Design issues in pivotal drug trials for drug sensitive tuberculosis (TB)

The urgent need for new anti-tuberculosis drugs raises the question of the design, conduct and analysis of the trials that will be required for licensing purposes. Current standard regimens are highly effective under controlled trial conditions with relapse rates of 5% or less. It is very unlikely better results can be achieved with new drugs, a clinically more relevant goal would be a regimen of comparable efficacy to standard treatment but of substantially shorter duration. In order for a new regimen to be licensed, it will be necessary to demonstrate that it is of comparable efficacy to the standard regimen. An important issue will be the choice of the margin of non-inferiority which needs to be justified both on statistical and clinical grounds; non-inferiority could be falsely concluded if a trial was not conducted appropriately, with substantial losses to follow-up or unsatisfactory laboratory procedures. It is particularly important therefore that such trials are conducted with a high degree of rigor. Analyses should be performed both by intention to treat, which is conservative and therefore biased towards no difference, and on a protocol correct population. Similar conclusions would be required from both analyses. Substantial developments have been made in tuberculosis bacteriology in recent years enhancing our ability to diagnose and differentiate strains of M. tuberculosis. Many of these techniques affect the design of trials but have yet to be evaluated in that setting. Non-inferiority pivotal trials require that, as far as practicable, the same techniques are used as were employed when the trials assessing the standard regimen were conducted.     

Old and new drugs in systemic therapy of pancreatic cancer

BACKGROUND: The incidence of pancreatic cancer nearly equals its death rate (97%). Two-year survival is about 10%. Chemotherapy treatment is problematic because of the palliative and limited duration of response. MATERIAL AND METHODS: The article analyzes the objective response and median survival time (MST) for old and new drugs in the treatment of pancreatic cancer. RESULTS: The most encouraging results to date come from studies of 5-fluorouracil (5FU) as an adjuvant therapy and of gemcitabine in the advanced disease, which is one of the most active and best tolerated drugs in recent years. However, with the introduction of new drugs or with different old drug associations, interesting results are also becoming evident. CONCLUSIONS: New approaches to CT treatment are necessary. Patient enrollment into rigorous and well conducted clinical trials, either at tumor diagnosis or after tumor recurrence, will generate new information regarding investigational therapies and it will offer improved therapies for patients with this disease.     

Hormone therapy and breast cancer: a review]

PURPOSE: Tamoxifen as adjuvant hormonal therapy after hormonosensitive-breast cancer surgery is well established nowadays, as well as its efficacy in first-line therapy of advanced hormonosensitive breast cancers. Research of drugs which could be effective, with little toxicity, and having a positive impact on cardiovascular disease or bone is an important issue. CURRENT KNOWLEDGE AND KEY POINTS: New drugs are in development or will soon be on the market to permit second or third lines of treatment with respect to effectiveness and quality of life, such as new anti-estrogens or selective estrogen receptors modulators or aromatase inhibitors. Their principal characteristics are reviewed through recent data. FUTURE PROSPECTS AND PROJECTS: Prevention of breast cancer is a pertinent question and major publications are presented. Finally, the controversy about the possible reintroduction of replacement hormonal therapy after breast cancer will be questioned through trials.     

Treatment of rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory disease that results in progressive disability and increased mortality. New therapeutic strategies are being recommended to initiate, earlier than in the past, more aggressive use of disease-modifying drugs in an effort to reduce joint destruction. In this article, the results of recent clinical trials with nonsteroidal anti-inflammatory drugs, intravenous "pulse" corticosteroids, and standard disease-modifying drugs are reviewed. In addition, preliminary results of trials with new experimental therapies, such as botanical and marine lipids, interferon-gamma, and monoclonal antibodies directed against leukocyte cell surface markers are discussed.     

Unmet need in the treatment of polymyalgia rheumatica and giant cell arteritis

For decades, aside from prednisone and the occasional use of immune suppressive drugs such as methotrexate, there was little to offer patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA). However, there is a great interest in various steroid sparing treatments in both these conditions. This paper aims to provide an overview of our current knowledge of PMR and GCA, examining their similarities and distinctions in terms of clinical presentation, diagnosis, and treatment, with emphasis placed on reviewing recent and ongoing research efforts on emerging treatment. Multiple recent and ongoing clinical trials are demonstrating new therapeutics that will provide benefit and contribute to the evolution of clinical guidelines and standard of care for patients with GCA and/or PMR.     

Approaches to vancomycin-resistant enterococci

PURPOSE OF REVIEW: This article reviews recent publications regarding new antimicrobial drugs for the treatment of vancomycin-resistant enterococci. RECENT FINDINGS: Newer drugs against vancomycin-resistant enterococci are now available or will soon be available. Quinupristin-dalfopristin, a streptogramin, and linezolid, an oxazolidinone, are effective and safe but only bacteriostatic against enterococi. Bacterial isolates resistant to either antibiotic have been described. Daptomycin, a lipopeptide antimicrobial, has good in-vitro bactericidal activity against enterococci, but very limited clinical data exist regarding the treatment of serious enterococcal infection with this compound. Ramoplanin, the first glycolipodepsipeptide antimicrobial in clinical trials, is not systemically absorbed after oral administration, and is being evaluated for the prevention of bloodstream infection in patients colonized with vancomycin-resistant enterococci. Oritavancin and dalbavancin (both glycopeptides) and tigecycline (a monocycline derivative) are being evaluated in phase II and III trials and are not yet commercially available. SUMMARY: Treatment of vancomycin-resistant enterococci continues to be problematical although these new drugs offer some hope. The rational use of antibiotics, strict guidelines for the use of new compounds, and adherence to infection control practices continue to be essential components of the management of vancomycin-resistant enterococci colonization and infection.     

Management of liver metastases from colorectal cancer

About 50% of colorectal cancer patients develop liver metastasis, and liver resection is considered the only curative therapy. However, the rate of recurrence is high, which contributes to poor prognosis. Since surgical resection coverage has increased because of improved hepatectomy including portal vein embolization, tumors shrink because of the effectiveness of recent chemotherapy, such as FOLFOX and FOLFIRI, and it has become possible for many patients whose cancer was judged unresectable before to undergo resection. Improvement of new anticancer drugs such as molecularly targeted biologics is greatly changing therapeutic systems of metastatic colorectal cancer, and it is time for us to innovate stage IV therapy. In this report, we will review new treatment strategies for metastatic liver cancer from colorectal cancer, clinical trials of new anticancer drugs for liver metastasis, surgery and ablation as local therapy, and further clarify complex therapeutic systems for metastatic liver tumors from colorectal cancer.     

心房颤动口服药物治疗的新选择

近年来,尽管导管消融和外科手术在心房颤动(房颤)的治疗中取得了令人瞩目的进展,但并未广泛应用,药物治疗依然处于首要地位。由于传统抗凝药和抗心律失常药的自身局限性,该领域新型药物的开发成为研究热点,而近年来多种新型口服药物的开发研制和临床试验的成功,为房颤的药物治疗带来新的希望。本文对此加以综述。     

FDA gives salvage therapy testing a push forward

Pharmaceutical companies like to test their drugs in patients who are less seriously ill, so that the drugs will look good. A recent FDA meeting focused attention on the need for more trials in advanced patients, the importance of long-term safety follow-up for all patients, and how the necessary trials and monitoring could be conducted.     

What Goes Into a Major Acute Coronary Syndrome Trial and What Will Future Trials Look Like?

Acute coronary syndromes (ACS) are common and carry a high risk of death and serious complications. Over the past three decades, the international cardiology community has collaborated in numerous large, well-designed randomized trials evaluating promising new treatments leading to important improvements in care for patients with ACS. Industry has funded most of the ACS trials of new pharmacologic treatments, but there are many independently funded trials evaluating treatment strategies such as percutaneous coronary intervention. Improvements in ACS care have led to challenges in demonstrating the efficacy of new treatments and many current trials are comparing one active treatment against another, although new paradigms including anti-inflammatory treatments and stem cell infusions are being tested against placebo. Developing new drugs for ACS is a very expensive process with many trials not showing any benefit, and much of this expense is related to the cost of large multicenter phase 3 trials. Reducing the administrative burden and associated costs of ACS trials is an important immediate goal if the strong tradition of large collaborative trials is to continue, as well as the need for health care providers to engage more actively in the clinical research process and support large multinational independently funded trials. We discuss methodologic issues of ACS trials with recent examples and provide some perspectives for the future.     

Recent developments in the use of antiplatelet agents to prevent cardiovascular events

Platelets are pivotal contributors to arterial thrombosis. Dual antiplatelet therapy with aspirin and clopidogrel has become the standard of care for the secondary prevention of cardiovascular events in patients with acute coronary syndromes and after percutaneous coronary intervention. Clinical evidence of the continued risk of cardiovascular events plus pharmacodynamic evidence of substantial variability in on-treatment platelet reactivity has supported the development of new therapeutic strategies, using established agents and new antiplatelet drugs. This article will highlight recent pivotal clinical trials seeking to advance the use of antiplatelet therapy in patients with cardiovascular disease.     

Novel Blockers of the Renin-Angiotensin-Aldosterone System in Chronic Heart Failure

Because of the impressive record of ACE inhibitors in patients with heart failure with reduced ejection fraction, the renin-angiotensin-aldosterone system continues to be pursued as a therapeutic target. Furthermore, the optimal treatment of patients with heart failure with preserved ejection fraction remains unclear. Early trials of direct renin inhibitors suggested that they may have a role, but recent results have not been encouraging. Preliminary trials of angiotensin-receptor/neprilysin inhibitors look positive. Whether these or other drugs will alter current recommendations remains to be seen.     

Bortezomib for previously untreated multiple myeloma

The treatment of newly diagnosed multiple myeloma (MM) has evolved rapidly over recent years. The availability of new effective drugs with novel mechanisms of action, such as bortezomib, in the last decade have resulted in a new scenario expected to impact favorably on the outcome of MM patients. In the transplant and nontransplant setting, several randomized trials have shown that front-line treatment with bortezomib-based combinations are superior to conventional treatment and have allowed for a significant increase of complete response rate, with a positive impact on progression-free survival. Furthermore, this drug appears to be active in patients with high-risk disease and comorbidities. Thus, bortezomib-containing regimens are now considered as a new standard of care for newly diagnosed myeloma patients. In this article, we will attempt to overview the results of bortezomib when administered as a standard component of front-line therapy for MM patients.     

What is new in HIV/AIDS research in developing countries?

HIV epidemic has had greatest impact in sub‐Saharan Africa (SSA) and mainly in East and Southern Africa with HIV prevalence in some parts going up to 30%. In the recent years, considerable HIV research on prevention, treatment and care, and vaccine has been conducted in many developing countries and provided evidence‐based knowledge to control the epidemic. However, there have also been disappointing results in HIV prevention trials such as in HIV vaccine and microbicide trials. Despite these outcomes, important lessons have been learnt that help in designing future trials. This article examines the recent advances in HIV research in developing countries. The most recent HIV prevention research has demonstrated the effect of male circumcision on HIV acquisition, and lack of impact of HSV‐2 treatment on HIV transmission and acquisition. Use of HIV antiretroviral drugs (ARVs) for HIV prevention is a new area that has attracted interest and a number of trials are examining the effect of oral Pre‐Exposure Prophylaxis on HIV acquisition and also looking at the potential of ARVs in reducing infectiousness. Progress has been made in HIV treatment, monitoring treatment efficacy and toxicity as well as evaluation of different models of ART delivery. HIV vaccine research has, however, faced most challenges despite many efforts that have been put in. Looking into the future, there are ongoing trials that will hopefully generate important information to strengthen HIV policies in the next few years. There are, however, many other gaps in HIV research that need to be urgently addressed.     

Therapeutic approaches for newly diagnosed multiple myeloma patients in the era of novel drugs

The treatment of newly diagnosed multiple myeloma (MM) has evolved rapidly over recent years. The availability of new effective drugs with novel mechanisms of action, such as thalidomide, lenalidomide and bortezomib in the last decade, has resulted in a new scenario expected to impact favorably on the outcome of patients with MM. The introduction of new drugs in the treatment of patients eligible for autologous stem cell transplantation (ASCT) has allowed for a significant increase of complete response rate with a positive impact on progression‐free survival. In patients not eligible for ASCT, randomized trials have shown that both thalidomide and bortezomib when combined with melphalan and prednisone (MP) are superior to MP and are now considered the standard of care. Ongoing trials are assessing whether MP plus lenalidomide or the combination of lenalidomide plus dexamethasone should be considered an attractive treatment option, while additional studies are needed to determine the role of routine maintenance or consolidation therapy with these new drugs. This new therapeutic armamentarium in light of adequate prophylaxis and supportive care allows clinicians to greatly improve the survival perspectives for both young and elderly patients. In this review, we report updated data for the front‐line therapy of MM, examining the role of new drugs either when administered as induction therapy before ASCT in younger patients or when combined with alkylating agents for the treatment of older patients. The most relevant articles on therapy of MM published from November 1982 to January 2010 (selected through PubMed), and recent meeting abstracts were used as sources for this review.     

In order to perform clinical trials efficiently in Japan--important issues regarding monitoring by sponsors]

The guideline for Good Clinical Practice (GCP) of new drugs was enforced as Ministerial Ordinance No. 28, dated March 27, by the Ministry of Health, Labor and Welfare. In Article 21 of the guideline, a sponsor shall prepare the operating procedures of monitoring, and perform monitoring in conformity with the procedures. The Pharmaceuticals and Medical Devices Agency (PMDA) performs the GCP review of the application of pharmaceuticals and medical devices, including both the document-based conformity review and on-site GCP review, in order to protect human subjects and ensure the integrity of data in clinical trials. The purpose of monitoring is to perform clinical trials ethically and scientifically. Important issues in monitoring raised by the GCP reviews by the PMDA are summarized in this study. Our findings both directly and indirectly reflect the verification of the GCP guidance of investigational sites. We hope that the appropriate monitoring will encourage investigators to perform clinical trials effectively, resulting in clinical trials conforming to the GCP guidelines. Our review will lead to more effective and safer new drugs and medical devices applied in Japan. This is not an official PMDA guidance or policy statement.     

The role of angiotensin-converting enzyme inhibitors in the treatment of hypertension

Angiotensin-converting enzyme (ACE) inhibitors continue to find new uses. The Heart Outcomes Prevention Evaluation study has demonstrated their wide application as a preventive measure for patients at high risk of cardiovascular disease, but the available clinical trials in hypertensive subjects do not so far suggest any clear superiority over conventional treatment. The available trials may have been underpowered to detect non-blood pressure-related benefits on smooth muscle growth, endothelial function, left ventricular hypertrophy, and plaque rupture, when used in relatively low-risk subjects with uncomplicated hypertension. Clinical trials have also shown that two or more drugs are needed to lower blood pressure even to 140/90. Few patients have uncomplicated hypertension, so the choice of their drugs will be powerfully influenced by their other clinical problems. Nevertheless, there is a strong case for an attack on the renin-angiotensin system. Whether this will be by ACE inhibition, angiotensin-II receptor blockade, or both, is the subject of current clinical trials.     

Is it ethical to use placebos in osteoporosis clinical trials?

Because there are now effective agents for treatment of osteoporosis, the question is being raised as to whether or not it is ethical to have placebo-controlled trials of new agents. It is ethical for patients who are at low risk of serious or irreversible harm to participate in placebo-controlled trials as long as they provide informed consent. Morbidity, mortality, and future fracture risk correlate with the presence of previous fractures, the number of previous fractures, whether or not the fracture is recent, and whether or not the fracture is clinically recognized. Lower-risk subjects who may be allowed to participate in placebo-controlled trials include those with low bone density but without a previous vertebral fracture, those with a single vertebral deformity that was not clinically recognized, and those with a vertebral fracture more than 2 years before. Higher-risk subjects who do not tolerate proven drugs or who have not responded to proven drugs may also participate. Even though it may be ethical for selected subjects to participate in placebo-controlled trials of new therapies for osteoporosis, steps should be taken to minimize their exposure (eg, unbalanced randomization, integration of outcomes, and powering trials to actual events rather than a projected number over 3 years), and treating patients who fracture or who fail to respond.     

Overview of the clinical efficacy of investigational anticancer drugs

The purpose of this overview was to make a broad inventory of investigational drugs for medicinal cancer treatment and, specifically, to indicate the evidence of clinical efficacy. Information was retrieved from electronic database searches in Medline and CANCERLIT and relevant published reviews. As the most recent findings are first reported as conference abstracts, an important basis for identification of new drugs and clinical results was a hand search of 13,392 abstracts from five major recent cancer conferences. A total of 209 investigational approaches or drugs were identified and classified into one of eight groups according to proposed mechanism of action. For 28 drugs/approaches survival data were available from randomized controlled trials. Statistically significant benefit was observed for only 12. In earlier phases no or modest anticancer activity was reported. It is speculated that the expanding knowledge in tumour biology might not easily translate into new substantially better anticancer drugs.     

Cardiovascular disease and type 2 diabetes mellitus: Regulating glucose and regulating drugs

Type 2 diabetes mellitus is a major and increasingly prevalent independent risk factor for cardiovascular morbidity and mortality worldwide. Glycemic control is a target of therapy and a principal marker of therapeutic success in diabetes, but whether lowering glucose is accompanied by a commensurate reduction in cardiovascular risk is a matter of ongoing controversy. It has become increasingly apparent from recent large-scale clinical outcome trials that glucose lowering is a poor predictor of cardiovascular outcome, and several instances of unexpectedly increased cardiovascular risk with antihyperglycemic drugs have sounded the alarm with regulatory agencies. This article reviews the critical facts that have led to a recent shift in the regulation of glucose-lowering drugs and makes the case for why new and existing antidiabetic medications should be assessed in clinical trials of cardiovascular outcome.