Ms. Beth Clay
Senior Vice President
Capitol Strategy Consultants, Inc.
18028 Rolling Meadow Way
Olney, MD 20831
Re: Data Quality Act Information Correction Request Regarding Pancreatic Cancer Clinical Trial Registered as NCT00003851 and NCI Contract P30-CA13696
Dear Ms. Clay:
Thank you for your "Data Quality Act Information Correction Request" letter, which was dated March 8, 2012, and was submitted under the National Institutes of Health (NIH) Guidelines for Ensuring the Quality of Information Disseminated to the Public. This office received your letter March 15, 2012.
In your letter, corrections were requested to the following NIH information products:
A) Gonzalez Regimen (PDQ®) cancer information summary, health professional version, maintained and disseminated by the National Cancer Institute (NCI).
B) Gonzalez Regimen (PDQ®) cancer information summary, patient version, maintained and disseminated by NCI.
C) A "Cancer Research Highlights" article entitled "Chemotherapy Provides Longer Survival than Enzyme Therapy for Pancreatic Cancer," which appeared in the September 8, 2009 issue (Volume 6, Number 17) of NCI’s biweekly electronic newsletter the NCI Cancer Bulletin, produced and disseminated by NCI.
D) Questions & Answers: The Phase III Gonzalez Protocol Trial, a Web page produced and maintained by the National Center for Complementary and Alternative Medicine (NCCAM) that contains links to NCI information products and to the published report of clinical trial NCT00003851, the latter being made initially available online August 17, 2009, by the Journal of Clinical Oncology.
E) The protocol summary for clinical trial NCT00003851, Gemcitabine Compared With Pancreatic Enzyme Therapy Plus Specialized Diet (Gonzalez Regimen) in Treating Patients Who Have Stage II, Stage III or Stage IV Pancreatic Cancer, which is accessible through the National Library of Medicine’s (NLM) ClinicalTrials.gov website.
F) "Research Spotlight: Study Finds Conventional Chemotherapy Better Than Enzyme Regimen for Patients With Inoperable Pancreatic Cancer," a Web page produced and maintained by NCCAM.
The following is NIH’s response to your request for corrections:
Part A: The Gonzalez Regimen Trial ? Study Design, Execution, and Publication of Results
The Gonzalez Regimen trial (NCT00003851) was initially designed as a randomized, controlled phase III trial in which patients with stage II-IV inoperable adenocarcinoma of the pancreas were to be randomly assigned to treatment with gemcitabine-based chemotherapy (the control arm) or the Gonzalez regimen (the experimental arm). The Gonzalez Regimen is a cancer management program that includes prescribed diets, nutritional supplements, coffee enemas, and pancreatic enzymes. The primary endpoint of the trial was overall survival, and the secondary endpoint was quality of life.
The trial was supported, in part, by a supplement to a grant that had been awarded to Columbia University Medical Center (New York, New York) by NCI. Funds for the supplement were provided by NCI and NCCAM, both of which are parts of NIH. Additional support was provided by a grant from the American Cancer Society to one of the trial’s investigators.
The trial opened to patient enrollment in late 1998 and was expected to accrue between 72 and 90 patients. Because few patients elected to participate in the trial as it was originally designed, the design was changed in July 2001 from that of a randomized controlled trial to that of a non-randomized controlled study in which patients were given a choice regarding the treatment they received.
In October 2005, the criterion for the "stopping rule" that had been established by the trial’s independent data safety monitoring committee was met and patient enrollment was suspended. An analysis of the trial data at that time indicated that treatment with gemcitabine-based chemotherapy was statistically significantly superior to treatment with the Gonzalez Regimen. Fifty-five eligible patients were participating in the trial when enrollment was suspended: 23 in the chemotherapy arm and 32 in the Gonzalez regimen arm.
A report of the trial’s findings was published online August 17, 2009 in the Journal of Clinical Oncology (JCO), which is a peer-reviewed journal produced by the American Society of Clinical Oncology. A print version of the report appeared in the April 20, 2010 issue of the JCO (Volume 28, Issue 12).1
Part B: Concerns Expressed About the Trial and Its Published Report
As indicated in your letter, several concerns have been raised about how the trial was conducted and how the results were reported. In particular:
- There were irregularities in the timing of informed consent for many patients, as well as in the documentation and maintenance of informed consent records for three patients.
- Some patients began treatment in the trial’s experimental arm after the maximum 8-week period following diagnosis that was allowed in the study’s protocol.
- Some patients were enrolled in the experimental arm who could not eat adequately at the time of enrollment and, therefore, were unable to comply with the Gonzalez regimen.
- One patient was enrolled in the experimental arm who lived alone and, therefore, lacked the level of social support required by the study’s protocol.
- Patients were enrolled in the trial who had histories of significant psychiatric illness in violation of the protocol’s eligibility criteria. These patients may have been unable to provide informed consent or participate in the study properly.
- The trial was terminated early, before enrollment of the minimum number of 72 patients specified in the protocol document.
- Dr. Nicholas Gonzalez, who developed the Gonzalez Regimen, was not listed as a trial investigator or an author on the study report, and he was not given an opportunity to review the manuscript of the study report before it was submitted for publication.
Part C: Investigations and Findings Regarding the Expressed Concerns
As indicated in your letter, these concerns were shared with the Office for Human Research Protections (OHRP) in the Department of Health and Human Services (HHS) and the Food and Drug Administration (FDA):
In June 2008, OHRP issued its final determinations regarding concerns about the trial’s informed consent process, patient enrollment, and early termination of the trial:2
- With respect to the failure to properly obtain and document informed consent in the trial, OHRP concluded that informed consent was not properly obtained and/or documented before the initiation of research activities involving 40 of 62 subjects considered for participation in the trial. However, OHRP also concluded that informed consent was obtained and documented before participating patients received any treatments in the trial. Moreover, OHRP officials expressed satisfaction that Columbia University Medical Center had instituted appropriate measures to address these problems and to avoid their recurrence in the future. Although any failure to obtain and document informed consent as required by HHS regulations is a serious matter, material evidence is lacking that other activities of the trial were improperly conducted or that the study’s findings are invalid.
- With respect to patient enrollment issues, OHRP found that two patients had been enrolled in the trial more than 8 weeks after diagnosis in contravention of the study’s protocol-specified eligibility requirements. These enrollment irregularities represented additional violations of HHS regulations. However, in an effort to maximize the validity of the study’s findings, the researchers excluded data from patients enrolled more than 8 weeks after diagnosis from the analyses reported in the JCO article. Moreover, no additional violations of HHS regulations with respect to patient enrollment were identified by OHRP.
- With regard to early termination of the study, OHRP found no violation of HHS regulations. The stopping rule established by the trial’s independent data safety monitoring committee is similar to stopping rules used in other clinical trials, and the committee’s recommendation to terminate the study early was approved by Columbia University Medical Center's Institutional Review Board (IRB).
- Finally, with respect to the issues related to the preparation, submission, and publication of a study report and authorship of the report, the existence of such issues, which is not uncommon, does not constitute evidence that the described study or its findings are invalid.
In September 2009, John Chabot, M.D., of Columbia University Medical Center, who was the principal investigator of the Gonzalez Regimen trial, was classified on the FDA’s Clinical Investigator Inspection List (CLIIL) as being deficient in the following Code of Federal Regulations (CFR) reference areas:3
- 03 ? Inadequate informed consent form (21 CFR 50.25)
- 05 ? Failure to follow investigational plan (21 CFR 312.60)
- 06 ? Inadequate and inaccurate records (21 CFR 312.62)
- 12 ? Failure to list additional investigators on Form 1572 (21 CFR 312.60)
Clinical Investigator Inspections are conducted as part of the FDA's Bioresearch Monitoring Program, the primary goal of which is to validate the quality of clinical studies upon which FDA drug approvals are based. The program also helps ensure that the rights and welfare of human subjects in the studies have been protected. The FDA posts final Clinical Investigator Inspection classifications on its website whether deficiencies are found or not. CFR reference area deficiencies range from administrative deficiencies, such as those listed for Dr. Chabot, to deficiencies involving the rights, safety, and welfare of study participants.4 The identification of CFR reference area deficiencies for an investigator is an indicator of failure to comply with certain federal regulations; it does not constitute evidence that a study conducted by the investigator or the study’s findings are invalid.
Part D: Specific Requests for Correction and NIH’s Responses
A) Gonzalez Regimen (PDQ®) cancer information summary, health professional version (Web address:http://www.cancer.gov/cancertopics/pdq/cam/gonzalez/healthprofessional)
1). Requestor: "The January update [January 13, 2012] was made to include a reference to the Journal of Clinical Oncology (JCO) Paper, however, there is no reference included to the HHS OHRP and FDA findings. It is therefore requested that under the Summary of Evidence section, below the listing of the information provided in Section I of this letter should be inserted."
NIH Response: The update toinclude the JCO citation in the Physician Data Query (PDQ®) information summary about the Gonzalez Regimen actually occurred in September 2009, and not this year. With regard to the summary itself, it is part of a collection of evidence-based cancer information summaries produced for NCI by editorial boards comprised of experts in cancer biology and medicine. These editorial boards include federal government employees and individuals drawn from the private sector. The editorial boards regularly review newly published results of cancer research conducted around the world, evaluate the strength of the evidence to support the use (or not) of specific cancer-related interventions, and synthesize their findings in summaries intended to describe the current state-of-the art in cancer-related care. NCI is required to maintain and disseminate these evidence-based, state-of-the-art cancer information summaries by federal law, specifically the Public Health Service Act, as amended in 1996.
It is important to note that the PDQ editorial boards are editorially independent of NCI. NCI supports but does not intervene in PDQ editorial processes. The content of the PDQ cancer information summaries, therefore, is determined solely by the editorial boards.
Because, as noted above, evidence is lacking that the administrative deficiencies identified in the Gonzalez Regimen trial by OHRP and the FDA materially affected other activities of the trial or the reported findings, the PDQ Cancer Complementary and Alternative Medicine (CAM) Editorial Board has decided that inclusion of the requested references is not warranted.
According to the developer of the Gonzalez regimen, most OTC preparations or other commercially available pancreatic enzymes are not effective against cancer.
B) Gonzalez Regimen (PDQ®) cancer information summary, patient version (Web address: http://www.cancer.gov/cancertopics/pdq/cam/gonzalez/patient)
...however, Dr. Gonzalez published comments on his Web site indicating his participation in the study and detailing his concerns about how the study was conducted, including patient compliance with the prescribed treatment in the enzyme arm."
2) Requestor: "A second egregious misrepresentation occurs in this document at Question 8. The document states: ’Is the Gonzalez regimen approved by the US Food and Drug Administration (FDA) for use as a cancer treatment in the United States?The FDA has not approved the Gonzalez regimen as a cancer treatment.’
"The FDA does not as a regulatory agency ’approve’ lifestyle/nutritional regimens, it is the role of the FDA to regulate specific products. If this question is to remain, a full explanation of the FDA should be provided. It is suggested that the following information be inserted.
"The FDA does not have a mechanism through which to approve cancer treatment regimens which include multiple methods including dietary approaches and nutritional supplements. The FDA regulates specific products. As such, the only portion of the Gonzalez Regimen that the FDA directly regulates for the purposes of ’approving’ are the claims which may be made in advertising and marketing the dietary supplements utilized in the treatment. To make a label claim for cancer treatment on a dietary supplement, a health claims approval is required. All foods and dietary supplements used, like all foods and supplements, are subject to rigorous FDA enforcement of food safety, quality control laws and good manufacturing laws and regulations. The NIH requires that all dietary supplements utilized in NIH-funded research maintain FDA quality control standards."
NIH Response: The PDQ Cancer CAM Editorial Board has changed the statement in question 8 to read as follows:
The FDA has not approved the Gonzalez regimen or any of its components as a cancer treatment.
C) "Cancer Research Highlights" article entitled "Chemotherapy Provides Longer Survival than Enzyme Therapy for Pancreatic Cancer" in the September 8, 2009 issue (Volume 6, Number 17) of the NCI Cancer Bulletin (Web address: http://www.cancer.gov/aboutnci/ncicancerbulletin/archive/2009/090809/page3)
Requestor: "The NCI Cancer Bulletin has failed to provide an important update to this report regarding the OHRP and FDA findings. It is requested that the information at Section I [of this letter] be provided as an electronic link to this article so that every reader will have this important information available. It is further requested that the NCI Cancer Bulletin issue a correction with the information at Section I provided so that its readers are fully up to date on these important findings."
NIH Response: As indicated above, the NCI Cancer Bulletin is NCI’s biweekly newsletter. Its "Cancer Research Highlights" articles are intended to provide brief summaries of recently published research findings that may be of interest to the cancer community at large. These articles are not intended to provide in-depth assessments of cancer research studies, including detailed evaluations of study strengths and potential limitations. Moreover, Cancer Research Highlights articles are not usually updated unless there is an error of fact (and then, by means of an erratum). As new research findings emerge on a specific topic, previous articles on that topic may be superseded by new ones, with possible cross-referencing. Since evidence is lacking that the administrative deficiencies identified in the Gonzalez Regimen trial by OHRP and the FDA materially affected other activities of the trial or the reported findings, and since the authors of the JCO article have not retracted their peer-reviewed report or issued corrections to it, there appears to be no basis for updating the Bulletin article or appending an erratum to it.
D) Questions & Answers: The Phase III Gonzalez Protocol Trial (Web address: http://nccam.nih.gov/news/19972000/121599.htm)
Requestor: "This important resource page provides links to other descriptors of the study as well as a link to the JCO paper and information about the study. However, it fails to provide information (or links) to the OHRP and FDA findings. This data is an essential component to insure the accuracy and quality of the data provided.
"It is requested that the information provided at Section I [of this letter] be inserted below the link to the NCI [Cancer] Bulletin link with a header: "Important Information Regarding OHRP and FDA Investigations of HHS Regulation Violations by the Principal Investigator."
NIH Response: This Web page provides links to scientific information about the Gonzalez Regimen trial, not to administrative or regulatory information. Given the absence of evidence that the administrative deficiencies identified by OHRP and the FDA materially affected other activities of the trial or the reported findings, as well as the fact that the authors of the JCO article have not retracted their peer-reviewed report or issued corrections to it, including the requested links would not seem to add essential information regarding the accuracy and quality of the other information on this page. NCCAM, therefore, has declined this request.
E) ClinicalTrials.gov summary of trial NCT00003851, Gemcitabine Compared With Pancreatic Enzyme Therapy Plus Specialized Diet (Gonzalez Regimen) in Treating Patients Who Have Stage II, Stage III or Stage IV Pancreatic Cancer (Web address: http://www.clinicaltrials.gov/ct2/show/NCT00003851)
Requestor: "This essential link to the study and central document to the clinical investigation provides a link to the publication in the JCO but fails to provide essential links to the OHRP and FDA investigations. It is therefore requested that the information provided at Section I [of this letter] is provided including the links to the OHRP and FDA website references. This modification is necessary to insure that the data on this page and regarding this study are accurate, transparent, and completely up to date.
NIH Response: Current requirements for clinical trial registration and results reporting in NIH’s ClinicalTrials.gov database, which is maintained by NLM, are defined in the Food and Drug Administration Amendments Act (FDAAA) of 2007.6Prior to implementation of this act, principal investigators or other responsible parties could use intermediaries to enter and update information about their research studies in ClinicalTrials.gov. When NCT00003851 was initially registered in ClinicalTrials.gov in 1999, NCI served as the intermediary for its registration and record updating. However, the FDAAA mandated that responsible parties must enter and update information about their trials themselves, i.e., they can no longer use intermediaries such as NCI. Consequently, NCI has suspended its activities in registering and updating information about trials in ClinicalTrials.gov with the exception of NCI-sponsored trials. Moreover, the Institute is in the process of returning authority for updating trial information and entering results data for the trials it registered previously to the appropriate responsible parties, even if the trials were registered prior to enactment of the FDAAA. These trial records are being transferred from NCI’s ClinicalTrials.gov account to the responsible party’s account, and it is up to the responsible party to update any information about the trial(s). As the principal investigator of NCT00003851, Dr. Chabot is the responsible party. Therefore, this request can only be addressed by him.
F) Research Spotlight: Study Finds Conventional Chemotherapy Better Than Enzyme Regimen for Patients With Inoperable Pancreatic Cancer (Web address: http://nccam.nih.gov/research/results/spotlight/082009.htm)
Requestor: "This page which provides a summary from Dr. Chabot’s article as well as a link to the paper in JCO fails to provide essential links to the OHRP and FDA investigations. It is therefore requested that the information provided at Section I [of this letter] is provided. This modification is necessary to insure that the reader is provided accurate information about this study."
NIH Response: As indicated by the requestor, this Web page provides a summary of the results of the Gonzalez Regimen trial as published in the JCO. Since evidence is lacking that the administrative deficiencies identified by OHRP and the FDA materially affected the trial’s findings, it is not clear that including the requested links is essential or will give the reader more accurate information about the trial. NCCAM, therefore, has declined this request. Also see the related response (D) above.
Part E: Concluding Remarks
We thank you for your comments and the opportunity to provide responses regarding the quality and accuracy of NIH’s information about the Gonzalez Regimen trial. You may appeal the decisions made about any, or all, of the identified NIH information products either in writing or electronically within 30 days of receiving this response letter. Your request should state the reasons for your appeal. It does not need to reference a tracking number. The request may be sent electronically to InfoQuality@od.nih.gov or in hard copy to Elizabeth M. Dean, Office of the Director, Office of Science Policy, National Institutes of Health, Building 1, Room 218, 9000 Rockville Pike, Bethesda, MD 20892. If the appeal is sent in hard copy, please clearly mark the appeal and the outside envelope with the phrase "Information Quality Appeal."
Please note that NIH always welcomes comments on its information products. Our goal is to provide the highest-quality, most-accurate, and most-useful health-related information to the public.
Richard E. Manrow, Ph.D.
Associate Director, Office of Cancer Content Management
Office of Communications and Education
National Cancer Institute, National Institutes of Health
6116 Executive Blvd., Suite 300A
Rockville, MD 20852
1. Chabot JA, Tsai WY, Fine RL, et al. Pancreatic proteolytic enzyme therapy compared with gemcitabine-based chemotherapy for the treatment of pancreatic cancer. Journal of Clinical Oncology 2010; 28(12):2058-2063. Epub ahead of print 2009 Aug 17. Available online at http://www.ncbi.nlm.nih.gov/pubmed/19687327. Date last accessed: May 15, 2012.
2. U.S. Department of Health and Human Services. Office for Human Research Protections. Letter to Steven Shea, MD, Columbia University Health Sciences. June 2, 2008. Available online at: http://www.hhs.gov/ohrp/detrm_letrs/YR08/jun08a.pdf. Date last accessed: May 15, 2012.
3. U.S. Food and Drug Administration. Clinical Investigator Inspection List (CLIIL) entry for John A. Chabot, MD (Investigator ID No. 430019). Inspection date: September 2, 2009. Available online at: http://www.accessdata.fda.gov/scripts/cder/CLIIL/index.cfm?fuseaction=Browse.Browse&NameFirstLetter=C&StartRow=121&SortField=LastName&SortRequest=0. Date last accessed: May 15, 2012.
4. U.S. Food and Drug Administration. Clinical Investigator Inspection List (CIIL) Database Codes. Database Code Definitions. Available online at: http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/EnforcementActivitiesbyFDA/ucm073059.htm. Date last accessed: May 15, 2012.
5. Gonzalez NJ. Pancreatic cancer, proteolytic enzyme therapy and detoxification. Excerpts from an interview with Kirk Hamilton. Clinical Pearls News 1999 (November). Available online at: http://www.dr-gonzalez.com/clinical_pearls.htm. Last accessed: May 18, 2012.
6. Congress of the United States of America. Food and Drug Administration Amendments Act of 2007, Public Law 110-85. Available online at: http://www.gpo.gov/fdsys/pkg/PLAW-110publ85/pdf/PLAW-110publ85.pdf. Last accessed: May 15, 2012.
Last Revised: 07/25/12