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.     

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.     

Responsibilities of Clinical Trial Investigators

Abstract

Never has compliance with Title 18 of the Code of Federal Regulations (CFR) Part 312, and with good clinical practices (GCPs) been of greater importance and under more public scrutiny than today. The current regulatory environment at the Food and Drug Administration (FDA) has fueled a keener awareness not only of how clinical investigators are conducting their research under Investigational New Drug (IND) regulations, but also how they are documenting the research activity. Further, the present climate at the Agency is geared to enforcement of the regulations and to application of sanctions when indicated.

This article describes the responsibilities that a clinical investigator legally assumes upon signing the Statement of Investigator, Form FDA 482, an interpretation of some of the regulations pertinent to IND research, and how to abide by the applicable regulations: what to do, how to do it, and what not to do.     

Olaratumab for advanced soft tissue sarcoma

Introduction: Olaratumab is a humanized IgG1 monoclonal antibody that blocks the platelet-derived growth factor receptor alpha (PDGFRα). Its antagonistic behavior inhibits the receptor’s tyrosine kinase activity, thereby, turning off the downstream signaling cascades responsible for soft tissue sarcoma tumorigenesis. In October 2016, olaratumab received Food and Drug Administration (FDA) approval for its use in combination with doxorubicin for treatment of advanced soft tissue sarcoma.

Areas covered: This drug profile takes a comprehensive look at the clinical studies leading to FDA approval of olaratumab as well as its safety and efficacy as a front-line treatment option for sarcoma patients. The literature search was primarily conducted using PubMed.

Expert commentary: The combination of olaratumab plus doxorubicin has provided a new front-line therapeutic option for soft tissue sarcoma patients. An open-label phase Ib and randomized phase II trial in patients with advanced soft tissue sarcoma demonstrated that the addition of olaratumab to doxorubicin prolonged progression-free survival by 2.5 months and overall survival by 11.8 months when compared to doxorubicin alone. Of importance, this clinically meaningful increase in overall survival did not come at the expense of a significantly greater number of toxicities. A phase III confirmatory trial (ClinicalTrials.gov Identifier NCT02451943) will be completed in 2020.     

QUALITY ASSURANCE IN CLINICAL TRIALS*

Abstract

A comprehensive review of Sections 314.l(f) [21 CFR 1982] and 314.2(f) [21 CFR 1983] and the impact of the proposed regulations, dated October 19, 1982, on Sections 6, 7, and 8 of the Application for FDA approval to market a new drug.     

Erdafitinib for the treatment of metastatic bladder cancer

ABSTRACT

Introduction: Since the approval of immune checkpoint inhibitors (ICIs), there has been continuing and significant progress in urothelial cancer (UC) treatment. However, only about one fifth of UC patients respond to ICI. Recently, erdafitinib was developed for treating locally advanced or metastatic UC (mUC) with FGFR3 or FGFR2 alterations, accounting for 15–20% of patients. Erdafitinib is the first targeted therapy ever approved for mUC.

Areas covered: This review summarizes the preclinical and clinical data on erdafitinib for UC. PubMed search and relevant articles presented at international conferences were used for the literature search.

Expert opinion: The FDA approval of erdafitinib provided a new treatment option for FGFR-altered UC progressing on platinum-based chemotherapy. It is not clear whether FGFR inhibitor is a preferred second-line treatment choice to ICI. Compared to ICI, erdafitinib has a better response rate in patients with visceral metastases. However, a shorter duration of response and toxicity profile of erdafitinib, particularly ocular toxicity, is an important consideration. Regular eye exams are recommended by the FDA. Tumor profiling during upfront therapy may help identify those who benefit at the time of progression. In summary, a high unmet need remains for new drugs in chemotherapy- and ICI-refractory UC.     

Pertuzumab for the treatment of breast cancer: a safety review

ABSTRACT

Introduction: Approximately twenty to thirty percent of newly diagnosed breast cancers are human epidermal growth factor receptor 2 (HER2) positive. The use of trastuzumab, and more recently pertuzumab, has significantly improved the progression free survival (PFS) and overall survival (OS) in this patient population. However, pertuzumab has side effects that can impact treatment tolerability and quality of life.

Areas covered: This review describes the safety and tolerability of pertuzumab, a monoclonal antibody targeted at HER2 approved by the United States Food and Drug Administration (FDA) for use in the neoadjuvant and first line metastatic settings.

Expert opinion: The combination of trastuzumab, pertuzumab, and chemotherapy is approved in the neoadjuvant and first line metastatic settings and should be strongly considered by providers. Further studies are needed to look at side effect prevention, novel pertuzumab containing regimens, and re-treating patients with pertuzumab.     

Cannabis policies in Canada: How will we know which is best?

BackgroundThe recent legalisation of cannabis in Canada by the Federal Government, along with the accompanying laws and regulations of provincial and territorial governments provides an opportunity to assess the expected benefits and harms of legalisation. While the legislative changes have been initiated by the federal government, much of the responsibility for the implementation falls onto the provinces and territories. These jurisdictions are responsible for regulating the wholesale distribution, retail structures, cannabis consumption, as well as a host of other regulations.MethodsKey characteristics of policies outlined are categorised according to a framework previously developed by the authors (2018). The categories are: (1) government regulation or control, (2) social costs that accompany its use, and (3) legal sanctions that accompany its production and use. Towards that end, we develop a framework for a cost benefit analysis (CBA) outlining in some detail the data that is needed to undertake a credible economic evaluation of cannabis policies.ResultsKey data issues discussed include consumer surplus, government receipts including legal and regulatory costs, impact on substitutes, change in profits to firms (growers, wholesalers, and retailers), incomes earned in the industry, health and other costs incurred by cannabis users.DiscussionThis paper presents a summary of the expected categories of costs and benefits given the various provincial cannabis policies. Additionally, it provides a framework for subsequent cost benefit analyses which can quantify said harms and benefits.     

A Conputerized System for Monitoring and Accounting of Investigational Drug Supplies in a Multi-Center Clinical Trial

Abstract

In any clinical trial involving investigational drugs, federal regulations require accurate and adequate drug accounting. In addition, it is advantageous to monitor individual patient compliance for its relationship to response to therapy, adverse reactions, etc. Accomplishing these objectives can be very time consuming, especially when there are multiple participating centers.

A computer system has been designed to meet these needs and was tested on a investigational drug supplies used in a multicenter clinical trials. The computer generated reports, which can be easily developed by a supporting statistical and data processing center are helpful in monitoring drug supplies at field stations and in achieving compliance with federal regulations. Sponsors of clinical trials, especially physicians, could use CDAS to assist in assuming the drug accountability responsibilities of a multicenter clinical trial.

To develop a CDAS similar to the one just described which can be used to monitor and verify the usage of all drug supplies used in a clinical trial, the sponsor must:

1) Identify each dispensible unit with a number (i.e. bottle number)

2) Package all drug supplies in patient kits.

3) Collect the appropriate drug accountability data on clinic visit forms

4) Supplement the study master file with appropriate drug shipping data, lot numbers and expiration dates.

The goal of any CDAS should be to monitor and account for all investigational drug supplies. Otherwise many of the problems identified by the FDA, such as lost drugs or laxity in drug accountability, may go undetected.     

Non-US Clinical Trial Data and the Food and Drug Administration

Abstract

Commercial requirements and the use of indigenous science for advertising purposes indicate that at least some studies will always be done in each country where medications are marketed. However, drug development is a transnational phenomenon where data from one country will be used to obtain marketing approval in another. Yet local regulatory and scientific requirements preclude the use of one set of data for all countries, which increases the cost of an already expensive process. In the US the FDA has historically expressed concerns about accepting foreign data as the sole basis for approval of an NDA. Despite the timolol case, foreign data are still used infrequently and only on an ad hoc basis. Data quality, verification, authentication, and inspection continue to be the most important problems in this area. Standardized protocols, and strict adherence to them; the use of investigators with a proven track record, ability, and appropriate training; frequent monitoring by United States drug sponsors; appropriate statistical analyses; a rigorous internal critique of the study; the use of anthropologists to deal with perceived and cryptic cross-cultural problems; and avoidance of “found” data will ameliorate problems with non-US data.     

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.     

Efficacy and safety of mipomersen sodium (Kynamro)

Introduction: Mipomersen is a first-in-class drug indicated as an adjunct to lipid-lowering medications and diet to reduce low-density lipoprotein-cholesterol (LDL-C), apolipoprotein B (apoB), total cholesterol (TC) and non-high density lipoprotein-cholesterol (non-HDL-C) in patients with homozygous familial hypercholesterolemia (HoFH).

Areas covered: This article summarizes the efficacy and safety profile of mipomersen based on literature, public materials available from the Endocrinologic and Metabolic Drugs Advisory Committee meeting (FDA) in review of the New Drug Application (NDA 203568) and the recent product label.

Expert opinion: Patients suffering from HoFH are characterized by elevated levels of LDL-C and are, therefore, at severely increased risk for cardiovascular disease (CVD). Currently available lipid-lowering therapies (LLT), such as statins, have been shown to lower LDL-C levels and CVD risk. However, in patients suffering from HoFH, additional therapy is urgently needed to further decrease LDL-C levels and CVD risk. Mipomersen (Kynamro) has recently been approved by the FDA as a novel LLT modality in patients with HoFH. Mipomersen has been show to result in highly relevant absolute LDL-C reductions in HoFH patients, and given the undisputed causal relationship between LDL-C levels and CVD risk, this additional LDL-C lowering is expected to result in a robust CVD risk reduction.     

Change in formulation and its potential clinical and pharmacoeconomic value: example of extended release venlafaxine

ABSTRACT

Introduction: The 505(b)(2) route of a New Drug Application (NDA) allows published literature or previous FDA findings of safety and effectiveness to be used for approval. Such drugs are not therapeutic equivalents (i.e., generics); instead, the FDA calls them pharmaceutical alternatives. A recent example is the approval of venlafaxine extended-release (ER) tablets, developed as an alternative to the widely used ER?venlafaxine capsules. The smaller size of the tablets makes them available in a 225-mg strength, which is the approved maximum dose in major depressive disorder after up-titration but currently unavailable in the capsule formulation, requiring patients on this dose to take two or three capsules; in addition, the tablets are priced at a discount compared to the capsules.

Methods: The objective of this review was to investigate how the change in formulation of ER?venlafaxine from capsules to tablets, as an example of such a change in formulation, can potentially offer value to patients and society, with a specific focus on pill burden, drug cost, and adherence. Based on a MEDLINE literature search, the pertinent literature was reviewed in a qualitative manner.

Review of the literature: Simplifying treatment regimens, reducing pill burden, and reducing drug costs are recognized strategies for improving adherence. This can be of particular benefit in psychiatric illness because of high rates of nonadherence to treatment. Lack of adherence may negatively impact treatment outcomes and increase disease cost. As such, the ER?venlafaxine tablets have the potential to reduce pill burden, improve adherence and outcomes, and reduce cost to patients and society. These preliminary findings need to be corroborated with more primary research and a systematic review of formulation changes.

Conclusion: A change in formulation of established therapies such as ER?venlafaxine has the potential to offer clinical and pharmacoeconomic benefits to patients and society.     

Regulation of the compounding of positron emission tomography drugs.

Controversial aspects of the regulatory framework for compounding drug products used in positron emission tomography (PET) are discussed. The Food and Drug Administration Modernization Act of 1997 (FDAMA), which amends the Federal Food, Drug, and Cosmetic Act (FFDCA), required that FDA establish approval (new drug application [NDA] and abbreviated new drug application [ANDA]) procedures and current good manufacturing practice (CGMP) requirements for PET drugs; this seems to conflict with differentiation between manufacturing and compounding in FFDCA. Compounding by pharmacists is implied in the FDAMA section on PET, but specific mention of "pharmacist" needs to be included. Congress apparently did not intend for compounded PET drugs to be regulated differently from other drugs. Although FDA has waived NDA and ANDA fees for three PET radiopharmaceuticals, revision of FDAMA to exempt PET drug products from regulations placed on manufacturing is needed. Without relief from the current regulations, many academic PET centers are likely to close; this would violate FDAMA's stated intent of making PET available to patients at reasonable cost. Also problematic is FDAMA's prohibition of compounding "regularly or in inordinate amounts" a product that is commercially available; the common PET radiopharmaceutical fludeoxyglucose F 18 injection, for example, is commercially available. A sensible alternative to NDA or ANDA and CGMP requirements would be the enforcement of USP standards for PET drugs by state boards of pharmacy.     

同情用药制度对我国罕见病患者用药可及性研究

目的：基于国内罕见病患者用药可及性现状,剖析国外同情用药的制度体系及实施成效,深入分析同情用药制度对国内罕见病患者的用药可及性问题,并提出贴合国内罕见病患者同情用药制度落实的细则。方法：查阅美国FDA发布的法规政策、技术指南、相关统计数据及文献资料,对美国同情用药的使用类别、申请及审批流程、费用支付方式等内容进行分析。结果与结论：美国已具备较为完善的同情用药制度体系,该制度在我国的建立或将成为国内罕见病患者用药可及的一条新路径,在一定程度上能够提高国内罕见病患者的用药可及性。     

A Degree in Medical Technology as Preparation for a Clinical Research Associate

Abstract

The curriculum for a Bachelor of Science degree in Medical Technology is aimed directly at the biological sciences. However, it also offers a strong support system in chemistry, technical writing and the humanities, and in the right location, gives the graduate experience with the persons, places and systems used for running clinical studies. Then building on this basic infrastructure by adding computer literacy, supervisory and interpersonal skills, an understanding of FDA regulations, and the principles of marketing, a medical technologist can begin the position of Clinical Research Associate well prepared.     

The Utilization of a Fax Program to Computer Process Case Report Forms Resulted in a Speedier NDA in a 13 Site Clinical Trial

Abstract

Galderma Labs recently completed a multi-center trial that compared the time to final NDA for lotion, gel and cream forms of an acne-related retinoid product (Adapalene^TM). the lotion and gel versions of Adapalene were tested with Galderma's traditional methodologies. the differentiating factor for the cream was the use of remote case report form collection fax technology. the cream study, using computer and fax technology, resulted in a quicker time to NDA for the cream than for the lotion and gel. This was the largest faxed CRF study ever done.     

A Degree in Medical Technology as Preparation for a Clinical Research Associate

Abstract

The curriculum for a Bachelor of Science degree in Medical Technology is aimed directly at the biological sciences. However, it also offers a strong support system in chemistry, technical writing and the humanities, and in the right location, gives the graduate experience with the persons, places and systems used for running clinical studies. Then building on this basic infrastructure by adding computer literacy, supervisory and interpersonal skills, an understanding of FDA regulations, and the principles of marketing, a medical technologist can begin the position of Clinical Research Associate well prepared.