Formal way to request an investigation at the FDA

This is a template to initiate a formal request for investigation regarding Lorqess's rat cancer issue mentioned on FDA Briefing document and during AdCom panel. Please Cut & Paste into Word document, sign, and send via certified mail to :

Office of Research Integrity

U.S. Department of Health and Human Services

1101 Wooton Parkway, Suite 750

Rockville , MD 20852

Please feel free to modify and/or enclose the online Petition as deemed necessary. Remember, there is strength in number...

(Full Credit recognized and given to letthetruthring)

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To: Office of Research Integrity

U.S. Department of Health and Human Services

1101 Wooton Parkway, Suite 750

Rockville , MD 20852

Request for Investigation of Research Misconduct

Allegation of Research Misconduct by Dr. Eric Colman (Respondent) in Review of NDA 22-529 (Lorcaserin hydrochloride)

The following is put forth:

Federal Regulation 42 CFR § 93 dealing with research misconduct applies to:

§ 93.102 (b)(1) allegations of research misconduct and research misconduct involving:

(ii) PHS supported biomedical or behavioral extramural or intramural research; and

(iv) PHS supported extramural or intramural activities that are related to biomedical or behavioral research or research training, such as the dissemination of research information;

Respondent is a PHS-supported researcher under 42 CFR § 93.102, 42 CFR § 93.221; 42 CFR § 93.222

Respondent is a Federal Drug Agency (FDA) employee and thus his work is directly supported by Public Health Service funds. He works for the Center for Drug Evaluation and Research. His activities in reviewing NDA 22529 qualify as “research” as they were a systematic evaluation designed to develop or contribute to specific knowledge relating broadly to public health by elucidating or confirming information about or the underlying mechanism relating to biological causes or diseases.

Federal Regulation 42 CFR § 93.103 defines research misconduct to include:

(b) Falsification is manipulating research materials, equipment, or processes, or changing or omitting data or results such that the research is not accurately represented in the research record.

Respondent’s written statements represent research misconduct as they do not accurately reflect the research

Complainant alleges in good faith that Respondent committed falsification by changing or omitting results such that the research was not accurately represented in the research record (FDA Briefing Document for NDA 22529). Such falsification occurred in the summary section discussing the safety of Lorcaserin, specifically the following paragraph:

“Malignancies in Rats: A number of malignant tumor types developed in rats treated with lorcaserin for up to two years. An excess number of malignant mammary tumors developed in female rats treated with lorcaserin at doses within 7-fold of the proposed clinical dose of 10 mg BID. Male rats developed malignant mammary tumors when treated with lorcaserin at doses 17-fold higher than the proposed clinical dose. Although the sponsor believes that lorcaserin-mediated increases in serum prolactin explain the excess risk for malignant breast tumors, FDA reviewers do not believe that the available data support this hypothesis. In addition to breast tumors, lorcaserin-treated rats had an excess number of malignant astrocytomas, squamous carcinomas of the subcutis, and malignant schwannomas. There were no imbalances in reports of cancer between lorcaserin and placebo-treated subjects in the phase 3 clinical studies.”

In the second sentence of the aforementioned paragraph, Respondent states “An excess number of malignant mammary tumors developed in female rats treated with lorcaserin at doses within 7-fold of the proposed clinical dose of 10 mg BID.” Malignant mammary tumors would only be any adenocarcinoma observed in the study. Respondent is a well-educated, medical professional, long familiar with the concept of statistical significance and long-familiar with the difference between benign tumors and malignant tumors. His statement about the excess number of malignant mammary tumors is patently false as there was no statistically significant excess of such tumors at the dose reported. Respondent has omitted significance levels provided to him by the study Sponsor for the incidence of malignant tumors at this level such that the research is not accurately represented in the research record (the FDA Briefing document).

In the third sentence of the aforementioned paragraph, Respondent states “Male rats developed malignant mammary tumors when treated with lorcaserin at doses 17-fold higher than the proposed clinical dose.” Again, Respondent is a well-educated, medical professional, long familiar with the concept of statistical significance. Only two tumors were seen at the reported dose level, a number that was far from statistically significant. Respondent has omitted significance levels provided to him by the study Sponsor such that the research is not accurately represented in the research record (FDA Briefing document).

In the 5^th sentence of the aforementioned paragraph, Respondent states “lorcaserin-treated rats had an excess number of malignant astrocytomas, squamous carcinomas of the subcutis, and malignant schwannomas.” Respondent recklessly or intentionally failed to mention that these results were only seen at a dosage of 55 times the human dose. These three tumor types were only significant when the rats were given 55 times the human dose, and there were absolutely zero tumors for all three of these tumor types at 5 times the human dose. Respondent has omitted significance levels and dosage levels provided to him by the study Sponsor in reporting this finding such that the research is not accurately represented in the research record (FDA Briefing document). Further, Respondent has put forth a statement that is at odds with the FDA’s own May 2002 ‘Guidelines to Industry’ which indicates that “the highest dose to be included in a carcinogenicity study should be based on one of the ICH endpoints" (referencing “Toxicity, Dose-Limiting PD Effects, Exposures 25 times Human AUC, Saturation of Absorption, Maximum Feasible Dose (MFD), or Limit Dose”). This Guidance is from Respondent’s own agency, and is guidance with which he undoubtedly is familiar. For Respondent to highlight a negative finding in a single sub-human species given 55 times the human level of a drug when the FDA acknowledges that the international standard is 25 times the human dosage underscores the extent of the alleged misconduct, i.e., the misrepresentation of the data submitted in NDA 22529.

In the 6^th sentence of the aforementioned paragraph, Respondent states “There were no imbalances in reports of cancer between lorcaserin and placebo-treated subjects in the phase 3 clinical studies.” This statement highlights Respondent’s inconsistency with regard to reporting results favorable to this drug application. Respondent has spent the whole tumor summary paragraph emphasizing non-significant data that casts the drug candidate in a negative light. In this instance the drug Lorcaserin evidenced fewer neoplasms (malignant or unspecified tumours) in a larger subject pool than did placebo (Table 97 of FDA Briefing document). Rather than state that Lorcaserin yielded a reduced number of tumors or that there was an “excess number” of tumors with the placebo, Respondent chooses the language “There were no imbalances in reports of cancer between lorcaserin and placebo-treated subjects”. Complainant agrees with this language and Respondent’s use of it here indicates he does understand the concept of statistical significance, and how the non-significant rat tumor findings should have been reported.

Federal Regulation 42 CFR § 93.104 requirements for findings of research misconduct:

A finding of research misconduct made under this part requires that— (a) There be a significant departure from accepted practices of the relevant research community; and (b) The misconduct be committed intentionally, knowingly, or recklessly; and (c) The allegation be proven by a preponderance of the evidence.

Respondent’s actions meet requirements for a showing of research misconduct

Respondent’s reporting of non-significant results, without qualification, as factual and relevant is a significant departure from accepted practices of the relevant research community. That non-significant findings are not to be reported as fact, especially without qualification, is so accepted throughout the medical research community that anyone who has taken a beginning statistics class accepts it as gospel. Indeed, a recent Journal of the Medical Association (JAMA) article questioned the motives of scientists who “spin” non-significant findings (JAMA. 2010;303(20):2058-2064.) Reporting of non-significant findings as fact, without any qualification, in a research record as important as an FDA brief for a new drug application, is a significant departure from accepted practices within the medical research community.

(b) Respondent’s misconduct was committed intentionally, knowingly, or recklessly. Respondent chose his own words in the Malignancies paragraph of the FDA brief. He understands the concept of statistical significance, as demonstrated by his failure to report the positive findings regarding neoplasms for human trials as anything other than “There were no imbalances in reports of cancer between lorcaserin and placebo-treated subjects”. Moreover, in reporting an excess number of three tumor types in male rats without indicating that this was only seen at 55 times the human dose, Respondent has put forth a statement that is at odds with the FDA’s own guidelines. May 2002 FDA Guidelines to Industry indicates that “the highest dose to be included in a carcinogenicity study should be based on one of the ICH endpoints and references." For Respondent to highlight in the FDA Brief a negative finding seen only in a single sub-human species at 55 times the human level when the FDA Guidance acknowledges that the international standard is 25 times the human dosage indicates that the misrepresentation of the data was done knowingly.

(c) A proper investigation will, by a preponderance of the evidence, indicate that Respondent did indeed commit such misconduct. The FDA brief was authored by him, and Respondent had full responsibility for its contents. These statements are not typos, they are summary declarations within an FDA briefing document intended to inform committee members and the public. Those statements were written knowingly and intentionally.

Addendum to Allegation

The recklessness of Respondent’s misreporting of the rat tumor findings is highlighted by the fact that within eight hours of the FDA Briefing document being released on September 14^th there were at least a ten media reports dealing with this brief such as the following from Reuters - FDA staff question Arena diet drug. All such media reviews highlighted the rat tumor data, and in a very negative fashion. All such media reports are a matter of public record and available to investigators.

The public record (Minutes of the meeting, interviews with hearing attendees) will further show that Respondent continued to show bias against this drug application at the Advisory Committee hearing itself in his statements there and in his failure to place an expert on the Committee that could speak to the significance of the rat data given that it was at odds with data from mice, monkeys, and humans and the testimony of the Sponsor’s nationally-recognized expert on the subject. The public record of the Committee proceedings will indicate that various panelists expressed a lack of understanding with regard to the rat tumor data.

Complainant requests a full and impartial investigation of this allegation of research misconduct by the Office of Research Integrity.