from http://web.archive.org/web/20060127012609/http://www.ucalgary.ca/md/CAH/research/files/reports/CumulativeClosures_pre02.html
Disclosure request 6 (d):
Name of manufacturer of the investigational product used in study titled
Randomized Controlled Trial of a Nutrient Supplement in the Treatment of Fibromyalgia.
Disclosure response 6 (d):
Evince International LLC.
Disclosure request 6 (e):
Name of manufacturer of the investigational products used in study titled
A double blind case controlled study of the effects of a vitamin and mineral supplement as an adjunctive therapy for Attention Deficit Hyperactivity Disorder.
Disclosure response 6 (e):
Melaleuca Inc., T J Clark, and Body Systems Technology Incorporated.
In each of the four consent forms provided to us, research subjects or their legal representatives were informed that the investigational drug / dietary supplement was safe on the basis of twelve children who had ostensibly taken them and experienced no adverse effects. The consent forms specifically stated that twelve children took the supplement without ill-effect. The consent forms did NOT disclose that it wasn't the same investigational drug they would be taking. This does not appear to constitute any form of informed consent
we've ever heard of. What's more, these twelve children turn out to be five children according to the University of Calgary database (above). Again, people are entitled to wonder why information disclosed conflicts with information held in the University of Calgary's own database.
Sources:
This is also very unfortunate because the children in the 1997 study titled A double blind case controlled study of the effects of a vitamin and mineral supplement as an adjunctive therapy for Attention Deficit Hyperactivity Disorder
were given (in addition to Ritalin) a combination of investigational products from Melaleuca Inc., Body Systems Technologies, and T.J. Clark Inc., with some 96 or so different ingredients, while the subsequent studies for which we were provided consent forms, used EmpowerPlus, manufactured by Evince International LLC which contained 36 ingredients.
In fact, it sounds as if the University of Calgary can't tell the difference between EmpowerPlus (distributed by Evince International LLC) and the Synergy Group of Canada Quad M.S. Research Program. A Non-Medical Nutritional Program.
©1996 The Synergy Group of Canada Inc. Available from http://www.circare.org/FOIA/SGCMSQuad.pdf
Source: Munn Gafuik J-A. University of Calgary Response to Access Request 01-015. Disclosure Request No. 6, identity of manufacturer of investigation nutritional supplement in studies (d) and (e) [p. 3], and List of Disclosures No. 6, for study (e) Melaleuca Inc., Body Systems, T.J. Clark [p. 3 of 4]. 2002-02-25. Available from http://www.circare.org/FOIA/ucati_01-015.pdf.
Compare this with:
Disclosure request 4:
Conjoint Health Research Ethics Board (CHREB) approval dates for the following studies:
All dates correspond to the entries in the University of Calgary's databases of approved or closed protocols with the exception of the study titled Open Trials of Nutritional Supplements for the Treatment of Children with Anxiety/Mood Problems.
The University of Calgary claims the Conjoint Health Research Ethics Board approved the study titled Open Trials of Nutritional Supplements for the Treatment of Children with Anxiety/Mood Problems
on 1999-05-26, yet there is no entry for this research in the University of Calgary databases of approved or closed protocols.
Why not?
Sources:
Disclosure request 13 (g):
Consent form for study titled
A double blind case controlled study of the effects of a vitamin and mineral supplement as an adjunctive therapy for Attention Deficit Hyperactivity Disorder.
Disclosure response 13 (g):
Refused on the grounds that it is the property of Dr. Kaplan.
The basis for this refusal is odd indeed. What about the four consent forms they did release? Aren't they Dr. Kaplan's property too? Presumably Calgary found some way around this property
issue so the subjects' parents and guardians could have a copy of what they signed. It would be awkward if they didn't.
Disclosure request 14:
Documentation of IRB approval of research studies approved by the University of Calgary Conjoint Health Research Ethics Board conducted on pediatric and adult subjects in Utah by R. C. Ferre M.D., co-investigator with Dr. Kaplan for studies titled
Open Trials of a Nutraceutical Treatment for Mental Disorders in AdultsandOpen Trials of Nutritional Supplements for the Treatment of Children with Anxiety/Mood Problemsas described in the methods section of: Kaplan BJ, Simpson JS, Ferre RC, Gorman CP, McMullen DM, Crawford SG. Effective mood stabilization with a chelated mineral supplement: An open-label trial in bipolar disorder. Journal of Clinical Psychiatry. 2001;62(12):936-944: http://altcancerweb.com/bipolar/alternative-treatments/effective-mood-stabization.pdf
Disclosure response 14:
No records exist.
Why don't records exist? Did the University of Calgary know about the Utah trial site or not? If not, why not?
If the University of Calgary did know about the American subjects, what on earth is the University of Calgary doing conducting research on our vulnerable citizens without ethical and scientific review?
Why did they conduct research on Americans when the Utah institutional review board explicitly refused to approve the research?
Why did Dr Kaplan publish a paper claiming the University of Calgary approved when it quite clearly did not, and could not approve enrollment of American research subjects in Utah.
Are persons outside of Canada somehow endowed with fewer rights? That's a happy thought.
See also: McNeilly PJ. Office for Human Research Protections Determination Letter to the University of Utah re: Kaplan BJ, Simpson JS, Ferre RC, Gorman CP, McMullen DM, Crawford SG. Effective mood stabilization with a chelated mineral supplement: An open-label trial in bipolar disorder. Journal of Clinical Psychiatry. 2001;62(12):936-944. 2002-08-19. Available from http://www.hhs.gov/ohrp/detrm_letrs/YR02/aug02e.pdf
Dr. Keith Archer, University of Calgary interim vice president, research [below] provides some odd information in his response. It was his understanding that:
nature of the supplementwas known to the independent reviewers involved in the Alberta Science and Research Authority grant application. How might EmpowerPlus have been known to them roughly one year before it was first created? And how might EmpowerPlus have been known to these reviewers when the grant application identified Melaleuca Inc. as the industry partner?
Archer K. Reply to Marvin Ross re: studies conducted by Bonnie Kaplan Ph.D. 2001-09-07. Available from http://www.circare.org/FOIA/uc_archer20010917.pdf
For readers unfamiliar with the story, this Health Canada Briefing Note will bring you up to speed:
ATIP1181, ATIP1182, ATIP1183: Health Canada. Briefing Note re: marketing of an unauthorized drug by The Synergy Group of Canada Inc. 2001-05-15. Available from http://www.circare.org/FOIA/hcati1_181183.pdf
On September 10, 2001-09-10, Health Canada left no room for doubt, miscommunication, alternative interpretation, or rhetoric: the director of the Therapeutic Products Division demanded that Dr Kaplan submit a Clinical Trials License Application within 30 days.
ATIP1380, ATIP1381: Peterson R. Health Canada. Letter to B. Kaplan re: required submission of Clinical Trial Application within four weeks. 2001-09-10. Available from http://www.circare.org/FOIA/hcati1_380381.pdf
The deadline came and went, and upon receiving no communication from Dr Kaplan, Health Canada wrote to Dr Ian Mitchell, head of the Office of Medical Bioethics at the University of Calgary, on 2001-10-11 to apprise him that Health Canada was awaiting Dr Kaplan's response, and should none arrive, the ongoing unapproved trials with EmpowerPlus must be terminated.
ATIP1442, ATIP1443: Peterson R. Health Canada. Letter to I. Mitchell M.D. re: required Clinical Trial Application from B. Kaplan for clinical trials with EmpowerPlus. 2001-10-11. Available from http://www.circare.org/FOIA/hcati1_442443.pdf
At length, on 2001-10-15, Health Canada received a Clinical Trials License Application from Dr. Kaplan. 10 days later, they returned the application along with dozens of questions and directives. The regulator's request for further information
is, in common parlance, a rejection. Such applications are not technically approved
but rather the regulators have a period of time in which to request further information, object, or ask for changes. If the investigator hasn't been contacted by the end of the specified interval, or receives a Letter of No Objection, he or she may begin the clinical trial. In this case, it seems that Dr Kaplan did not provide the requested information, and as a result, Health Canada designated the application unsatisfactory
and demanded the randomized clinical trial on subjects with bipolar disorder be terminated. The status of the fibromyalgia trial is unclear; though Health Canada included it in this CTA/IND review, it may have ended earlier.
Akoury M. Health Canada letter to Ian Mitchell with attached document, Information Request to Bonnie J. Kaplan Ph.D., re: studies titled
Nutraceutical Treatment of Mental Disorders in Adults: An RCT with Bipolar DisorderandFibromyalgia Clinical Study.(2001-10-25) 2002-01-04. Available from http://www.circare.org/FOIA/hc_cta_20020104.pdf
Few people will ever see regulatory correspondence like this (it's proprietary, though publicly disclosed in this case) so the issues might not leap out immediately. In our opinion, the regulator rightly objected to an unethical and unscientific trial design. And keep in mind too that this unauthorized trial had been underway for at least one year.
What's unnerving about this situation is that Health Canada described precisely what information Dr. Kaplan was required to include for successful review in their letter of 2001-09-11. Some might assume that Health Canada was holding the investigational product to unreasonably high standards or was otherwise demanding information simply to hold up this research — but this would be incorrect. Health Canada asked Dr. Kaplan to describe the standard features of her trial design: stopping rules, rescue medications, withdrawal criteria, how subjects would be monitored for toxicity, what outcome measures she planned to use to assess the efficacy of the investigational drug, and safety data on the risks associated with chronic vitamin and mineral toxicity from the high dosages in EmpowerPlus.
Stop and think about this for a minute: Health Canada did not dictate specifics – only that these design features exist. In the informed consent, Dr. Kaplan assured prospective research subjects that the investigational drug was unlikely to harm them: all Health Canada requested was that she forward the information upon which she based her opinion. The informed consent and the research protocol, ostensibly approved by CHREB, surely described the psychometric testing which subjects would complete at various points in the trial, so all that was required was she forward what she clearly should possess. Yet she did not. Why?
The returned CTA application requested the missing information be submitted within four days, but Health Canada received no reply within a month. Perhaps at this point, it might have been the long silence that prompted Health Canada to write to Dr. Mitchell in his capacity as REB chair, and demand the trials be terminated. Dr. Kaplan's silence is puzzling.
Health Canada's General Comments
confirmed the painfully obvious: the investigator did not provide the specific information requested, which she should have had at her finger tips. Some of this is fundamental information necessary to justify research on human subjects. It's difficult to understand why the University Calgary approved this research in the absence of some very basic information.
adverse event reports), it's safe to assume they asked because none had been provided. Why not? How could the Calgary REB approve research without this information? If no safety information could be supplied to Health Canada, what was the basis of the claim the drug was likely to be safe in the informed consent?
Why did Health Canada have to direct Dr. Kaplan to disclose to her research subjects that there was no evidence to suggest EmpowerPlus would have an effect on bipolar disorder?
Why did they need to require Dr. Kaplan to explain the serious risk of not treating bipolar disorder to her prospective research subjects? Did she believe she could cure bipolar disorder, as was trumpeted by Reuters in 2001?
Why did Health Canada have to demand that research subjects be informed about the risks of chronic vitamin and mineral toxicity?
In case you're wondering about the source of the IND/CTA documents, look at the fax memo at the top of the first page: Dr. Kaplan sent this to Anthony Stephan, principal of Truehope and the Synergy Group of Canada Inc. We found it posted on the internet with the title Letter from Health Canada
at http://www.taxtyranny.ca/images/HTML/Truehope/truehope.html
Res ipsa loquitur.
Last Updated: 2012-08-10
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