Posts tagged: Clinical trials

Introduction

In a life cycle of a drug from its discovery till launch, a series of crucial steps are involved in order to comply with regulatory requirements as per respective local regulatory authority. These steps from discovering a new drug to its launch in the market contributes to research and development in the pharmaceutical industry. The process is time consuming and may take several years for completion.

Steps involved in research and development in the modern pharmaceutical industry are as follows, i) early drug discovery, ii) preclinical studies, iii)clinical development, iv) review and approval by applicable regulatory bodies, v) post marketing surveillance.

Identifying a potential target-

Early drug discovery involves target identification and validation, hit discovery, assay development and screening, high throughput screening, hit to lead and lead optimization. Target identification begins with identifying the function of potential therapeutic agents and its role in the disease. It can be approached by direct biochemical methods, genetic interactions or computational interface. However, a combined approach may be required to fully characterize on-target and off-target interactions in order to understand molecular action mechanisms. Main motive of hit discovery is to identify molecules with potential interactions with drug targets.

Assay development-

Different types of assays can be used for assay development and compound screening, ranging from biochemical to cell-based assays. The choice of the assay depends on the biology of the drug target protein, scale of the compound screen, the equipment infrastructure, etc. Factors required for assay development are; i) Pharmacological importance of the assay– ability to identify compounds with the desired mechanism of action, ii) Reproducibility– is readily reproducible across assay plates, screen days and the length of the drug discovery programme, iii) Quality– pharmacology of the standard compounds falls within predefined limits, iv) Effects of compounds in the assay– should not be sensitive to the concentrations of solvents used in the assay.

Screening methods-

High throughput screening, (HTS) involves screening of the entire compound library against the drug target. Knowledge-based screening is a method of selecting from the chemical library smaller subsets of molecules with potential activity at the target protein. Fragment screening is making very small molecular weight compound libraries which are screened at high concentrations. Physiological screening is a tissue-based approach with the response more in direction with the desired in vivo effect.

Lead optimization-

Drug-like molecules must go through different phases to identify the hit lead molecule and optimization with a potency of 100nM – 5mM at the drug target. The refinement process involves generating dose-response curves in primary assay for each hit. Followed by examining the surviving hits in a secondary assay. Generation of rudimentary structure-activity relationship, SAR data and identifying the essential elements in the structure linked with the activity. Lastly, in vitro assays providing significant data with regards to absorption, distribution, metabolism and excretion (ADME) properties as well as physicochemical and pharmacokinetic (PK) measurements. Overall, the aim is to achieve a lead compound optimized with desirable effects on the target that can provide therapeutic benefits within an acceptable safety window. Average time required for this step is 2-6 months.

A glance at preclinical trials-

Preclinical studies or non clinical studies, carries out testing on animals to accurately model the desired biological effect of a drug in order to predict treatment outcomes in patients determining its efficacy, and to identify all toxicities associated with the drug to predict adverse effects for safety assessment. There are two types of preclinical studies, i) in vitro, ii) in vivo, iii) ex vivo assay and iv) in silico. In compliance with good laboratory practices, GLP, in vitro studies are carried out outside of living organisms in a test tube, glass or petri dish. On the other hand, in vivo studies are those which involve living organisms, including animal studies and human clinical trials. Ex vivo assay refers to a medical procedure in which an organ, cell or tissue are taken from the living body for treatment testing such as skin biopsies or isolated samples from tumor biopsy. In silico studies refers to using computer simulations to predict the reaction of a compound with specific proteins or pathogens. 

Goal of preclinical studies involve determination of pharmacokinetics, proof of concept, formulation, optimization & bioavailability, establishing safe dose, therapeutic dose, lethal dose and maximum tolerated dose. The compound from drug discovery is modified through preclinical studies and becomes Investigational New Drug, IND. IND application is filed for review and approval as per guidelines and standards of local and national regulatory authority. On an average the time required for this phase is approximately ranging from 1-6 years.

A complete overview of Clinical trials-

Clinical development of drug discovery begins after approval of IND for further testing. Clinical trials are conducted for testing of the new drug classified into several phases.

Phase 0 and Phase I-  Phase 0 is known as human micro dosing studies, which involves 10-15 individuals who are administered with small amounts of sub therapeutic dose mainly to determine pharmacokinetics, oral bioavailability and half-life of the drug. Phase 0 trials are often skipped to direct Phase I trials unless some of the data is inconsistent from previously conducted preclinical studies. Phase I studies are conducted amongst healthy volunteers to test the safety, tolerability, pharmacokinetics & pharmacodynamics, side effects & adverse effects, optimum dose, half-life and formulation method for the drug. In circumstances when testing for diseases like cancer or HIV, the treatment for which is likely to make healthy individuals ill, clinical patients are selected as an exception. Phase I trials are not randomized and hence are vulnerable to selection bias. This phase involves 20-100 individuals. Phase I trials can be further divided into, i) Single ascending dose, Phase I (a) in which a small number of participants are entered sequentially at a particular dose while monitoring them for a period of time to confirm safety. If no adverse effects are noted, then dose is escalated for newer groups. It is continued until pre-calculated pharmacokinetic safety levels are achieved or intolerable side effects are noted, it is the point where drug reaches at maximum tolerated dose, MTD; ii) Multiple ascending dose, Phase I (b) in which group of participants receives multiple low doses of the drug, which is subsequently escalated for further group of participants up to a predetermined level. It helps in determining pharmacokinetics and pharmacodynamics of multiple doses of the drug along with its safety and tolerability.

Phase II- Phase II trials are performed on larger groups (50–300) and are designed to assess biological activity and effect of the drug. Trial design of Phase II trials are either as case series, which demonstrates safety and efficacy in a selected group of participants, or as randomized controlled trials ,RCT, where some participants receive the drug/device and others receive placebo/standard treatment. Phase II studies are divided into Phase II (a) and Phase II (b). Phase II (a) studies are pilot studies designed to demonstrate clinical efficacy or biological activity of the drug. Phase II (b) studies determine the optimal dose at which the drug shows biological activity with minimal side-effects. It is also known as maximum effective dose, MaxED.

Phase III- Phase III trials are conducted in a large patient population of 300-3000 individuals determining the efficacy of the new drug in comparison to existing standard treatment. They are time consuming and expensive with complicated trial designs such as Randomized controlled multicentre trials with single, double or triple blinded factors in order to avoid bias and clean results. Phase III (a) studies are trial designed and executed to obtain statistically significant data for new drug approval by regulatory authority. Phase III trials that continue while awaiting regulatory approval in order to provide life-saving drugs to patients until the drugs are available in the market are categorized as Phase III (b) studies. Label expansion studies by the sponsor also fall under this category.

Phase IV- If the new drug successfully passes through Phase I, II, and III, with desirable outcomes, the manufacturing, preclinical and clinical data is then submitted as a new drug application, NDA, for review and marketing approval by national applicable regulatory authority. Post approval the new drug is marketed and Phase IV trials begin, which is post marketing surveillance of the new drug and lasts for up to 5 years. The entire process from developing a drug from preclinical research till marketing can take approximately 12-18 years. A Phase IV trial is a drug monitoring trial to assure long-term safety and effectiveness of the drug, vaccine, device or diagnostic test. These trials involve the safety surveillance, i.e, pharmacovigilance and ongoing technical support of a drug after it receives regulatory approval to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive reasons, such as finding a new market for the drug, or other reasons, for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials. The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being withdrawn from the market or restricted to certain uses; examples include cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).

Conclusion

Thus Research & Development is essential when it comes to the pharmaceutical industry, since R&D services not only generate income for the companies involved in the research but it often saves lives. Reliable Pharmaceutical R&D services allow for companies to have technical and manufacturing procedures, quality control measures and production scope aspects as per required standards.