Michelle Sharp, PharmD Director, US Regulatory Affairs Lilly Corporate Center Indianapolis, IN 46285

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DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Silver Spring, MD 20993 TRANSMITTED BY FACSIMILE Michelle Sharp, PharmD Director, US Regulatory Affairs Lilly

1 DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Silver Spring, MD TRANSMITTED BY FACSIMILE Michelle Sharp, PharmD Director, US Regulatory Affairs Lilly Corporate Center Indianapolis, IN RE: NDA # Adcirca TM (tadalafil) Tablets MACMIS #18219 Dear Dr. Sharp: This letter notifies Eli Lilly and Company (Lilly), and by copy, United Therapeutics, which promotes Adcirca (tadalafil) Tablets (Adcirca) for Lilly, 1 that 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 a web page 2 and two patient videos 3 for Adcirca. The web page is false or misleading because it omits risks associated with Adcirca. The patient videos are false or misleading because they overstate the efficacy of Adcirca. Thus, the web page and the patient videos misbrand the drug in violation of the Federal Food, Drug, and Cosmetic Act (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). In addition, the web page and the patient videos were not submitted to FDA under cover of Form FDA-2253 as required by 21 CFR (b)(3)(i). Background According to its FDA-approved product labeling (PI), Adcirca is indicated for the treatment of pulmonary arterial hypertension (WHO Group ) to improve exercise ability. Adcirca is contraindicated in patients who are using any form of organic nitrate, either regularly or intermittently, because Adcirca potentiates the hypotensive effect of nitrates. Adcirca is also contraindicated in patients with a known serious hypersensitivity to tadalafil (Adcirca or Cialis). Adcirca is also associated with several important risks. The PI contains numerous Warnings and Precautions, including cardiovascular effects, interaction with alpha blockers and antihypertensives, use with alcohol, use with potent CYP3A inhibitors or inducers, use in patients with renal impairment and hepatic impairment, effects on the eye such as risk of non-arteritic anterior ischemic optic neuropathy (NAION), hearing impairment, combination with other phosphodiesterase 5 (PDE5) inhibitors, and prolonged erection. 1 DDMAC was informed of this agreement on May 22, 2009 via letter correspondence from Lilly. 2 Adcirca webpage, at: (last accessed Jan. 26, 2010). 3 Patient videos entitled Traci and Carolyn at: (last accessed Jan. 26, 2010).

2 Michelle Sharp Page 2 Furthermore, the following adverse events are associated with Adcirca: headache, myalgia, nasopharyngitis, flushing, respiratory tract infection (upper and lower), pain in extremity, nausea, back pain, dyspepsia, and nasal congestion (including sinus congestion). The Clinical Studies section of the PI states, The primary efficacy endpoint was the change from baseline at week 16 in 6-MWD [minute walk distance].... In the ADCIRCA 40 mg treatment group, the placebo-adjusted mean change increase in 6-MWD [minute walk distance] was 33 meters (95% C.I meters; p=0.0004). Omission of Risk Information Web Page 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. Although the web page presents the most common side effects associated with Adcirca, it fails to include any of the Contraindications or Warnings and Precautions information for this drug product (see Background section above). Because the web page omits these important risks, it misleadingly suggests that Adcirca is safer than has been demonstrated by substantial evidence or substantial clinical experience. We further note that the web page fails to include any indication of where a viewer can get more risk information about the drug. Overstatement of Efficacy Patient Videos Promotional materials are misleading if they represent or suggest that a drug is more effective than has been demonstrated by substantial evidence or substantial clinical experience. The patient videos present statements made by Adcirca users, Traci and Carolyn. Traci s statements (in pertinent part) include the following: The first symptoms I had was breathlessness. Starting out with a little bit of breathlessness and turning into stairs being a problem for me. Getting up a flight of stairs and then coming very close to blacking out or blacking out and just complete breathlessness as if I ran a mile, really fast, as hard as I could. Just chest pounding, heart pounding, you know sweating, just complete exhaustion with just the smallest of things. I can walk, and stairs don t bother me [after Adcirca treatment].... Bending over used to make me breathless, picking up my cat used to make me breathless and it doesn t affect me anymore. It went from walking five minutes and wanting to go home to walking one-half hour to one hour and not caring if I went home. From going to the mall and getting tired and wanting to go home in an hour to spending the night at the mall. Breathing, being able to get a full breath because before when I would breathe, it was almost like I had smog. Exercising and stairs and heat used to bother me and it didn t bother me anymore [after Adcirca treatment].

3 Michelle Sharp Page 3 Carolyn s statements (in pertinent part) include the following: I couldn t take a deep breath... I couldn t breathe. At night, I just couldn t catch my breath... I would wake up short of breath.... I can t run along the beach with them [kids] or I can t play with them... like I used to because I don t have the wind to do it or the oxygen to do it. I could walk a block without stopping and having to take a deep breath [after taking Adcirca]. I don t have to drag my oxygen tank with me as many places as I used to. [After taking Adcirca] Your breathing is better... your stamina is better... you could do a lot more and it takes you by surprise because I mean you couldn t do it before. I went on this [Adcirca], I don t have to use my oxygen tank, so that s a great benefit. I have been able to put more things into my day because I don t have to stop and rest as much as I used to and that to me is the biggest benefit of them all. I am exercising again... and I couldn t exercise [before Adcirca], now I am walking on the treadmill. You know and I am walking along the beach, slowly I am beginning to do a lot more of the exercising that I used to be able to do As far as I am concerned, everyday I am beginning to do a lot more. I am moving more, I am breathing better. Traci s and Carolyn s statements seriously misrepresent what is known about the efficacy of Adcirca. First, Traci s and Carolyn s statements misleadingly imply that patients treated with Adcirca will greatly increase their walking time and distance (e.g., from... five minutes... to one hour, spending all night at the mall, now I am walking on the treadmill, and walking along the beach ). These statements significantly exaggerate what was demonstrated in the clinical trials for Adcirca. As stated above, the placebo-adjusted mean change increase in 6-MWD was 33 meters. Thus, there is only data to support that study subjects can increase their walking distance by 33 meters in six minutes. Second, Traci s and Carolyn s statements misleadingly imply that patients treated with Adcirca will experience an improvement in their symptoms of PAH (e.g., breathlessness), and an improvement in WHO functional class (e.g. walking, exercising more). According to the Adcirca clinical trials, secondary endpoints, such as the change in Borg dyspnea (or breathlessness) scale and WHO functional class, tended to show numerical improvement; however, these endpoints did not show a statistically significant improvement with the 40 mg dose of Adcirca compared to placebo. Furthermore, Carolyn s statements misleadingly imply that Adcirca will reduce the need for an oxygen tank in patients who needed it prior to Adcirca therapy. FDA is not aware of any substantial evidence or substantial clinical experience to support these claims of improvement in PAH symptoms or daily functioning, or a reduction in the need for an oxygen tank. If you have data to support these claims, please submit them to FDA for review. Furthermore, Traci s statements include the following:... I just couldn t believe that I could have a short life... it was just too unbelievable to me to believe that I could just have years, a couple of years, no way. In addition, Traci and Carolyn make the following statements, respectively (emphasis added):

4 Michelle Sharp Page 4 I got a phone call from Dr. Shapiro, who introduced me to Adcirca... I jumped at the idea that something could help me and I ve been on it for three and a half years now. I started taking Adcirca... November 16, I am going on four years. These claims imply that Adcirca has demonstrated long-term benefits (i.e., up to four years), including a potential survival benefit, when this has not been demonstrated by substantial evidence or substantial clinical experience. According to clinical trials for Adcirca, patients from the placebo-controlled study entered a long-term extension study. However, the patients in the study were only treated with Adcirca for six months to one year. In addition, among other issues, this study did not have a control group, and according to Adcirca s PI, [w]ithout a control group, these data must be interpreted cautiously. Furthermore, FDA is not aware of any substantial evidence or substantial clinical experience demonstrating the effect of treatment with Adcirca on survival. If you do, in fact, have data to support these claims, you should submit them to FDA for review. Failure to Submit Under Form FDA-2253 FDA regulations require companies to submit specimens of 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 and Biologics for Human Use) and is required to include a copy of the product s current professional labeling. A copy of the web page and the patient videos were not submitted to FDA under cover of Form FDA at the time of their initial publication, as required by 21 CFR (b)(3)(i). Conclusion and Requested Action For the reasons discussed above, the web page and the patient videos misbrand Adcirca in violation of the Federal Food, Drug, and Cosmetic Act (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). In addition, the web page and the patient videos were not submitted to FDA under cover of Form FDA-2253 at the time of their initial publication, as required by 21 CFR (b)(3)(i). DDMAC requests that Lilly immediately cease the dissemination of violative promotional materials for Adcirca such as those described above. Please submit a written response to this letter on or before February 10, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Adcirca that contain violations such as those described above, and explaining your plan for discontinuing use of such violative 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 , facsimile at In all future correspondence regarding this matter, please refer to MACMIS # in addition to the NDA number. We remind you that only written communications are considered official.

5 Michelle Sharp Page 5 The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that your promotional materials for Adcirca comply with each applicable requirement of the Act and FDA implementing regulations. Sincerely, {See appended electronic signature page} Zarna Patel, PharmD Regulatory Review Officer Division of Drug Marketing, Advertising, and Communications CC: Kerry McKenzie, Regulatory Affairs Manager United Therapeutics 55 T.W. Alexander Drive Research Triangle Park, NC 27709

6 Application Type/Number Submission Type/Number Submitter Name Product Name NDA ORIG-1 ELI LILLY CO ADCIRCA This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature /s/ ZARNA PATEL 01/27/2010

According to the INDICATIONS AND USAGE section of its FDA-approved product labeling (PI):

According to the INDICATIONS AND USAGE section of its FDA-approved product labeling (PI): DEPARTMENT OF HEALTH & HUMAN SERVICES Public Health Service Food and Drug Administration Silver Spring, MD 20993 TRANSMITTED BY FACSIMILE Karen L. Walles, M.S. Assistant Director, Regulatory Affairs 3