Capitol Strategy Consultants, Inc Government Relations

04/02/2012

HHS Information Quality Web Site

Capitol Strategy Consultants, Inc
Government Relations

Request for Correction

[ Full Table of Contents ]

March 8, 2012

Delivered Via Fax: (301) 480-4269

The Honorable Francis S. Collins, M.D., Ph.D.
Director
National Institutes of Health
9000 Rockville Pike
Bethesda, MD 20892

RE: Data Quality Act Information Correction Request Regarding Pancreatic Cancer Clinical Trial Registered as NCT00003851 and NCI Contract P30-CA13696

Dear Dr. Collins:

The National Institutes of Health's (NIH) website is a valuable tool for families exploring treatment options. It is critically important for the public to have accurate and up-to-date information available, including 'the rest of the story' when findings of violations of federal research guidelines have been found. The passage of the Data Quality Act into law (Section 515 of Public Law 106-554) and its implementation in 2002 was intended to insure that Federal Agencies assure the quality and integrity of the information provided to the public and provides a mechanism for the public to notify the agency when there are errors or omissions in information published.

Especially at the NIH, health information made available to the public should be accurate, transparent, unbiased, and up to date. Findings for instance of scientific misconduct or research irregularity should be inserted in all resources online referencing the study in question as these findings are of vital importance to any consumer in their investigation of health information.

Cancer continues to touch practically every family in the United States. I was a member of the staff of the National Institutes of Health's (NIH) Office of the Director's Office of Alternative Medicine during the early 1990s and therefore am aware that more than 70 percent of the public calls were for information about cancer and alternative therapies. Those calls were from patients and their loved ones eager to get accurate information about complementary and alternative therapies. I would in later years lead the health care team for a Congressional Committee conducting an oversight investigation into the role of complementary and alternative medicine in the US health system and coordinated several hearings related to cancer diagnosis and treatment.

Gemcitabine Versus Gonzalez Regimen Study

I like many Americans was pleased at the announcement in 1999 that the NIH (National Center for Complementary and Alternative Medicine and the National Cancer Institute) was funding a head to head comparison of an alternative protocol to the conventional standard for one of medicine's toughest challenges, pancreatic cancer. I am referring to Clinical Trial NCT 00003851 (Project Number: P30-CA1369) entitled "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." This study, the first of its kind at the NIH was widely reported and the public was anxious to see a fair evaluation conducted. Sadly, a fair evaluation did not occur, the NIH can make no conclusions based on the study, and the public has not been fully informed about the many scientific, operational, and procedural challenges that undermined the study occurring under the management of the conventional team supervising the project.

I became aware of the Gonzalez regimen while at the NIH. Over these last 18 years I have on many occasions unrelated to interactions with Dr. Gonzalez met his patients, individuals who turned to him when conventional cancer approaches were unsuccessful-patients with independently confirmed stage III and IV cancers of varying types who have recovered to good health to lead full and productive lives.

When the study was originally designed, it was determined by the NIH that an academic research institution would lead the trial, rather than the 'alternative guy' in order to insure the study was well run. This proved to be the downfall of the study as it was the academic team, the principal investigator in particular, who would violate numerous federal regulations regarding human subject protections and study management. In what most would see as irregular, the principal investigator would publish the findings without sharing the data with the entire research team. Throughout the study, it would be Dr. Gonzalez and colleague Dr. Isaacs that would bring the attention of the NIH management team to the irregularities. Your predecessors were made aware of the problems through an exhaustive report provided by Dr. Gonzalez through Congressman Dan Burton. Sadly, the Office of the Director appeared to ask the very individuals responsible for the oversight of the study to conduct its inquiry and prepare a response, while doing nothing to correct the issues.

After a failed attempt to publish in 2006, when the Columbia team misrepresented the facts of Dr. Gonzalez's participation in the study to a top medical journal, Dr. Gonzalez filed a complaint of scientific misconduct with Columbia University1 which to date has not been responded to by the university.

Three years later, Dr. Chabot and researchers from Columbia would publish in the Journal of Clinical Oncology, [(Chabot JA, Tsai, W, Fine, RL, et al) Pancreatic Proteolytic Enzyme Therapy Compared With Gemcitabine-Based Chemotherapy for the Treatment of Pancreatic Cancer] without affording the involved NIH staff or the Gonzalez team the opportunity to review the data and the article. This is confirmed as a footnote to the article: "The National Institutes of Health, which was the funding agency, had oversight of the design and monitored the conduct of the study; however, the National Institutes of Health had no direct involvement in patient management; data collection; analysis and interpretation of the data; or preparation, review, or approval of the manuscript... "2 Earlier this year, I requested that the Journal retract the paper given the outcomes of the Office of Human Research Protections (OHRP) and the Food and Drug Administration investigations.

At Dr. Gonzalez's request, The OHRP conducted an investigation of the management of this study by principal investigator Dr. John Chabot and Columbia University. They determined:

  • "Informed consent for the 40 of 62 subjects referenced by CUMC was not documented prior to the start of research activities, nor was the requirement for documentation waived by the CUMC IRB for subjects in this study." [As required by HHS regulations at 45 CFR 46.117(a)]3.
  • "The enrollment of subjects 113 and 129 did not meet all eligibility criteria and represented a change in the research activity that was implemented without IRB approval." [As required by HHS regulations at 45 CFR 46.103(b)(4)(iii)4

Based on an inspection of September 2009, the FDA reports on its Clinical Investigator Inspection List5 that John Chabot had the following deficiencies:

Deficiencies
  Reasons CFR citation
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 1572 21 CFR 312.60

Given that he was found to have 'inadequate and inaccurate records' by the FDA, and that none of the non-Columbia investigators or the NIH were involved in data analysis prior to publication, the data cannot be trusted or considered valid. Dr. Gonzalez was not afforded the opportunity to review the data, to participate in the review of the findings with Columbia and only found out about the paper upon its publication online.

One of the major problems with the study, which is not addressed in the paper, is the high rate of non-compliance to the enzyme protocol of many of the patients Dr. Chabot referred to that arm of the study — a challenge that occurred in part because Dr. Chabot referred patients who did not truly meet the study requirements and there was no wash out period included even though one had been recommended by Dr. Ernst Wynder. Dr. Gonzalez repeatedly reported that the patients did not comply with the protocol long enough (or at all) in order to gain any credible data. This problem was confirmed in the January 2005 letter to Dr. Chabot from Dr. Linda Engel of the NIH.

Upon further analysis of some of the data he was provided, Dr. Gonzalez was able to surmise that the two patients in the enzyme arm that actually fully adhered to the protocol were the longest surviving patients in the study at the time of the project's completion, including one patient surviving 3.5 years, with advanced pancreatic cancer. None of this information appears in the Chabot article. Dr. Gonzalez has presented these findings to Dr. Briggs, Director of the National Center for Complementary and Alternative Medicine, who after a face to face meeting has chosen not to respond to his follow up letter or to follow through on their discussion of exploring outcomes of highly compliant patients in alternative cancer protocols.

Setting aside the invalidity of the study based on poor record keeping and inaccurate data for the purpose of discussion, had Dr. Chabot included the entire study team in the paper preparation, the stated conclusion, "Among patients who have pancreatic cancer, those who chose gemcitabine-based chemotherapy survived more than three times as long (14.0 v 4.3 months) and had better quality of life than those who chose proteolytic enzyme treatment." would surely have been different. A vibrant discourse on the challenges of obtaining referrals from conventional oncologists to an alternative therapy protocol, discussion of hospital-based treatment versus private practice directed therapy which is implemented in the home, sometimes hundreds or thousands of miles from the practitioner's office; and finally the effect that patient compliance and the lack of a washout periods had on the nutritional arm with a comparison to other research observations would certainly have provided a better picture of the study and its outcomes. Science would have been better served.

Furthermore, the conclusion that the chemotherapy arm had the longest survivals is not entirely accurate, given that the two longest survivors in the study at the time of its completion were the two patients who fully complied with the nutrition arm, one for more than three years. To put this in perspective, in the classic 1997 study of Gemzar, approved by the FDA for treatment of pancreatic cancer, out of 126 patients treated not one lived longer than 19 months.

Any family looking at treatment options for pancreatic cancer needs to know that the question of whether the Gonzalez protocol of enzyme therapy is equal to or superior to the conventional approach of gemcitabine with and without other chemotherapeutic agents is a question that remains unanswered. Sadly, now 20 years after Congress first instructed the NIH to investigate and validate alternative therapies, there are still few accurate answers. Anyone who visits the NIH website looking for information on this study deserves to have the full truth about the study at every page which references the study. To my knowledge neither the NCCAM nor the NCI advisory committees have been fully briefed on these studies, and Dr. Gonzalez has not been provided the opportunity to present his concerns to these bodies.

It is important to note as well, that had Dr. Gonzalez been the individual found to have committed these above mentioned violations, the NIH would have issued press statements and every major media outlet would have run headline news stories about the OHRP and FDA findings. There would have been calls for the doctor's medical license to be suspended and access to federal research dollars barred. Why this has not occurred with Dr. Chabot and Columbia is unfathomable. The violations that were confirmed by OHRP and FDA were only a handful of the irregularities that took place, but which the investigators were comfortable confirming. Each and every violation that was confirmed was egregious. The public are entitled to have the NIH provide this information in order to be fully transparent and accurate.

Data Quality Act Request

The public in their search for information are entitled to have these findings be provided in conjunction with every discussion of this study and the Gonzalez regimen. Therefore, in accordance with the guidelines6 provided by the Department of Health and Human Services, the web pages provided below (at II below) should immediately be amended to include the following information:

I. Specific Recommendation for Requested Correction:

The study entitled, "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." has concluded and the principal investigator published "Pancreatic Proteolytic Enzyme Therapy Compared With Gemcitabine-Based Chemotherapy for the Treatment of Pancreatic Cancer" in the Journal of Oncology. Neither the NIH staff, nor Dr. Gonzalez was afforded the opportunity to review the data or a draft of the paper before publication.

The findings within the journal are not definitive and conflict with the earlier findings in published studies and the Best Case Series of the Gonzalez Regimen. It is important to note when considering the data from this study that two investigative units independent of the National Institutes of Health conducted investigations of the principal investigator (Dr. John Chabot) and Columbia University. Both investigations found irregularities which are noted below:

  1. The Office of Human Research Protections (ORRP) at the Department of Health and Human Services conducted an investigation investigating Dr. John Chabot and Columbia University and determined:
    • "Informed consent for the 40 of 62 subjects referenced by CUMC7 was not documented prior to the start of research activities, nor was the requirement for documentation waived by the CUMC IRB8 for subjects in this study." [As required by HHS regulations at 45 CFR 46.117(a)]9
    • "The enrollment of subjects 113 and 129 did not meet all eligibility criteria and represented a change in the research activity that was implemented without IRB approval." [As required by HHS regulations at 45 CFR 46.103(b)(4)(iii)]10
  2. A September 2009 investigation by the US Food and Drug Administration as reported on its Clinical Investigator Inspection List11 determined that John Chabot during this trial failed to follow the investigational plan [a violation of HHS regulations at 21 CFR 312.60], had an inadequate informed consent form [a violation of HHS regulations at 21 CPR 50.25], kept inadequate and inaccurate records [a violation of HHS regulations at 21 CFR 312.62] and failed to list additional investigators on FDA Form1572 [a violation of HHS regulations at 21 CFR 312.60].

It should also be noted that NIH correspondence to the principal investigator in 2005 confirms that the two study arms were not comparable and concluded, “...the current study has not yielded a clear answer to the question that it was designed to answer...”12

II. Specific Material That Needs to Be Corrected:

A review of the NIH website found the below web pages that discuss the study and have errors and omissions.

A. Publication Title: Gonzalez Regimen (PDQ®) Health Professionals Page

Date: Last Updated on January 13, 2012

Publication Number or Website URL:
http://www.cancer.gov/cancertopics/pdg/cam/gonzalez/healthprofessional/p...

Specific Reason for believing information does not comply: The January update 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.

A second error occurs in the following paragraph: "Pancreatic enzymes sold as OTC dietary supplements are regulated as foods, not drugs. Dietary supplements in the United States are therefore sold without a requirement of a market approval by the FDA, as long as they do not claim to treat or prevent a specific disease or condition. According to the developer of the Gonzalez regimen, OTC preparations or other commercially available pancreatic enzymes are not effective against cancer. [3]"

The last sentence in this paragraph, to be most accurate and informative to the reader should be as follows: "The developer of the Gonzalez regimen makes no claims on the label or labeling or other marketing materials that the commercially available pancreatic enzymes sold as dietary supplements cure, treat, prevent, or mitigate cancer."

B. Publication Title: Gonzalez Regimen (PDQ®) Patient Page

Date: Last Updated: February 10, 2012

Publication Number or Website URL:
http://www.cancer.gov/cancertopics/pdq/cam/gonzalez/patient/page1/AllPages

Specific Reason for believing information does not comply: This February 2012 update provides in the Overview the following: "A later nonrandomized, controlled clinical trial compared the effectiveness of standard treatment with that of the Gonzalez regimen in patients whose pancreatic cancer could not be removed by surgery. Patients treated with standard chemotherapy survived an average of 14 months and patients treated with the Gonzalez regimen survived only an average of 4.3 months. In addition, patients treated with chemotherapy reported a better quality of life than those treated with the Gonzalez regimen (see Question 6)."

The document concludes Question 6 with the following: "In this study, one group of patients followed the Gonzalez regimen while another group was given standard treatment (chemotherapy). Results in the two groups were compared to see if the Gonzalez regimen works better than the standard treatment and if it has bad side effects. Results of the study were reported in the peer-reviewed Journal of Clinical Oncology in April 2010. Patients treated with standard chemotherapy survived a median of 14 months and patients treated with the Gonzalez regimen survived a median of 4.3 months. Patients treated with chemotherapy reported a better quality of life than those treated with the Gonzalez regimen. Dr. Gonzalez published comments on his Web site."

This very important article, which is likely a key document used by patients newly diagnosed with pancreatic cancer to insure the quality, integrity and accuracy of the data should have two corrections included. The first, in the Overview as a bullet point after the reference to the clinical trial should read:

  • It is important to note that two federal agencies investigated the management of this study and found that Dr. Chabot and Columbia University violated a number of HHS regulations. (Explanation at Question 6.)
  • It is important to note also that the majority of patients approved by Dr. Chabot for treatment with Dr. Gonzalez never followed the prescribed therapy adequate or for any period of time, and hence were not actually "treated."

At the conclusion of Question 6 the information provided at Section I of this letter should be inserted.

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 role 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 includes 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."

C. Publication Title: NCI Cancer Bulletin, Article Entitled, "Chemotherapy Provides Longer Survival than Enzyme Therapy for Pancreatic Cancer"

Date: September 8, 2009

Publication Number or Website URL:
http://www.cancer.gov/aboutnci/ncicancerbulletin/archive/2009/090809/pag...

Specific Reason for believing information does not comply:
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 provided at Section I be provided via electronic link to this article so that every reader will have the 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.

D. Publication Title: Questions & Answers: The Phase III Gonzalez Protocol Trial

Date: Last Modified January 10, 2012

Publication Number or Website URL: http://nccam.nih.gov/news/19972000/121599.htm

Specific Reason for believing information does not comply: This important resource page provides links to other descriptors of the study as well as a link to the JCOpaper 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 be inserted below the link to the NCI Clinical Bulletin Link with a header: "Important Information Regarding OHRP and FDA Investigations of HHS Regulation Violations by the Principal Investigator."

E. Publication Title: Clinical Trials .Gov: 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

Date: Last Updated September 15,2009

Publication Number or Website URL: http://clinicaltrials.gov/ct2/show/NCT00003851

Specific Reason for believing information does not comply: This essential link to the study and central document to the clinical investigation provides a link to the publication in JCObut fails to provide essential links to the OHRP and FDA investigations. It is therefore requested that the information provided at Section I 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.

F. Publication Title: Research Update: Study Finds Conventional Chemotherapy Better Than Enzyme Regimen for Patients With Inoperable Pancreatic Cancer

Date: Last Modified January 6,2012

Publication Number or Website URL: http://nccam.nih.gov/research/results/spotlight/082009.htm

Specific Reason for believing information does not comply: 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 is provided. This modification is necessary to insure that the reader is provided accurate information about this study.

III. How person submitting the complaint is affected by the information error: I am an expert in complementary and alternative medicine policy. I also am a consultant to Dr. Gonzalez and therefore, have significant knowledge and background on this material.

However, I am specifically affected by this information error as a consumer of health information provided by the NIH. I have family members who have been affected by cancer, and even have an extended family member who three decades ago was a cancer patient treated successfully at the NIH Clinical Center. Pancreatic cancer is a devastating diagnosis. Any individual diagnosed or their loved ones searching information on the NIH website deserve to have an accurate and complete picture about this study provided in every location in which this study is discussed. Given the high profile nature of the launch of the study, any standard search engine search looking at treatment options or research is likely to bring the consumer to the NIH's website. An individual looking at a pancreatic cancer diagnosis has a short window of opportunity in which to make treatment decisions, and thus needs to have information provided accurately and in a simple-to-find location.

It should not be up to the patient to search out the OHRP and FDA findings on the internet, rather the NIH should incorporate these findings into the NIH reports. In line with the spirit and letter of the Data Quality Act, the above referenced pages need to be corrected with the requested information.

III. Contact:

Beth Clay
Senior Vice President
Capitol Strategy Consultants, Inc.
18028 Rolling Meadow Way
Olney, MD 20832
Tel: 202-49 8-4461
Fax: 202-3 18-7557
Email: bclay@dc-strategy.com

I look forward to your prompt reply and seeing the corrections made on the NIH web pages.

Always,

/s/

Beth Clay
Senior Vice President

cc:
Dr. Nicholas Gonzalez
The Honorable Dan Burton, Member of Congress
The Honorable Tom Harkin, United States Senate
Elizabeth M. Dean, OD/OSP/NIH - delivered via email: InfoQuality@nih.gov


Endnotes

1. http://www.dr-gonzalez.com/dean_columbia_12_06.pdf accessed on March 5, 2012.

2. Chabot JA, Tsai WY, Fine RL, Chen C, Kumah CK, Antman KA, Grann VR.J Clin Oncol. 2010 Apr 20;28(12):2058-63. Epub 2009 Aug 17. http://jco.ascopubs.org/content/28/12/2058. full access on March 5,2012.

3. http://www.hhs.gov/ohrp/detrmJetrs/YR08/feb08e.pdf

4. http://www.hhs.gov/ohrp/detrmJetrs/YR08/jun08a.pdf

5. http://www.accessdata.fda.gov/scripts/cder/CLIIL/index.cfm?fuseaction=Br...

6. http://aspe.hhs.gov/infoquality/Guidelines/partl.shtml#e accessed on March 5, 2012.

7. (Columbia University Medical Center)

8. (Columbia University Medical Center Institutional Review Board)

9. http://www.hhs.gov/ohrp/detrm_letrs/YR08/feb08e.pdf accessed on March 5, 2012

10. http://www.hhs.gov/ohrp/detrm_letrs/YR08/jun08a.pdf

11. http://www.accessdata.fda.gov/scripts/cder/CLlIL/index.cfm?fuseaction=Br...

12. January 27, 2005 letter to Dr. John Chabot from Dr. Linda Engel, NIH http://www.drgonzalez.com/engel_1_05.pdf accessed online on March 5, 2012.

Last Revised:  April 2, 2012