Drug Discovery and Drug Development

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Drug Development and Discovery

Drug Discovery and Drug Development

Table of Contents

Drug development now is a highly complex, tedious, competitive, costly and commercially risky process. From the synthesis/identification of the molecule to marketing, a new drug takes at least 10 years and cost of 500-1000 million US $.

Drug development and discovery

Stages in New Drug Development –

Broadly, the process can be divided into three main components.

1. Drug Discovery :

During which candidate molecules are chosen on the basis of their pharmacological properties.

2. Preclinical Development :

During which a wide range of non-human studies (e.g. toxicity testing, pharmacokinetic analysis and formulation) are performed.

3. Clinical Development :

During which the selected compound is tested for efficacy, side effects and potential dangers in volunteers and patients.
Stages of new drug development

The Drug Discovery Phase

We first need to choose a new molecular target.

1. Target Selection (choosing a molecule to target with a drug)

A “target is produced within the pharmaceutical industry. Generally the “target” is the naturally existing cellular or molecular structure involved in the pathology of interest. Where the drug-in-development is meant to act.

  • The target may be a protein molecule, enzyme, transport molecule, Ion channel, Tubulin, Immunophilin, which is involved in particular disease.
  • Even at this early stage in drug discovery it is critical that researches pick a target that is “drugable”, I.e., One can potentially interact with and be affected by a drug molecule.

Target selection for Drug discovery and development

2. Lead Finding (Finding a promising molecule [a “lead compound”] that could become a drug)

It involves cloning of the target protein-normally the human form, because the sequence variation among species is often associated with pharmacological differences and it is essential to optimize for activity in humans.

  • Compounds obtained from plants, animals or marine organisms are much more troublesome to produce commercially.
  • The main disadvantage of natural products as lead compounds is that they are often complex molecules that are difficult to synthesize or modify by conventional synthetic chemistry, so that lead optimization may be difficult and commercial production very expensive.

3. Lead Optimization (Alter the structure of lead candidates to improve properties)

Lead compounds found by random screening are the basis for the next stage.

  • Lead compounds that survive the initial screening are the “optimized” or altered to make them more effective and safer (increase the potency)
  • In this phase, the tests applied include a broader range of assays on different test systems, including studies to measure the activity and time course of the compounds in vivo and checking the unwanted effects in animals, evidence of genotoxicity and usually for oral absorption.

The objective of the lead optimization phase it to identify one/more drug candidates suitable for further development.

Even at this early stage, researchers begin to think about how the drug will be made, considering formulation (the recipe for making a drug, including inactive ingredients used to hold it together and allow it to dissolve at the right time), delivery mechanism (the way the drug is taken – by mouth, injection, inhaler) and large-scale manufacturing (how you make the drug in large quantities).

Pre-clinical Development (Lab and animal testing to determine if the drug is safe enough for human testing)

  • Pre clinical studies assess the safety of the molecule prior to the drug administration into the human body.
  • Pre Clinical studies can be studied on animals and in vitro where in animal studies, we use species namely rodents (rats, mice) and non rodents (rabbit, guinea pig)

Note :
– Vivo = life (latin)
– Vitro = Glass (latin)

Pre-clinical development - Rodents experiment

The aim of preclinical development is to satisfy all the requirements that have to be met before a new compound is deemed ready to be  tested for the first time in humans. The work falls into four main categories:

  1. Pharmacological testing to check that the drug does not produce any obviously hazardous acute effects such as bronchoconstriction, cardiac dyshythmias, blood pressure changes and ataxia. This is termed safety pharmacology.
  2. Preliminary toxicological testing to eliminate genotoxicity and to determine the maximum non-toxic dose of the drug (usually when given daily for 28 days, and tested in two species). As well as being checked regularly for weight loss and other gross changes, the animals so treated are examined minutely post mortem at the end of the experiment to look for histological and biochemical evidence of tissue damage.
  3. Pharmacokinetic testing, including studies on the absorption, metabolism, distribution and elimination (ADME studies) in the species of laboratory animals used for toxicology testing, so as to link the pharmacological and drug exposure.
  4. Chemical and pharmaceutical development to assess the feasibility of large-scale synthesis and purification, to asses the stability of the compound under various conditions and to develop a forumulation suitable for clinical studies.

When a compound deserving trial in man is identified by animal studies, the regulatory authorities are approached who on satisfaction issue an ‘investigational new drug’ (IND) licence. The drug is formulated into a suitable dosage form and clinical trails are conducted in a logical phased manner. To minimize any risk, initially few subjects receive the drug under close supervision. Later, larger numbers are treated with only relevant monitoring. Standards for the design, ethics, conduct, monitoring, auditing, recording and analyzing data and reporting of clinical trails have to be laid down in the form of ‘Good clinical Practice’ (GCP) guidelines by an ‘International Conference on Harmonization’ (ICH).

GLP covers aspects like record-keeping procedures, data analysis, instrument calibration and staff training. The aim of GLP is to eliminate human error as far as possible, and to ensure the reliability of the data submitted to the regulatory authority, and laboratories are regularly monitored for compliance to GLP standards. The strict discipline involved in working to this code is generally ill-suited to the creative research needed in the earlier stages of drug discovery, so GLP standards are not usually adopted until projects get beyond the discovery phase.
Roughly half the compounds identified as drug candidates fail during the preclinical development phase; for the rest, a detailed dossier (the ‘investigator brochure’) is prepared for submission along side specific study protocols to the regulatory authority such as the European Medicines Evaluation Agency or the US Food and Drugs Administration, whose permission is required to proceed with studies in humans. This is not lightly given and the regulatory authority may refuse permission or require further work to be done before giving approval.
Non-clinical development work continues throughout the clinical trails period, when much more data, particularly in relation to long-term and reproductive toxicity in animals has to be generated. Failure of a compound at this stage is very costly, and considerable efforts are made to eliminate potentially toxic compounds much earlier in the drug discovery process by the use of in vitro, or even in silico, methods.

Clinical Development

Clinical development proceeds through five distinct but overlapping phases of clinical trails.
Clinical trail

Phases 0 Trail :

The FDA has recently endorsed “microdosing,” or the “Phase 0 Trail”, which allows researchers to test a small drug dose in fewer human volunteers to quickly weed out drug candidates that are metabolically or biologically ineffective.

Phase – 1 : Human Pharmacology and Safety

Phase 1 studies are performed on a small group (normally 20-80) of volunteers – often healthy young men but sometimes patients, and their aim is to check for signs o any potentially dangerous effects, for example on cardiovasuclar, respiratory, hepatic or renal function; tolerability (does the drug produce any unpleasant symptoms, for example headache, nausea, drowsiness) and pharmacokinetic properties (is the drug well absorbed? Is absorption affected by food? What is the time course of the plasma concentration? Is there evidence of cumulation or non-lineral kinetics?).
Phase 1 studies may also test for pharmacodynamic effect in volunteers, sometimes called ‘proof-of-concept’ studies (e.g. does a novel analgesic compund block experimentally induced pain in humans? How does the effect vary with dose?).

Phase – 2 : Therapeutic exploration and dose ranging

Phase 2 studies are performed on groups of patients (normally 100-300) and are designed to determine pharmacodynamic effect in patients and if this is confirmed to establish the dose regimen to be used in the definitive phase 3 study. Often, such studies will cover several distinct clinical disorders (e.g. depression, anxiety states and phobias) to identify the possible therapeutic indications for the new compound and the dose required. When new drug targets are being studied, it is not until these phase 2 trials are complted that the team finds out whether or not its initial hypothesis was correct, and lack of the expected effect is a common reason for failure.

Phase – 3 : Therapeutic confirmation/comparison

Phase 3 studies are the definitive double-blind, randomized trials, commonly performed as multicentre trials on thousands of patients, aimed at comparing the new drug with commonly used alternatives. These are extremely costly, difficult to organize and often take years to complete, particularly if the treatment is designed to retard the progression of a chronic disease. It is not uncommon for a drug that seemed highly effective in the limited patient groups tested in phase 2 to look much less impressive under the more rigorous conditions of phase 3 trials.

At the end of phase 3, the drug will be submitted to the relevant regulatory authority for licensing. The dossier required for this is a massive and detailed compilation of preclinical and clinical data. Evaluation by the regulatory authority normally takes a year or more, and further delays often arise when aspects of submission have to be clarified or more data are required. Eventually, about two-thirds of submissions gain marketing approval. Overall, only 11.5% of compounds entering Phase 1 are eventually approved. Increasing this proportion by better compound selection at the laboratory stage is one of the main challenges for the pharmaceutical industry.

Phase 4 – Post marketing surveillance/studies

Phase 4 studies comprise the obligatory post marketing surveillance designed to detect any rare or long-term adverse effects resulting from the use of the drug in a clinical setting in many thousands of patients. Such events may necessitate limiting the use of the drug to particular patient groups, or even withdrawal of the drug.

Uncommon/idiosyncratic adverse effects, or those that occur only after long-term use and unsuspected drug interactions are detected at this stage. Patterns of drug utilization and additional indications may emerge from the surveillance data.

Further therapeutic trials involving special groups like children, elderly, pregnant/lactating women, patients with renal/hepatic disease, etc. (which are generally excluded during clinical trials) may be undertaken at this stage. Modified release dosage forms, additional routes of administration, fixed dose drug combinations, etc. may be explored.

As such, many drugs continue their development even after marketing.

Overview

Discovery

Pre-Discovery

Goal: Understand the disease and choose a target molecule.
How: Scientists in pharmaceutical research companies, government, academic and for-profit research institutions contribute to basic research.

Discovery

Goal: Find a drug candidate.
How: Create a new molecule or select an exxisting molecule as the starting point. Perform tests on that molecule and then optimize (change its structure) it to make it work better.

Pre-clinical

Goal: Test extensively to determine if the drug is safe enough for human testing.
How: Researchers test the safety and effectiveness in the lab and in animal models.

Development

IND

Goal: Obtain FDA approval to test the drug in humans.
How: FDA reviews all preclinical testing and plans for clinical testing to determine if the drug is safe enough to move to human trials.

Clinical Trials

Goal: Test in humans to determine if the drug is safe and effective.
How: Candidate drug is tested in clinical setting in three phases of trials, beginning with tests in a small group if healthy volunteers and moving into larger groups of patients.

Review

Goal: FDA reviews results of all testing to determine if the drug can be approved for patients to use.
How: The FDA reviews hundreds of thousands of pages of information, including all clinical and preclinical findings, proposed labeling and manufacturing plans. They may solicit the opinion of an independent advisory committee.

Manufacturing

Goal: Formulation, scale up and production of the new medicine.

Ongoing studies

Goal: Monitor the drug as it is used in the larger population to catch any unexpected serious side effects.

Reference

  • Essenetials of medical pharacology – KD Tripathi
  • Rang and Dale’s Pharmacology
  • Innovation / inside R and D

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