Overview of Drug Development
Mark Chang, John Balser, Jim Roach, Robin Bliss in Innovative Strategies, Statistical Solutions and Simulations for Modern Clinical Trials, 2019
Pre-clinical development is a stage of research that bridges between Discovery and Clinical Trials (trials in human subjects/patients). After a lead compound has been identified, it is subjected to a development process to optimize its properties. The development process includes pharmacological studies of the lead compound to influence and optimize the therapeutic index. Pre-clinical research includes in vitro (in tubes), ex vivo (in cells/tissues but outside an organism), and in vivo (in animals) tests. Preclinical research includes pharmacology and toxicology studies as well as pharmacodynamics and pharmacokinetics studies. Many iterations are carried out and at the end of this process, an optimized compound will hopefully be selected to move forward into clinical studies.
Overview of Drug Development
Pritam S. Sahota, James A. Popp, Jerry F. Hardisty, Chirukandath Gopinath, Page R. Bouchard in Toxicologic Pathology, 2018
Even with the harmonized format, each region still has specific ways to review data. For example, the marketing application in Japan looks for more of a scientific story than other regions and typifies the regional differences in data review (Figure 1.1). In the review of the Japan New Drug Application (NDA), the linear development of the candidate drug is of the most interest. In this way, the rationale for each study must be justified by the results of previous studies; dose selection is based on previous results and not solely on dose multiples or maximum tolerated dose (MTD). As a result, the entire thought process in the preclinical development of the drug is laid out for the reviewer in such a way that this development continuum, from early pharmacology to carcinogenicity testing, is evident in the data presentation.
Microfluidic Systems to Study the Biology of Human Diseases and Identify Potential Therapeutic Targets in Caenorhabditis elegans
Iniewski Krzysztof in Integrated Microsystems, 2017
Drug discovery is the process of identifying drugs for human diseases. Typically, this involves screening for a large number of chemical compounds against certain targets in cells using in vitro and in vivo disease models [1]. In general, the process includes five stages: target identification and validation, lead screening, optimization, preclinical development, and clinical trials. A protein or biochemical pathway that plays a key role in the origin or progression of the disease is identified in the target identification and validation stage. The lead screening stage involves screening of a large number of chemical compounds against the biomolecular target protein or gene in order to identify candidates with potential therapeutic effect. This is followed by an optimization stage in which small chemical modifications of the initial lead compounds are made and screened to produce an optimal chemical species. The preclinical stage involves testing the candidates in various other animal models for efficacy as well as toxicity, and finally, in the clinical stage, testing is carried out in humans on a smaller scale. If successful, the drug is made commercially available in the market.
Therapeutic interventions for spinal muscular atrophy: preclinical and early clinical development opportunities
Published in Expert Opinion on Investigational Drugs, 2021
Laurent Servais, Giovanni Baranello, Mariacristina Scoto, Aurore Daron, Maryam Oskoui
Treatments approved or in late-phase development have been recently reviewed [24]. The aim of this review is to focus on treatments in late phase pre-clinical development or in the early phases of clinical development. We conducted a pragmatic review of the literature to identify these treatments, ensuring completeness using the CureSMA drug pipeline list (https://www.curesma.org/wp-content/uploads/2020/11/2020_Sept-Graphic-Pipeline_v5.pdf) and analysis of trials in SMA registered with clinicaltrials.gov trials. We also discuss drugs currently approved for other indications that have potential for impact in SMA that have not yet been evaluated in a well-conducted clinical trial. The SMN1 and SMN2 pre-mRNAs and mechanisms of the drugs discussed are shown schematically in Figure 1.
10th European immunogenicity platform open symposium on immunogenicity of biopharmaceuticals
Published in mAbs, 2020
S. Tourdot, A. Abdolzade-Bavil, J. Bessa, P. Broët, A. Fogdell-Hahn, M. Giorgi, V. Jawa, K. Kuranda, N. Legrand, S. Pattijn, J. A. Pedras-Vasconcelos, A. Rudy, P. Salmikangas, D. W. Scott, V. Snoeck, N. Smith, S. Spindeldreher, D. Kramer
The risk factors identified at each stage of drug development are scored to develop a bioanalytical strategy for clinic as discussed below. The risk assessment and bioanalytical strategy based on the activities performed during pre-clinical development can be provided as part of the Investigational New Drug (IND) application. The main components would include a brief background on the therapeutic protein with respect to its modality (e.g., monoclonal antibody, multi-domain, cell/viral/nucleic acid) and the target and disease indication. The structure/sequence-based risk, any posttranslational-related attributes, as well as disease state risk can all be summarized as part of this risk assessment. If there is prior experience in the clinic, a summary of the results related to immunogenicity and its impact on exposure, efficacy and safety can be provided. This initial assessment can then support the development of the sampling strategy in clinic with a high probability of risk driving the frequent monitoring vs low level of risk factors leading to reduced monitoring and a collect and hold strategy. The bioanalytical assays to support such a strategy can also be streamlined with minimal assay development for molecules with a low probability of risk vs additional characterization (e.g., titer, domain specificity) for molecules with a high probability of risk.
Tackling the tumor microenvironment – how can complex tumor models in vitro aid oncology drug development?
Published in Expert Opinion on Drug Discovery, 2023
Megan C. Cox, Rita Mendes, Kathleen N. Halwachs, Giacomo Domenici, Catarina Brito, Erwin R. Boghaert
Cancer is a major therapeutic challenge with an estimated worldwide incidence of 19.3 × 106 new cases in 2020 [1] and a mortality of approximately 107 individuals per year. Pharmaceutical cancer therapy has evolved from cytotoxic cancer drugs to targeted therapy with small molecule inhibitors and biotherapeutics. Recently, immune and gene therapy became available [2]. Despite advances in therapy options and improved understanding of the pathophysiology of cancer, the estimated success rate of clinical trials for novel cancer drugs is 3.4% [3]. The capacity of the traditional preclinical development cascade to predict clinical efficacy has therefore been questioned [4]. Response to cancer therapy is not only dependent on the response of isolated cancer cells but is also determined by the millieu in which the cancer cell resides (tumor microenviroment, [TME] [5]). Therapeutic response also changes during progression because cancer evolution generates intrapatient and intratumoral heterogeneity of histological tumor composition [6]. Hence, a predictive preclinical model must not only mimic the ‘organotypic’ configuration [7] but also reflect the evolution of the disease. Because cancer progression may take several years, even the most advanced complex preclinical cancer models reflect limited aspects of the disease. We will review benefits and shortcomings of existing complex in vitro models for drug testing and suggest design improvements to address discovery and development needs.
Related Knowledge Centers
- Adme
- Clinical Trial
- Drug Development
- Drug Discovery
- Pharmacodynamics
- Toxicity
- Pharmacokinetics
- Medical Device
- Prescription Drug
- Approved Drug