4. Drug discovery and development process:

Though as PV associate we do not have direct role in drug discovery and development process but we need to be aware of process for better assessment of information.

Drugs/medicines are developed in three different phases – target selection and validation, discovery, and development phase and it takes well over 10 years of careful planning and research for a medicine to go from molecule to a marketable treatment.

Target Selection & Validation phase:

Target selection defined as the decision to focus on finding an agent with a particular biological action that is anticipated to have therapeutic utility- is influenced by a complex balance of scientific, medical and strategic considerations.

A research director faces considerable challenges trying to make consistently good decisions concerning target selection. The task is comparable to a treasure hunt with many enticing clues about where to dig, leading often to large, empty holes. Target selection criteria include plausibility of the hypothesis, feasibility of identifying and testing a selective chemical entity, the risk-to-benefit ratio of the compound, the length of clinical trials, and likelihood that the drug would be an improvement over current therapies.

Here are the steps involved in this phase: 

1. Define the unmet medical need (disease) and understand the molecular mechanism of the disease: Diseases occur when the normal body processes are altered or not functioning properly. When developing a medicine, it is important to understand in detail (at the level of the molecules) what has gone wrong. In this step, molecular  level analysis of medical condition will be studied to know the exact cause of disease. 
2. Identify a therapeutic target in that pathway (e.g gene, key enzyme, receptor, ion-channel, nuclear receptor) – The ‘target’ may be: a molecule that has been produced in excess, interfering with normal body function; a molecule that is not being produced in normal amounts; or a molecule that has an abnormal structure. For example, in diabetes, there is either a lack of insulin production or cells don’t respond to it, and in cancer there can be too much of a chemical messenger signalling the cells to grow abnormally.
3. Demonstrate that target is relevant to disease mechanism using genetics, animal models, lead compounds, antibodies, RNAi, etc. Approaches:

• Genetic manipulation of target genes (in vitro) – knocking down the gene (shRNA, siRNA, miRNA), knocking out the gene (CRISPR, ZFNs), knocking in the gene (viral transfection of mutant genes)
• Antibodies — interacting to the target with high affinity and blocking further interactions
• Chemical genomics — chemical approaches against genome encoding protein

Let us see an example to prevent cancer cell growth: 

• The nucleus acts as the control centre for the cell – it contains the genetic material.
• The receptor allows chemical messengers to communicate with the nucleus.

When a chemical messenger, in this case the ‘growth factor’, combines with the growth factor receptor on the cell surface, a message is generated inside the cell. This then communicates with the nucleus, which then stimulates the cell to divide. When the signalling is uncontrolled, the cellular growth leads to cancer. Blocking the receptor in cancer cells will prevent transmission of the message to the nucleus and thus prevent uncontrolled cell growth.

If you can block the receptor in cancer cells, this will:

• stop the message being sent, and
• prevent uncontrolled cell growth.

The ‘target’ in this example is therefore the growth factor receptor. 

Drug Discovery phase: 

Once the target is selected lead compound will be identified.

A lead compound is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful, that could potentially be developed into a new drug by optimizing its beneficial effects and minimizing its side effects.

How the lead compounds are identified:

1. Collection of compounds (“compound library”)/Random screening: All compounds including synthetic chemicals, natural products of plant, marine and microbial origin from given series are tested. Ex: Antibiotics like streptomycin and tetracyclines were found by this method.

2. Compound from published literature

3. Drug metabolism studies: Metabolism of drug occurs as an attempt by metabolising enzymes. Structural modifications are done in drug molecule by enzymes to increase its polarity. Ex: Sulfanilamide is identified through drug metabolism studies.

4. Clinical observation: Drugs possesses more than one pharmacological activities. The main activity is called as therapeutic effect and rest of action is known as side effects of drug. Such drugs may be used to improve the potency of secondary effects. 

Ex: Viagra: Pfizer’s blockbuster erectile dysfunction drug. Sildenafil, the active ingredient in Viagra, was originally developed to treat cardiovascular problems. During clinical trials abnormal erections were reported hence drug was redeveloped to add indication of erectile dysfunction.

5. Structure-based design (“rational drug design”): Target’s structure and mode of interaction with drug molecule is identified here and drugs are designed according to the target. With this method one can develop drugs with greater potency, higher selectivity and less adverse effects. 

Drug development phase: 

Once researchers identify a promising lead compound for development, they conduct experiments to gather information on:

• How it is absorbed, distributed, metabolized, and excreted.
• Its potential benefits and mechanisms of action.
• The best dosage.
• The best way to give the drug (such as by mouth or injection).
• Side effects or adverse events that can often be referred to as toxicity.
• How it affects different groups of people (such as by gender, race, or ethnicity) differently.
• How it interacts with other drugs and treatments.
• Its effectiveness as compared with similar drugs.

At this stage in the process, thousands of compounds may be potential candidates for development as a medical treatment. After early testing, however, only a small number of compounds look promising and call for further study.

Here is the example of AstraZeneca’s potent proton-pump inhibitor, esomeprazole (Nexium), is used for treating peptic ulcer and esophageal reflux, resulting in sales in excess of $2 billion within three years of launch. Nexium is the S-isomer of the highly successful racemic omeprazole (Losec, Prilosec). Astra scientists were attempting to improve the kinetic yolk of omeprazole by reducing hepatic clearance. Of several hundred compounds tested, only four, including the S- and R- isomers of omeprazole, looked promising. The R-isomer showed the best kinetic profile in the rat. Both the R- and S- isomers of omeprazole were equally potent acid-secretion inhibitors in vitro, and both had equivalent kinetics and potency profiles in dogs. A research director having to decide which isomer to take into human studies might have suspended the program, based on the poor predictive value of the animal data. But a decision was made to compare both isomers in humans and unlike the rat and the dog, the S- isomer of omeprazole had the optimal pharmacokinetic profile.

Preclinical Research: 

Before testing a drug in people, researchers must find out whether it has the potential to cause serious harm, also called toxicity. The two types of preclinical research are:

– in vitro (e.g. enzyme assay)
– in vivo (animal model or pharmacodynamic assay)

Usually, preclinical studies are not very large. However, these studies must provide detailed information on dosing and toxicity levels. After preclinical testing, researchers review their findings and decide whether the drug should be tested in people.

Drug developers, or sponsors, must submit an Investigational New Drug (IND) application to FDA before beginning clinical research.

In the IND application, developers must include:

• Animal study data and toxicity (side effects that cause great harm) data 
• Manufacturing information 
• Clinical protocols (study plans) for studies to be conducted 
• Data from any prior human research 
• Information about the investigator 

Clinical Research:

While preclinical research answers basic questions about a drug’s safety, it is not a substitute for studies of ways the drug will interact with the human body. “Clinical research” refers to studies, or trials, that are done in people. As the developers design the clinical study, they will consider what they want to accomplish for each of the different Clinical Research Phases and begin the Investigational New Drug Process (IND), a process they must go through before clinical research begins.

Designing Clinical Trials:

Researchers design clinical trials. These trials follow a specific study plan, called a protocol, that is developed by the researcher or manufacturer. Before a clinical trial begins, researchers review prior information about the drug to develop research questions and objectives. Then, they decide:

• Who qualifies to participate (selection criteria) 
• How many people will be part of the study 
• How long the study will last 
• Whether there will be a control group and other ways to limit research bias 
• How the drug will be given to patients and at what dosage 
• What assessments will be conducted, when, and what data will be collected 
• How the data will be reviewed and analyzed 

Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late-stage, large scale, Phase 3 studies.

Clinical Research Phase Studies

Phase 0 clinical trial:

Phase 0 involves exploratory, first-in-human (FIH) trials that are run according to FDA guidelines. Also called human microdose studies, they have single sub-therapeutic doses given to 10 to 15 subjects and yield pharmacokinetic data or help with imaging specific targets without introducing pharmacological effects. Pharmaceutical companies perform Phase 0 studies to decide which of their drug candidates has the best pharmacokinetic parameters in humans.

Phase 1 clinical trial:

Study Participants: 20 to 100 healthy volunteers or people with the disease/condition.

Length of Study: Several months

Purpose: Safety and dosage, absorption and metabolism, effects of organs and tissues.

Approximately 70% of drugs move to the next phase

In this phase it is important to enroll a relatively healthy patient population with as few complications and concomitant diseases as possible.

Food effect studies are often conducted to investigate the potential impact of food intake on the absorption of the drug. These studies are usually run as a crossover study, with volunteers being given two identical doses of the drug, one after fasting and one after a meal.

Phase 2 clinical trial:

Study Participants: Up to several hundred people with the disease/condition.

Length of Study: Several months to 2 years

Purpose: Efficacy, short term side effects and dose range

Approximately 33% of drugs move to the next phase

Phase 3 clinical trial:

Study Participants: 300 to 3,000 volunteers who have the disease or condition

Length of Study: 1 to 4 years

Purpose: Efficacy and monitoring of adverse reactions

Approximately 25-30% of drugs move to the next phase

Phase 4 clinical trial:

Study Participants: Several thousand volunteers who have the disease/condition

Purpose: Benefit/risk relationship of drug, Less common and longer term side effects and Labeling information.

Phase IV trials are also known as post-marketing surveillance trials involving safety surveillance (pharmacovigilance) and ongoing technical support after approval. 

However, not all Phase IV studies are post-marketing surveillance studies. There are multiple observational designs and evaluation schemes that can be used in Phase IV studies to assess the effectiveness, cost-effectiveness, and safety of an intervention in real-world settings. 

Phase IV studies may be required by regulatory authorities (e.g. change in labelling, risk management/minimization action plan) or may be undertaken by the sponsoring company for competitive purposes or other reasons. This could entail the drug being tested in a certain new population (e.g. pregnant women). The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period.

The outcome of the ‘clinical trial’ decides whether the drug candidate is safer and effective enough in treating the disease. At this point, new drug applications (NDA) with all the essential evidence, including quality, preclinical and clinical data collected during development of the drug candidate, are submitted to the relevant regulatory authorities, e.g., the United States Food and Drug Administration (USFDA), which oversees the development, approval, and marketing of drugs. They need to approve the drug applications so that the company can commercialize the drug in their jurisdictions (e.g., a New Drug Application (NDA) in USA, and Marketing Authorization Application (MAA) in Europe).

Pharmacovigilance role in drug development: 

1. PV is an iterative process focusing on detection of unidentified safety issues, identification of risk factors, quantifying risks and preventing patients from being adversely affected unnecessarily. 
2. PV requires submission of the reports on adverse events during clinical trials to regulatory authorities within a specified time frame, notification of such events to all investigators and ethics committees. 
3. Annual reports, a summary and analysis of all the serious adverse events, new safety findings from animal studies, and evaluations of benefit and risk are also required. 
4. PV plays a considerable role when the drug is commercialized. 
5. Reporting the safety reviews is mandatory for companies in a marketing phase. 
6. PV is a very essential and expected part of the drug discovery and development process. 
7. PV is essential to establish good clinical practices for improving the understanding of the drug safety issues during the drug development.