Trial registration and results disclosure: impact of US legislation on sponsors, investigators, and medical journal editors

BACKGROUND: Recently enacted federal legislation, the Food and Drug Administration Amendments Act of 2007 (FDAAA), mandates public registration and disclosure of results of "applicable" clinical trials of drugs, biologics and devices on www.clinicaltrials.gov. The law calls for registering more information about more trials than has been the policy of many medical journal editors to date. Beginning December 2007, results disclosure will occur in three stages initially with links to information from the FDA and NIH about FDA-approved products, as well as to Medline citations. A Basic Results Database will appear in September 2008, and an Expanded Results Database two years later. Results for trials of FDA-approved products must be posted within 12 months of trial completion. Such postings will not be peer reviewed or contain explanatory text or discussion. Sponsors who file regulatory submissions (IND, NDA, 510(k), PMA, etc.) to the FDA must certify compliance with FDAAA's registration and disclosure provisions. The FDA's determination of such compliance will be made public, and if non-compliance is not cured within 30 days, sponsors may be fined up to $10,000/day. CONCLUSIONS: FDAAA requirements differ in a number of ways from those of the International Committee of Medical Journal Editors (ICMJE) and other journal editors, creating potential conflicts for sponsors and investigators who must comply with the law, and a need for better alignment of editors' policies with the law. The public will have access to massive amounts of clinical trial data as a result of FDAAA but it is unclear this will be useful to patients and prescribing physicians.     

Current Thoughts on Crossover Designs

Abstract

In this paper a historical perspective will be developed regarding the use by drug sponsors of crossover designs in clinical trials in reference to new drug application (NDA) submissions to FDA and FDA's concerns with these designs. From the standpoint of drug sponsors, drug researchers and FDA statistical reviewers the possible impact of a report by the former Biometric and Epidemiological Methodology Advisory Committee (BEMAC) of the FDA and of recommendations contained in 22 FDA clinical guidelines on the matter of crossover designs will be discussed. Additionally, current experience gained from the FDA's statistical evaluation of crossover designs will be briefly presented and some constructive suggestions will be made to guide drug sponsors and drug researchers regarding the use of crossover designs in clinical trials.     

FDA《新药和生物制品的获益-风险评估供企业用的指导原则》介绍

美国食品药品管理局（FDA）于2021年9月发布了《新药和生物制品的获益-风险评估供企业用的指导原则》（草案），详细介绍了FDA目前采用的新药审评的获益-风险评估的"获益-风险框架"方法。该指导原则用最大的篇幅讨论了新药注册申请人为FDA获益-风险评估提供信息、上市前应采取的行动，也简要介绍了上市后应采取的措施。中国目前还没有类似的指导原则，详细介绍FDA该指导原则，期望对国内药品监管部门的新药和新生物制品的获益-风险评估有所启迪，特别是对药品注册申请人在新药和新生物制品全生命周期，尤其是在开发过程中，为药品监管部门提供获益-风险评估信息的行动有帮助，从而有益于加速药品审评的进程以及对申报药品做出准确审评结论。     

A Survey of Payer Perspectives on Cannabis Use Disorder

Background: Cannabis use disorder (CUD) as described/defined in DSM 5, is characterized by impaired control of marijuana use and related personal, health, and legal consequences. CUD is a serious public health problem, affecting nearly 6 million individuals in the United States. There are no FDA approved medications to treat this disorder. The lack of available treatment options contributes to uncertainties by drug sponsors about formulary and reimbursement decision-making for CUD pharmacotherapies. Objective: To addresses this gap by presenting the first findings on managed care payers' perceptions of CUD treatments and clinical trial end points. Methods: An online survey was conducted with 50 payers from managed care organizations. The survey inquired about perceptions of unmet need in CUD treatment, relevant clinical trial end points, disease knowledge, and likelihood of review of new pharmacotherapies. Results: The majority of payers (62%) reported that they were at least moderately familiar with CUD treatment end points. Most (80%) rated the unmet need for new pharmacotherapies for CUD as at least moderately important. Payers rated the most important end points for clinical trials as abstinence and decreased resource utilization. Most participants said an FDA approved CUD treatment would be formally reviewed by payers within 6 months (58%) or a year (36%). Conclusions: Based on these findings, payers see an unmet need for CUD treatment. Furthermore, FDA-approved pharmacotherapies for CUD will likely be reviewed quickly by payers, especially if data are provided on the likelihood of achieving abstinence and reduced resource utilization.     

Pharmaceutical industry perspective on risk evaluation and mitigation strategies: manufacturer take heed

Introduction: Enactment of the Food and Drug Administration Amendments Act of 2007 (FDAAA) authorized the FDA to require manufacturers to submit Risk Evaluation and Mitigation Strategy (REMS) when it was deemed necessary to ensure that a drug's benefit outweigh its risk. REMS apply to new drug applications (NDAs), abbreviated new drug applications (ANDAs) and biologics license applications (BLAs). The objective of this review is to describe the impact of REMS requirements on the pharmaceutical industry.

Areas covered: Articles were identified in MEDLINE searches through October 11, 2011, using the MeSH terms and keywords pharmaceutical industry, risk management, United States Food and Drug Administration, REMS, ETASU, and Medication Guide in various combinations.

Expert opinion: The new powers ascribed to the FDA are notable, as they add enforceability to safety strategies that were not part of FDA's prior risk management tools, risk minimization action plans (RiskMAPs). Failure to comply with REMS can lead to financial penalties up to $10 million, and a drug could be deemed misbranded if the REMS is not followed. The new approach to risk management via FDAAA has elevated the rigor with which manufacturers must fulfill postmarketing safety commitments.     

Assessing the adoption of clinical trial results summary disclosure to patients and the public

ABSTRACT

Introduction: There is a broad global acknowledgment that the timely and effective communication of clinical trial results is not only essential to the development, diagnosis, and treatment of medical conditions but also meets an ethical obligation to inform patients and the public.

Areas covered: At this time, less than 2% of all clinical trials completed or terminated within the past three years returned plain language summaries to study volunteers. This estimate is far below our forecast made 10 years ago when we evaluated a pilot effort to demonstrate a feasible and efficient process for communicating summary results to patients. At that time, we anticipated that research sponsors would embrace the obligation and in so doing would improve their relationship with and trust among their study volunteers and patient communities. This article discusses why adoption remains low and suggests that the absence of clear regulatory requirements and their enforcement are the primary cause.

Expert opinion: The authors anticipate that the regulatory environment will tighten and that public, patient and patient advocate appetite and expectation for the disclosure of clinical trial results summaries in plain language will intensify during the next 18 months. These pressures will compel research sponsors to accelerate adoption.     

FDA对研究者在新药和医疗器械临床研究期间安全性报告的要求

上市前药物和医疗器械安全性信息主要来自临床试验,而观察受试者对试验药物和器械反应的是研究者,因此,研究者的不良事件报告至关重要。为帮助研究者确认临床研究期间非预期的安全性信息并遵守安全性报告要求,美国食品药品管理局（FDA）于2021年9月发布了“研究者职责-研究性药物和器械的安全性报告”指导原则（草案）,详细说明了对研究者在IND和IDE研究中向申请人和伦理委员会报告的要求。我国目前还没有类似的指导原则,详细介绍FDA的该指导原则,以期对我国新药和新医疗器械研究者在临床研究期间识别非预期的安全信息并按要求及时报告有帮助并对该方面的监管有所启示。     

An update on emerging drugs in osteosarcoma: towards tailored therapies?

ABSTRACT

Introduction: Current treatment of conventional and non-conventional high-grade osteosarcoma (HGOS) is based on the surgical removal of primary tumor and, when possible, of metastases and local reccurrence, together with systemic pre- and post-operative chemotherapy with drugs that have been used since decades.

Areas covered: This review is intended to summarize the new agents and therapeutic strategies that are under clinical evaluation in HGOS, with the aim to increase the cure probability of this highly malignant bone tumor, which has not significantly improved during the last 30–40 years. The list of drugs, compounds and treatment modalities presented and discussed here has been generated by considering only those that are included in presently ongoing and recruiting clinical trials, or which have been completed in the last 2 years with reported results, on the basis of the information obtained from different and continuously updated databases.

Expert opinion: Despite HGOS is a rare tumor, several clinical trials are presently evaluating different treatment strategies, which may hopefully positively impact on the outcome of patients who experience unfavorable prognosis when treated with conventional therapies.

Trial registration: ClinicalTrials.gov identifier: NCT01459484.

Trial registration: ClinicalTrials.gov identifier: NCT01669369.

Trial registration: ClinicalTrials.gov identifier: NCT00134030.

Trial registration: ClinicalTrials.gov identifier: NCT00180908.

Trial registration: ClinicalTrials.gov identifier: NCT00470223.

Trial registration: ClinicalTrials.gov identifier: NCT01532687.

Trial registration: ClinicalTrials.gov identifier: NCT02357810.

Trial registration: ClinicalTrials.gov identifier: NCT03163381.

Trial registration: ClinicalTrials.gov identifier: NCT02432274.

Trial registration: ClinicalTrials.gov identifier: NCT02048371.

Trial registration: ClinicalTrials.gov identifier: NCT02389244.

Trial registration: ClinicalTrials.gov identifier: NCT02243605.

Trial registration: ClinicalTrials.gov identifier: NCT02867592.

Trial registration: ClinicalTrials.gov identifier: NCT03210714.

Trial registration: ClinicalTrials.gov identifier: NCT03526250.

Trial registration: ClinicalTrials.gov identifier: NCT03213678.

Trial registration: ClinicalTrials.gov identifier: NCT03718091.

Trial registration: ClinicalTrials.gov identifier: NCT03233204.

Trial registration: ClinicalTrials.gov identifier: NCT03698994.

Trial registration: ClinicalTrials.gov identifier: NCT03220035.

Trial registration: ClinicalTrials.gov identifier: NCT03220035.

Trial registration: ClinicalTrials.gov identifier: NCT02689336.

Trial registration: ClinicalTrials.gov identifier: NCT03678883.

Trial registration: ClinicalTrials.gov identifier: NCT01962103.

Trial registration: ClinicalTrials.gov identifier: NCT02945800.

Trial registration: ClinicalTrials.gov identifier: NCT01669369.

Trial registration: ClinicalTrials.gov identifier: NCT03598595.

Trial registration: ClinicalTrials.gov identifier: NCT02644460.

Trial registration: ClinicalTrials.gov identifier: NCT02517918.

Trial registration: ClinicalTrials.gov identifier: NCT03002805.

Trial registration: ClinicalTrials.gov identifier: NCT02013336.

Trial registration: ClinicalTrials.gov identifier: NCT02536183.

Trial registration: ClinicalTrials.gov identifier: NCT02557854.

Trial registration: ClinicalTrials.gov identifier: NCT02390843.

Trial registration: ClinicalTrials.gov identifier: NCT03643133.

Trial registration: ClinicalTrials.gov identifier: NCT03006848.

Trial registration: ClinicalTrials.gov identifier: NCT03676985.

Trial registration: ClinicalTrials.gov identifier: NCT03277924.

Trial registration: ClinicalTrials.gov identifier: NCT03190174.

Trial registration: ClinicalTrials.gov identifier: NCT02304458.

Trial registration: ClinicalTrials.gov identifier: NCT02406781.

Trial registration: ClinicalTrials.gov identifier: NCT02502786.

Trial registration: ClinicalTrials.gov identifier: NCT03860207.

Trial registration: ClinicalTrials.gov identifier: NCT03320330.

Trial registration: ClinicalTrials.gov identifier: NCT03610490.

Trial registration: ClinicalTrials.gov identifier: NCT02100891.

Trial registration: ClinicalTrials.gov identifier: NCT02508038.

Trial registration: ClinicalTrials.gov identifier: NCT03356782.

Trial registration: ClinicalTrials.gov identifier: NCT01953900.

Trial registration: ClinicalTrials.gov identifier: NCT03618381.

Trial registration: ClinicalTrials.gov identifier: NCT03462316.

Trial registration: ClinicalTrials.gov identifier: NCT02487979.     

When government agencies turn to unregulated drug sources: Implications for the drug supply chain and public health are grave

Objective

To highlight how sourcing practices for lethal injections drugs are undermining state and federal regulatory structures established to preserve the security and integrity of the medicines supply chain in the United States.

Novel inhibitors in development for hepatocellular carcinoma

Importance of the field: The multikinase inhibitor sorafenib was the first agent to demonstrate a survival benefit for patients with locally advanced or metastatic hepatocellular carcinoma (HCC). Although sorafenib represents a landmark in the treatment of HCC and proved molecularly targeted therapy to be effective in this disease, it represents just the first step towards an improvement in systemic therapy. Since then, novel inhibitors have been evaluated in early clinical trials, showing potential activity.

Areas covered in this review: This article aims to review novel inhibitors emerging in the field of advanced HCC. An Internet-based search was performed to identify abstracts, clinical trials (www.clinicaltrials.gov, last accessed 30 November 2009), and original research and review articles.

What the reader will gain: Readers will gain a comprehensive survey of current molecularly targeted therapy approaches in advanced HCC. In addition, challenges such as the design of clinical trials, the assessment of radiological response, the role of combination therapy, and future developments in molecularly targeted therapy are discussed.

Take home message: Sorafenib is the standard of care in patients with advanced HCC. However, promising novel inhibitors are under investigation. Combined molecularly targeted therapies according to an individual genomic and proteomic profiling will probably lead to more personalised medicine in advanced HCC.     

Designs of RADIANCE 1 and 2:carotid ultrasound studies comparing the effects of torcetrapib/atorvastatin with atorvastatin alone on atherosclerosis*

ABSTRACT

Objective: The RADIANCE studies were designed to assess the effects of torcetrapib/atorvastatin (T/A) compared with atorvastatin alone on slowing atherosclerotic progression in patients with heterozygous familial hypercholesterolemia (RADIANCE 1) or mixed hyperlipidemia (RADIANCE 2), as measured by change in carotid intima-media thickness (CIMT).

Research design and methods: RADIANCE 1 and 2 were random­ized, double-blind, controlled trials with a duration of 2 years. In both studies, eligible subjects began treatment with atorvastatin during a run-in period and were titrated to target LDL?C levels defined by NCEP ATP III guidelines. Subjects then proceeded to a double-blind randomized treatment period where they received one of two regimens: (i) fixed combination T/A (torcetrapib dose, 60?mg), or (ii) atorvastatin alone. In both regimens, the dose of atorvastatin was established during the run-in period (20–80?mg, RADIANCE 1; 10–80?mg RADIANCE 2). B-mode ultrasonography was performed in duplicate at baseline and at end of study, and every 6 months in between.

Main outcome measures: The primary efficacy measure in both studies was the annualized rate of change in maximum CIMT of 12 pre-defined carotid segments. Further outcome measures included lipid and safety assessments.

Current status: The number of subjects randomized was 904 in RADIANCE 1 and 752 in RADIANCE 2. Results are anticipated in 2007.

Trial registration: ClinicalTrials.gov identifier: NCT00136981.

Trial registration: ClinicalTrials.gov identifier: NCT00134238.     

FDA“新型冠状病毒肺炎：评价治疗或预防药物和生物制品的主方案”指导原则介绍

正在兴起的主方案临床研究模式有加快药物开发、缩短开发时间等优点,但实施起来也有一定难度。美国食品药品监督管理局（FDA）为了给治疗或预防新型冠状病毒肺炎（COVID-19）药物的主方案申请人排忧解难,于2021年5月发布了“COVID-19：评价治疗或预防药物和生物制品的主方案”技术指导原则,对COVID-19药物主方案设计、实施和统计学提出了许多建议。详细介绍FDA的该指导原则,希望对我国开展这方面的研究工作及其监管有益,也对结合国情制定类似的指导原则有启示。     

Pharmacodynamics,pharmacokinetics and clinical efficacy of telavancin in the treatment of pneumonia

Introduction: Telavancin is a novel lipoglycopeptide derivative of vancomycin that has activity against Gram-positive aerobic and anerobic bacteria, for the treatment of serious infections, including complicated skin and skin structure infections (cSSSI) and pneumonia.

Areas covered: This article was compiled through searches on telavancin up to December 2015 in the PubMed and the clinicaltrials.gov databases; the FDA and European Medicine Agency (EMA) websites. In our review, particular attention was paid to those articles that reviewed the pharmacokinetic characteristics of the drug and animal models of infection. We also searched for evidence of the efficacy of telavancin as demonstrated in clinical trials, safety and tolerability data and have compiled a summary of clinical trials on telavancin in pneumonia.

Expert opinion: Telavancin is approved in Europe and the USA for the treatment of nosocomial pneumonia caused by methicillin resistant Staphylococcus aureus when other alternatives are not suitable.     

Nanoparticle-Based Medicines: A Review of FDA-Approved Materials and Clinical Trials to Date

In this review we provide an up to date snapshot of nanomedicines either currently approved by the US FDA, or in the FDA clinical trials process. We define nanomedicines as therapeutic or imaging agents which comprise a nanoparticle in order to control the biodistribution, enhance the efficacy, or otherwise reduce toxicity of a drug or biologic. We identified 51 FDA-approved nanomedicines that met this definition and 77 products in clinical trials, with ~40% of trials listed in clinicaltrials.gov started in 2014 or 2015. While FDA approved materials are heavily weighted to polymeric, liposomal, and nanocrystal formulations, there is a trend towards the development of more complex materials comprising micelles, protein-based NPs, and also the emergence of a variety of inorganic and metallic particles in clinical trials. We then provide an overview of the different material categories represented in our search, highlighting nanomedicines that have either been recently approved, or are already in clinical trials. We conclude with some comments on future perspectives for nanomedicines, which we expect to include more actively-targeted materials, multi-functional materials (“theranostics”) and more complicated materials that blur the boundaries of traditional material categories. A key challenge for researchers, industry, and regulators is how to classify new materials and what additional testing (e.g. safety and toxicity) is required before products become available.     

FDA 2007修正案对于美国制药行业的影响及对我国药品安全监管的启示

2007修正案是美国近40年来最重大的一次医药行业法律法规改革,其涉及的领域覆盖医药管理的各个方面,其制药企业需修改以往的部分工作程序以适应2007修正案的新要求。2007修正案为我国药品监管部门的工作,特别是药品安全监督工作具有借鉴意义,我国在药品安全管理中应与国际接轨,变原有的事后危机管理模式为新型的全面化过程管理。     

Safety of pharmacotherapy options for bulimia nervosa and binge eating disorder

Introduction: Eating disorders represent a set of psychiatric illnesses with lifelong complications and high relapse rates. Individuals with eating disorders are often stigmatized and clinicians have a limited set of treatments options. Pharmacotherapy has the potential to improve long term compliance and patient commitment to treatment for eating disorders.

Areas covered: This review will examine the efficacy and safety profile of the FDA-approved medications for the treatment of bulimia nervosa (BN) and binge eating disorder (BED). This will include the evaluation of fluoxetine for BN, and lisdexamfetamine for BED. Safety information will be review from randomized control trials (RCT), open label trials, and case reports.

Expert opinion: Fluoxetine for BN and lisdexamfetamine for BED are relatively safe and well-tolerated. Despite these properties, these two medications represent a limited arsenal for the pharmacological treatment of eating disorders. Thus, more research-based strategies are needed to develop safe, effective, and more targeted therapies for eating disorders.     

EGFR targeting drugs in the treatment of head and neck squamous cell carcinoma

Importance of the field: Head and neck cancer is the sixth most common cancer worldwide. Despite intense efforts to improve different treatment modalities, mortality rates in advanced cases remain high.

Areas covered in the review: EGFR targeting mAb cetuximab (Erbitux) has been approved for the treatment of locally advanced head and neck squamous cell carcinoma (HNSCC) in combination with radiotherapy and for recurrent or metastatic HNSCC. Here, we review recent scientific advances, as well as future research goals regarding EGFR inhibitors in the treatment of HNSCC. Information was compiled by searching the PubMed, Web of Knowledge and American Society of Clinical Oncology databases for articles published before October 2009. The search terms included ‘head and neck cancer’, ‘EGFR’, ‘cetuximab’, ‘panitumumab’, ‘zalutumumab’, ‘nimotuzumab’, ‘erlotinib’, ‘gefitinib’ and ‘lapatinib’. The National Institutes of Health registry of clinical trials (www.clinicaltrials.gov) was used to search for clinical trials in HNSCC.

What the reader will gain: The background scientific rationale, clinical efficacy and development of EGFR inhibitors in HNSCC are discussed.

Take home message: Cetuximab significantly improves survival of patients with locally advanced or metastatic HNSCC. Treatment strategies combining EGFR inhibitors with multimodality approaches may eventually increase cure rate in HNSCC.     

Fixed combinations of dorzolamide-timolol and brimonidine-timolol in the management of glaucoma

Importance of the field: The emergence of fixed-combination drugs for the treatment of glaucoma has, to some extent, changed the medical management of glaucoma. The potential benefits of these drugs include a reduction in the total number of drops and preservatives instilled per day and improved patient comfort factors, which may contribute to better compliance. Combination medications may also improve therapeutic efficacy and play an important role in controlling medication cost. However, the fixed dosing may be a disadvantage in some cases.

Area covered in this review: This review describes the composition, pharmacokinetics, mode of action, efficacy, side effects, and safety profile of fixed-combination dorzolamide–timolol and fixed-combination brimonidine–timolol.

What the reader will gain: Understanding of the pros, cons, and safety profile of two FDA approved fixed-combination antiglaucoma medication.

Take home message: Fixed-combination medications may be a reasonable adjunct to prostaglandins if a large drop in the intraocular pressure (IOP) is desired and adding only one medication is unlikely to reach the target IOP range. Both mentioned drugs are effective in reducing the IOP and further clinical studies will help identify differences in efficacy between the two. The clinician must make an individualized assessment of the medication's risk-benefit profile for each patient.