Benjamin J. Del Tito, Jr., Ph.D.
Executive Vice President, Regulatory Affairs & Project Management
Auxilium Pharmaceuticals, Inc.
40 Valley Stream Parkway
Malvern, PA 19355

RE:  BLA # 125338
        XIAFLEX™ (collagenase clostridium histolyticum) for injection, for intralesional use
        MACMIS # 18562

Dear Dr. Del Tito:

As part of its 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 direct-to-consumer (DTC) patient brochure (0210-023.a) for Xiaflex (collagenase clostridium histolyticum) for injection, for intralesional use (Xiaflex) submitted by Auxilium Pharmaceuticals, Inc.  (Auxilium) under cover of Form FDA-2253.  The patient brochure is misleading because it broadens the indication for Xiaflex, overstates the efficacy of Xiaflex, minimizes the risks associated with the use of Xiaflex and omits material facts.  Thus, the patient brochure misbrands the drug in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & 321(n). Cf. 21 CFR 202.1(e)(3)(i); (e)(5) & (e)(6)(i). 

Background

According to the Indications and Usage section of the FDA-approved product labeling (PI):

Xiaflex is indicated for the treatment of adult patients with Dupuytren’s contracture with a palpable cord. 

Xiaflex is associated with warnings and precautions regarding tendon rupture and other serious injury to the injected extremity, including possible permanent injury, such as tendon rupture or ligament damage.  Xiaflex is also associated with warnings and precautions regarding patients with abnormal coagulation and allergic reactions.  The most common adverse reactions reported in 25% or more of patients treated with Xiaflex and at an incidence greater than placebo were peripheral edema (e.g., swelling of the injected hand), contusion, injection site reaction, injection site hemorrhage, and pain in the injected extremity. 

In the two clinical studies evaluating Xiaflex (Studies 1 and 2) through Day 90, 98% of Xiaflex-treated patients and 51% of placebo-treated patients had an adverse reaction after up to 3 injections.  Over 95% of Xiaflex-treated patients had an adverse reaction of the injected extremity after up to 3 injections. 

In Studies 1 and 2, the primary endpoint was to evaluate the proportion of patients who achieved a reduction in contracture of the selected primary joint (MP or PIP) to within 0° to 5° of normal, 30 days after the last injection of that joint on Days 30, 60, or 90 (after up to 3 injections).  In Study 1, 64% and 7% of patients achieved a reduction in contracture of metacarpophalangeal (MP) and proximal interphalangeal (PIP) joints to 0° to 5° after up to 3 injections in the Xiaflex and placebo groups, respectively.  In study 2, 44% and 5% of patients achieved a reduction in contracture of MP and PIP joints to 0° to 5° after up to 3 injections in the Xiaflex and placebo groups, respectively.  The proportion of patients who achieved a contracture reduction of the primary joint to 0° to 5° after the first Xiaflex injection was 39% and 1% in Study 1 and 27% and 5% in Study 2 in the Xiaflex and placebo groups, respectively. 

Broadening of Indication

Promotional materials are misleading if they suggest that a drug is useful in a broader range of conditions or patients than has been demonstrated by substantial evidence or substantial clinical experience.  The patient brochure presents claims such as the following:

•  “FOR THE TREATMENT OF DUPUYTREN’S CONTRACTURE” (front cover)
•  “In early Dupuytren’s disease stages, lumps (or nodules) and dimples may appear in the palm.  During these stages, the disease may have minimal impact on your daily activities.” (page 2)
•  “XIAFLEX™ is the only FDA-approved nonsurgical treatment for Dupuytren’s contracture.” (page 4)
•  “There is no cure for Dupuytren’s disease.  Surgical and nonsurgical treatments [i.e., Xiaflex] focus on improving the disease’s signs and symptoms.” (page 4)

The totality of these claims misleadingly suggests that Xiaflex is indicated to treat all patients with Dupuytren’s disease, including patients with early Dupuytren’s disease without a palpable cord.  Xiaflex is only approved to treat adult patients with Dupuytren’s contracture with a palpable cord.  The implication that Xiaflex is appropriate for any patient with Dupuytren’s contracture or Dupuytren’s disease thus misleadingly broadens the indication of the drug.  We note that the patient brochure contains the statement that Xiaflex is for “adults with Dupuytren’s contracture with a cord that can be felt” at the bottom of page 4.  However, this is not sufficient to mitigate the overall misleading impression created by the previously described statements that are prominently presented earlier in the brochure. 

Overstatement of Efficacy

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 brochure presents several claims that misleadingly overstate the efficacy of Xiaflex. 

For example, the patient brochure contains the following claim on page 6:

•  “XIAFLEX™ treatment eliminates contracture in up to two-thirds of patients.”

This claim misleadingly overstates the efficacy of Xiaflex for a number of reasons.  First, it implies that Xiaflex can permanently “eliminate” contracture, when this has not been demonstrated by substantial evidence or substantial clinical experience.  Dupuytren’s contracture is an incurable disease that reoccurs after treatment, including after Xiaflex injections.  Second, this claim is based on the selective presentation of only the most favorable efficacy results from one of the two clinical studies evaluating Xiaflex.  Specifically, in Study 1, 64% of patients achieved a reduction in contracture of the selected primary joint (MP and PIP) to within 0° to 5° of normal, 30 days after the last injection of that joint on Days 30, 60, or 90 (after up to 3 injections).  However, in Study 2, only 44% of patients achieved such a reduction. 

The patient brochure also contains presentations about the consequences of Dupuytren’s disease progression, such as the following on page 2 (emphasis added):

•  “As it [Dupuytren’s disease] progresses, it can have an increasing impact on how you use your hand. 
In early Dupuytren’s disease stages, lumps (or nodules) and dimples may appear in the palm.  During these stages, the disease may have minimal impact on your daily activities. 
As the disease progresses, rope-like cords may appear under the skin of the palm, causing one or more fingers to permanently bend toward the palm.  This could prevent you from straightening your finger and interfere with your ability to do everyday tasks.”

While the patient brochure does not directly assert that Xiaflex will correct these problems of Dupuytren’s progression, the totality of the above claims, when evaluated in the context of the branded patient brochure as a whole, implies that Xiaflex treatment can reduce the likelihood or severity of the consequences of disease progression described above.  FDA is not aware substantial evidence or substantial clinical experience to support the implication that Xiaflex treatment will result in an improvement in hand function or a direct, positive and broad impact on activities of daily living.  In Xiaflex clinical studies, the primary efficacy endpoints were all measures that assessed the change in the degree of the Dupuytren’s contracture (i.e., the proportion of patients who achieved a reduction in contracture of the selected primary joint (MP or PIP)) (see Background section).  Although Xiaflex treatment demonstrated a reduction in contracture of the selected primary joint for a greater proportion of patients compared to placebo, we are not aware of studies demonstrating that this reduction in contracture corresponds with the suggested overall improvement in a patient’s hand function or general activities of daily living.  If you have data to support these claims, please submit them to FDA for review. 

Minimization of Risk

The patient brochure includes presentations of risk information that suggest Xiaflex is safer, has fewer, or less incidence of, or less serious risks than has been demonstrated, thereby minimizing the risks associated with Xiaflex.  For example, the patient brochure presents the following information under the heading, “XIAFLEX Side Effects and Safety” on page 7 (emphasis original):

•  Most Common Side Effects.  The most common XIAFLEX side effects are generally mild or moderate and usually resolve within 4 weeks with no additional treatment.  The most common side effects occur in the treated finger or hand and include: . . . 

We are not aware of substantial evidence to support the claim that the most common side effects of Xiaflex are “mild or moderate,” and the characterization of the most common side effects in this manner serves to minimize the severity and frequency of the common adverse reactions associated with the drug.  As discussed in the Background section, the drug is associated with painful common adverse reactions, and up to 98% of Xiaflex-treated patients in clinical trials had an adverse reaction. 

This presentation of the “Most Common Side Effects” is followed by a presentation headlined “Other Side Effects” (emphasis original) at the bottom of page 7, which provides a listing of serious side effects that can occur with Xiaflex.  The placement of the serious risks under this headline at the bottom of the page serves to further minimize the presentation of risk information in the piece by failing to give readers a clear signal that the information presented in this location relates to the serious side effects that Xiaflex can cause.  The presentation of the serious risks in this manner undermines the communication of this important information to patients. 

Omission of Material Fact

Promotional materials are misleading if they fail to reveal material facts in light of the representations made by the materials.  The patient brochure includes two sections on pages 5-6, one titled “How XIAFLEX Is Administered” and the next titled “What to Expect From Treatment.” The “How XIAFLEX Is Administered” section describes the “Injection Procedure (Day 1)” during which the physician injects Xiaflex, and states “Your doctors will use a small needle to inject XIAFLEX directly into the cord” and then discusses what will happen directly “[a]fter the injection.” This section then discusses an “Extension Procedure (Next Day Follow-Up)” during which the physician may attempt to extend the finger “after your injection”.  The next section (“What to Expect From Treatment”) first describes “Improvement in Contracture” and includes the misleading claim discussed above that “XIAFLEX™ treatment eliminates contracture in up to two-thirds of patients.” A section discussing the potential for “Additional Follow-up Visits” appears after this presentation of “What to Expect” regarding “Improvement in Contracture.”

The totality of these presentations misleadingly omits important contextual information regarding Xiaflex.  Specifically, these presentations strongly imply that treatment with Xiaflex is likely to consist of a single injection when, in fact, the drug is injected three times during each injection procedure on a single day, and multiple injection procedures may be needed.  Furthermore, the presentation suggests the claimed efficacy results (elimination in contracture in up to two-thirds of patients) occur after a single injection.  However, according to the Clinical Studies section of the PI, the claimed results, which are taken from Study 1, were evaluated 30 days after the last administration of Xiaflex of that joint on Days 30, 60, or 90 (i.e., on 3 separate days) (emphasis original).  Thus, these results include patients who had to return for additional follow-up injection procedures, and are not representative of what patients can expect after a single injection procedure (and as noted previously, these results also reflect a selective presentation of only the most favorable clinical trial information). 

These presentations fail to appropriately disclose this material information about the administration of Xiaflex. 

Conclusion and Requested Action

For the reasons discussed above, the patient brochure misbrands Xiaflex in violation of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 352(a) & 321(n). Cf. 21 CFR 202.1(e)(3)(i); (e)(5) & (e)(6)(i). 

DDMAC requests that Auxilium immediately cease the dissemination of violative promotional materials for Xiaflex such as those described above.  Please submit a written response to this letter on or before June 24, 2010, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Xiaflex 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 20705-1266 facsimile at 301-847-8444.  In all future correspondence regarding this matter, please refer to MACMIS # 18562 in addition to the BLA 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 Xiaflex comply with each applicable requirement of the Act and FDA implementing regulations. 

Sincerely,

Twyla Thompson, Pharm.D. 
Regulatory Review Officer
Division of Drug Marketing,
Advertising, and Communications