Lynda Tetarenko
Director, Regulatory Affairs
Celgene Corporation
86 Morris Avenue
Summit, New Jersey 07901

RE: NDA # 021660
      Abraxane® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound)
      MA # 177

Dear Ms. Tetarenko:

The Office of Prescription Drug Promotion (OPDP) of the U.S. Food and Drug Administration (FDA) has reviewed a white paper authored by Abraxis¹, titled “Nab Technology: A Drug Delivery Platform Utilising Endothelial gp60 Receptor-based Transport and Tumour-derived SPARC for Targeting” (AB1543) (white paper) for Abraxane® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) (Abraxane). The white paper was obtained by an OPDP representative at the Abraxis Bioscience (Abraxis) promotional exhibit booth in the commercial exhibit hall at the American Society of Clinical Oncology (ASCO) 2010 Annual Meeting in Chicago, Illinois (IL). The white paper broadens the indication for Abraxane, makes unsubstantiated effectiveness and superiority claims, and omits and minimizes important risk information associated with the use of Abraxane. Thus, the white paper misbrands the drug in violation of the Federal Food, Drug, and Cosmetic Act (FD&C Act). 21 U.S.C. 352(a) & (f)(1); and 321(n). 21 CFR 1.21, 201.100(c)(1), & 201.128; Cf. 21 202.1(e)(5), (e)(6)(i) & (ii). This promotional activity also promotes the drug as safe and effective for additional uses for which it is under investigation, in violation of 21 CFR 312.7(a). In addition, the white paper was disseminated at ASCO without the full FDA-approved product labeling (PI) for Abraxane, in violation of 21 CFR 201.100(d). Furthermore, Abraxis failed to submit the white paper to FDA under cover of Form FDA 2253 as required by 21 CFR 314.81(b)(3)(i).

Background

Abraxane was approved in 2005 as a 505(b)(2) application referencing the antineoplastic drug Taxol® (paclitaxel) injection. The FDA-approved PI states that Abraxane is “indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.”

Abraxane is associated with serious risks, as detailed in the Boxed Warning,
Contraindications, Warnings, Precautions, and Adverse Reactions sections of the PI. These risks include, but are not limited to, bone marrow suppression (primarily neutropenia), possible teratogenic effects on a developing fetus, and sensory neuropathy. The most important adverse reactions associated with Abraxane were neutropenia (all cases) (80%), sensory neuropathy (any symptoms) (71 %), myalgia/arthralgia (any symptoms) (44%), anemia (all) (33%), nausea (any symptoms) (30%), diarrhea (any symptoms) (27%), infections (24%), vomiting (any symptoms) (18%), and mucositis (any symptoms) (7%).

Upon reviewing the white paper (reprinted from the Drug Delivery Report), OPDP sent a letter of inquiry (LOI) to Abraxis and PharmaVentures, the consulting company that publishes the Drug Delivery Report, to determine the nature of the relationship between these two companies. The response from Abraxis and Celgene, dated November 3, 2010, indicates that the Drug Delivery Report is not a peer reviewed publication, the white paper was authored by Dr. Neil Desai, Senior Vice President of Research and Development at Abraxis, and that Abraxis (b) (4) of the white paper. The response also communicated that the white paper was only available in the Abraxis Medical Information booth at selected medical conferences such as ASCO 2010 and that dissemination was restricted to individual requests by persons identified as having clear business interests in the research and development of similar technology-based products or by persons with confirmed interests in third party partnerships. Furthermore, the response alleges that the white paper was not made available to the conference’s primary audience (physicians or others involved in the decision process for treating patients) or to the commercial sales force.

In contrast to the statements made in the LOI response, an OPDP representative obtained a copy of the white paper from the Abraxis promotional exhibit booth at the 2010 ASCO conference. The placement of the white paper on the counter top at the Abraxis promotional exhibit booth in the commercial exhibit hall during open exhibit hours made it available to all conference attendees, including physicians and other healthcare providers involved in the decision matrix for treating patients. The OPDP representative was neither approached by an Abraxis representative when the white paper was obtained nor was a PI offered or attached to the piece.

Additionally, we note that the white paper bears an Abraxis material ID code, similar to those used as identifiers on promotional materials when they are submitted to the FDA under cover of Form FDA 2253.

Broadening of Indication/ Promotion of Unapproved New Uses

The white paper suggests that Abraxane is safe and effective in a broader range of conditions and patients than is reflected in the drug’s FDA-approved PI. For example, the white paper contains numerous claims related to the use of Abraxane for the first-line treatment of patients with metastatic breast cancer (MBC), including the following claim:

• “In a randomised Phase II clinical trial of first-line treatment of MBC in 300 patients, administration of Abraxane at 150 mg/m2 weekly or 300 mg/m2 q3w resulted in longer progression-free survival compared to Taxotere (100 mg/m2 q3w) while the 100 mg/m2 qw dose of Abraxane resulted in equivalent progression-free survival but a much improved toxicity profile compared to Taxotere (Gradishar et al. 2006).” (page 39)

As noted in the Background section, Abraxane is approved for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. The broadening of indication for MBC is exacerbated by the fact that the white paper fails to disclose the full approved indication for Abraxane, including the important limitations to the indication.

Furthermore, the white paper contains numerous claims related to the use of Abraxane in a broad range of additional cancers for which it is under investigation, including the following:

• “More importantly, our studies demonstrated that increased SPARC levels in tumours correlate with enhanced response to Abraxane. . . . In head and neck cancer patients there was correlation between high levels of SPARC expression and tumour response to Abraxane (Trieu et al. 2006).” (pages 38-39)

• “In one recent multi-centre Phase II study of patients with non small-cell lung cancer (NSCLC), Abraxane administered as a single agent at a dose of 260 mg/m2 q3w was found to be well tolerated and yielded a response rate of 16% and a disease control rate of 49% (Green et al. 2006), with median time to progression and median survival at 6 and 11 months, respectively.” (page 39)

• “In a multi-centre Phase II study of patients with metastatic melanoma, preliminary data showed that Abraxane administered at 100 mg/m2 q3/4w (previously treated patients) or 150 mg/m2 q3/4w (chemotherapy-naïve patients) was generally well tolerated except for incidence of peripheral neuropathy, with progression-free survival and overall survival of 3.5 and 12.9 months for the previously treated patients, and 4.5 and 9.6 months for the naïve patients, respectively.” (pages 39-40)

The white paper also presents the claim, “The advantages of nab technology can be directly translated into clinical benefits for Abraxane.” (emphasis added, page 39)

Promotion of an investigational new drug is prohibited under FDA regulations at

21 CFR 312.7(a), which states that, “A sponsor or investigator, or any person acting on behalf of a sponsor or investigator, shall not represent in a promotional context that an investigational new drug is safe or effective for the purposes for which it is under investigation or otherwise promote the drug. This provision is not intended to restrict the full exchange of scientific information concerning the drug, including dissemination of scientific findings in scientific or lay media. Rather, its intent is to restrict promotional claims of safety or effectiveness of the drug for a use for which it is under investigation and to preclude commercialization of the drug before it is approved for commercial distribution.”

The distribution of the white paper at the Abraxis promotional exhibit booth at the ASCO conference demonstrates that this material was being presented in a promotional context. In addition, the above claims and presentation promote Abraxane as safe and effective for the first-line treatment of patients with MBC, head and neck cancer, NSCLC, and metastatic melanoma, when it has not been approved for use in these cancers. The above claims also specifically conclude that the drug has an “improved toxicity profile compared to Taxotere” and is “well tolerated.” The PI does not include any information about the safety or efficacy of Abraxane in the treatment of first-line MBC, head and neck cancer, NSCLC, or metastatic melanoma. Thus, claims such as those noted above misbrand Abraxane by creating new intended uses for which the PI lacks adequate directions for use, in violation of 21 U.S.C. 352(f)(1), and promote the drug as safe and effective for the purposes for which it is under investigation, in violation of 21 CFR 312.7(a).

Unsubstantiated Effectiveness Claims

Promotional materials are misleading if they contain representations or suggestions that a drug is better or more effective than has been demonstrated by substantial evidence or substantial clinical experience. The white paper includes statements about the “targeted” delivery of Abraxane to tumor cells, including the following (emphasis added):

• “Nanoparticle albumin-bound (nab TM) technology is a patented novel nanotechnology-based drug delivery platform developed by Abraxis Bioscience, which exploits the natural properties of albumin to achieve a safe, solvent-free, efficient and targeted drug delivery. Abraxane is the first successful example of nab technology-based drug-delivery, and consists of paclitaxel protein-bound particles for injectable suspension (albumin bound).” (page 37)

• “Thus, the albumin-paclitaxel complexes are fully capable of utilising the natural albumin pathways, including gp60 and caveolae-mediated transcytosis and increased intratumoral accumulation, through association with tumour-derived SPARC protein. . . to achieve enhanced drug targeting and penetration in tumours (Desai, Trieu, Yao et al. 2006).” (page 38)

• “Nab technology achieved improved and targeted drug delivery to tumours by exploiting the following natural properties of albumin:

• It acts as a drug carrier to enhance the solubility of hydrophobic drugs.
• It accumulates selectively and actively in tumours.
• It actively transports across the endothelium of blood vessels via gp60 and caveolae-mediated transcytosis.
• It increases retention in the tumour interstitium by association with the albumin- binding protein SPARC.
• It facilitates the diffusion of lipophilic drug across cell membranes.” (page 40)

These claims and use of those terms where emphasis is added misleadingly suggest that “nab technology” and the resulting paclitaxel/albumin formulation of Abraxane actively target the paclitaxel to tumor cells and that this targeted delivery enhances the efficacy and safety of the drug. The DESCRIPTION section of the PI states that Abraxane “is an albumin- bound form of paclitaxel with a mean particle size of approximately 130 nanometers.” The CLINICAL PHARMACOLOGY - MECHANISM OF ACTION section of the Abraxane PI states that Abraxane “is an antimicrotubule agent that promotes the assembly of microtubules from tubulin dimers and stabilizes microtubules by preventing depolymerization.” The CLINICAL PHARMACOLOGY – HUMAN PHARMACOKINETICS section of the PI states that “[T]he large volume of distribution indicates extensive extravascular distribution and/or tissue binding of paclitaxel.” We are unaware of any evidence to support claims suggesting that the paclitaxel/albumin complex has or that the “nab technology” results in tumor-targeting properties, or that albumin facilitates the delivery of water-insoluble compounds, such as paclitaxel, to tumors. Additionally, we are not aware of any evidence to support the claims that albumin delivers paclitaxel to humans via gp60 and caveolae-mediated transcytosis or that SPARC increases accumulation of the paclitaxel/albumin in the tumor interstitium. If you have data to support such claims, please submit them to FDA for review.

Unsubstantiated Superiority Claims/Minimization of Risk Information

Promotional materials are misleading if they contain a representation or suggestion that a drug is safer or more effective than another drug when this has not been demonstrated by substantial evidence or substantial clinical experience.

The white paper contains the following presentation related to the “natural properties” of albumin in Abraxane and its advantages over “conventional” forms of paclitaxel (emphasis added):

• “Due to its poor water solubility, the conventional paclitaxel formulation (Taxol®, made by Bristol-Myers Squibb Co.) contains a high concentration of Cremophor-EL® (polyethoxylated castor oil, made by BASF), which is associated with significant toxicities including allergic, hypersensitivity and anaphylactic reactions that require premedication and prolonged peripheral neuropathy. In addition, paclitaxel is sequestered by Cremophor micelles, which prolongs the systemic exposure and increases drug toxicity.” (page 37)

• “Nanoparticle albumin-bound (nab TM) technology is a patented novel nanotechnology-based drug delivery platform developed by Abraxis Bioscience, which exploits the natural properties of albumin to achieve a safe, solvent-free, efficient and targeted drug delivery. Abraxane is the first successful example of nab technology-based drug delivery, and consists of protein-bound particles for injectable suspension (albumin bound). Abraxane, or nab-paclitaxel, is a Cremophor-free, albumin-bound 130-nm particle form of paclitaxel.” (page 37)

This presentation suggests that Abraxane is safer than other forms of paclitaxel (e.g., Taxol) because its formulation contains the naturally-occurring protein albumin. The claims also suggest that Abraxane is safer than other chemotherapeutic agents used to treat MBC because it does not contain solvents that may cause serious toxicities. OPDP is not aware of substantial evidence or substantial clinical experience to support the assertion that Abraxane is safer than other forms of paclitaxel or other chemotherapeutic agents used to treat MBC. If you have data to support such claims, please submit them to FDA for review. Additionally, these claims minimize the potentially serious risks of Abraxane such as bone marrow suppression (primarily neutropenia), possible teratogenic effects on a developing fetus, and sensory neuropathy.

Omission and Minimization of Risk Information

Promotional materials are misleading if they fail to reveal facts that are material in light of 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 white paper makes numerous efficacy claims for Abraxane but omits important risk information about the drug. For example, the white paper completely omits the warning regarding possible teratogenic effects on a developing fetus and the following adverse reactions associated with the use of Abraxane: myalgia/arthralgia (any symptoms) (44%), anemia (all) (33%), nausea (any symptoms) (30%), diarrhea (any symptoms) (27%), infections (24%), vomiting (any symptoms) (18%), and mucositis (any symptoms) (7%).

We note that the white paper includes the following statement regarding the adverse reactions of hypersensitivity, neuropathy, and neutropenia:

• “The incidence of grade 4 neutropenia and hypersensitivity reactions with Abraxane were significantly lower than in the Taxol group. Grade 3 neuropathy was higher for Abraxane due to higher dosage but was easily managed and improved quickly (Gradishar et al. 2005).” (page 39)

However, the white paper fails to provide any material risk information from the Boxed Warning, Contraindications, Warnings, and Precautions sections of the PI related to the risks associated with Abraxane. Moreover, the above claims minimize the significance of the overall incidence of neutropenia and neuropathy in patients treated with Abraxane. According to the PI, in clinical trials the incidence of neutropenia (<2.0 x 109/L) was 80% and 82% in the Abraxane and paclitaxel groups, respectively. Additionally, the Abraxane PI indicates that in clinical trials 71 % of patients (10% severe) and 56% of patients (2% severe) in the Abraxane and paclitaxel groups, respectively, experienced sensory neuropathy. In

fact, 3% of patients discontinued the use of Abraxane due to sensory neuropathy. The above claims are particularly concerning in light of the Boxed Warning regarding neutropenia and Precaution regarding sensory neuropathy.

By omitting and minimizing serious and significant risk information associated with the use of Abraxane, the white paper misleadingly suggest that Abraxane is safer than has been demonstrated by substantial evidence or substantial clinical experience.

Failure to Provide Adequate Directions for Use

The white paper was not disseminated at ASCO with the full FDA-approved PI for Abraxane, in violation of 21 CFR 201.100(d).

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. Abraxis failed to submit a copy of the white paper referred to in this letter to FDA under cover of Form FDA 2253 at the time of their initial dissemination as required by 21 CFR 314.81(b)(3)(i).

Conclusion and Requested Action

For the reasons discussed above, the white paper misbrands Abraxane in violation of the FD&C Act. 21 U.S.C. 352(a) & (f)(1); and 321(n). 21 CFR 1.21, 201.100(c)(1), 201.128. Cf. 21 CFR 202.1(e)(5), (e)(6)(i) & (ii). Furthermore, this promotional activity promotes the drug as safe and effective for new uses for which it is under investigation, in violation of 21 CFR 312.7(a). In addition, the white paper does not appear to have been disseminated with the full FDA-approved PI for Abraxane, in violation of 21 CFR 201.100(d), or submitted to the FDA under cover of Form FDA 2253 as required by 21 CFR 314.81(b)(3)(i).

OPDP requests that Celgene immediately cease the dissemination of violative promotional materials for Abraxane such as those described above. Please submit a written response to this letter on or before January 9, 2012, stating whether you intend to comply with this request, listing all promotional materials (with the 2253 submission date) for Abraxane that contain violations such as those described above, and explaining your plan for discontinuing use of such violative materials.

Please direct your response to the undersigned at the Food and Drug Administration, Center for Drug Evaluation and Research, Office of Prescription Drug Promotion, Division of Professional Promotion, 5901-B Ammendale Road, Beltsville, Maryland 20705-1266 or by facsimile at (301) 847-8444. Please note that the Division of Drug Marketing, Advertising, and Communications (DDMAC) has been reorganized and elevated to the Office of Prescription Drug Promotion (OPDP). OPDP consists of the Immediate Office, the Division of Professional Promotion (DPP) and the Division of Direct-to-Consumer Promotion (DDTCP). To ensure timely delivery of your submissions, please use the full address above and include a prominent directional notation (e.g., a sticker) to indicate that the submission is intended for OPDP. In addition, OPDP recently migrated to a different tracking system. Therefore, OPDP letters will now refer to MA numbers instead of MACMIS numbers. Please refer to the MA # in addition to the NDA number in all future correspondence relating to this particular matter. OPDP reminds 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 Abraxane comply with each applicable requirement of the FD&C Act and FDA implementing regulations.

Sincerely,

Nisha Patel, Pharm.D.
Regulatory Review Officer
Division of Professional Promotion
Office of Prescription Drug Promotion

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1 We note Celgene’s correspondence dated, October 22, 2010, which stated that the direct or indirect parent corporation of all Abraxis legal entities was acquired by Celgene Corporation effective October 15, 2010.