Current Status of Ind/Nda Regulations

Abstract

In order to improve the investigational drug development process, the efficiency of the Agency's drug approval process and the Agency's dealings with applicants while still maintaining the high level of public health protection, the Food and Drug Administration has undertaken the revision of the current regulations and policies for investigational new drug applications and new drug applications. On October 19, 1982, the FDA published in the Federal Register a proposal for revision of the NDA regulations, and on June 9, 1983, the Agency published a proposal for revision of the IND regulations.

The status of the proposed revisions is discussed along with projections of their impact on the American public, pharmaceutical industry, and the FDA. Since the revised regulations will refer to several guidelines, the status and scope of the guidelines are described. In addition, changes that have already been put into effect prior to finalization of the proposed regulations are described.     

The "treatment IND (investigational new drugs)": public policy considerations.

A major activity occupying the U.S. Food and Drug Administration for several years has been a rewrite of the FDA's IND and NDA regulations which govern the clinical testing of investigational new drugs and the process for subsequent market approval for those drug entities. In March of 1987, the FDA "reproposed" that portion of the 1983 IND rewrite dealing with the "treatment use" of investigational new drugs during the clinical testing phases of new drug development or during the period between the completion of clinical testing and NDA approval. The Treatment IND reproposal resulted in substantial controversy immediately following its publication in the Federal Register. This article compares the key features of the Treatment IND regulations as reproposed with those of the Final Rule and summarizes the major points of contention among the various interest groups affected. With its new Treatment IND regulations, the FDA appears to have placed itself squarely between competing interests and public policy considerations. The essential purpose and role of the FDA is to determine the inherent safety and effectiveness of new therapeutic medications. Debate on the Treatment IND regulations has raised a number of questions as to the regulations' own safety and efficacy in achieving that objective. It is likely the Treatment IND implementation will engender as much controversy as the regulations as originally reproposed.     

The safety of ixekizumab in psoriasis drug therapy

ABSTRACT

Introduction: Ixekizumab, a humanized IgG4 monoclonal antibody that selectively binds and neutralizes interleukin IL-17A, has been approved by the United States Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of moderate to severe plaque psoriasis (2016), active psoriatic arthritis (FDA 2017, EMA 2018), and active ankylosing spondylitis (FDA 2019).

Areas covered: This review evaluates the safety profile of ixekizumab for the treatment of moderate-to-severe psoriasis. A literature search was performed for articles published through November 2019.

Expert opinion: These studies show that ixekizumab demonstrates a favorable safety profile. Antidrug antibodies can be detected in up to 17% of patients but they do not significantly affect clinical response or safety of the treatment. Injection site reactions, erythema or pain, develop in up to 10% of the patients during the first 12 weeks of treatment, an incidence similar to that of etanercept. Infections overall do not cause a safety problem; mucocutaneous Candida infections, occur at a rate of in 1.9/100 patient-years, but are easily managed and usually do not determine treatment discontinuation. The occasional de novo appearance or exacerbation of preexistent inflammatory bowel disease remains a cause of concern, and requires close monitoring of patients at risk.     

The efficacy and safety of amifostine for the acute radiation syndrome

ABSTRACT

Introduction: A radiation countermeasure that can be used prior to radiation exposure to protect the population from the harmful effects of radiation exposure remains a major unmet medical need and is recognized as an important area for research. Despite substantial advances in the research and development for finding nontoxic, safe, and effective prophylactic countermeasures for the acute radiation syndrome (ARS), no such agent has been approved by the United States Food and Drug Administration (FDA).

Area covered: Despite the progress made to improve the effectiveness of amifostine as a radioprotector for ARS, none of the strategies have resolved the issue of its toxicity/side effects. Thus, the FDA has approved amifostine for limited clinical indications, but not for non-clinical uses. This article reviews recent strategies and progress that have been made to move forward this potentially useful countermeasure for ARS.

Expert opinion: Although the recent investigations have been promising for fielding safe and effective radiation countermeasures, additional work is needed to improve and advance drug design and delivery strategies to get FDA approval for broadened, non-clinical use of amifostine during a radiological/nuclear scenario.     

Clinical Investigation in Animals

Abstract

The Code of Federal Regulations Part 511 addresses the requirements for new animal drugs for investigational use. In 1977, the Food and Drug Administration proposed new rules for the conduct of clinical trials. Although these are only proposed regulations, the FDA uses them as guidelines when conducting audits of clinical investigators. These proposed Good Clinical Practice Regulations have resulted in an improvement in the manner animal clinical studies are now conducted. We feel the results have been positive for all concerned, the public, sponsor and the Food and Drug Administration.     

What do providers want to know about opioid prescribing? A qualitative analysis of their questions

ABSTRACT

Background: In 2012, the US Food and Drug Administration (FDA) responded to the opioid crisis with a Risk Evaluation and Mitigation Strategy, requiring manufacturers of extended-release/long-acting opioids to fund continuing medical education based on the “FDA Blueprint for Prescriber Education.” Topics in the Blueprint are “Assessing Patients for Treatment,” “Initiating Therapy, Modifying Dosing, and Discontinuing Use,” “Managing Therapy,” “Counseling Patients and Caregivers about Safe Use,” “General Drug Information,” and “Specific Drug Information.” Based on the FDA Blueprint, Boston University School of Medicine's “Safe and Competent Opioid Prescribing Education” (SCOPE of Pain) offers live trainings for physicians and other prescribers. During trainings, participants submit written questions about the curriculum and/or their clinical experiences. Methods: The objective was to compare themes that arose from questions asked by SCOPE of Pain participants with content of the FDA Blueprint in order to evaluate how well the Blueprint answers prescribers’ concerns. The authors conducted qualitative analyses of all 1309 questions submitted by participants in 29 trainings across 16 states from May 2013 to May 2015, using conventional content analysis to code the questions. Themes that emerged from participants’ questions were then compared with the Blueprint. Results: Most themes fell into the topic categories of the Blueprint. Five main themes diverged: Participants sought information on (1) safe alternatives to opioids, (2) overcoming barriers to safe opioid prescribing, (3) government regulations of opioid prescribing, (4) the role of marijuana in opioid prescribing, and (5) maintaining a positive provider-patient relationship while prescribing opioids. Conclusions: In addition to learning the mechanics of safe opioid prescribing, providers want to understand government regulations and effective patient communication skills. Aware of the limitations of opioids in managing chronic pain, providers seek advice on alternatives therapies. Future updates to the FDA Blueprint and other educational guidelines on opioid prescribing should address providers’ additional questions.     

Are biosimilars patentable?

Introduction: This paper explores whether, and under what circumstances, a biosimilar approved in the United States under the Biologics Price Competition and Innovation Act (hereafter ‘BPCIA’) can be patented. The possibility that a biosimilar product could have meaningful patent protection arises from specific requirements for biosimilarity under the BPCIA, which account for the fact that manufacturing processes of biologics are inherently imprecise. The requirements for biosimilar approval may provide sufficient leeway to a biosimilar applicant to patent structural or formulation differences that provide non-clinical but business-relevant advantages over the reference molecule, such as improved shelf-life or ease of manufacture, without compromising clinical biosimilarity.

Areas covered: Examination of the BPCIA and related Acts, Food and Drug Administration (FDA) guidance papers, case law, patent database searching, and relevant scholarly articles.

Expert opinion: Legislative and regulatory requirements for the approval of a biosimilar under the BPCIA are focused on clinical results and allow a degree of leeway for differences to exist between a biosimilar’s structure and non-clinical components and those of the biosimilar’s reference molecule. This leeway can be exploited to provide the biosimilar with potentially patentable business-relevant advantages over its reference product while maintaining clinical biosimilarity to the reference product.     

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

ABSTRACT

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.     

我国药品附条件批准程序实施情况及相关思考

目的：对我国药品附条件批准上市相关政策和实施情况进行深入分析和探讨,参考美国与欧盟药品附条件上市政策,对我国附条件批准上市的实施和推进提出建议。方法：通过梳理药品注册管理办法发布后国家药品监督管理局(NMPA)药品附条件批准上市申请审评审批法规政策实施情况,重点围绕当前法规中的准入条件、准入程序、上市后监管要求、撤销情形以及撤销程序进行综述,针对实施过程中发现的问题,借鉴美国食品药品管理局(FDA)药品加速审批(Accelerate Approval)与欧洲药品管理局(EMA)药品附条件批准(Conditional Marketing Authorisation)经验以及对各国附条件政策进行比较分析,探讨我国药品附条件批准上市政策的发展方向。结果与结论：为了加快具有突出价值的临床急需药品上市,缩短新技术临床应用时间,美国与欧盟均设立了相对完备的附条件上市法规政策及程序。我国的附条件批准制度虽然建立时间较短,但有欧美的经验作为参考,结合我国的临床实践和监管需要, 相关法规也在趋于完善。未来,监管部门更多需要考虑的是对程序和技术要求的细化、制度之间的衔接 (如疫苗的紧急使用授权与附条件批准制度),以及加强上市后监管等方面。     

Preparing the Nda Summary: How to,How Not to and why

Abstract

The four parts of this presentation are: 1) some practical advice on preparing an NDA Optional Expanded Summary and Evaluation (summary); 2) a look at the NDA regulations as guidelines rather than as detailed instructions; 3) comments from FDA reviewers on common shortcomings in summaries and some insight into the FDA reviewer's job, and 4) a look at how the proposed new regulations would affect the preparation of a summary.

Presented at the annual meeting of the Associates of Clinical Pharmacology, March 1, 1984, at the Sheraton El Conquistador Hotel, in Tucson, AZ.     

Sodium oxybate for the treatment of fibromyalgia

Introduction: Gamma-hydroxybutyrate (GHB) is a short-chain fatty acid that is synthesized within the CNS, mostly from its parent compound gamma amino butyric acid (GABA). GHB acts as a neuromodulator/neurotransmitter to affect neuronal activity of other neurotransmitters and so, stimulate the release of growth hormone. Its sodium salt (sodium oxybate: SXB) was approved by the Food and Drug Administration (FDA) for the treatment of narcolepsy. SXB has shown to improve disrupted sleep and increase NR3 (slow-wave restorative) sleep in patients with narcolepsy. It is rapidly absorbed and has a plasma half-life of 30 – 60 min, necessitating twice-nightly dosing. Most of the observed effects of SXB result from binding to GABA-B receptors.

Areas covered: Several randomized, controlled trials demonstrated significantly improved fibromyalgia (FM) symptoms with SXB. As seen in narcolepsy trials, SXB improved sleep of FM patients, increased slow-wave sleep duration as well as delta power, and reduced frequent night-time awakenings. Furthermore, FM pain and fatigue was consistently reduced with nightly SXB over time. Commonly reported adverse events included headache, nausea, dizziness and somnolence. Despite its proven efficacy, SXB did not receive FDA approval for the management of FM in 2010, mostly because of concerns about abuse.

Expert opinion: Insomnia, fatigue and pain are important clinical FM symptoms that showed moderate improvements with SXB in several large, well-designed clinical trials. Because of the limited efficacy of currently available FM drugs additional treatment options are needed. In particular, drugs like SXB – which belong to a different drug class than other Food and Drug Administration (FDA)-approved FM medications such as pregabalin, duloxetine and milnacipran – would provide a much-needed addition to presently available treatment options. However, the FDA has set the bar high for future SXB re-submissions, with requirements of superior efficacy and improved risk mitigation strategies. At this time, no future FDA submission of SXB for the fibromyalgia indication is planned.     

Bepotastine besilate for the treatment of perennial allergic rhinitis

ABSTRACT

Introduction: Bepotastine besilate (BB) is a second-generation H1-antihistamine that, as an ophthalmic solution, is approved in the United States by the Food and Drug Administration (FDA) for the treatment of allergic conjunctivitis. In other countries, the oral presentation of BB is widely used for the improvement of symptoms of allergic rhinitis (AR) as well as urticaria and chronic pruritus with results similar to those by other drugs of the same class.

Areas covered: This article was created from a comprehensive literature search with information taken from clinical trials. The articles that have been selected evaluate the clinical and non-clinical pharmacology of BB as well as its use in AR and its efficiency in the improvement of symptoms, its safety, common adverse effects, and overall experiences of its use.

Expert opinion: BB is effective and well-tolerated in the treatment of allergic rhinitis. Side effects are infrequent in patients with AR who do not have kidney or liver disease. Clinical trial experience with oral bepotastine outside the United States has confirmed its safety. BB can be useful as a therapeutic option in patients with AR who would like to explore an alternative to the currently available once-daily oral H1-antihistamines.     

Progress in New Drug Regulation

Abstract

Since the enactment of the Drug Amendments of 1962, there has been no progress in reform of new drug regulation for three reasons. The recommendations for reform have come from outside FDA, and thus have had no leverage or clout. Congress has no interest in reforming drug regulation. The FDA bureaucracy has no incentive to reform the system. Progress in new drug regulation will therefore be extremely difficult in the future and may not be achievable.     

Medical countermeasures for unwanted CBRN exposures: Part I chemical and biological threats with review of recent countermeasure patents

Introduction: The threat of chemical, biological, radiological, and nuclear (CBRN) warfare has been addressed as the uppermost risk to national security since the terrorist attacks on 11 September 2001. Despite significant scientific advances over the past several decades toward the development of safe, non-toxic and effective countermeasures to combat CBRN threats, relatively few countermeasures have been approved by the US Food and Drug Administration (US FDA). Therefore, countermeasures capable of protecting the population from the effects of CBRN attack remain a significant unmet medical need. Chemical and biological (CB) threat agents can be particularly hazardous due to their effectiveness in small quantities and ease of distribution.

Area covered: This article reviews the development of countermeasures for CB threats and highlights specific threats for which at least one countermeasure has been approved following the FDA Animal Rule. Patents of CB countermeasures since 2010 have been included.

Expert opinion: Nine CB countermeasures have received FDA approval for use in humans following the Animal Rule, and a number of promising CB countermeasures are currently under development. In the next few years, we should expect to have multiple countermeasures approved by the FDA for each indication allowing for more flexible and effective treatment options.     

美国药品标识监管体系研究

目的：通过研究和分析美国药品说明书和标签监管体系,重点阐述现有监管制度上的环节要求,以期为完善我国药品说明书和标签监管体系提供较为全面的参考和借鉴,进一步提高用药安全水平。方法：采用非接触性研究中的内容分析方法,广泛查询FDA及美国联邦政府的官方网站、中国知网数据库等,收集整理与美国标识监管体系相关的资料,包括法律文件8个、指南36个及50余个FDA官网网页资料和报告文件等。结果与结论：围绕上市前、上市后和信息公开管理,并通过不断修订加强法律法规,美国药品标识逐步形成了法律、法规及指南3个层面的逻辑清晰的完整监管体系。我国药品说明书和标签监管体系建设工作相差明显,应尽快建立我国药品说明书和标签功能定位监管认识的新视角,完善上市前、上市后和信息公开管理制度机制,抓住《药品管理法》修订的契机,系统性安排药品说明书和标签立法工作计划,开展全国调研,为全面规范药品说明书和标签管理提供科学保障。     

Nonhuman primates as models for the discovery and development of radiation countermeasures

Introduction: Despite significant scientific advances over the past six decades toward the development of safe and effective radiation countermeasures for humans using animal models, only two pharmaceutical agents have been approved by United States Food and Drug Administration (US FDA) for hematopoietic acute radiation syndrome (H-ARS). Additional research efforts are needed to further develop large animal models for improving the prediction of clinical safety and effectiveness of radiation countermeasures for ARS and delayed effects of acute radiation exposure (DEARE) in humans.

Area covered: The authors review the suitability of animal models for the development of radiation countermeasures for ARS following the FDA Animal Rule with a special focus on nonhuman primate (NHP) models of ARS. There are seven centers in the United States currently conducting studies with irradiated NHPs, with the majority of studies being conducted with rhesus monkeys.

Expert opinion: The NHP model is considered the gold standard animal model for drug development and approval by the FDA. The lack of suitable substitutes for NHP models for predicting response in humans serves as a bottleneck for the development of radiation countermeasures. Additional large animal models need to be characterized to support the development and FDA-approval of new radiation countermeasures.     

Dendrimers as drugs: discovery and preclinical and clinical development of dendrimer-based microbicides for HIV and STI prevention

Starpharma focuses on the use of dendrimers as drugs in their own right, in contrast to dendrimers as drug delivery vehicles or diagnostics. This contextual review describes how dendrimers offer a unique platform for exploring chemical diversity on the nanoscale and how the production of dendrimer libraries covering a diverse array of macromolecular structures can be used in drug discovery and development. Using Starpharma's work on the prevention of HIV and sexually transmitted infections (STIs) through the development of microbicide candidates as an example, the process from which SPL7013 emerged as a development candidate is described. Following a range of preclinical studies, Starpharma submitted an investigational new drug application (IND) for SPL7013 gel (VivaGel) to the United States Food and Drug Administration (FDA) in June 2003, the first such submission for a dendrimer-based drug. The first clinical trial under this IND was completed in 2004.     

Update and trends on pharmacokinetic studies in patients with impaired renal function: practical insight into application of the FDA and EMA guidelines

Introduction: The incidence of kidney dysfunction increases with age and is highly prevalent among patients with hypertension. Since many therapeutic compounds are primarily eliminated through the kidneys, impaired renal function can have negative consequences on drug disposition, efficacy and safety. Therefore, regulatory agencies such as the Food and Drug Administration (FDA) and European Medicines Agency (EMA) have issued detailed guidelines for new drug applications to determine posology requirements for patients with renal impairment.

Areas covered: The current review highlights and contrasts agency requirements for pharmacokinetic renal impairment clinical studies. While many of the guidelines are similar among the two agencies, glomerular filtration rate (GFR) determination and reporting differ. Design considerations for a reduced, full or dialysis renal impairment study, as well as modifications to the FDA’s draft guidance are discussed. Furthermore, scenarios where pharmacokinetic modelling analysis can benefit a drug development program are also reviewed. Moreover, practical solutions for patient recruitment challenges are addressed.

Expert commentary: We summarize how ‘one size does not fit all’ for GFR assessment, and recommend when to use certain modalities. Finally, we highlight the need for the pharmaceutical industry to engage therapeutic experts to assist in protocol development for renal impairment studies, as these experts understand the nuances of this special population and recommended guidelines.