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PRO Labeling claims in Antineoplastic agents Caron M, Emery MP MAPI Research Trust, Lyon, France Table 2: List of Antineoplastic Agents approved with with a PRO labeling claim - FDA (Source: PROLabels - March 2010) Objectives Type of Other PROs Date of To review PRO labeling claims achieved in antineoplastic products in Europe and in the US. Type Brand endpoint Primary measured Approval INN MAH Therapeutic Indication(s) Labeling claim of PRO Agency Name (PROs in endpoint(s)* not included (for this (in label) label) in label indication) Sarcoma, Kaposi - Panretin gel is indicated for topical S1. The patients’ assessment of their overall satisfaction with treatment of cutaneous lesions in patients with AIDS-related the drug effect on all treated lesions significantly favored Treatment Panretin gel over vehicle (p=0.0001). S2. Responses to Ligand Kaposi's sarcoma. Panretin gel is not indicated when satisfaction, systemic anti-KS therapy is required (e.g., more than 10 Panretin gel were seen both in previously untreated patients Alitretinoin Panretin® Pharmaceuticals Inc. and in patients with prior systemic and/or topical KS treatment. Subjective Secondary Response rate None 02/02/1999 FDA new KS lesions in the prior month, symptomatic lymphedema, The physician's and the patient's subjective assessments of Methods (CA, USA) symptomatic pulmonary KS, or symptomatic visceral all treated lesions both showed a response rate of 47% for assessments of involvement). There is no experience to date using Panretin panretin and 11% for all treated lesions gel with systemic anti-KS treatment. vehicle (p=0.0003). PROLabels database was searched with neoplasm and oncology as keywords to identify antineoplastic agents with PRO labeling claims approved or revised in Europe since 1995 and Osteolytic metastases - Aredia is indicated, in conjunction Study 1: Decreases in pain scores from baseline Novartis with standard antineoplastic therapy, for the treatment of occurred at the last measurement for those Aredia Percentage of patient in the US since 1998. FDA and EMEA websites and guidances were reviewed. osteolytic bone metastases of breast cancer and osteolytic patients with pain at baseline (P=.026) but not in the Pamidronate Pharmaceutical lesions of multiple myeloma. The Aredia treatment effect Pain and narcotic developping any Aredia placebo group. Study 2: The changes from baseline Secondary None 22/09/1998 FDA Anti-emetic and analgesic products were not included, as well as generic drugs (such as Docetaxel Teva, Docetaxel Winthrop, Temomedac, Temozoline Teva, Topotecan Actavis). disodium Corporation appeared to be smaller in the study of breast cancer in the bone pain score and analgesic score was use skeletal-related event patients receiving hormonal therapy than in the study of (NJ, USA) significantly worse for placebo patients than for Aredia (SRE) those receiving chemotherapy, however, overall evidence patients in these trials. of clinical benefit has been demonstrated. Astra Zeneca Prostatic neoplasms - CASODEX 50 mg is an androgen receptor Survival, inhibitor indicated for use in combination therapy with a luteinizing Assessment of the Quality of Life questionnaires did Health-related Bicalutamide Casodex® Pharmaceuticals LP hormone-releasing hormone (LHRH) analog for the treatment of not indicate consistent significant differences between Secondary time to NS** 19/12/2008 FDA Stage D2 metastatic carcinoma of the prostate. o CASODEX 150 mg the two treatment groups. quality of life (DE, USA) daily is not approved for use alone or with other treatments. progression Gemcitabine Eli Lilly and Company Carcinoma, Non-Small-Cell Lung - Gemzar is indicated in In both studies no significant differences were observed Health-related Gemzar® combination with cisplatin for the first-line treatment of patients in QOL between the Gemzar plus cisplatin arm and the Secondary Survival NS** 25/08/1998 FDA Results (IN, USA) with inoperable, locally advanced (Stage IIIA or IIIB), or metastatic quality of life hydrochloride (Stage IV) non-small cell lung cancer. comparator arm. ® In the first study, patients treated with Gemzar had statistically Among the 130 antineoplastic products approved, 19 were identified with PRO claims - eleven in the U.S, eight in Europe (including one in both agencies - Hycamtin ) - for fourteen significant increases in clinical benefit response (table 4). Clinical benefit response was achieved by 14 patients treated with Clinical benefit different indications: non-small cell lung carcinoma, prostatic neoplasms, small cell lung carcinoma, Kaposi sarcoma, chronic myeloid leukemia, astrocytoma, pleural malignant mesothelioma, Gemzar and 3 patients treated with 5-FU. One patient on the response Gemzar arm showed improvement in all 3 primary parameters Primary Pancreatic Neoplasms - Gemzar is indicated as first-line (pain intensity, analgesic consumption, and performance status). Performance (clinical improvement breast neoplasms, head & neck neoplasms, thyroid neoplasms, stomach neoplasms, colorectal neoplasms, osteolytic metastases and ovarian neoplasms (see Table 1 and Table 2). treatment for patients with locally advanced (nonresectable Eleven patients on the Gemzar arm and 2 patients on the 5-FU status, Pain (all 3 included Gemcitabine Eli Lilly and Company arm showed improvement in analgesic consumption and/or pain based on analgesic ® Stage II or Stage III) or metastatic (Stage IV) adenocarcinoma intensity, Pain: Gemzar intensity with stable performance status. Two patients on the in “clinical consumption, pain NS** 25/08/1998 FDA Survival was primary endpoint for 13 products. Other primary endpoints included time to progression, response rate and response duration. hydrochloride (IN, USA) of the pancreas. Gemzar is indicated for patients previously Gemzar arm showed improvement in analgesic consumption Use of rescue treated with 5-FU. or pain intensity with improvement in performance status. One benefit intensity, performance ® patient on the 5-FU arm was stable with regard to pain intensity medication PROs included in labels were primary endpoints in only two cases: one product used in prostatic neoplasms (Novantrone - improvement in pain) and one product approved for pancreatic and analgesic consumption with improvement in performance response”) status, and weight ® status. No patient on either arm achieved a clinical benefit change) neoplasms (Gemzar - clinical benefit response including pain intensity, use of rescue medication and performance status). Both products were approved at the FDA. response based on weight gain. - The second study showed a clinical benefit response rate of 27%. Health-related quality of life was clearly mentioned in the label of 8 products (5 approved by the EMEA including 3 approved after the publication of the EMEA and FDA guidances, Physical, functional, and 3 by the FDA, all approved before the publication of the guidances). Of these 8 products, 3 approved by the EMEA and 1 by the FDA had an indication for non small cell lung carcinoma. Physical, functional, and treatment-specific biologic response modifier scales from the FACT-BRM and treatment- (Functional Assessment of Cancer Therapy - Biologic specific biologic Response Modifier) instrument were used to assess response modifier Table 1: List of Antineoplastic Agents approved with a PRO labeling claim - EMEA (Source: PROLabels - March 2010) Leukemia, myeloid, chronic - Gleevec™ (imatinib patient-reported general effects of interferon toxicity in scales from the Imatinib ™ Novartis 1067 patients with CML in chronic phase. After one Survival Gleevec mesylate) is indicated for the treatment of newly FACT-BRM Secondary None 22/01/2002 FDA mesylate (Switzerland) diagnosed adult patients with Philadelphia chromosome month of therapy to six months of therapy, there was (progression-free) positive chronic myeloid leukemia (CML) in chronic phase. a 13%-21% decrease in median index from baseline (Functional Type of Other PROs Date of in patients treated with interferon, consistent with Assessment of Type increased symptoms of interferon toxicity. There was Cancer Therapy - Brand endpoint Primary measured Approval no apparent change from baseline in median index INN MAH Therapeutic Indication(s) Labeling claim of PRO Agency for patients treated with Gleevec. Biologic Response Name (PROs in endpoint(s)* not included (for this Modifier) instrument. (in label) label) in label indication) In study 1, patients receiving irinotecan reported significantly better results for the global health status, on two of five Global health Pharmacia & Upjohn Colorectal neoplasms - CAMPTOSAR is indicated for functional subscales, and on four of nine symptom subscales. status, functional Breast neoplasms - TAXOTERE in combination with Irinotecan ® patients with metastatic carcinoma of the colon or rectum As expected, patients receiving irinotecan noted significanly Aventis Pharma S.A. In both arms, quality of life measured by the Health-related Time to Camptosar Co, division of Pfizer and symptom Secondary Survival None 14/06/1996 FDA ® doxorubicin is indicated for the treatment of patients with EORTC questionnaire was comparable and stable Secondary None 27/11/1995 EMEA hydrochloride whose disease has recurred or progressed following initial more diarrhea than those receiving best supportive care. In Study Docetaxel Taxotere Inc (NY, USA) 2, the multivariate analysis on all 15 subscales did not indicate (France) locally advanced or metastatic breast cancer who