Successful drug development despite adverse preclinical findings part 2: examples

To illustrate the process of addressing adverse preclinical findings (APFs) as outlined in the first part of this review, a number of cases with unexpected APF in toxicity studies with drug candidates is discussed in this second part. The emphasis is on risk characterization, especially regarding the mode of action (MoA), and risk evaluation regarding relevance for man. While severe APFs such as retinal toxicity may turn out to be of little human relevance, minor findings particularly in early toxicity studies, such as vasculitis, may later pose a real problem. Rodents are imperfect models for endocrine APFs, non-rodents for human cardiac effects. Liver and kidney toxicities are frequent, but they can often be monitored in man and do not necessarily result in early termination of drug candidates. Novel findings such as the unusual lesions in the gastrointestinal tract and the bones presented in this review can be difficult to explain. It will be shown that well known issues such as phospholipidosis and carcinogenicity by agonists of peroxisome proliferator-activated receptors (PPAR) need to be evaluated on a case-by-case basis. The latter is of particular interest because the new PPAR α and dual α/γ agonists resulted in a change of the safety paradigm established with the older PPAR α agonists. General toxicologists and pathologists need some understanding of the principles of genotoxicity and reproductive toxicity testing. Both types of preclinical toxicities are major APF and clinical monitoring is difficult, generally leading to permanent use restrictions.     

Chloroacetanilide herbicide-induced rat enterochromaffin cell tumors: a case study within the context of the IPCS framework,for analyzing the relevance of a cancer mode of action for humans

The WHO International Programme on Chemical Safety (IPCS) framework for analyzing the relevance of a cancer mode of action (MoA) for humans (IPCS cancer-HRF) is an application to assess human relevance of tumorigenic hazards found through rodent bioassays. The chloroacetanilide herbicides, butachlor and alachlor, induced enterochromaffin-like (ECL) cell tumors in rat stomachs, at the highest doses. This study analyzed the human relevance of this tumor by applying the IPCS cancer-HRF using published data. In a postulated MoA, early key events (KEs) included decreased mucosal thickness in the fundic region, due to reduced parietal cells. The following KEs included increased pH of gastric acid and hypergastrinemia, leading to enhanced cell proliferation and hyperplasia, and resulting in the outcome of an ECL cell tumor. The data showed consistencies in dose-response and temporal concordance with the KEs and specificity in the tumor response, providing strengthened evidence of the KEs. While the early KE was not the same, similar MoAs have already been established for omeprazole and ciprofloxacin. The integrated data indicated that the postulated MoAs were biologically plausible. Alternative MoAs were excluded.. Based on sufficient evidence, an MoA was established in rats. When addressing chemically inducible MoAs of human relevance, KEs of hypergastrinemia and trophic ECL cell hyperplasia were judged to not be qualitatively and quantitatively plausible in humans. The MoA in rats is unlikely to be present in humans; however, the potential effects on parietal cells cannot be excluded. Thus, the IPCS cancer-HRF is very useful for assessing human relevance.     

Pharmacogenetics of opioid analgesics in dogs

Genetic variation causes interindividual variability in drug absorption, distribution, metabolism and excretion. These pharmacokinetic processes will influence the observed efficacy and toxicity of a drug. Polymorphisms in the genes encoding the metabolizing enzymes, transport proteins and receptors have been linked to the inconsistency in responses to opioid treatment in humans and laboratory animals. Pharmacogenetics is relatively less developed field in veterinary medicine compared to significant advances in knowledge on genetic basis of variation in drug responses and clinical applications in human medicine. This review discusses the opioid drug metabolism and possible genetic polymorphism of metabolizing enzymes in dogs. Polymorphism of genes encoding opioid drug transporter proteins and its effect on opioid response and opioid receptor gene variants are also discussed. Due to the scarcity of studies reported on opioid pharmacogenetics in dogs, relevant studies in humans and rodents have also been discussed to indicate current trends and potential targets for research in dogs.     

Clinical trials in spontaneous disease in dogs: a new paradigm for investigations of sepsis

Objective: To provide evidence that naturally occurring sepsis in dogs provides a unique opportunity to test new therapies in clinically relevant settings. Data sources: Human and veterinary literature. Human data synthesis: Sepsis is a devastating condition responsible for most intensive care unit deaths. Most clinical trials targeting inflammatory mediators of sepsis have failed to improve outcome in clinical patients despite promising results in laboratory animal models. Animal models of sepsis fail to reproduce the clinical syndrome and therefore lead to conclusions that may not be relevant to clinical care. Veterinary data synthesis: Sepsis is recognized but not well‐characterized in companion animal species. Despite some species variability, the cardiopulmonary response to sepsis in dogs is similar to humans. Additionally, inflammatory and coagulation changes that accompany canine sepsis are consistent with those documented in humans. Sepsis secondary to canine parvoviral infection offers the advantages of relative population homogeneity, predictable course, and easy early diagnosis. The disadvantages of canine parvovirus are that it affects a predominantly young and healthy population and results in low mortality with aggressive supportive care. Septic peritonitis and pneumonia have high mortality but can be challenging to diagnose, have a variable course, and affect a heterogeneous population, which can be an advantage or a disadvantage. Conclusions: Similar to trials currently being performed in canine cancer patients, veterinary clinical trials of new sepsis therapeutics may provide a unique opportunity to advance the treatment of sepsis in dogs, humans, and other species. Spontaneous sepsis from canine parvovirus, peritonitis, and pneumonia are common clinical conditions in which therapeutics can be tested.     

Veterinary Randomized Clinical Trial Reporting: A Review of the Small Animal Literature

The randomized clinical trial (RCT) is a valuable research method for the evaluation of new treatment and prevention regimens in veterinary medicine. Reporting of clinical trials in other disciplines has not been complete. Without complete information on the conduct and results of a clinical trial, readers cannot optimize their use of the information presented. This report represents an objective review of randomized clinical trials in the veterinary small animal literature from 1986 to 1990. Results indicate that RCT reports in the small animal veterinary literature are incomplete. The importance of reporting on particular aspects of RCT research is described.     

FDA fast-tracking of pet population control drugs

Theriogenologists have been studying estrus prevention and termination of pregnancy in dogs for at least 2 decades. However, drugs approved for estrus suppression are few. No dog or cat abortifacients or male dog and cat sterilants have been approved. Marketed drugs with alternate indications that have antiestrus and antihormonal activity might be good candidates for study after obtaining an INAD from FDA. With the support of the original drug sponsor or manufacturer and appropriate safety and effectiveness studies, these products may be studied for additional label claims. New (not previously approved) drugs additionally need detailed information regarding the synthesis and manufacturing controls. Drugs offering substantial benefit over existing therapeutics may be eligible for expedited review. Prior to starting any studies in this area, clinical investigators and sponsors should communicate with FDA, an INAD must be granted, and the protocol submitted for evaluation. Approvability is evaluated after establishment of safety and effectiveness in clinical field trials.     

INVITED REVIEW—NEUROIMAGING RESPONSE ASSESSMENT CRITERIA FOR BRAIN TUMORS IN VETERINARY PATIENTS

The evaluation of therapeutic response using cross‐sectional imaging techniques, particularly gadolinium‐enhanced MRI, is an integral part of the clinical management of brain tumors in veterinary patients. Spontaneous canine brain tumors are increasingly recognized and utilized as a translational model for the study of human brain tumors. However, no standardized neuroimaging response assessment criteria have been formulated for use in veterinary clinical trials. Previous studies have found that the pathophysiologic features inherent to brain tumors and the surrounding brain complicate the use of the response evaluation criteria in solid tumors (RECIST) assessment system. Objectives of this review are to describe strengths and limitations of published imaging‐based brain tumor response criteria and propose a system for use in veterinary patients. The widely used human Macdonald and response assessment in neuro‐oncology (RANO) criteria are reviewed and described as to how they can be applied to veterinary brain tumors. Discussion points will include current challenges associated with the interpretation of brain tumor therapeutic responses such as imaging pseudophenomena and treatment‐induced necrosis, and how advancements in perfusion imaging, positron emission tomography, and magnetic resonance spectroscopy have shown promise in differentiating tumor progression from therapy‐induced changes. Finally, although objective endpoints such as MR imaging and survival estimates will likely continue to comprise the foundations for outcome measures in veterinary brain tumor clinical trials, we propose that in order to provide a more relevant therapeutic response metric for veterinary patients, composite response systems should be formulated and validated that combine imaging and clinical assessment criteria.     

Canine lymphoma: a review

Canine lymphoma (cL) is a common type of neoplasia in dogs with an estimated incidence rate of 20–100 cases per 100,000 dogs and is in many respects comparable to non-Hodgkin lymphoma in humans. Although the exact cause is unknown, environmental factors and genetic susceptibility are thought to play an important role. cL is not a single disease, and a wide variation in clinical presentations and histological subtypes is recognized. Despite this potential variation, most dogs present with generalized lymphadenopathy (multicentric form) and intermediate to high-grade lymphoma, more commonly of B-cell origin. The most common paraneoplastic sign is hypercalcemia that is associated with the T-cell immunophenotype. Chemotherapy is the treatment of choice and a doxorubicin-based multidrug protocol is currently the standard of care. A complete remission is obtained for most dogs and lasts for a median period of 7–10 months, resulting in a median survival of 10–14 months. Many prognostic factors have been reported, but stage, immunophenotype, tumor grade, and response to chemotherapy appear of particular importance. Failure to respond to chemotherapy suggests drug resistance, which can be partly attributed to the expression of drug transporters of the ABC-transporter superfamily, including P-gp and BCRP. Ultimately, most lymphomas will become drug resistant and the development of treatments aimed at reversing drug resistance or alternative treatment modalities (e.g. immunotherapy and targeted therapy) are of major importance. This review aims to summarize the relevant data on cL, as well as to provide an update of the recent literature.     

Potential of plant polyphenols to combat oxidative stress and inflammatory processes in farm animals

Polyphenols are secondary plant metabolites which have been shown to exert antioxidative and antiinflamma tory effects in cell culture, rodent and human studies. Based on the fact that conditions of oxidative stress and inflammation are highly relevant in farm animals, polyphenols are considered as promising feed additives in the nutrition of farm animals. However, in contrast to many studies existing with model animals and humans, potential antioxidative and antiinflammatory effects of polyphenols have been less investigated in farm animals so far. This review aims to give an overview about potential antioxidative and antiinflammatory effects in farm animals. The first part of the review highlights the occurrence and the consequences of oxidative stress and inflammation on animal health and performance. The second part of the review deals with bioavailability and metabolism of polyphenols in farm animals. The third and main part of the review presents an overview of the findings from studies which investigated the effects of polyphenols of various plant sources in pigs, poultry and cattle, with particular consideration of effects on the antioxidant system and inflammation.     

Conduct,Oversight, and Ethical Considerations of Clinical Trials in Companion Animals with Cancer: Report of a Workshop on Best Practice Recommendations

Development of effective and safe treatments for companion animals with cancer requires the collaboration of numerous animal health professionals and the full engagement of animal owners. Establishing ‘Best Practice Recommendations’ for clinical trials in veterinary oncology represents an important step toward meeting the goal of rigorous clinical trial design and conduct that is required to establish valid evidence. Likewise, optimizing patient welfare and owner education and advocacy is crucial to meet the unique ethical obligations to both owners and animals enrolled in these clinical trials and to ensure trust in the team conducting the research. To date, ‘Best Practice Recommendations’ for clinical trial conduct have not been reported for veterinary oncology. This document summarizes the consensus of a workshop held in November, 2014 to identify relevant ethical principles and to ensure responsible conduct of clinical research in companion animals with cancer. It is intended as a working document that will be updated as advances in science and ethical considerations require. To the extent possible, existing guidelines for the conduct and oversight of clinical trials in humans have been adapted for veterinary trials to avoid duplicative effort and to facilitate integration of clinical trials such that translational research with benefits for both companion animals and humans are encouraged.     

Evidence‐Based Medicine: The Design and Interpretation of Noninferiority Clinical Trials in Veterinary Medicine

Noninferiority trials are clinical studies designed to demonstrate that an investigational drug is at least as effective as an established treatment within a predetermined margin. They are conducted, in part, because of ethical concerns of administering a placebo to veterinary patients when an established effective treatment exists. The use of noninferiority trial designs has become more common in veterinary medicine with the increasing number of established veterinary therapeutics and the desire to eliminate potential pain or distress in a placebo‐controlled study. Selecting the appropriate active control and an a priori noninferiority margin between the investigational and active control drug are unique and critical design factors for noninferiority studies. Without reliable historical knowledge of the disease response in the absence of treatment and of the response to the selected active control drug, proper design and interpretation of a noninferiority trial is not possible. Despite the appeal of conducting noninferiority trials to eliminate ethical concerns of placebo‐controlled studies, there are real limitations and possible ethical conundrums associated with noninferiority trials. The consequences of incorrect study conclusions because of poor noninferiority trial design need careful attention. Alternative trial designs to typical noninferiority studies exist, but these too have limitations and must also be carefully considered.     

A review of the Western language equine acupuncture literature

A thorough review of the existing Western language equine acupuncture literature was conducted and studies selected based on the existence of objective criteria for evaluation. When the most rigorously designed studies were evaluated, the results do not support the contention that acupuncture has clinically relevant effects. Randomized, controlled clinical trials are sorely needed to resolve issues of efficacy.     

Thromboelastography: a tool for measuring hypercoagulability, hypocoagulability, and fibrinolysis

Objective: To describe the technique of thromboelastography (TEG) and review the applications of this coagulation test in humans and small animals. Data sources: Data sources included scientific reviews and original research publications. Human data synthesis: TEG in humans has been used for documentation of hypercoagulable and hypocoagulable states and has been shown to be beneficial in patient management. Veterinary data synthesis: Clinical evaluation of TEG in veterinary medicine is limited; however, recent reports have documented evidence of hypercoagulability in dogs with parvovirus and protein‐losing nephropathy. Additionally, many of the research models may be relevant to veterinary patients. Conclusions: TEG provides information about coagulation that is not available through routine coagulation tests. The application of TEG monitoring to veterinary patients shows promise; however, prospective clinical studies are needed.     

Toxicogenomic biomarkers for liver toxicity

Toxicogenomics (TGx) is a widely used technique in the preclinical stage of drug development to investigate the molecular mechanisms of toxicity. A number of candidate TGx biomarkers have now been identified and are utilized for both assessing and predicting toxicities. Further accumulation of novel TGx biomarkers will lead to more efficient, appropriate and cost effective drug risk assessment, reinforcing the paradigm of the conventional toxicology system with a more profound understanding of the molecular mechanisms of drug-induced toxicity. In this paper, we overview some practical strategies as well as obstacles for identifying and utilizing TGx biomarkers based on microarray analysis. Since clinical hepatotoxicity is one of the major causes of drug development attrition, the liver has been the best documented target organ for TGx studies to date, and we therefore focused on information from liver TGx studies. In this review, we summarize the current resources in the literature in regard to TGx studies of the liver, from which toxicologists could extract potential TGx biomarker gene sets for better hepatotoxicity risk assessment.     

A critical review of the effectiveness of rodent pharmaceutical carcinogenesis testing in predicting for human risk

The pharmaceutical industry and regulatory agency toxicology testing paradigms in the United States currently appear successful, in part because of the continuously increasing life expectancy and the declining age-adjusted cancer rates in the United States. Although drugs likely have a minimal impact on the population statistics for cancer rates, pharmaceutical pathologists and toxicologists must focus on the individual risk for pharmaceutical carcinogenesis. As our understanding of carcinogenesis increases exponentially, and after hundreds if not thousands of rodent cancer tests, significant improvement in the precision of human pharmaceutical carcinogenesis hazard identification should now be possible and would enable a reduction in the substantial false-negative and false positive-rates reported herein. The appropriate use of acute, subchronic, chronic, and special toxicology tests to identify the major associated cancer risk factors, specifically, hormonal modulation, immunosuppression, genetic toxicity, and chronic toxicity, can be recognized through this review of pharmaceutical carcinogens. Significant opportunities exist for improving the effectiveness and efficiency of the current cancer risk assessment paradigm.     

Pharmacotherapy for Behavioral Disorders in Pet Birds

The effective use of psychoactive medications in avian patients is limited by the lack of controlled studies. Appropriate dosages, predictable therapeutic effects, pharmacokinetic data, and information about toxicity are often lacking. A variety of psychoactive agents have been used in avian patients to treat disorders such as feather chewing or picking, self-mutilation of soft tissue, and anxiety, but larger clinical trials and placebo-controlled trials are needed to determine efficacy and safety of these agents. The decision to use psychoactive medication in an avian patient and the choice of medication should be based on existing data for the particular species and an understanding of the drug’s mechanisms and indications. For any behavioral disorder, the need for pharmaceutical intervention requires the following: a thorough physical examination and baseline pretreatment laboratory testing, as indicated by physical examination findings and symptoms; an established diagnosis based on complete behavioral and medical histories; a signed owner consent statement; a behavior modification plan with appropriate environmental modifications; knowledge of the drug, side effects, indications, and mechanisms of action; and realistic expectations about treatment outcomes. Use of antipsychotic agents, serotonin reuptake inhibitors, tricyclic antidepressants, opioid antagonists, benzodiazepines, and hormonal therapies are described.     

Intra-articular administration of antibiotics in horses: Justifications,risks, reconsideration of use and outcomes

Antibiotics have been injected intra-articularly by equine veterinarians for decades, either prophylactically when other drugs are administered for osteoarthritis or therapeutically to treat septic arthritis. This route of administration has also more recently gained attention in human orthopaedic clinical practice, particularly as an alternative to systemic antibiotic administration to treat infections following prosthetic arthroplasty. While the rationale for injecting antibiotics intra-articularly has been largely focused on achieving high local drug concentrations, there has been relatively little focus on pharmacokinetic parameters of antibiotics administered by this route, or on the potential for local toxicity. The increasing incidence of antibiotic resistance in veterinary and human medicine prompts reconsideration of off-label antibiotic usage and evaluation of evidence-based dosing strategies. The purpose of this review was to summarise the current literature describing intra-articular antibiotic usage, including specific studies where pharmacokinetics, potential safety and toxicity have been evaluated. This review will advance practitioners’ understanding of the use of intra-articularly administered antibiotics, including the overall pros and cons of the approach.     

Integration and modelling of pharmacokinetic and pharmacodynamic data to optimize dosage regimens in veterinary medicine

In veterinary drug development procedures, pharmacokinetic (PK) and pharmacodynamic (PD) data have generally been established in separate, parallel studies to assist in the design of dosage schedules for subsequent evaluation in clinical trials. This review introduces the concept of PK/PD modelling, an approach in which PK and PD data are generated in the same study, and used to derive numerical values for PD parameters based on drug plasma concentrations. The PD parameters define the efficacy, potency and slope (sensitivity) of the concentration-effect relationship. It is proposed that the parameters derived from PK/PD modelling may be used as an alternative and preferred approach to dose titration studies for selecting rational dosage regimens (both dose and dosing interval) for further evaluation in clinical trials. In PK/PD modelling, the explicative variable for effect is the plasma concentration profile. The PK/PD approach provides several advantages over dose-titration studies, including determination of a projected dosage regimen by investigation of a single dose, in contrast to dose-ranging studies which by definition require testing of multiple dosage. Implementation of PK/PD modelling in the veterinary drug development process is currently constrained by the limited number of veterinary studies performed to date, and the consequently limited understanding of PK/PD concepts and their absence from regulatory authority guidelines. Nevertheless, PK/PD modelling has major potential for rational dosage regimen determination, as it considers and quantifies the two main sources of interspecies variability (PK and PD). It is therefore applicable to interspecies extrapolation and to multiple species drug development. As well as the currently limited appreciation of PK/PD principles in the veterinary scientific community, a further constraint in implementing PK/PD modelling is the need to validate PK/PD approaches and thereby gain confidence in its value by pharmaceutical companies and regulatory authorities.     

Human and bovine respiratory syncytial virus vaccine research and development

Human (HRSV) and bovine (BRSV) respiratory syncytial viruses (RSV) are two closely related viruses, which are the most important causative agents of respiratory tract infections of young children and calves, respectively. BRSV vaccines have been available for nearly 2 decades. They probably have reduced the prevalence of RSV infection but their efficacy needs improvement. In contrast, despite decades of research, there is no currently licensed vaccine for the prevention of HRSV disease. Development of a HRSV vaccine for infants has been hindered by the lack of a relevant animal model that develops disease, the need to immunize immunologically immature young infants, the difficulty for live vaccines to find the right balance between attenuation and immunogenicity, and the risk of vaccine-associated disease. During the past 15 years, intensive research into a HRSV vaccine has yielded vaccine candidates, which have been evaluated in animal models and, for some of them, in clinical trials in humans. Recent formulations have focused on subunit vaccines with specific CD4+ Th-1 immune response-activating adjuvants and on genetically engineered live attenuated vaccines. It is likely that different HRSV vaccines and/or combinations of vaccines used sequentially will be needed for the various populations at risk. This review discusses the recent advances in RSV vaccine development.     

鸡蛋中兽药残留形成过程及防控措施分析

应用药物治疗产蛋期蛋鸡的感染性疾病时,常会引发鸡蛋中的兽药残留问题。这些残留的兽药会直接危害消费者的生命健康（如过敏反应等）,此外,还会诱导人体内的细菌产生耐药性,造成人类感染性疾病的治疗困难。本文结合鸡蛋的形成过程,对鸡蛋中兽药残留的特点、形成过程及防控措施进行了详细分析。