Released by FDA: 3/7/00.  Posted by FDA:  6/13/00

Ronald G. Van Valen 
Associate Director 
Novartis Pharmaceuticals Corporation 
Drug Regulatory Affairs 
59 Route 10 
East Hanover, NJ 07936-1080

RE:    NDA50-737, 50-738 
         Neoral (cydosporine capsules far microemulsion) Soft Gelatin Capsules 
         Neoral (cyclosporine oral solution for microemulsion) Oral Solution 
         MACMIS#: 8498

Dear Mr. Van-Valen:

As part of our routine monitoring program, the Division of Drug Marketing, Advertising, and Communications (DDMAC) has become aware of promotional materials for Neoral Soft Gelatin Capsules and Neoral Oral Solution by Novartis Pharmaceuticals Corporation that violate the Federal Food, Drug and Cosmetic Act (Act) and its implementing regulations.  Reference is made to promotional materials NPS-0001, NPS-1003-A, NPS- 1004, CNPS-1004, CNPS-lO06, NPS-2006, NPS-2007, NPS-2008, NPS- 2009, NPS-2010, NPS-201 1 B,C, NPS-2012, NPS-2014, NPS-2017, NPS- 8016, CNEO-1 114, NPS-8008 and NPS-9102.

False and Misleading Claims

Efficacy

You are making false and misleading claims in your materials by presenting higher efficacy rates for Neoral compared to the efficacy rates found in the pivotal studies. You claim that 87% of patients achieve remission by week 16.  However, the percentages for achieving remission in the pivotal studies are 51.1%, 79.1% and 80.6% for 8, 16 and 24 weeks respectively in the efficacy population, and 49%, 80.2% and 82.9% for 8, 16, and 24 weeks respectively in the intent-to-treat population. Therefore, as stated in our March 3, 1998, launch comments to you, this claim is false or misleading because it suggests that Neoral is more effective than has been demonstrated.

Rotation with other therapies

In your promotional materials (including NEO-2046, CNPS-1004 and NPS- 8008), you make the claim that Neoral can be rotated with other therapies to limit the side effects associated with the long-term use of a single drug.  This claim implies it is an option to alternate, but does not communicate that continuous treatment is NOT recommended.  This claim is misleading because it is not consistent the information from the prescribing information that states, Long term experience with Neoral in psoriasis patients is limited and continuous treatment for extended periods greater than one year is not recommended.  Alternation with other forms of treatment should be considered in long term management of patients with this life long disease.

Unsubstantiated Claims

Several of your materials present statements that comment on the negative psychosocial impact of psoriasis.  For example, For many patients, the chief disability isn’t physical its psychological and Psoriasis has been linked to low self-esteem, depression, obesity, increased alcohol consumption and suicide.  These claims in the context of promotion of Neoral, are false or misleading because they imply that Neoral has an effect on psychosocial functioning that has not been demonstrated.

In your promotional material NPS 2014-A, you list under the heading titled, Quality of Life Issues: 

• Decreased ability to work and/or manage a home 
• Restricted recreational activities 
• Limited personal and/or social relationships 
• Physically painful and/or emotionally disabling

These claims, in the context of promotion of Neoral, are misleading because they imply that Neoral has an effect on physical, mental and social functioning that has not been demonstrated by substantial evidence.  

Furthermore, in your promotional material NPS-2007, under the heading titled, Neoral Promotes Patient Satisfaction, you make claims such as I’ve got my life back — the Neoral difference and Neoral makes me feel like a normal human being. These claims are false and misleading because they make implied and explicit claims that Neoral promotes patient satisfaction that are not supported by substantial evidence.

Brief Summary

Professional journal

According to regulations, all advertisements for any prescription drug shall present a true statement of information in brief summary relating to side effects, contraindications and effectiveness.  You placed advertisements for Neoral in a “wrap-around” fashion in the May 1999 issue of SKIN & AGING (CNPS-1004) and also the September 1999 issue of THE LANCET (CNEO-1114).  These presentations are two separate and distinct advertisements (back and front covers) and each requires an accompanying brief summary.  However, the front cover advertisement is not accompanied by a brief summary.  Further, the Psoriasis and Transplant brief summaries presented on the respective back panels of the journals are missing information from the ADVERSE REACTIONS and WARNINGS sections of the approved labeling.

Lack of Risk Information

Visual aid

Your promotional piece N PS-i 004-A lacks fair balance or is otherwise misleading because it presents several statements that minimize the risk of developing kidney failure while taking Neoral, without presenting the serious boxed warning information about kidney failure. For example, you quote, “[A]lthough some loss of renal function occurs in many patients, it is mild, reversible, and acceptable given the benefits that derive from treatment.”  You however, do not present the boxed warning that states that Neoral in recommended dosages can cause nephrotoxicity.  In addition, the warning section of the prescribing information states that since cyclosporine is a potent immunosuppressive agent with a number of potential side effects, the risks and benefits of using Neoral should be considered before treatment, of patients with psoriasis. 

Similarly, your presentation on skin malignancy and lymphoma presents statements that minimize the risk for developing these diseases without presenting the boxed warning from the prescribing information about these diseases.  For example, you state that the relative risk of developing lymphoma and/or skin malignancies with cyclosporine is comparable to that observed in psoriasis patients treated with other systemic agents. However, you do not present the boxed warning that states that psoriasis patients previously treated with PUVA and to a lesser extent, methotrexate or other immunosuppressive agents, are at an increased risk of developing skin malignancies when taking Neoral.

Note pad

Your promotional piece NPS -2012 (note pad) is lacking in fair balance because it presents the claim, “remission accomplished” without presenting any risk information.

Photographs

The photographs and slides in your promotional piece NPS-8016¹ do not accurately represent severe, recalcitrant psoriasis and are therefore, are false and misleading because they suggest that Neoral is useful in a broader range of conditions than indicated.

Action Requested

You should immediately cease distribution of these promotional materials and all other promotional materials for Neoral that contain the same or similar claims or presentations cited in this letter.  You should submit a written response to us, on or before March 21, 2000, describing your intent and plans to comply with the above. In your letter to us, you should include a list of all promotional materials that were discontinued, and the discontinuation dates.

You should direct your response to me by facsimile at (301) 594-6771, or at the Food and Drug Administration, Division of Drug Marketing, Advertising, and Communications, HFD-42, Rm. 17B-20, 5600 Fishers Lane, Rockville, MD 20857. We remind you that only written communications are considered official.  In all correspondence regarding this particular submission, please refer to MACMIS ID# 8498 in addition to the NDA number.

Sincerely,

Cheryl Y. Roberts 
Regulatory Review Officer 
Division of Drug Marketing, 
   Advertising and Communications

 

¹  Response of patient 02-005 in study OLP-452