US Food and Drug Administration and European Medicines Agency Launch Good Clinical Practices Initiative

Reporting standards for adverse events after medical device use in the peripheral vascular system

Novel emerging technologies such as tissue engineering, which utilize the approaches of molecular and cell biology, biotechnology, as well as materials science and engineering, are being used in the development of a wide range of biomedical products developed by industries regulated by the U.S. Food and Drug Administration (FDA). The FDA's mission is to promote and protect the public health by ensuring the safety and effectiveness of pharmaceuticals and medical devices, including those manufactured by novel technology, as assessed by scientific principles and methods. Regulatory review is conducted on a product-by-product basis. To accomplish its mission over the wide range of products in its regulatory purview, the FDA has six centers, each staffed with the scientific and regulatory expertise to evaluate the products in the center's jurisdiction. Recent legislative and regulatory changes are designed to simplify and facilitate the administrative process for evaluating novel combination products emanating from such interdisciplinary technology as tissue engineering and to resolve questions of product regulatory jurisdiction. Under the new procedures, the FDA may designate a lead FDA center for product review based on the primary mode of action of the combination product, with additional center(s) designated to assist in the evaluation in a collaborative or consultative capacity. In addition, FDA centers have increased their cooperation and information sharing with regard to evolving interdisciplinary technology. The FDA InterCenter Tissue Engineering Initiative was established to develop information on intercenter efforts in the evaluation of tissue engineering applications and to identify areas for further consideration. The FDA InterCenter Tissue Engineering Working Group, comprised of staff from the Center for Biologies Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH), Center for Drug Evaluation and Research (CDER), and Center for Veterinary Medicine (CVM) has developed a Draft Report considering recent developments in tissue engineering and scientific and regulatory issues in the product application areas. The Working Group has identified generic safety and effectiveness issues for consideration by the research and development community in its development of products. The FDA centers are using multiple approaches at their disposal in the evaluation of tissue engineered products including research, data and information monitoring, regulatory guidance, training and education, and cooperation with public and private groups.

Pancreatic Enzyme Replacement Product, Pancrelipase, Gains Federal Approval

Selected Developments in Biotechnology Law and the Biotechnology Industry

The US Food and Drug Administration Centers for Regulatory Science and Innovation: Current Activities and Future Promise to Accelerate Innovations.

Medical products (devices, drugs, or biologics) contain information in their labeling regarding the manner in which the manufacturer has determined that the products can be used in a safe and effective manner. The Food and Drug Administration (FDA) approves medical products for use for these specific indications which are part of the medical product's labeling. When medical products are used in a manner not specified in the labeling, it is commonly referred to as off-label use. The practice of medicine allows for this off-label use to treat individual patients, but the ethical and legal implications for such unapproved use can be confusing. Although the responsibility and, ultimately, the liability for off-label use often rests with the prescribing physician, medical physicists and others are also responsible for the safe and proper use of the medical products. When these products are used for purposes other than which they were approved, it is important for medical physicists to understand their responsibilities. In the United States, medical products can only be marketed if officially cleared, approved, or licensed by the FDA; they can be used if they are not subject to or specifically exempt from FDA regulations, or if they are being used in research with the appropriate regulatory safeguards. Medical devices are either cleared or approved by FDA's Center for Devices and Radiological Health. Drugs are approved by FDA's Center for Drug Evaluation and Research, and biological products such as vaccines or blood are licensed under a biologics license agreement by FDA's Center for Biologics Evaluation and Research. For the purpose of this report, the process by which the FDA eventually clears, approves, or licenses such products for marketing in the United States will be referred to as approval. This report summarizes the various ways medical products, primarily medical devices, can legally be brought to market in the United States, and includes a discussion of the approval process, along with manufacturers' responsibilities, labeling, marketing and promotion, and off-label use. This is an educational and descriptive report and does not contain prescriptive recommendations. This report addresses the role of the medical physicist in clinical situations involving off-label use. Case studies in radiation therapy are presented. Any mention of commercial products is for identification only; it does not imply recommendations or endorsements of any of the authors or the AAPM. The full report, containing extensive background on off-label use with several appendices, is available on the AAPM website (http://www.aapm.org/pubs/reports/).

The US Food and Drug Administration (FDA) is a federal agency that has authority to regulate a variety of drugs, biologics, foods, cosmetics, and devices. During the course of regulatory review, the FDA provides the public with opportunities to ‘‘weigh in’’ regarding the process. One such avenue is via the citizen petition process. Under FDA regulations, any individual, group, or company can submit a citizen petition to the agency requesting the FDA Commissioner to ‘‘issue, amend, or revoke a regulation/order OR take or refrain from taking any other form of administrative action.’’ This process has long been used for a variety of purposes such as demanding a response from the FDA regarding drug importation or requesting a ban on the use of latex gloves in health care settings. Recently, there has been some controversy surrounding citizen petitions as brand name pharmaceutical manufacturers have been accused of misusing the process in order to delay or prevent the timely approval of generic competitors. In addition, there has been concern regarding health care organizations and individuals with financial ties to manufacturers submitting letters of support for certain citizen petitions. For example, in February 2003, sanofiaventis submitted a citizen petition to the FDA arguing against the approval of generic versions of enoxaparin (Lovenox). During the time period when the FDA was developing a response to the petition, the North American Thrombosis Forum, the Society of Hospital Medicine, and a Duke University medical researcher all wrote letters to the FDA arguing that generic versions of enoxaparin may not be as safe as brand name Lovenox, essentially supporting the citizen petition filed by sanofi-aventis. None of these organizations or individuals mentioned their existing financial relationships with sanofi-aventis in their letters to the FDA. The citizen petition process is initiated with submission of the petition to the Dockets Management Branch of the FDA. The petition is then dated, assigned a docket number, referred to the appropriate FDA center, such as the Center for Drug Evaluation and Research (CDER), and posted on a Web site (www.regulations.gov) for open comment. Filing a petition immediately triggers more review by the FDA regarding the issue(s) at hand. Historically, the filing of a citizen petition regarding a generic drug approval could add months to years to the time period required to receive marketing approval. The majority of such filings are ultimately rejected by the FDA. According to a Washington Post article, 20 of 21 citizen petitions filed by brand name manufacturers from 2003 to July 2006 were ultimately denied by the FDA. In June 2011, the FDA published a guidance document for industry containing nonbinding recommendations on the process entitled ‘‘Citizen Petitions and Petitions for Stay of Action Subject to Section 505(q) of the Federal Food, Drug, and Cosmetic Act.’’ This document provides a description of the FDA interpretation of subsection 505(q) of the Food, Drug, and Cosmetic Act as related to citizen petitions. This subsection states that the FDA may not delay the approval of a pending abbreviated new drug application (ANDA) or 505(b)(2) application (ie, a medication that contains the same active ingredient as a previously approved product, but now has a different delivery mechanism or indication) unless a formal determination that ‘‘a delay is necessary to protect the public health’’ is made based upon the information within the citizen petition. Within 30 days of making the determination, the FDA must notify the ANDA/ 505(b)(2) applicant of the decision, provide clarification or additional data that the applicant must submit if applicable to allow for further review of the petition, and summarize the specific substantive issues within the citizen petition that form the basis for the delay determination. The subsection also allows for the FDA to deny a citizen petition at any time that was ‘‘submitted with the primary purpose of delaying the approval of an application’’ and ‘‘does not on its face raise valid scientific or regulatory issues.’’ The FDA must take final action on the petition no later

9590 Background: PROs are frequently used within industry-sponsored clinical trials and phase III registration trials. Recently, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMEA) have produced draft PRO guidance. The aim of this study was to evaluate this regulatory guidance with reference to the current expert and literature evidence base on the use of PROs in cancer trials and existing QoL tools (EORTC QLQ C30 and LC13). Methods: We conducted a systematic evaluation of both FDA and EMEA guidance and undertook quantitative analyses of 47 leading world key cancer research organizations that provided a formal response to the FDA guidance. In addition, we evaluated grey literature, 25 websites, and consulted over 20 key opinion leaders. Finally, we undertook a systematic literature review (medline 1990–2007) to evaluate conformity between regulatory positions and the scientific literature. Results: In comparison with the EMEA, the FDA has a more prescriptive approach, requiring tools with robust conceptual frameworks and psychometric studies. Current state assessment, advocated by the FDA, was contradicted by 88% of 25 reviewers addressing this issue (p < 0.001). Most expert reviewers (79 % of 14 non-significant) challenged the EMEA’ s and FDA’ s views that a general QOL claim requires improvement in all domains. Minor modifications or translations triggering full re-validation, was not considered realistic by nearly all organizations (97% of 32 p < 0.0001). In addition, substantial disagreement with FDA and EMEA exists on the subject of blinding (100% of 17 p < 0.0001). However, the Minimum Important Difference (MID) is in general agreed with by organizations (86% of 28 p < 0.05). Limited literature exists to support the debatable issues of the PRO guidance. On the whole, existing instruments (e.g. EORTC QLQ-LC13, MDASI) appear to meet FDA and EMEA requirements sufficiently. Conclusions: The regulatory PRO guidance were appreciated by the research community. However, differences on philosophical and design topics are evident. While this guidance is already impacting on trial design, we hope our evaluation will encourage dialogue between all parties, bringing harmony to such positions. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration AstraZeneca

Back to table of contents Previous article Next article Professional NewsFull AccessDrug's Availability Doesn't Mean FDA Has Approved ItJun YanJun YanSearch for more papers by this authorPublished Online:16 Nov 2007https://doi.org/10.1176/pn.42.22.0005There may be thousands of drug products being prescribed and dispensed to patients in the United States that have never been reviewed by the Food and Drug Administration (FDA) for safety and efficacy or approved for marketing. The agency is now taking steps to address the potentially large problem.In June 2006, the FDA released a guidance document, “Marketed Unapproved Drugs—Compliance Policy Guide,” to clarify the rules regarding drugs on the market that have not been reviewed or approved by the agency's normal process and the agency's plan to enforce them.Many of these unapproved drugs are advertised and listed in reference books such as the Physicians' Desk Reference, prescribed by physicians, and dispensed or sold to patients, according to the FDA guidance document. Physicians and pharmacists are usually not aware of the unapproved status of these drugs, which can be distributed based on a 10-digit number known as the National Drug Code (NDC). The NDC number is issued to all types of drug products, including unapproved investigational drugs, and does not guarantee a drug's approval status. These products' labeling information does not distinguish their approval status, nor is the labeling necessarily reviewed by the FDA for safety claims and indications.The FDA says on its Web site that most of these products remain on the market illegally for “a variety of historic reasons.” Most became available before the Federal Food, Drug, and Cosmetic Act was revised in the 1960s to require that a new drug be evaluated by the FDA for efficacy as well as safety. Before these regulations, new drugs only needed to be shown as safe, and drugs deemed the same or similar to approved drugs needed no independent review and approval process by the agency. The labels of these products may not conform to current regulatory standards and may carry unapproved claims and indications. Although the FDA had contracted with the National Academy of Sciences/National Research Council to evaluate the effectiveness of thousands of products approved only for safety between 1938 and 1962, not all products have gone through the approval process.Even the drug products deemed illegal have not all been forced off the market. Other provisions in the regulations have allowed older drugs without labeling updates to slip through the cracks.It is unknown how many currently marketed drugs are unapproved, and the agency does not maintain a complete list of these products. The guidance estimated that “several thousand drug products are marketed illegally without required FDA approval” today and admits that the agency is“ unable to take action immediately against all. . .illegally marketed products” because of a lack of resources.Since the release of the guidance last year, the FDA has been systematically issuing sanctions against certain unapproved products by demanding their withdrawal from the market or convincing some manufacturers to go through the official process by filing a New Drug Application for the agency's review in order to legalize their products and update the product labeling. A short list of drugs and manufacturers against which enforcement actions have already been taken is posted on the FDA's Web site.The guidance document claims that the enforcement priorities are given to drugs that have potential safety risks, lack evidence of effectiveness, are fraudulently promoted and sold, “present direct challenges to the new drug approval and [over-the-counter] drug monograph systems,” or are reformulated to evade FDA enforcement action. Priority is also given to unapproved new drugs that violate the regulations in other ways.In 2006, unapproved products containing quinine and carbinoxamine with unapproved labeling were targets. This September, the agency announced that it will take “enforcement action” against manufacturers of unapproved hydrocodone-containing cough syrups, citing reports of medication errors due to formulation changes in the unapproved products and confusion over their brand names. The agency is also concerned that “no hydrocodone cough suppressant has been established as safe and effective in children under 6 years of age, and some of these unapproved products carry labels with dosing instructions for children as young as 2 years old,” warned Steven Galson, M.D., M.P.H., director of the FDA's Center for Drug Evaluation and Research in a press release.The FDA Web page lists selected drugs and companies that have been cited for enforcement actions, but includes no psychiatric drugs. However, the FDA has not released a complete list of all unapproved drug products on the market. Psychiatrists may be treating patients who are taking, for example, unapproved hydrocodone, levothyroxine, and quinine products (for restless legs syndrome).Additional information about unapproved drugs and FDA actions is posted at<www.fda.gov/cder/drug/unapproved_drugs/default.htm>.“ Guidance for FDA Staff and Industry: Marketed Unapproved Drugs—Compliance Policy Guide” is posted at<www.fda.gov/cder/guidance/6911fnl.pdf>.▪ ISSUES NewArchived

More transparency for clinical trial data: The decision by the European Medicines Agency to make clinical trial reports publicly available could provide a boon for biomedical research.

NCATS advisory council recommends strategies to strengthen CTSA program.

FDA Vows to Improve Drug-Safety Assessments

Standardizing Safety Assessment and Reporting for Neonatal Clinical Trials

In 1998, the Food and Drug Administration (FDA) Center for Drug Evaluation and Research (CDER) developed regulations requiring the assessment of pharmaceuticals for use in pediatric populations (U.S. Food and Drug Administration [FDA], 1998). In 2003, the Pediatric Research Equity Act (PREA) was enacted to amend the Federal Food, Drug, and Cosmetic Act to authorize the FDA to require certain research into drugs used in pediatric patients (Pediatric Research Equity Act of 2003). PREA was reauthorized under FDAAA (Food and Drug Administration Amendments Act, 2007) when the Pediatric Review Committee (PeRC) was established and made permanent under FDASIA (Food and Drug Administration Safety and Innovation Act, 2012). The result is that, in the United States, pharmaceutical development for pediatric use requires a pediatric study plan (PSP) to be submitted to the agency and for pediatric clinical trials to be conducted before submission of a New Drug Application (NDA). A similar process exists in Europe following issuance of the Paediatric Regulation (Pediatric Regulation, Regulation (EC) No 1901/2006) requiring that a Paediatric Investigation Plan (PIP) be submitted to the European Medicines Agency (EMA) before the conduct of pediatric clinical trials and before submission of a Marketing Authorization Application (MAA). Regulatory guidance regarding the need and conduct of nonclinical studies in juvenile animals is currently provided by the FDA Guidance for Industry, Nonclinical Safety Evaluation of Pediatric Drug Products (CDER, 2006), the EMEA Guideline On The Need For Non-Clinical Testing In Juvenile Animals On Human Pharmaceuticals For Pediatric Indications (EMEA/CHMP/SWP/169215/2005), and the Japanese Guideline on the Nonclinical Safety Study in Juvenile animals for Pediatric Drugs (Japan, 2012). Work is currently ongoing to harmonize these guidelines under the auspices of the International Conference on Harmonization (ICH S11). Any need for nonclinical testing in juvenile animals should be made based on the intended pediatric clinical plan and the weight-of-evidence of all available data, including animal data and human safety data. Critical to the design of juvenile animal studies is the selection of species and age relative to the age of the human pediatric population and the target organs of concern. A strong understanding of comparative organ system development between humans and laboratory animals is essential. Current nonclinical regulatory guidance focuses on “late developing organ systems” such as the central nervous system, skeletal growth, immune, reproductive, pulmonary, renal, gastrointestinal, and hepatobiliary systems. However, with the emergence of rare disease targets that impact children from birth (including those considered “premature”) there has been an increased focus in recent years on pediatric-only indications and treatment of children under the age of 2 years where all organ systems are undergoing structural and/or functional development and where juvenile animal studies may provide the primary nonclinical support. The following series of papers on development of the lung and kidney, gastrointestinal, and reproductive systems provide updates to the corresponding International Life Sciences Institute–Health and Environmental Sciences Institute publications in 2003 (Beckman and Feuston, 2003; Hew and Keller, 2003; Marty, Chapin, Parks, & Thorsrud 2003; Zoetis & Hurtt, 2003a, 2003b) and 2005 (Walthall, Cappon, Hurtt, & Zoetis, 2005). In addition, two new reviews are included addressing development of the ear and eye. Each review provides a tabulated summary of development comparing human with common laboratory animals. Jim Ridings GlaxoSmithKline, Ware, United Kingdom

Back to table of contents Previous article Next article Professional NewsFull AccessFDA Wants M.D.s to Enlist in War Against Illegal AdsJun YanJun YanSearch for more papers by this authorPublished Online:18 Jun 2010https://doi.org/10.1176/pn.45.12.psychnews_45_12_002AbstractThe Food and Drug Administration (FDA) has launched a campaign to recruit physicians and health care professionals to report potentially illegal advertisements and promotions by drug companies.This outreach effort, termed the “Bad Ad” program, is being implemented by the FDA's Division of Drug Marketing, Advertising, and Communications (DDMAC).A Web site at <www.fda.gov/badad> has been set up to educate health care professionals about the types of drug advertisements and promotions that violate the law. Among the examples are overstating efficacy, omitting or downplaying safety risks, and promoting off-label indications.Drug companies are prohibited from discussing or promoting unapproved indications of their products, but it is not illegal for them to distribute articles published in peer-reviewed medical journals that investigate or review unapproved uses of a medication.The FDA is encouraging physicians and other professionals to report suspected violations they encounter at medical conferences, in professional and lay media, in materials they receive, at company-sponsored presentations, and during sales-representatives' visits. Complaints can be submitted, with supporting materials or other evidence, to the agency by e-mail at [email protected]gov, telephone at (877) RX-DDMAC, or mail. The reports can be submitted anonymously, but the agency recommends that those filing a complaint provide their name and contact information for follow-up and collection of additional materials.“This is a reasonable effort on the part of the FDA,” said David Fassler, M.D., APA treasurer and a child and adolescent psychiatrist in Vermont. He is also a clinical professor of psychiatry at the University of Vermont. “At a minimum, it may help educate physicians about the regulations governing ads and promotions.”He suggested, however, that the initiative indicates the FDA's lack of resources when it comes to reviewing drug-marketing activities. “Improving compliance will ultimately require a substantial increase in the resources available for monitoring and enforcement,” he said.The DDMAC, housed in the FDA's Center for Drug Evaluation and Research, is in charge of monitoring and regulating the advertisements and promotional activities for prescription drugs. Medical devices and over-the-counter drugs are not regulated by this division.Although spontaneous reports from health care professionals have occasionally led to investigation and regulatory actions, the DDMAC has traditionally focused its reviews on advertising materials voluntarily submitted by drug companies, complaints filed by competitor drug companies, and surveillance of medical conferences. In a public letter posted on the Bad Ad program Web site, FDA Commissioner Margaret Hamburg, M.D., wrote that the “FDA's ability to monitor other promotional activities, which may occur in any number of settings, is limited.”In 2009, the DDMAC issued 38 enforcement letters to pharmaceutical companies, up from 22 letters in 2008.According to Hamburg's letter, the DDMAC will have exhibits at major medical conferences to educate physicians and others about drug-marketing regulations and to promote the Bad Ad program. She urged practitioners to assist the FDA in identifying and stopping misleading drug promotion. ISSUES NewArchived