Reproductive toxicity testing of pharmaceutical compounds to support the inclusion of women in clinical trials

1997 ◽  
Vol 16 (5) ◽  
pp. 239-246 ◽  
Author(s):  
Chris Parkinson ◽  
Kate E Thomas ◽  
Cyndy E Lumley
Keyword(s):  
Clinical Trials ◽  
Drug Development ◽  
Animal Studies ◽  
Clinical Investigation ◽  
Reproductive Toxicity ◽  
Toxicity Testing ◽  
Toxicity Tests ◽  
Toxicity Studies ◽  
Important Concern ◽  
The Usa

1 The potential for toxicity to reproduction and the developing fetus is an important concern requiring attention during the development of new medicines. However, there are differences in the opinions of the regulatory authorities in Europe, Japan and the USA regarding the nature and amount of data from reproductive toxicity tests that should be available at the various stages of clinical development. 2 Forty-one companies or their subsidiaries from Eur ope, Japan and the USA provided data for a ques tionnaire-based study, carried out in 1994, to ascertain the practices of pharmaceutical companies and their views on an ideal approach to the timing of reproduc tion and development toxicity studies in relation to clinical investigation. 3 Differences were identified in the stage of drug development at which animal studies were completed, the sequence of completion of specific studies, and the extent of reproduction testing completed to support the inclusion of women in clinical trials. 4 A harmonised, but flexible, guideline, encompassing the timing of reproductive toxicity studies in relation to clinical trials, would permit better integration between clinical and non-clinical studies in an international drug development programme.

scholarly journals Characteristics of registered clinical trials assessing treatments for COVID-19: a cross-sectional analysis

BMJ Open ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. e039978 ◽  
Author(s):  
Hemalkumar B Mehta ◽  
Stephan Ehrhardt ◽  
Thomas J Moore ◽  
Jodi B Segal ◽  
G Caleb Alexander
Keyword(s):  
Clinical Trials ◽  
Clinical Investigation ◽  
Scientific Progress ◽  
Cross Sectional ◽  
Design Elements ◽  
Cross Sectional Analysis ◽  
Therapeutic Benefits ◽  
Wide Range ◽  
The Usa ◽  
Sectional Analysis

ObjectivesThe coronavirus disease 2019 (COVID-19) pandemic has prompted many initiatives to identify safe and efficacious treatments, yet little is known regarding where early efforts have focused. We aimed to characterise registered clinical trials assessing drugs or plasma treatments for COVID-19.Design, setting and participantsCross-sectional analysis of clinical trials for the treatment of COVID-19 that were registered in the USA or in countries contributing to the WHO’s International Clinical Trials Registry Platform. Relevant trial entries of drugs or plasma were downloaded on 26 March 2020, deduplicated, verified with reviews of major medical journals and WHO websites and independently analysed by two reviewers.Main outcome(s)Trial intervention, sponsorship, critical design elements and specified outcomesResultsOverall, 201 clinical trials were registered for testing the therapeutic benefits of 92 drugs or plasma, including 64 in monotherapy and 28 different combinations. Only eight (8.7%) products or combinations involved new molecular entities. The other test therapies had a wide range of prior medical uses, including as antivirals, antimalarials, immunosuppressants and oncology treatments. In 152 trials (75.7%), patients were randomised to treatment or comparator, including 55 trials with some form of blinding and 97 open-label studies. The 49 (24.4%) of trials without a randomised design included 29 single armed studies and 20 trials with some comparison group. Most trial designs featured multiple endpoints. Clinical endpoints were identified in 134 (66.7%) of trials and included COVID-19 symptoms, death, recovery, required intensive care and hospital discharge. Clinical scales were being used in 33 (16.4%) trials, most often measures of oxygenation and critical illness. Surrogate endpoints or biomarkers were studied in 88 (42.3%) of trials, primarily assays of viral load. Although the trials were initiated in more than 17 countries or regions, 100 (49.8%) were registered in China and 78 (37.8%) in the USA. Registered trials increased rapidly, with the number of registered trials doubling from 1 March to 26 March 2020.ConclusionsWhile accelerating morbidity and mortality from the COVID-19 pandemic has been paralleled by early and rapid clinical investigation, many trials lack features to optimise their scientific value. Global coordination and increased funding of high-quality research may help to maximise scientific progress in rapidly discovering safe and effective treatments.

Reproductive Toxicity Tests: Retrospect and Prospect

1988 ◽  
Vol 7 (5) ◽  
pp. 423-427 ◽  
Author(s):  
F.M. Sullivan
Keyword(s):  
Breast Milk ◽  
Sodium Valproate ◽  
Reproductive Toxicity ◽  
New Drugs ◽  
Toxicity Tests ◽  
Pharmacokinetic Studies ◽  
Transplacental Carcinogenesis ◽  
Recent Developments ◽  
The Usa ◽  
Japanese Guidelines

1 The design of the classical three segment reproductive test for new drugs is described and the relative merits of the USA/EEC and the Japanese guidelines are discussed. 2 The importance of pharmacokinetic studies in the interpretation of teratology studies and extrapolation to humans is mentioned in relation to caffeine, sodium valproate and cyclophosphamide. 3 Changing ideas on the design of multi-generation studies are reviewed. 4 Recent developments in the fields of behavioural teratology, chemicals in breast milk and transplacental carcinogenesis are described.

DESIGN OF EARLY CLINICAL TRIALS FOR NEW CONTRACEPTIVE METHODS

1974 ◽  
Vol 77 (1_Suppla) ◽  
pp. S266-S278
Author(s):  
Daniel R. Mishell ◽  
Harold A. Nash
Keyword(s):  
Clinical Trials ◽  
Large Scale ◽  
Clinical Investigation ◽  
Toxicity Testing ◽  
Field Trials ◽  
New Drugs ◽  
Animal Testing ◽  
Good Continuation ◽  
Large Scale Field ◽  
Pharmaceutical Agents

ABSTRACT A plan is outlined to shorten the current suggested duration of animal testing prior to clinical investigation with certain types of pharmaceutical agents. For many new drugs, especially steroids, after a pharmacologic profile is established, long term toxicity testing can usually be shortened prior to initiation of 6 months clinical trials involving about 1000 women. Clinical trials of this magnitude usually correlate very well with ultimate performance of contraceptive drugs, provided proper selection of subjects is performed with resultant good continuation rates. It is thus possible with certain new antifertility candidates to safely shorten the duration of both toxicological and clinical studies before initiating large scale field trials.

Statistical methods for in silico tools used for risk assessment and toxicology

2022 ◽  
Vol 0 (0) ◽  
Author(s):  
Nermin A. Osman
Keyword(s):  
Risk Assessment ◽  
In Silico ◽  
Animal Studies ◽  
Toxicity Testing ◽  
Toxicity Assessment ◽  
Chemical Toxicity ◽  
Industrial Chemicals ◽  
Structure Activity Relationships ◽  
Structure Activity ◽  
The Usa

Abstract In silico toxicology is one type of toxicity assessment that uses computational methods to visualize, analyze, simulate, and predict the toxicity of chemicals. It is also one of the main steps in drug design. Animal models have been used for a long time for toxicity testing. Animal studies for the type of toxicological information needed are both expensive and time-consuming, and to that, ethical consideration is added. Many different types of in silico methods have been developed to characterize the toxicity of chemical materials and predict their catastrophic consequences to humans and the environment. In light of European legislation such as Registration, Evaluation, Authorization, and Restriction of Chemicals (REACH) and the Cosmetics Regulation, in silico methods for predicting chemical toxicity have become increasingly important and used extensively worldwide e.g., in the USA, Canada, Japan, and Australia. A popular problem, concerning these methods, is the deficiency of the necessary data for assessing the hazards. REACH has called for increased use of in silico tools for non-testing data as structure-activity relationships, quantitative structure-activity relationships, and read-across. The main objective of the review is to refine the use of in silico tools in a risk assessment context of industrial chemicals.

ACE-2-Receptors of the Epidermis, Dermal Vascular Walls and Sebaceous Gland Cells: The Way of COVID-19 Entry into the Body?

2020 ◽  
Author(s):  
Stefan Bittmann
Keyword(s):  
Clinical Trials ◽  
Viral Infection ◽  
Sebaceous Gland ◽  
The Body ◽  
Viral Agent ◽  
Therapy Options ◽  
Vascular Walls ◽  
Fish Market ◽  
The World ◽  
The Usa

Since the outbreak near a fish market in Wuhan, China, in December 2019, researchers have been searching for an effective therapy to control the spreading of the new coronavirus SARS-CoV-2 and inhibit COVID-19 infection. Many countries like Italy, Spain, and the USA were ambushed by this viral agent. To date, more than 2.5 million people were infected with SARS-CoV-2. There is no clear answer, why SARS-CoV-2 infects so many people so fast. To date of April 2020, no effective drug has been found to treat this new severe viral infection. There are many therapy options under review and clinical trials were initiated to get clearer information, what kind of drug can help in this devastating and serious situation. The world has no time.

Acute Toxicity Testing with Juvenile White Sturgeon (Acipenser transmontanus)

1998 ◽  
Vol 33 (1) ◽  
pp. 95-110 ◽  
Author(s):  
W.R. Bennett ◽  
A.P. Farrell
Keyword(s):  
Acute Toxicity ◽  
Swimming Performance ◽  
Juvenile Fish ◽  
Toxicity Testing ◽  
White Sturgeon ◽  
Acipenser Transmontanus ◽  
Toxicity Tests ◽  
Fraser River ◽  
Acute Toxicity Tests ◽  
Acute Toxicity Testing

Abstract The primary goal of this study was to investigate the possibility of using early life stages of white sturgeon (Acipenser transmontanus) (eggs, larvae and fry) as a species relevant to the Fraser River, B.C., for the acute and sublethal toxico-logical testing of forest industry effluents. Here we report the first successful acute toxicity tests for 8-day-old larvae and 42-day-old fry exposed to several chemicals known to be released into the Fraser River (i.e., 6 monochlorovanillin [6 MVAN], 4,5 dichloroguaiacol [4,5 DCG], 4,5 dichlorocatechol [4,5 DCAT], pentachlorophenol [PCP], and didecyldimethylammonium chloride [DDAC]). In most cases, white sturgeon fry were at the lower end of the range for acute toxicity values for chlorinated phenolic compounds, when compared with other juvenile fish species, and they were extremely sensitive to DDAC. The larval stage was usually more sensitive than the fry stage. Acute toxicity tests with fertilized eggs were unsuccessful. A postexposure growth study was inconclusive because neither control nor toxicant-exposed larvae and fry withstood the additional handling used for measuring body mass. At 62-days-old, fry were more tolerant of handling. This allowed measurement of their swimming performance. Although we have concerns about the reliability of using larvae for acute toxicity testing at this time, 60-day-old white sturgeon fry would appear to be both a sensitive and relevant species for assessing environmental impacts relevant to the Fraser River.

Clinical Drug Development for the Treatment of Pulmonary Arterial Hypertension: Collaboration With the Pharmaceutical Industry and Regulatory Agencies

2010 ◽  
Vol 9 (4) ◽  
pp. 214-219
Author(s):  
Robyn J. Barst
Keyword(s):  
Clinical Trials ◽  
Pulmonary Arterial Hypertension ◽  
Drug Development ◽  
Phase 1 ◽  
Preclinical Studies ◽  
Phase 2 ◽  
Phase 3 ◽  
Preclinical Testing ◽  
New Drug ◽  
Pulmonary Arterial

Drug development is the entire process of introducing a new drug to the market. It involves drug discovery, screening, preclinical testing, an Investigational New Drug (IND) application in the US or a Clinical Trial Application (CTA) in the EU, phase 1–3 clinical trials, a New Drug Application (NDA), Food and Drug Administration (FDA) review and approval, and postapproval studies required for continuing safety evaluation. Preclinical testing assesses safety and biologic activity, phase 1 determines safety and dosage, phase 2 evaluates efficacy and side effects, and phase 3 confirms efficacy and monitors adverse effects in a larger number of patients. Postapproval studies provide additional postmarketing data. On average, it takes 15 years from preclinical studies to regulatory approval by the FDA: about 3.5–6.5 years for preclinical, 1–1.5 years for phase 1, 2 years for phase 2, 3–3.5 years for phase 3, and 1.5–2.5 years for filing the NDA and completing the FDA review process. Of approximately 5000 compounds evaluated in preclinical studies, about 5 compounds enter clinical trials, and 1 compound is approved (Tufts Center for the Study of Drug Development, 2011). Most drug development programs include approximately 35–40 phase 1 studies, 15 phase 2 studies, and 3–5 pivotal trials with more than 5000 patients enrolled. Thus, to produce safe and effective drugs in a regulated environment is a highly complex process. Against this backdrop, what is the best way to develop drugs for pulmonary arterial hypertension (PAH), an orphan disease often rapidly fatal within several years of diagnosis and in which spontaneous regression does not occur?

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