Getting a little ahead of a supplemental approval in its promotional materials for the oncology drug Gleevec (imatinib) helped land Novartis AG a “notice of violation” letter from FDA’s Office of Prescription Drug Promotion.

OPDP singled out three “GISTexchange Case Highlights” that the company had submitted for approval, referring to the drug’s pre-existing approval for patients with Kit (CD117) positive [KIT+] unresectable and/or metastatic malignant gastrointestinal stromal tumors.

The letter is dated Jan. 9, 22 days before Novartis announced full FDA approval to expand labeling for Gleevec to include three years of treatment following surgery to remove KIT+ GISTs based on final clinical data showing a survival advantage with the extended regimen Also see "Gleevec Extends Post-Surgery GIST Survival Significantly; Wins Full Adjuvant Approval" - Pink Sheet, 1 February, 2012.. The data are from an open-label Phase III trial in which the primary endpoint was recurrence-free survival within the first five years after surgery.

And yet, one of OPDP’s criticisms of the “case highlights” in the Novartis promotions was that the company had discussed the case of a patient in whom, “following five years of Gleevec therapy, disease progression was observed [and] six months after starting Gleevec, a [computed tomography] CT scan revealed a decrease in the size of the hepatic metastases. … Subsequent CT monitoring over several years showed stable disease. After five years on Gleevec at 400 mg/d, a restaging CT revealed progressive disease.”

OPDP found the implied claim unacceptable. “While these claims may be an accurate summary of this particular patient’s treatment, this promotional case study misleadingly implies that Gleevec 400 mg once daily has been shown to provide all patients with metastatic KIT+ GIST with progression free survival (PFS) lasting five years. FDA is not aware of substantial evidence or substantial clinical experience to support this suggestion.”

“A selected case study of one patient’s treatment response does not constitute substantial evidence,” OPDP added. “As described in the PI, patients receiving Gleevec 400 mg/day in the pivotal studies experienced a median PFS of 18.9 months (95% CI 17.4-21.2). The five-year duration of PFS experienced by the patient described in this Case Highlight is significantly longer than the median PFS observed in clinical trials for Gleevec in the KIT+ unresectable and/or metastatic malignant GIST patient population.” A disclaimer did not offset the problem, the agency said.

“Novartis takes these matters seriously, ceased dissemination of these materials immediately, and responded to the FDA by the requested response date of January 24, 2012,” the company said in a statement. “We will continue to have active discussions with the FDA to fully understand all of the concerns.”

Gleevec sales were $4.66 billion in 2011, a 9% increase from 2010, according to Novartis’ annual report. The drug received accelerated approval in 2008 for adjuvant use in GIST patients who were at increased risk for a recurrence of the disease after a National Cancer Institute-led trial in that setting was stopped because it had met its primary endpoint of recurrence-free survival in patients who took it for a year after surgery Also see "Gleevec Buoyed By GIST Trial Results; Novartis Will Seek Adjuvant Indication" - Pink Sheet, 13 April, 2007..

Individual Patient Cases Are Misleading, OPDP Says

In another sense, the NOV letter to Novartis is part of an FDA enforcement tradition – OPDP and its predecessor, the Division of Drug Marketing, Advertising and Communications, have long frowned on the misuse of individual patient histories in drug promotions Also see "Testimonials Lead To Overbroad Claims, DDMAC Warning Letter Says" - Pink Sheet, 19 April, 2010..

In addition to the five-year-survival case, the two other “case highlights” OPDP cited Novartis for are also for individual patients, and as such are unrepresentative, according to the agency. For example, the company had written of one patient that “follow-up MRIs with and without contrast were performed 2 years after the initial diagnosis and showed that the abdomen and pelvis were completely unremarkable,” which OPDP said was tantamount to claiming “that this extremely positive result, i.e., a complete response (CR) to therapy, defined as the disappearance of all target lesions, which in this case lasted for at least two years, is representative of the typical response that patients may expect from Gleevec.”

This is not an acceptable implication, OPDP says, considering that in a Phase II study of 147 patients cited in the drug label, only one patient had a complete response, and even that one lasted 11 months, going on to complain about a claim that “the patient has been on Gleevec for over 3½ years, and remains free of disease and any supervening medical problems.” The implications here are also unjustified, the letter says.

Similarly, the case of a different patient whose “melana resolved and hemoglobin remained between 9.5 and 10.0 g/dL” after three months on Gleevec” was misleading because it “implies that Gleevec is effective at treating melana, a symptom often present in patients with GIST, when, to our knowledge, this has not been demonstrated by substantial evidence or substantial clinical experience.”

Novartis also directly made unjustified efficacy claims, according to the letter, including that “progressive disease may occur in about 13% of patients with unresectable or metastatic GIST treated with Gleevec 400 mg/d,” whereas in fact a combined analysis of the two pivotal Phase III clinical studies showed that 75% of the patients with unresectable or metastatic GIST treated with Gleevec 400 mg/day progressed.

Additionally, OPDP cited Novartis for using a retrospective subgroup analysis of one of the Phase III studies that led to Gleevec’s approval for unresectable or metastatic KIT+ GIST to claim that “a randomized, Phase III study reported that approximately 1 in 3 patients who had progressive disease while being treated with Gleevec 400 mg/d benefited from dose escalation to 800 mg/d.”

This claim “is derived by combining the percentage of patients achieving a partial response and patients who had stable disease. However, in patients with GIST, stable disease is not considered to be an accurate or valid indicator of therapeutic effect due to drug therapy because stable disease may be a reflection of the natural disease process. Moreover, this retrospective subgroup analysis is insufficient to provide substantial evidence to support promotional claims pertaining to the effectiveness of Gleevec,” OPDP says.

Questionable promotional claims based on retrospective analyses are another frequent source of FDA enforcement action on promotional materials Also see "Otsuka Busulfex's Overall Survival Claim Does Not Survive CDER Advertising Scrutiny" - Pink Sheet, 4 November, 2011..

FDA Cites Gleevec For Promoting Unapproved Indications Three Weeks Before Expanding Label

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