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AXCAN Scandipharm Inc 7/13/10

  

Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 Silver Spring, MD 20993
 

 

TRANSMITTED BY FACSIMILE


Frank Verwiel, M.D.
President and Chief Executive Officer
Axcan Pharma US, Inc.
22 Inverness Center Parkway, Suite 310
Birmingham, AL 35242


RE: NDA # 20-451 & 21-525
Photofrin® (porfimer sodium) for injection
MACMIS #18813

WARNING LETTER

Dear Dr.Verwiel,

As part of its routine monitoring and surveillance program, the Division of Drug Marketing,Advertising, and Communications (DDMAC) of the U.S. Food and Drug Administration (FDA) has reviewed an Axcan Pharma US, Inc. (Axcan) webpage1 containing three patient success story videos for Photofrin® (porfimer sodium) Injection (Photofrin) titled: A Pulmonary Patient’s Experience; Minimally Invasive Treatment for High-Grade Dysplasia in Barrett’s Esophagus; and One Patient’s Success Story. The webpage and embedded videos omit and minimize risk information, overstate the efficacy of and make unsubstantiated claims about Photofrin. Thus the webpage and videos misbrand Photofrin in violation of Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & (n); 321(n), and FDA implementing regulations. See 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i) & (e)(7)(viii). Furthermore, Axcan failed to submit the pieces to FDA under cover of Form FDA 2253 as required by 21 CFR 314.81(b)(3)(i). The webpage and embedded videos are concerning from a public health perspective because they suggest that Photofrin is safer and more effective than has been demonstrated by substantial evidence or substantial clinical experience.

Background

Photofrin is indicated, among other things, for (emphasis in original):

Endobronchial Cancer
PHOTOFRIN is indicated for the treatment of microinvasive endobronchial non-small-cell lung cancer (NSCLC) in patients for whom surgery and radiotherapy are not indicated.
PHOTOFRIN is indicated for the reduction of obstruction and palliation of symptoms in patients with completely or partially obstructing endobronchial NSCLC.

High-Grade Dysplasia in Barrett’s Esophagus
PHOTOFRIN is indicated for the ablation of high-grade dysplasia in Barrett’s esophagus patients who do not undergo esophagectomy.

Photofrin is associated with a number of serious risks. The contraindications for Photofrin include:

• PHOTOFRIN is contraindicated in patients with porphyria.
• Photodynamic therapy (PDT) is contraindicated in patients with an existing tracheoesophageal or bronchoesophageal fistula.
• PDT is contraindicated in patients with tumors eroding into a major blood vessel.
• PDT is not suitable for emergency treatment of patients with severe acute respiratory distress caused by an obstructing endobronchial lesion because 40 to 50 hours are required between injection with PHOTOFRIN and laser light treatment.
• PDT is not suitable for patients with esophageal or gastric varices, or patients with esophageal ulcers >1 cm in diameter.

Photofrin is also associated with several warnings and precautions including:

• Tracheoesophageal or bronchoesophageal fistula can occur if esophageal tumor is eroding into trachea or bronchial tree
• High risk of bleeding in patients with esophageal varicies
• High risk for fatal massive hemoptysis with endobronchial tumors that are: large, centrally located; cavitating; extensive, extrinsic to the bronchus
• After treatment of HGD in BE, monitor endoscopic biopsy every three months, until four consecutive negative evaluations for HGD have been recorded
• Use with extreme caution for endobronchial tumors in locations where treatment-induced inflammation could obstruct the main airway leading to life-threatening respiratory distress
• Photosensitivity can be expected; ocular sensitivity is possible. According to the PI, “All patients who receive PHOTOFRIN will be photosensitive and must observe precautions to avoid exposure of skin and eyes to direct sunlight or bright indoor light (from examination lamps, including dental lamps, operating room lamps, unshaded light bulbs at close proximity, etc.) for at least 30 days.
Some patients may remain photosensitive for up to 90 days or more….”
• Allow 2-4 weeks between PDT and subsequent radiotherapy
• Substernal chest pain may occur after treatment and may require analgesics
• Esophageal stenosis occur frequently after treatment of HGD in BE
• Patients with hepatic or renal impairment may need longer precautionary measures for photosensitivity

The most common adverse events associated with Photofrin use during clinical trials in obstructing endobronchial cancer were dyspnoea, photosensitivity reaction, hemoptysis, pyrexia, cough and pneumonia. In the superficial endobronchial tumor clinical trials, the most common adverse events were exudate, photosensitivity reactions, bronchial obstruction, edema and bronchostenosis.

The most common adverse reactions associated with high-grade dysplasia in Barrett’s Esophagus clinical trials were photosensitivity reaction, esophageal stenosis, vomiting, chest pain, nausea, pyrexia, constipation, dysphagia, abdominal pain, pleural effusion, and dehydration.

Omission and Minimization of Risk Information

Promotional materials are misleading if they fail to reveal material facts in light of the representations made by the materials or with respect to consequences that may result from the use of the drug as recommended or suggested by the materials. The Success Stories webpage and the embedded videos A Pulmonary Patient’s Experience and Minimally Invasive Treatment for High-Grade Dysplasia in Barrett’s Esophagus are misleading because they present numerous efficacy claims for Photofrin but fail to disclose any risk information. We note that there is a “Please refer to Full Prescribing Information” link on the webpage, which in turn leads to another webpage where the Full Prescribing Information can be downloaded; however, this does not correct the misleading omission of risk from the webpage or from the embedded videos. Additionally, we note that a number of other webpages (including but not limited to: About Photofrin; Treatment Options for Barrett’s HGD; and PDT for Non-Small Cell Lung Cancer) found on the Photofrin promotional website, www.photofrin.com, are misleading for similar reasons.

The embedded video titled One Patient’s Success Story profiles a patient with High Grade Dysplasia and features an interview with Dr. Bergein Overholt. The video makes numerous efficacy claims regarding Photofrin therapy but drastically minimizes the numerous risks associated with Photofrin. Specifically, the only risk disclosed during the interview portion of the video by Dr. Overholt is that “The initial side effect is the drug stays in the body for a month so patients are sensitive to sunlight for a month, but that is a minor inconvenience compared to the alternatives.” This misleadingly understates the risk of photosensitivity; according to the PI, patients will be photosensitive for at least 30 days, but may remain photosensitive for up to 90 days or more. We note that common adverse events are also presented at the end of the video in small, static font. However, this presentation severely minimizes the risks of Photofrin by omitting the numerous contraindications, warnings, and precautions associated with the drug, some of which can be fatal. Furthermore, the limited presentation of risk information in the video is not presented in a manner that is comparably prominent to the presentation of efficacy claims.

Overstatement of Efficacy and Unsubstantiated Claims

Promotional materials are misleading if they represent or suggest that a drug is better or more effective than has been demonstrated by substantial evidence or substantial clinical experience. The Photofrin Success Stories webpage contains a promotional video titled Minimally Invasive Treatment for High-Grade Dysplasia in Barrett’s Esophagus, which consists of a news clip that interviews a patient and his physician, during which they discuss how the patient was diagnosed with Barrett’s Esophagus, his experience with PDT treatment
and other possible treatment options for Barrett’s Esophagus.

The video starts with the following statements:

• “Well, doctors say it is the most dramatically increasing cancer out there, especially with white men. It also has a very low survival rate. But the good news is just published research shows a nonsurgical treatment used to kill cancer cells is also successful in preventing their development.”

The physician in the video states:

• “It’s the first trial that’s ever been shown that a treatment can decrease the cancer risk from Barrett’s Esophagus. Prior to this the only thing physicians had as an option was to tell the patient to remove their esophagus or to wait until a cancer develops and then remove the esophagus. . . .”

The patient in the video states:

o “I feel fantastic. I haven’t felt this good for 50 years . . . . It’s fantastic because I wouldn’t be here without it.”

These presentations in the video misleadingly overstate the efficacy of Photofrin. We are not aware of support for the implication that Barrett’s Esophagus patients’ options consist either of taking Photofrin and achieving excellent results (“feeling fantastic”), having their
esophagus removed, or not taking Photofrin and succumbing to esophageal cancer (“I wouldn’t be here without it”), despite the suggestions in the video to the contrary. According to clinical studies in the PI for Photofrin, patients can also be managed and respond completely on an acid suppressive therapy such as omeprazole. Other treatment options are also available (e.g., radiofrequency, endoscopic mucosal resection, other ablative techniques). Additionally, it is not standard practice to remove a patient’s esophagus before a diagnosis of cancer, and the development rate of esophageal cancer is estimated at less than 1% per year.2. These presentations in the video therefore misleadingly portray the disease state and overstate the demonstrated efficacy of Photofrin.

The promotional video titled A Pulmonary Patient’s Experience found on the Photofrin Success Stories webpage also overstates the efficacy of the drug. The video primarily consists of an interview with a patient and her physician, during which they discuss how she was diagnosed with NSCLC and her experience with PDT treatment.

The physician in the video states:

• “[S]he came to us with the diagnosis of non-small cell carcinoma . . . . She’s now approaching 3 years from the time of diagnosis and treatment with definitive photodynamic therapy and remains free of recurrent disease.”

The patient in the video states:

• “. . . [T]hey came in and told me I had cancer of the windpipe and my lung . . . . From the very beginning to this point I would absolutely say that there was no other option to me at all, nothing else that I could’ve done that would’ve worked the way this has worked. I don’t think I’ve missed a step in the life that I was taking. I think that I’ve been able to live probably even a better life.”

These presentations misleadingly overstate the efficacy of Photofrin. Specifically, the claims in the video imply a three-year survival benefit for NSCLC patients who take Photofrin. According to the PI for Photofrin, there are two patient populations that were studied in relation to endobronchial cancer, “microinvasive” and “obstructing”. While the median time to tumor recurrence for patients in the microinvasive population was 2.7 years and median survival was 2.9 years, the obstructing population had a median duration of symptom benefit of 63 days and median survival was 6 months. The selective presentation of the more favorable survival data from the microinvasive population, along with the lack of contextual information regarding which type of NSCLC the patient portrayed in the video has, misledingly suggests that most NSCLC patients may live “free of recurrent disease” 3 years from the time of diagnosis, when this has not been demonstrated by substantial evidence or substantial clinical experience.

The video also misleadingly overstates the efficacy of Photofrin by suggesting it allows NSCLC patients to live life free of any effects of their underlying disease, i.e., “. . . . I don’t think I’ve missed a step…I’ve been able to live probably even a better life.” While Photofrin may improve some pulmonary symptoms and offer some NSCLC patients a survival benefit, we are not aware of any evidence to support the suggestion that Photofrin will allow patients to live unaffected by their underlying disease. In addition, this statement ignores the potential adverse effects of treatment with Photofrin. If you have substantial evidence or substantial clinical experience to support these claims, please submit them to FDA for review.

The Photofrin Success Stories webpage contains the following claim adjacent to the embedded videos (emphasis in original):

• “photodynamic therapy milestones
The curative properties of light were described in Ancient Greece by Herodotus, who is thought to be the father of heliotherapy Read more…”

We note that this claim contains a link to an external article on light therapy; however, when presented on a branded product page for Photofrin along with videos promoting the use of Photofrin, this claim suggests that Photofrin, a photodynamic therapy, is a curative therapy. FDA is not aware of any data which supports Photofrin as a cure for any of the conditions for which it is indicated. The treatment effects of Photofrin as described in the PI consist of symptom improvement or response, including complete response (in a portion, but not all patients), for varying periods of time. We are not aware of substantial evidence or substantial clinical experience to support the suggestion that Photofrin results in a cure/permanent elimination of any of the conditions in the indication. This presentation thus misleadingly overstates the efficacy of Photofrin.

Failure to Submit Under Form FDA 2253

FDA regulations require companies to submit any labeling or advertising devised for promotion of the drug product at the time of initial dissemination of the labeling and at the time of initial publication of the advertisement for a prescription drug product. Each submission is required to be accompanied by a completed transmittal Form FDA 2253 (Transmittal of Advertisements and Promotional Labeling for Drugs for Human Use) and is required to include a copy of the product’s current product labeling. You did not submit a copy of the webpage or videos referred to in this letter to FDA under cover of Form FDA 2253 at the time of their initial publication as required by 21 CFR 314.81(b)(3)(i).

Conclusion and Requested Action

For the reasons discussed above, the video and website misbrand Photofrin in violation of the Act, 21 U.S.C. 352(a) & (n); 321(n), and FDA’s implementing regulations. See 21 CFR 202.1(e)(3)(i); (e)(5); (e)(6)(i) & (e)(7)(viii). Furthermore, the website was not submitted under
cover of Form FDA 2253, as required by 21 CFR 314.81(b)(3)(i).

DDMAC requests that Axcan immediately cease the dissemination of violative promotional materials for Photofrin such as those described above. Please submit a written response to this letter on or before July 27, 2010, stating whether you intend to comply with this request, listing all violative promotional materials for Photofrin such as those described above, and explaining your plan for discontinuing use of such materials. Because the violations described above are serious, we request, further, that your submission include a comprehensive plan of action to disseminate truthful, nonmisleading, and complete corrective messages about the issues discussed in this letter to the audience(s) that received the violative promotional materials.

Please direct your response to me at the Food and Drug Administration, Center for Drug Evaluation and Research, Division of Drug Marketing, Advertising, and Communications, 5901-B Ammendale Road, Beltsville, MD 20705-1266, or facsimile at 301-847-8444. In all future correspondence regarding this matter, please refer to MACMIS 18813 in addition to the NDA number. We remind you that only written communications are considered official.

The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Photofrin comply with each applicable requirement of the Act and FDA implementing regulations.

Failure to correct the violations discussed above may result in FDA regulatory action, including seizure or injunction, without further notice.


Sincerely,
{See appended electronic signature page}
Thomas W. Abrams, RPh, MBA
Director
Division of Drug Marketing,
Advertising and Communications

 

 

 

Application
Type/Number
 
Submission
Type/Number
Submitter NameProduct Name
NDA-21525ORIG-1AXCAN
SCANDIPHARM
INC
 
PHOTOFRIN (PORFIMER
SODIUM) INJ 75MG
 
NDA-20451ORIG-1AXCAN PHARMA
US INC
 
(PORFIMER
SODIUM) IV INJ 75MG
 

 

 


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This is a representation of an electronic record that was signed
electronically and this page is the manifestation of the electronic
signature.
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/s/
----------------------------------------------------
THOMAS W ABRAMS
07/13/2010

1 http://www.photofrin.com/success_stories.php?lang=1, last accessed July 13, 2010.

2 See http://digestive.niddk.nih.gov/ddiseases/pubs/barretts/index.htm#risk, last accessed June 1, 2010.