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62-483: The historical events leading to the proposal of the Good Laboratory Practice (GLP) regulations are crucial for understanding why these regulations are important for assuring the quality and integrity of nonclinical safety data. These regulations were developed in response to concerns about the reliability and consistency of safety data used in assessing the potential risks of chemicals and products to humans and

124-652: A pathologist in August 1971, and IBT finalized its safety analysis of PCBs in November 1971. Irregularities in IBT's data were discovered in April 1976 by Adrian Gross, an investigator at the Food and Drug Administration , whose aide retrieved one of the laboratory's naproxen studies that had been conducted for Syntex , a pharmaceutical company recently outed by a whistleblower . Gross examined

186-509: A "man of high scientific standards who also knew how to make a dollar", Calandra was an effective entrepreneur; his laboratory was contracted by the Department of Defense to evaluate irradiationally preserved food within its first year of operation. By 1960, IBT reported that its professional staff included twelve biologists, five chemists, a mathematician, four physicians and a veterinarian, and that it employed sixteen technicians. Calandra

248-581: A Branch of Canada's Health and Welfare Department, to, that said: "All long-term rodent studies and multigenerational reproductive studies performed by IBT are considered invalid," and noted that the Canadian government had sent letters to a number of chemical companies pointing out that many had "failed to submit the information required by the Environmental Protection Agency and the Canadian health protection branch." Documentation obtained from

310-664: A CMP and are found to operate in accordance with GLP principles are recognized as GLP compliant. In OECD-member countries, testing facilities seeking recognition as GLP compliant can apply to the national CMP. The CMP then conducts inspections to assess if the test facility adheres to the OECD Principles of GLP. In other countries, CMPs have the authority to inspect any test facility that claims to conduct studies according to GLP standards. The chemicals industry, which includes industrial chemicals, pharmaceuticals, pesticides, biocides, food and feed additives, and cosmetics, ranks as one of

372-480: A court case against Monsanto, that he had observed PCB data falsification during his employment as an assistant toxicologist at IBT. The Ecologist claimed in a 2007 article that IBT had provided expert testimony against Douglas Gowan during a court case in which Monsanto allegedly sought to discredit and silence him over the wanton disposal of PCBs and other toxic waste at Brofiscin Quarry . In April, 1980

434-472: A handful of the invalid studies have been replaced, the agency said, and most of the pesticides continue to be sprayed on fields and forests." Good Laboratory Practice regulation in the United States resulted from the episode. The Law Reform Commission of Canada noted in a 1987 report that Canadian agriculture 's increasing dependence on pesticides had led to inaction against many of those approved on

496-499: A subsequent official statement as being "entirely inadvertent." IBT was criminally implicated in 1977 for producing fraudulent studies on widely used household and industrial products, including Nemacur, Sencor , Naprosyn , and trichlorocarbanilide . The magnitude of IBT's scientific misconduct was considered to have been extensive: 618 of 867 (71%) of studies audited by the FDA were invalidated for having "numerous discrepancies between

558-530: A testing animal whose body had "too badly decomposed." Revelations of suspected scientific misconduct would go on to be presented in March 1977 at Senate Subcommittee on Health and Scientific Research hearings held by U.S. Senator Ted Kennedy (D-MA), in which the integrity of safety data produced by IBT, as well as G. D. Searle & Company and Biometric Testing, Inc., was publicly called into question by FDA officials. Calandra vacated his role as president of

620-582: A variety of Canadian and American sources by the Regina Leader-Post included sloppy or inadequate record keeping that invalidated test results. In a number of cases, sick test animals were replaced with healthy ones, resulting in invalid test results. In October 1983, three former officials of the company were convicted by a US federal jury of fabricating key product safety tests used to gain government approval for marketing two popular pesticides and two commonly used drugs. They were convicted after one of

682-513: A wide variety of companies such as 3M , American Cyanamid , American Seed, Avitrol Corp, BFC, Black Leaf Chemical, Buckman , Casoron , Chemagro, Chevron , Ciba‑Geigy , Conrel, Diamond Shamrock , Dow Corning , DuPont , FMC , Glyco, Gulf , MGK, Mobay , Mobil , Monsanto , Montedison , Nissan , Noram, Olin , Penwalt, Procter & Gamble , PPG, Sandoz , Shell , Thompson-Hayward, Uniroyal , Upjohn , US Borax , Velsicol Chemical Company , Vertac Chemical Corporation, and Zoecon, as well as

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744-459: Is a more comprehensive framework applicable to a wider range of nonclinical studies conducted for regulatory purposes across different EPA programs. The OECD Principles of Good Laboratory Practice (GLP) cover the testing of chemicals or chemical products in non-clinical settings, either in laboratory conditions or environmental settings, such as greenhouses and field experiments. These principles exclude studies involving human subjects. Depending on

806-513: Is instrumental in achieving this harmonization. The MAD system aims to avoid conflicting or redundant national regulations, foster cooperation among national authorities, and eliminate trade barriers. Under this system, OECD countries and full adherents agree that safety tests conducted according to OECD Test Guidelines and Good Laboratory Practice in one country should be accepted by others for assessment purposes—a principle known as "tested once, accepted for assessment everywhere." This approach saves

868-454: Is recognized by other OECD member countries, such as Australia, Canada, Korea, and the USA. This recognition also extends to some non-OECD countries that fully adhere to the mutual acceptance of data (MAD) under OECD Council Decision C(97)114/Final, including Brazil, India, Malaysia, Singapore, and South Africa, as well as Argentina for industrial chemicals, pesticides, and biocides only. In June 2004,

930-620: Is specific to the registration and use of pesticides in the United States. 40 CFR Part 792 , Good Laboratory Practice Standards , covers the broader application of GLP standards for nonclinical laboratory studies conducted for assessing the safety or efficacy of chemical substances, including pesticides, under various regulatory programs overseen by the EPA . This regulation applies to nonclinical laboratory studies conducted for various purposes beyond pesticides, encompassing studies related to chemicals, drugs, food additives, and other substances regulated by

992-470: The Federal Register on August 24, 2016 , which aimed to require a comprehensive quality system approach known as a GLP Quality System to enhance the current quality system approach for nonclinical laboratory studies. This system would be mandatory for safety and toxicity studies that support or are intended to support applications or submissions for products regulated by the FDA. Proposed modifications to

1054-512: The Final Rule in June 1979 which became effective on June 20, 1979. Proposed amendments were introduced on October 29, 1984. The GLP amendment Final Rule was published on September 4, 1987 and became effective on October 5, 1987. The Environmental Protection Agency (EPA) had also encountered similar problems in data submitted to it, and issued its own draft GLP regulations in 1979 and 1980, publishing

1116-733: The United States Army , the Department of Defense, the Environmental Protection Agency, the Food and Drug Administration, the National Cancer Institute , and the World Health Organization . Eric Francis and Marie-Monique Robin have cited IBT's research into the safety of polychlorinated biphenyl , which was not investigated, as also being potentially fraudulent. Philip Smith later testified on October 28, 1991, during

1178-411: The regulation of pesticides in the United States and Canada . IBT was founded in 1953 by Joseph C. Calandra, an Italian American professor of pathology and biochemistry at Northwestern University . Calandra, the first of his family to pursue higher education , contributed to the concept of toxicologically innocuous doses during his tenure at Northwestern. Described by his colleagues as

1240-475: The 1950s, 1960s, and 1970s, IBT operated the largest facility of its kind and performed more than one-third of all toxicology testing in the United States . IBT was later confirmed of engaging in extensive scientific misconduct and fraud, which resulted in the indictment of its president and several top executives in 1981 and convictions in 1983. The revelations of misconduct by IBT Labs led to reforms in

1302-605: The 1981 grand jury indictment of several key IBT officials, a federal trial began on April 4, 1983, to evaluate whether IBT had committed scientific fraud. According to a May 13 article in The Wall Street Journal , "investigators charged that three big chemical companies—[ Monsanto , Olin Corporation , and FMC Corporation ]—knowingly submitted flawed data to the EPA in support of a widely used swimming pool chlorinator that

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1364-592: The Dockets Management Branch (HFA-305) and shared with the Agency's Bioresearch Monitoring (BIMO) program managers and district offices to ensure consistency. Consequently, the US FDA published the 1981 Questions & Answers - Good Laboratory Practice Regulations document to consolidate and clarify these responses. This Q&A document categorizes responses by specific GLP provisions to make them more useful for both

1426-433: The EPA, reflecting a broader framework for ensuring the quality and reliability of nonclinical study data used in regulatory decision-making. While both 40 CFR Part 160 and 40 CFR Part 792 address GLP standards for laboratory studies, they differ significantly in terms of scope, applicability, and the specific regulatory context in which they operate. Part 160 is tailored to pesticide registration under FIFRA, whereas Part 792

1488-459: The EPA. This part has a broader scope and is applicable to a wider range of substances and regulatory programs. It covers a more diverse range of nonclinical studies, including those related to chemical substances other than pesticides. This could include studies conducted for assessing the safety of industrial chemicals, pharmaceuticals, food additives, and other substances subject to EPA regulation. It operates across various regulatory programs within

1550-443: The FDA headquarters and field offices. The FDA has signed a memorandum of understanding (MOU) with Canada , France , Germany , Italy , Japan , The Netherlands , Sweden , and Switzerland to enhance cooperation on good laboratory practice (GLP) for nonclinical laboratory studies supporting product approvals, aiming to facilitate information exchange and inspections for regulatory oversight. Proposed amendments were published in

1612-534: The Final Rules in two separate parts ( 40 CFR 160 and 40 CFR 792 ) in 1983. The FDA requires nonclinical laboratory studies on new drugs, food additives, and chemicals to assess their safety and potential effectiveness in humans in compliance with 21 CFR Part 58, Good Laboratory Practice for Nonclinical Studies under the Federal Food Drug and Cosmetic Act and Public Health Service Act . These regulations set

1674-533: The GLP Quality System include additional responsibilities for testing facility management and SOP maintenance, along with expanded definitions applicable to all nonclinical laboratory studies, aiming to enhance roles and functions aligned with the revised testing facility definition and to establish a framework for improving data reliability in regulatory decision-making. The EPA's Good Laboratory Practice Standards (GLPS) compliance monitoring program guarantees

1736-679: The GLP compliance status of the testing facility where the study was conducted is assessed by referring to inspection information from national GLP compliance monitoring programs. OECD member countries where non-clinical health and environmental safety testing follows the OECD Principles of Good Laboratory Practice (GLP) have established national GLP Compliance Monitoring Programs (CMP) responsible for overseeing GLP compliance of test facilities within their jurisdictions. These CMPs verify GLP compliance through inspections of test facilities and audits of GLP studies. Test facilities that undergo periodic inspections by

1798-704: The Heads of Medicines Agencies released a new recommendation paper on the principles of Good Laboratory Practices (GLP) for clinical trial applications governed by the EU Clinical Trials Regulation (Regulation (EU) No 536/2014) . This paper was developed in collaboration with relevant groups from the European Medicines Agency (EMA) and the European Commission (EC) to clarify the applicable regulatory requirements and ensure transparency regarding

1860-492: The Heads of Medicines Agency issued a Q&A document in 2017 addressing Good Laboratory Practice (GLP) requirements within the context of clinical trials for human medicines . This document aims to provide clarification and guidance on GLP principles applicable to non-clinical safety studies conducted as part of clinical trial applications. In March 2024, the Clinical Trials Coordination Group (CTCG) of

1922-727: The Organisation for Economic Cooperation and Development (OECD) and adopted by the European Union (EU). European GLP Regulations and Directives also apply to European Economic Area (EEA) member states which include Iceland, Liechtenstein, and Norway. GLP principles govern the non-clinical safety testing of substances in various products, mandated by product-specific legislation in the EU/EEA . Directive 2004/9/EC mandates EU/EEA countries to designate GLP inspection authorities and includes requirements for reporting and mutual acceptance of data within

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1984-469: The Regina Leader-Post obtained and published a Canadian government list of more than 97 chemicals tested by IBT for which studies were considered "suspect". In June, 1980 an additional nine chemicals were added. According to Fagin and Lavelle in Toxic Deception , Wright tampered with safety data for Machete and monosodium cyanurate, both Monsanto products. IBT performed safety tests on Dinoseb , which

2046-413: The US FDA published a comparison chart of FDA and EPA Good Laboratory Practice (GLP) regulations alongside OECD Principles for GLP, aiding in understanding the key differences and similarities in GLP standards across these regulatory bodies. The Principles of Good Laboratory Practice (GLP) ensure the quality and accuracy of data in chemical testing and help prevent fraud. These principles are developed by

2108-541: The United States government and various chemical and pharmaceutical companies, both from the U.S. and abroad, and submitted toxicology data to several federal agencies, covering a wide range of products including drugs, insecticides, herbicides, food additives, pesticides, cosmetics, and cleaning products. These issues were made public in the hearings at the US Congress, which led to the FDA's publication of Proposed Regulations on GLP on November 19, 1976, and establishment of

2170-540: The accuracy and reliability of test data submitted to the Agency to support pesticide product registration under the Federal Insecticide, Fungicide and Rodenticide Act (FIFRA), section 5 of the Toxic Substances Control Act (TSCA), and in accordance with testing consent agreements and rules issued under section 4 of TSCA. The Agency utilizes data obtained from laboratory inspections and audits to oversee

2232-526: The basis of IBT's research data. Agriculture Canada banned use of Reglone until further safety testing could be conducted and evaluated by Health and Welfare Canada , though application of the chemical continued illegally on a significant majority of lentils produced. Chlorbromuron, cyprazine, dinitramine, and phosphamidon were also banned "because their manufacturers did not promise replacement studies," with Allidochlor and Captan being restricted. According to various reports, IBT's clientele included

2294-631: The chemical and pharmaceutical sectors, leading to more stringent product testing requirements and the development of inspection programs targeting laboratories conducting animal research. These initiatives, initiated by the Office of New Drugs and the Office of Marketed Drugs in 1969 and later expanded with the Office of Compliance, included inspections of facilities with questionable study validity or misconduct tips, revealing significant quality control issues and deficiencies in animal toxicological testing standards and data reporting. Industrial BioTest Labs (IBT)

2356-416: The chemicals industry from the expense of duplicative testing for products marketed in multiple countries. Although the receiving government must accept the study, it retains the discretion to interpret the study results according to its own criteria. According to OECD Council Decision C(97)186/Final , chemical testing data generated in any OECD member country following OECD Test Guidelines and GLP principles

2418-544: The company's new financial prowess, Calandra oversaw considerable expansion of the company and constructed two new facilities. IBT began conducting tests on polychlorinated biphenyls (PCBs) in 1969. In 1970, Calandra began construction of a large $ 2 million laboratory and made two executive appointments: Moreno Keplinger as Manager of Toxicology and James Plank as Group Lead of Rat Toxicology. In March 1971, IBT hired Paul L. Wright, one of Monsanto 's toxicologists , to oversee its PCB testing. Donovan E. Gordon joined IBT as

2480-478: The development of FDA-regulated products. GLP compliance inspections are assessed and performed under the Agency's Bioresearch Monitoring (BIMO) program and carried out by trained BIMO inspectors. Serious noncompliance is dealt with by procedures ranging from study rejection to laboratory disqualification. Since June 20, 1979, the FDA has received many questions about Good Laboratory Practice (GLP) regulations (21 CFR 58). The responses to these inquiries are stored in

2542-426: The environment. The EU has established Mutual Recognition Agreements for GLP with Israel, Japan, and Switzerland. Industrial Bio-Test Laboratories Industrial Bio-Test Laboratories ( IBT Labs ) was an American industrial product safety testing laboratory. IBT conducted significant quantities of research for pharmaceutical companies, chemical manufacturers and other industrial clients; at its height during

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2604-566: The environment. The GLP regulations aim to standardize procedures and practices in nonclinical studies to ensure accurate, reliable, and traceable data. This background helps highlight the significance of adhering to GLP standards in research and regulatory contexts. GLP was first introduced in New Zealand and Denmark in 1972. During the 1960s and 1970s in the United States, a growing concern for environmental issues and health impacts of chemicals prompted increased federal regulation, particularly in

2666-495: The integrity of hundreds of studies produced by IBT and other large independent laboratories." Keith Schneider reported in the Winter 1983 edition of Amicus Journal that "IBT performed over 2,000 key product safety tests approved by federal scientists to market 212 agricultural pesticides. After a seven-year review of its files, in 1983 the EPA reported that it had determined that only 16 percent of IBT's testing results were valid. Just

2728-978: The internal market. Annex I of the Directive incorporates OECD Revised Guides for Compliance Monitoring Procedures for GLP, along with OECD Guidance for the Conduct of Test Facility Inspections and Study Audits. It ensures compliance with these guidelines during laboratory inspections and study audits. This directive replaced Directive 88/320/EEC as of 11 March 2004. Directive 2004/10/EC , the second core EU GLP Directive, harmonizes laws and administrative provisions for applying GLP principles and verifying their implementation in chemical substance tests. It includes GLP principles in Annex I and requires EU/EEA countries to ensure that laboratories conducting safety studies on chemical products comply with OECD GLP principles. It replaces Directive 87/18/EEC. The Clinical Trials Facilitation Group (CTFG) of

2790-436: The laboratory on March 25 and was succeeded by A. J. Frisque, who had previously worked as a research executive at Nalco. Plank parted ways with IBT in April, and Philip Smith, who would later testify against the laboratory, was "fired and given 20 minutes to clean out his office" in approximately June 1977. That same month, on June 2, IBT would also shred more of its internal documents, an action which Frisque characterized in

2852-570: The laboratory. "As I got into it and worked on these things more, and found out more, and worked with IBT people more, and looked at the evidence of other practices in the industry, I decided I couldn't defend IBT's practices," Thompson testified. Testimony drew to a close on September 22. Closing arguments concluded on October 4 and juror deliberation ensued. The case was decided by John Albert Nordberg on October 21, 1983. The United States Environmental Protection Agency (EPA) announced on July 11, 1983, that 34 pesticides would be pulled from

2914-463: The largest industrial sectors in the world. Harmonizing national approaches to chemical regulation offers several benefits: it streamlines requirements for industry, provides governments with a common framework for collaboration, and reduces trade barriers. The OECD Mutual Acceptance of Data (MAD) system, comprising a series of OECD Council Decisions along with OECD Guidelines for Testing Chemicals and OECD Principles of Good Laboratory Practice (GLP) ,

2976-613: The level of information required about GLP status in Clinical Trial Applications. This will assist researchers and sponsors in understanding what is expected and how to include the necessary information to support their applications. GLP supports the sharing of test data between countries, which helps avoid repeated testing, benefits animal welfare, and saves money for businesses and governments. Having common GLP standards also makes it easier to share information and prevents trade barriers, while helping to protect human health and

3038-563: The location or governing rules in an OECD-member country, the OECD Principles of GLP might also extend to non-clinical safety testing of other regulated items, like medical devices. Examples studies conducted under GLP in OECD-member countries include: Safety testing data must be submitted to regulatory authorities for product marketing authorization. During the review process, the submitted data undergoes verification to ensure compliance with Good Laboratory Practice (GLP) standards. Additionally,

3100-445: The longest criminal trials in US history, involving six months of testimony and nearly eleven days of jury deliberation. At the time it was regarded as "the most massive scientific scandal in the history of this country and perhaps the world." The decision was subsequently appealed and upheld in United States of America v. Moreno L. Keplinger, Paul L. Wright, and James B. Plank . Following

3162-420: The market unless manufacturers provided additional safety data within 90 days, although an indefinite exception was made for those who committed to do so at a later time. Environmental organizations characterized the EPA's response as insufficient and negligent, expressing a desire for more decisive action. In September 1983, the agency revealed that it was still a "long way from solving problems associated with

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3224-442: The registration or re-registration of pesticide products under FIFRA. It includes studies related to human health and environmental effects of pesticides. It focuses specifically on studies related to pesticide products, including toxicity studies, residue chemistry studies, environmental fate studies, and other types of studies required for pesticide registration. It operates within the context of pesticide regulation under FIFRA, which

3286-418: The requirements outlined in 21 CFR Part 58, laboratories conducting nonclinical studies can ensure that the data generated are of high quality, reliable, and suitable for submission to the Agency as part of product approval processes. Compliance with GLP regulations helps to protect the safety and welfare of humans and animals involved in studies and contributes to the overall integrity of scientific research in

3348-434: The standards for conducting nonclinical laboratory studies that support or are intended to support applications for research or marketing permits for products such as food additives, drugs, medical devices, or biological products. Conducting these studies with rigorous adherence to scientific principles and quality control is crucial, as the decisions based on their outcomes directly affect human health and safety. By adhering to

3410-428: The study conduct and data." Consequently, IBT would later be described as being "at the center of one of the most far-reaching scandals in modern science, as thousands of its studies were revealed through EPA and FDA investigations to be fraudulent or grossly inadequate." Although the criminal case against IBT and its employees was proceeding, information about which chemicals were "suspect" because of IBT's misconduct

3472-416: The study further; it struck him as being unrealistic and piqued his interest. The FDA proceeded to probe IBT, and Gross personally inspected its facilities on April 11 and July 12, 1976. During Gross' physical inspection of the laboratory, he gained access to the study's raw safety data and found frequent references to an unknown acronym, "TBD/TDA," which he said perplexed him until learning that it denoted

3534-452: The use of pesticides and industrial chemicals. 40 CFR Part 160 , Good Laboratory Practice Standards pertains specifically to the Good Laboratory Practice (GLP) standards for pesticide chemicals. It establishes the requirements for conducting studies and generating data used for the registration of pesticides under the Federal Insecticide, Fungicide, and Rodenticide Act (FIFRA). This regulation applies primarily to studies conducted to support

3596-516: Was himself instructed by Wright to similarly falsify data on trichlorocarbanilide tests. Calandra requested a mistrial to have cardiac surgery and received approval on July 11. Keplinger, Plank and Wright resultingly argued that they should also receive a mistrial because his absence would undermine their case, but their request was denied on July 12. Testimony included that of an attorney retained by Nalco to defend IBT, Merrill Thompson, who refused to participate during earlier investigations of

3658-531: Was kept confidential by the Canadian and American government agencies responsible to regulating them. In early 1980 the Regina Leader-Post obtained a Canadian government agency list of 106 chemicals about which there were concerns. The Regina Leader-Post also obtained a letter written Jan. 25, 1980 by R.O. Read, who was Chief of the Division of Additives and Pesticides in the Bureau of Chemical Safety Health Protection,

3720-512: Was president and director and John H. Kay was the associate director. At that time, it listed its research areas as "industrial toxicology, food, drugs, cosmetics, pharmacology, radioisotopes, medical, dental, and veterinary products". By the early 1960s, IBT had attained a significant reputation for producing quality work at a reasonable price. As of mid-decade, it had annual revenue estimated at nearly $ 2 million US. Nalco Chemical acquired IBT in 1966 for an estimated $ 4.5 million. Utilizing

3782-435: Was suspected of causing kidney and bladder problems." All three companies denied allegations of wrongdoing and reaffirmed the safety of their products. On May 25, Cornelius Garrett testified that "[no] research animals survived the entire testing period" for either Sencor or Nemacure. Garrett also testified that Smith instructed him to falsify subject data, which he said was a "common practice". Smith testified that he

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3844-481: Was the most notable case where thousands of safety tests for chemical manufacturers were either falsely claimed to have been performed or were of such poor quality that police investigators could not determine the extent of the work completed, despite superficially delivering test results as specified in their contracts with the manufacturers. IBT, a contract laboratory based in Northbrook, Illinois, conducted research for

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