Abstract
Therapeutic cancer vaccines are an immunotherapy that targets tumor antigens to induce an active immune response. To date, Provenge® is the only therapeutic cancer vaccine approved by the United States Food and Drug Administration. Although therapeutic cancer vaccines have not been approved by the European Medicines Agency (EMA), they have been approved in several countries other than the United States (US) and the European Union (EU). Provenge® is the only approved cancer vaccine that showed significant primary endpoint efficacy in a phase III study at the time of approval. Retrospective analysis of 23 completed or terminated phase III studies showed that 74% (17/23) failed to demonstrate significant efficacy in the primary endpoint. The reasons for failure were surveyed in 13 of the 17 studies. Despite efforts to minimize tumor burden, including surgery and induction chemotherapy before therapeutic cancer vaccine therapy, 69% (9/13) of the phase III studies failed. These findings indicate that tumor burden may not be the only prognostic factor. Immunological response has often been used as a predictive factor, and a small number of sub-group analyses have succeeded in showing that immunological response is associated with the efficacy of therapeutic cancer vaccines. Being a prognostic factor, inclusion of immunological response in addition to tumor stage in the eligibility criteria or sub-group analysis may minimize study population heterogeneity, a key factor in the success of phase III studies.
Introduction
According to the World Health Organization (WHO), cancer is still a leading cause of death worldwide, responsible for 7.6 million deaths (13% of all deaths) in 2008. The Surveillance, Epidemiology and End Results (SEER) program in the United States (US) reported that from 2002 to 2008, the overall 5-y relative survival rate for cancer was only 65.4%. Thus, the discovery of novel cancer therapies to prolong survival, or to provide curative treatment for cases with no satisfactory alternatives, is still essential. Since the approval of herceptin (anti-HER2 antibody) by the FDA (Food and Drug Administration) in 1998, other antibody-based drugs, showing reasonable tolerability and efficacy, have been successfully launched. Antibody-based drugs are categorized as passive specific immunotherapy. Targeted drugs such as these are expected to reduce safety risks for normal cells and to improve efficacy compared with cytotoxic chemotherapies.
Therapeutic cancer vaccines are categorized as active specific immunotherapeutic agents; they selectively target tumor antigens to induce an active immune response. Although, therapeutic cancer vaccines have been in development for several decades, few vaccines have been approved. In 2010, Provenge® was the first cancer vaccine to be approved by the US FDA.
Therapeutic cancer vaccine formulations are categorized into 3 categories: cell, gene and protein/peptide.
Cell
Cell formulations consist of patient-derived tumor cells and dendritic cells (DC) that mimic tumor antigens to stimulate the patient’s immune system. Tumor cell vaccines are derived from patient tumors and are detoxified. After processing, they are injected into patients as a tumor antigen to stimulate an immune response. Dendritic cells (DC) are the dominant antigen presenting cells (APCs) that induce T-cell activation. Exposure of DCs to tumor antigens in vitro leads to the presentation of tumor antigens on major histocompatibility complex (MHC) molecules on their surface; these cells are then re-injected into patients. Thus, cell formulations require cell processing despite the presence of MHC, to elicit a response to tumor antigens.
Gene
Gene formulations involve gene transfer of tumor antigen using plasmid DNA, viruses, or bacteria. Gene transduction of tumor antigen is expected to immunize patients.
Protein/peptide
Protein/peptide formulations of tumor-associated antigens bind to MHC in vivo and are used to trigger an immune response in patients. Anti-idiotypic antibody is another type of this formulation. Anti-idiotypic antibodies bind to immunoglobulins in the hypervariable region, which is associated with individual antigenicity. Protein/peptide formulations are thought to mimic the structure of antigen determinants and acts like tumor antigens in vivo.
Although there are a variety of therapeutic cancer vaccine formulations, the intended effect of all formulations is to induce or amplify the host immune response in vivo. While general regulatory guidelines for each type of formulation have been developed to some extent, there are few guidelines on clinical evaluation methods for therapeutic cancer vaccines, although the FDA has issued recommendations for industry guidance, “Clinical Considerations for Therapeutic Cancer Vaccines” in 2011. We believe that approval of therapeutic cancer vaccines is largely influenced by clinical evaluation. The objective of this study was to provide suggestions to improve clinical evaluation methods of therapeutic cancer vaccines by reviewing historical cases and developmental trends of therapeutic cancer vaccines in phase III studies. We believe the information obtained from our investigation will lead to an improvement in the development of therapeutic cancer vaccines.
Results
A total of 31 completed, discontinued, or on-going therapeutic cancer vaccine projects were identified, which had 23 completed or terminated studies. Six approved projects had 5 completed or terminated studies (). Eleven discontinued projects, including 3 unknown projects, had 13 completed or terminated studies (). Fourteen on-going projects had 5 completed or terminated studies ().
Table 1. Approved therapeutic cancer vaccines
Table 2. Discontinued therapeutic cancer vaccines after Phase III study
Table 3. Ongoing therapeutic cancer vaccines in Phase III
Therapeutic cancer vaccine approvals
Approved therapeutic cancer vaccines are listed in . Approval of therapeutic cancer vaccines has not been limited to the US or the EU. Two cell formulation therapies, DCVax®-Brain and M-VaxTM, were approved in Switzerland. HybriCell, Oncophage® and CIMAVax EGF® are approved for use in Brazil, Russia and Cuba and Peru, respectively. In contrast to the US and EU countries, phase III completion is often not required for approval in these countries. In fact, the study phase at the time of approval in these countries varied from phase I to phase III. Provenge® is the only therapeutic cancer vaccine to be approved based on phase IIIb data, which demonstrated significant efficacy of Provenge® with regard to overall survival (OS).Citation19,Citation30 In 4 cases (DCVax®-Brain, HybriCell, M-VaxTM and CIMAVax EGF®), only early phase studies (phase I and II) were completed at the time of approval. Because Oncophage® did not significantly affect efficacy in the primary endpoint, a withdrawal assessment report was issued by the EMA in 2009. However, Russia approved Oncophage® in 2008.
Results from phase III studies of therapeutic cancer vaccines
Twenty-three completed or terminated phase III studies of therapeutic cancer vaccines were included in our retrospective analysis. As shown in , and , only 17% (4/23) of the phase III studies were successful in demonstrating significant primary endpoint efficacy, whereas 74% (17/23) of the studies failed to do this. Only 1 phase III trial was unsuccessful because of patient safety, and 1 study did not aim to evaluate the efficacy or safety of therapeutic cancer vaccines. Thus, demonstration of significant efficacy in the primary endpoint is a critical hurdle in the successful development of therapeutic cancer vaccines.
As shown in , most of the approved therapeutic cancer vaccines are cell formulations [67% (4/6)]. Interestingly, most phase III studies in our analysis used peptide/protein formulations as opposed to cell formulations: in 30% (7/23), 9% (2/23) and 61% (14/23) of completed or terminated studies, the therapeutic cancer vaccines were cell formulations, gene formulations and peptide/protein formulations, respectively.
Successful phase III studies
Phase III studies of Provenge®, G17DT immunogen (single agent), OncoVAX® and BiovaxID® showed significant efficacy in terms of primary endpoint. The primary endpoint of a pivotal phase III study (D9902B) of Provenge® was changed after data from a supporting phase III study (D9901) were analyzed. This case of Provenge® indicates that trial and error in the definition of the primary endpoint continues during phase III and that the results of a supporting concurrent phase III study may influence the design of other studies. With regard to the OncoVAX® case, a phase IIIa study demonstrated the rationale for selecting the target study population as patients with Stage II colorectal cancer for future phase III studies. This implies that the target study population could be identified from a pre-specified stratified population in 1 study.
Provenge® for prostate cancer
Provenge® is an autologous DC vaccine, activated against the cancer using prostate-specific tumor antigens; hence, it is expected to stimulate the immune system against prostate cancer. It targets prostatic acid phosphatase (PAP).
Phase I/II: A phase I/II study was conducted to evaluate the safety, time to progression (TTP) and immune tolerance to PAP antigens. T-cell responses to PAP were observed in 38% (10/26) of patients after treatment with Provenge®. Anti-PAP antibodies did not exist at baseline, but 52% (16/31) of patients had detectable levels of antibodies after treatment. The median TTP was 34 weeks for responders compared with 13 weeks for non-responders (p < 0.027).Citation43
Phase III: Three phase III studies on Provenge® have been completed: D9901, D9902A and D9902B. The primary endpoint of D9901 and D9902A was not OS but TTP. In the D9901 study, the median OS was significantly higher in the Provenge® arm (25.9 mo) than in the placebo arm (21.4 mo) [hazard ratio (HR) = 1.71; 95% confidence interval (CI), 1.13 to 2.58; p = 0.010].Citation30,Citation44 However, the method of OS analysis was not specified in advance, and the study could not prove the clinical benefit in terms of the primary endpoint. The median TTP was 11.7 weeks in the Provenge® arm and 9.1 weeks in the placebo arm (HR = 1.45; 95% CI, 0.99 to 2.11; p = 0.052). In the D9902A study, both OS and TTP were not significantly different between the groups; the median OS was 19.0 mo in the Provenge® arm and 15.7 mo in the placebo arm (HR = 1.27; 95% CI, 0.78 to 2.07; p = 0.331).Citation30 According to the FDA’s regulatory history, after the analysis of OS in the D9901 study, the protocol of the D9902B study was amended to elevate OS as the primary endpoint. Originally, the primary endpoint was TTP and time to development of disease-related pain. Consequently, the median OS in the D9902B study was 25.8 mo in the Provenge® arm and 21.7 mo in the placebo arm (HR = 0.78; 95% CI, 0.61 to 0.98; p = 0.03).Citation19 Data from the D9901 and D9902A studies were integrated, and a survival benefit was demonstrated (23.2 mo in the Provenge® arm vs. 18.9 mo in the placebo arm; HR = 1.50; 95% CI, 1.10 to 2.05; p = 0.011), which became supportive evidence for the D9902B study.Citation30
OncoVAX® for colorectal cancer
OncoVAX® comprises autologous tumor cells and is used with Bacillus Calmette-Guerin (BCG) as an immunomodulating adjuvant. Immune response to the tumor-specific antigens is expected following administration.
Phase III: OncoVAX® was evaluated in patients with Stage II or III colorectal cancer in a phase IIIa study. The protocol specified separate analysis according to stage in advance. Significant efficacy was observed for Stage II colorectal cancer.Citation7 The primary endpoint was recurrence-free survival (RFS): the 5-y RFS was 37.7% in the control arm and 21.3% in the OncoVAX® arm (HR = 0.493; 95% CI 0.271 to 0.897; p = 0.018). Although statistically significant efficacy was observed for Stage II cases, this was not observed for Stage III cases. According to the company’s official website, Vaccinogen Inc. is conducting a phase IIIb study to evaluate disease-free survival as the primary endpoint in patients with Stage II colorectal cancer.
Reasons for phase III efficacy failure
Heterogeneity in the study population is a contributing factor to efficacy failure in phase III therapeutic cancer vaccine trials (). Heterogeneity in the study population was mainly attributed to tumor stage and immunological response. However, tumor burden was minimized in 69% (9/13) of the studies by surgery or induction drug therapy. Therapeutic cancer vaccines were used postoperatively in 38% (5/13) of the studies. Thirty-one percent (4/13) of the studies include patients that responded to induction drug therapy before therapeutic cancer vaccine therapy.
Table 4. Reasons of the Phase III failure to primary endpoint with therapeutic cancer vaccine
Tumor stage
Some studies have reported the influence of tumor burden on the efficacy of therapeutic cancer vaccines. For example, in PANVAC-VF, Madan et al. pointed out that for second-line therapy of metastatic pancreatic cancer, tumor burden was a factor responsible for failure to meet the primary endpoint of OS.Citation38 On the other hand, 2 phase III studies of Oncophage® reported that subset analysis according to tumor stage, as defined by the American Joint Committee on Cancer (AJCC), showed clinical benefit in patients with a better prognosis, although this benefit was not statistically significant.
Oncophage® for renal cell cancer
Oncophage® is a heat-shock protein (glycoprotein 96)-peptide complex derived from autologous tumors.Citation15 The gp96 peptide complex is taken up by DCs, resulting in T-cell stimulation.
Phase II: A phase II trial in patients with metastatic renal cell carcinoma (RCC) was conducted to evaluate the TTP and response rate (RR) of Oncophage®, with or without the addition of interleukin-2 (IL-2).Citation40 The RR was 6.6% for Oncophage® and 5.1% for Oncophage® with IL-2. The median TTP was 65 d (95% CI, 62 to 88 d) for Oncophage® and 168 d (95% CI, 122 to 233 d) for Oncophage® with IL-2. Some trials on the use of IL-2 were conducted, and McDermott et al. reported that the response rate was 23.2% for high-dose IL-2 vs. 9.9% for IL-2/interferon alfa-2b.Citation41 Thus, in phase II trials, Oncophage® did not show the expected clinical benefit compared with the existing therapy.
Phase III: A randomized, open-label, placebo-controlled phase III trial was conducted to determine the efficacy of Oncophage® on the primary endpoint of RFS in patients with RCC. Patients with localized, resectable RCC and no evidence of distant metastases (n = 728) were randomized to receive Oncophage® (n = 361) or observation only (n = 367). The number of recurrence events was 136 (37.7%) in the Oncophage® arm and 146 (39.8%) in the observation arm (HR = 0.923; 95% CI, 0.729 to 1.169; p = 0.506).Citation15 RFS was not significantly different between the Oncophage® arm and the observation arm. However, subset analysis indicated that intermediate-risk patients in the Oncophage® arm might show improvement in RFS and OS. Patients with stage I, II or III (T1, T2, T3a) tumors according to AJCC were included in the intermediate-risk subset.Citation15 These data were not sufficient for Oncophage® approval by EMA. Patients with a better prognosis may have influenced the results of these studies.
Oncophage® for stage IV melanoma
Phase III: A randomized, open-label, placebo-controlled phase III trial was conducted to determine the efficacy of Oncophage® on the primary endpoint of OS in patients with Stage IV melanoma. Patients (n = 322) were randomized to receive Oncophage® (n = 215) or physician’s choice (PC) (n = 107). OS was not significantly efficient between the Oncophage® arm and the PC arm (HR = 1.16; 95% CI, 0.69 to 1.71; p = 0.32).Citation14 However, exploratory landmark analysis indicated that the combination of M1a and M1b (AJCC), but not M1c, substage patients showed a trend toward increased survival (HR = 0.45; 95% CI, 0.21 to 0.96; p = 0.03).Citation14
SpecifidTM for non-Hodgkin’s lymphoma
SpecifidTM is a patient-specific Id-KLH therapeutic vaccine. The variable region of the immunoglobulin molecule of a B cell has a specific antigen-binding site. Anti-idiotypic determinants are used to mimic antigens. Because the variable regions of immunoglobulins from tumor cells are different from those from normal cells, this vaccine is specific to tumors.
Phase II: A phase II trial in patients with follicular B-cell lymphoma was conducted to evaluate event-free-survival (EFS), RR and safety of SpecifidTM plus granulocyte-monocyte colony-stimulating factor, following rituximab treatment. The RR was 60%, and the median EFS was 15.2 mo (95% CI, 11.6 to 20.2). The median EFS of previously untreated patients was 20.8 mo and that of relapsed patients was 13.5 mo. An anti-Id humoral immune response was observed in 20% (17/83) of evaluated patients. An anti-Id cellular immune response was observed in 72% (13/18) of evaluated patients.Citation32 According to Koc et al., published studies had indicated that the median EFS associated with single-agent rituximab therapy was 18 to 26 mo in previously untreated patients and 6 to 13 mo in relapsed patients.Citation32 Thus, SpecifidTM was regarded as comparable with rituximab in a phase II study.
Phase III: A randomized, blinded, placebo-controlled phase III trial was conducted to demonstrate the efficacy of SpecifidTM on the primary endpoint of TTP in patients with follicular lymphoma. Eligible patients received rituximab for 4 weeks. Those showing stable disease (SD), partial response (PR), or complete response (CR) (n = 349) were assigned to the SpecifidTM arm (n = 174) or the placebo arm (n = 175). The TTP was 9.0 mo in the SpecifidTM arm and 12.6 mo in the placebo arm (HR = 1.384; 95% CI, 1.053 to 1.819; p = 0.019). TTP was shorter in the SpecifidTM arm than in the placebo arm. It was suggested that uneven distribution of the Follicular Lymphoma International Prognostic Index scores between the SpecifidTM and placebo arms may have influenced the results.Citation20
Immunological Response
The humoral immune response was evaluated using enzyme-linked immunosorbent assay (ELISA) in studies for Provenge®, BEC2, SpecifidTM, G17DT immunogen and MyVax®.Citation12,Citation19,Citation23,Citation42 Cellular immune response was evaluated using a T-cell proliferation assay, intracellular cytokine staining (ICS), and enzyme-linked immunosorbent spot (ELISPOT) in studies for Provenge® and MyVax®, SpecifidTM and PANVAC-VF, respectively.Citation19,Citation42,Citation32,Citation46 Consequently, a correlation between immune response and clinical response was observed with BEC2 and G17DT immunogens. The survival of responders was better than that of non-responders in studies of both BEC2 and G17DT immunogens.
BEC2 for small cell lung cancer
BEC2 is an anti-idiotypic antibody that mimics GD3, a ganglioside expressed on the tumor cell surface. Because GD3 is overexpressed in 60% of small cell lung cancer (SCLC) tissues, a clinical anti-GD3 response is expected to effectively treat SCLC.Citation23
Phase III: A randomized, placebo-controlled phase III trial was conducted to determine the efficacy of BEC2 on the primary endpoint of OS in patients with small cell lung cancer (SCLC). Patients (n = 515) were assigned to the BEC2 arm (n = 257) or the observation arm (n = 258). The median OS was 16.4 mo in the BEC2 arm and 14.3 mo in the observation arm (HR = 1.12; 95% CI, 0.91 to 1.37; p = 0.2834).Citation23 OS and PFS were not significantly different between the 2 arms. Only one-third of patients that could be evaluated developed a humoral response to GD3. However, survival was longer in responders than in non-responders, but this difference was not statistically significant (19.2 mo for responders and 13.9 mo for non-responders; p = 0.0851). Although only 60% of SCLC tissues express GD3, GD3 expression was not evaluated or stratified in the study.Citation23
G17DT immunogen for pancreatic cancer
Gastrin is a gastrointestinal hormone, and gastrin-stimulated tumors are detected in the pancreas and duodenum. G17DT immunogen is an antigastrin-17 immunogen that was developed to inhibit gastrin-stimulated tumor growth.
Phase II: A phase II study in patients with pancreatic cancer was conducted to evaluate antibody response, safety, tolerability and preliminary efficacy.Citation34 Of those patients receiving 100 µg or 250 µg, 67% (20/30) showed an antibody response to G17DT. The median OS of all participants was 187 d (95% CI, 141.45 to 232.55). The median OS of the antibody responders was 217 d (95% CI, 177.1 to 256.9), whereas that of the antibody non-responders was 121 d (95% CI, 38.9 to 203.1). This difference was significant (p = 0.0023).
Phase III: A randomized, double-blinded, placebo-controlled phase III trial was conducted to determine the efficacy of G17DT on the primary endpoint of OS in patients with advanced pancreatic cancer. Patients (n = 154) were randomized to the G17DT arm (n = 79) or the placebo arm (n = 75). The median OS was 151 d in the G17DT arm and 82 d in the placebo arm (p < 0.03), indicating the improved OS in patients in the G17DT arm. In addition, patients who developed an anti-G17DT response had significantly improved survival compared with non-responders (p = 0.003).Citation12 In contrast, a randomized, double-blinded, placebo-controlled phase III trial of G17DT in combination with gemcitabine in patients with advanced pancreatic cancer failed to show any significant benefit with regard to the primary endpoint of OS. The OS was 178 d in the G17DT arm and 201 d in the placebo arm (HR = 1.19; p = 0.10). However, anti-G17 antibody titer levels were associated with increased OS.Citation12,Citation35
Discussion
One of the reasons for the continued interest in the field of cancer immunotherapy is the success of antibody-based drugs, i.e., passive specific immunotherapy. Therapeutic cancer vaccines are expected to have an impact on the immune system as active specific immunotherapy, resulting in better tolerability and efficacy compared with conventional treatment. However, for most therapeutic cancer vaccines, clinical evidence of efficacy is still regarded as limited.
Clinical evaluation methods for therapeutic cancer vaccines continue to remain a challenge. Because of the therapeutic effect of cancer vaccines on the host immune response, traditional methods of determining cancer drug efficacy are not applicable.Citation27 Our retrospective analysis showed that 74% (17/23) phase III studies on therapeutic cancer vaccines failed to show a statistically significant effect of the vaccines on the primary endpoint. Studies have indicated that the use of tumor stage as the only prognostic factors in phase III trials is not sufficient. Immunological response will help improve the probability of success in phase III trials by minimizing study population heterogeneity.
Study population heterogeneity was a major factor contributing to the failure of therapeutic cancer vaccines in phase III studies. For example, SpecifidTM was regarded as comparable with rituximab in a phase II study, despite the fact that TTP was shorter in the SpecifidTM arm than in the placebo arm. As summarized by Dalgleish or Finke et al., promising results from phase I or II studies are not always reproducible in phase III studies.Citation13,Citation26 One of the reasons for this is the population heterogeneity within a study. Inclusion criteria that are too broad or lack stratification may prevent the detection of significant efficacy responses induced by therapeutic cancer vaccines in phase III studies. Restriction of the patient population only to those for whom efficacy is predicted in advance, will improve the probability of success of these studies. Therefore, identification of prognostic factors for therapeutic cancer vaccines is important for the future success of therapeutic cancer vaccine development.
Tumor stage categorization, whether determined according to AJCC or other methods of tumor scoring, is an important prognostic factor. For example, the OncoVAX® phase III study, in which analysis was stratified according to tumor stage (Stage II and III), resulted in the identification of a favorable study population (Stage II) for further phase III studies. Some studies have suggested that tumor progression results in tumor-induced immunosuppression.Citation9,Citation28 Therefore, if tumor burden is already high before therapeutic cancer vaccine therapy, the immune response stimulated by the vaccine may be reduced. Thus, tumor stage is a key consideration in study design.Citation9 Although most of the studies in our retrospective analysis based their eligibility criteria on the tumor stage (), they failed to show a significant effect in primary endpoint efficacy. Several studies have indicated that tumor substage according to tumor burden or metastasis may impact cancer vaccine efficacy.Citation14,Citation15 However, 69% (9/13) of the studies failed to demonstrate vaccine efficacy despite efforts to minimize tumor burden, including surgery and induction drug therapy, before therapeutic cancer vaccine therapy.
Some researchers have reported that certain chemotherapies, such as cyclophosphamide, deplete the regulatory T-cell population, which allows the proliferation of antigen-specific T cells.Citation45 Further, rituximab improves B-cell depletion, which may cause delayed induction of the humoral response after vaccination.Citation21 These results suggest that minimal residual disease may not be the only prognostic factor for therapeutic cancer vaccine efficacy. The characteristics of any pretreatment or combination drug should be taken into account when planning a study, because these may have an impact not only on the tumor burden but also on the immune system, which may result in patient heterogeneity in a study.
Our retrospective analysis suggested that there may be room to consider immunological response as an important prognostic factor for therapeutic cancer vaccine efficacy. Currently, immune response is not used often as a prognostic factor, but as a predictive factor. Our survey showed that ELISAs were predominantly used in the evaluation of the humoral immune response in the studies examined. In contrast, assays for the assessment of the cellular immune response were varied and included the T-cell proliferation assay, ICS and ELISPOT. Irrespective of the method used, the response was defined as positive if the value exceeded the pre-defined threshold when compared with a baseline value. Further to these results, the correlation between the immune response and clinical outcome becomes a target for discussion. Thus, currently, immune response is mainly used as a surrogate marker to predict clinical outcome. However, immune response is also expected to be a prognostic factor. Patient immune condition prior to treatment should be assessed to narrow down or stratify the patient population and reduce patient heterogeneity in a study.
According to Galon et al.,Citation29 a task force for immunoscoring was initiated as a new possible approach for the classification of cancer by the Society of Immunotherapy of Cancer, the European Academy of Tumor Immunology, the Cancer and Inflammation Program, the National Cancer Institute, National Institute of Health and La Fondazione Melanoma. If immunological response is able to predict the future efficacy of therapeutic cancer vaccines with regard to the primary endpoint, it will be key to the success of phase III trials and provide scientific rationale for patient selection.
Methods
A retrospective analysis was performed using information obtained from ClinicalTrials.gov. and published articles. All clinical trials registered on ClinicalTrials.gov as of June 25, 2012, were searched using the following terms: condition, “cancer”; treatment, “vaccine therapy”; and study type, “interventional studies.” Phase III studies that were completed, terminated or in progress were selected from the search results and therapeutic cancer vaccine products were verified by manual review. Other phase III studies were also identified by literature searches via PubMed and company homepage. One product for 1 indication is defined as 1 project. Projects were categorized as approved, discontinued and ongoing, and are summarized in a table. Completed or terminated phase III studies were identified from the list to survey the reasons for study failure. Study results and product information were obtained from publically available articles.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
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