The Lifecycle of a Drug (Pharmakon) or Biologic is initiated to address a disease or an ailment for which there is an unmet clinical need or to improve existing therapies. The Process involved in developing a new drug from the initial idea to the marketing of a finished product is a complex and stringent process that takes 12–15 years approx. and costs around $1 billion.
Any development process should ensure that the drug possesses quality, safety efficacy and compliance with the regulatory requirements.
Pharmaceutical products (Drugs, Biologics) involve 05 stages from target identification to finished product.
1. Drug Discovery & Development
2. Non-Clinical Development
3. Clinical & CMC Development
4. Regulatory Review & Market Approval
5. Post Marketing Surveillance
Stage 1: Discovery & Development
A knowledge of the physiology of a system and the pathophysiology of a particular disease is a fundamental step in the discovery process. Biological pathways implicated in disease states are identified through basic research, which also involves formulating a hypothesis to find a target (gene, RNA, or protein) and designing a product with therapeutic benefits. Target selection and validation are the most crucial step in the development of a new medication.
Once the therapeutic target is identified, the biological mechanism is investigated to validate its efficacy, safety, and meet clinical, commercial needs; above all target should be “DRUGGABLE”. The ‘HIT’ compounds are screened for biological activity using combinatorial chemistry and HTS (high throughput Screening).
The combinatorial chemistry-generated library is screened for biological activity, in an in- vitro system, in which a known biochemical process, which is thought to mimic a human disease or disorder, is agonized or antagonized.
High throughput and other compound screens are developed and run to identify molecules that interact with the drug target, chemistry programmes are run to improve the potency, selectivity and physiochemical properties of the molecule, the development of biological assays to be used for the identification of molecules with activity at the drug target and data continue to be developed to support the hypothesis that intervention at the drug target will have efficacy in the disease state.
There are two types of assays, cell-based assays and biochemical assays.
Cell-based assays (CBA), targets membrane receptors, ion channels and nuclear receptors to produce a functional effect leading to compound activity.
Biochemical assays (BCA), targets to both receptor and enzyme targets, measuring the affinity of the test compound for the target protein.
The factors to be considered in Assay development are:
- Pharmacological relevance
- Reproducibility Costs
- Assay quality
- Effects of compounds in Assay
The assays should be designed to provide important information with regard to absorption, distribution, metabolism and excretion (ADME) properties as well as physicochemical and pharmacokinetic (PK) measurements.
The number of doses required to reach steady state depends on the lead’s pharmacokinetic profile in the same animal model. These pharmacology evaluations assist in the selection of dose levels and route and frequency of administration for preliminary and definitive toxicology, safety and tolerance human trials.
Compounds are screened for Drug-like properties such as Lipinski Rule, clogP, Caco2 permeability, and hERG affinity which maintained their potency and selectivity at the principal target to generate ‘LEAD’ series for further development. Lead compound`s metabolism in the pharmacological and proposed toxicological animal species is evaluated to assists in selecting the species that are similar to humans for definitive toxicology studies.
The compounds are optimized for favourable properties, improving on deficiencies in the lead structure. Once the lead is optimized, candidate referred to be suitable and recommended for pre-clinical development to assess the safety and toxicity profile to address feasibility to administer in to humans.
Stage 2: Non-Clinical Development (GLP)
Pre-Clinical Assessment:
The main objective of the Pre-clinical assessment is to explore primary Pharmaco-dynamic data and early toxicity, to identify hazards, evaluate risks and provide basis for risk management.
The animal studies are conducted to determine the test article does not have a toxicity profile that could cause adverse experiences in humans at pharmacological doses for which toxicological characterization of discovery lead is necessary.
- In-vitro toxicology assessment: The potential for toxic effects (cell death, change in cell function) may be determined using in vitro techniques, such as cell-based systems or microarrays.
- Acute (single dose) toxicity: Deal with the potential adverse effects of single doses providing information about possible dose levels for first applications to humans, and the possible effects to be expected with (accidental or intentional) over-dosing.
- Dose-Range-Finding Studies: These studies are performed to determine an MTD.
- Pilot 14-day Study: A dose level that causes toxic changes, such as morbidity or salivation, and one that produces the no-toxic-effect are determined during 14-day studies.
The results from the pharmacology and pre-clinical studies are documented in technical reports and used to prepare a regulatory agency submission for the initiation of human clinical trials.
Non-Clinical Assessment:
The Non-Clinical development is highly regulated by regional, national, and international guidelines and must be carried out in stringent environment in compliance to GLP requirements. Research studies intended for submission to a regulatory agency are to be conducted according to GLP regulations, as published by regulatory authorities in all the leading pharmaceutical markets.
Safety pharmacology:
The early pharmacological/pharmacodynamic studies are intended to investigate the mode of action or effects of substance in relation to desired therapeutic target.
Sub-chronic/chronic (repeated dose) toxicity:
To characterize the toxicological profile of the candidate on repeated administration, and gives information on toxic effects, potential target organs, effects on physiological functions, haematology, clinical chemistry, pathology and histopathology.
Genotoxicity:
These studies are conducted to detect compounds which induce genetic damage directly or indirectly, the usual approach is to carry out a battery of tests which provide information on gene mutations, structural chromosome aberrations and numerical chromosome aberrations.
Carcinogenicity:
To identify the tumorogenic potential in animals and to assess the relevant risk to humans.
Reproductive toxicity:
The primary goal of reproductive toxicity studies is therefore to characterize the toxicological profile of the pharmaceutical with respect to effects on:
- Fertility and early embryonic development
- Embryo-foetal development
- Pre- and postnatal development, including maternal function
Safety information to support clinical development phases
| Stage | Information Required |
| Phase 0 | Single dose toxicity (sub acute study) 02 rodent species |
| Phase I | Repeated dose toxicity 02 species (01 rodent and 01 non-rodent mammal) |
| Phase II | Repeated dose toxicity 02 mammalian species (01 rodent and 01 non-rodent) |
| Phase III | Carcinogenicity |
| Product Label | Mutagenicity, Carcinogenicity, Reproductive toxicology (Impairment of fertility, Teratogenicity, and peri/post-natal developmental effects) |
During early preclinical development, the primary goal is to determine the candidate is reasonably safe for initial use in human and if it exhibits pharmacological activity that justifies commercial development.
A very detailed compilation of non-clinical data of investigational drug candidate supporting the dosage, frequency, method of administration and safety monitoring procedures should be submitted in the form of Investigational Brochure (IB) to support the clinical management of the study subjects.
Any investigator or a sponsor must get approval from regulatory authorities to investigate a new drug in humans. An application (IND or CTA) should describe the general investigation plan and the protocols ensuring human studies.
Researcher or a healthcare professional must enlighten volunteer participating in a trail about consequences to make a choice to accept or reject such test or treatment which familiarly considered as Informed Consent (IC).
Every trail plan, protocols and IC must be reviewed and approved in accordance G to GCP by IRB/IEC. They have authority to approve, recommend modifications in, or disapprove trails those are non-compliant with regulations.
Stage 3: Clinical Development: (GCP)
Phase 0
Phase 0 studies are conducted in response to exploratory IND investigations are intended to expedite the clinical evaluation of new candidates to support the performance of first-in-human testing of new investigational drugs at sub-therapeutic doses based on reduced manufacturing and toxicological requirements, allowing the demonstration of drug-target effects and assessment of pharmacokinetic-pharmacodynamic relationships in humans earlier in clinical development.
Phase 0 trials include a small number of subjects (10 to 15) to gather preliminary data on the lead’s pharmacokinetics (what the body does to the drugs) that can be utilized to rank drug candidates in order to decide which has the best pharmacokinetic parameters in humans to take forward into further development.
Phase 0 studies offer the molecular proof-of-concept investigations ensuring promise of rational selection of agents for large-scale development as well as the molecular identification of potential therapeutic failures early in the development process.
Phase I
Phase I trials are the first stage of testing in human subjects involving a group of 20–100 healthy volunteers designed to assess the safety, tolerability, pharmacokinetics, and pharmaco-dynamics of a drug including dose-ranging, also called dose escalation studies, so that the best and safest dose can be found and to discover the point at which a compound is too poisonous to administer.
The tested range of doses will usually be a fraction of the dose that caused harm in animal testing.
Phase Ia:
A small group of subjects are given a single dose of the drug and observed for a period of time to confirm safety. Typically, 03 participants are monitored sequentially at a particular dose for adverse side effects, and the pharmacokinetic data are roughly in line with predicted safe values, the dose is escalated, and a new group of subjects is given a higher dose. If unacceptable toxicity is observed in any of the participants, an additional number of participants are treated at the same dose until pre-calculated pharmacokinetic safety levels are reached, or intolerable side effects start showing up (at which point the drug is said to have reached the maximum tolerated dose (MTD)).
Phase Ib:
Multiple ascending dose studies investigate the pharmacokinetics and pharmacodynamics of multiple doses of the drug, looking at safety and tolerability. In these studies, a group of patients receives multiple low doses of the drug, while samples are collected at various time points and analyzed to acquire information on how the drug is processed within the body. The dose is subsequently escalated for further groups, up to a predetermined level.
Food effect:
A short trial designed to investigate any differences in absorption of the drug by the body, caused by eating (pre-determined meal) before the drug is given. These studies are usually run as a crossover study, with volunteers being given two identical doses of the drug while fasted, and after being fed.
Phase II
Once a dose or range of doses is determined, the next goal is to evaluate whether the drug has any biological activity or effect. Phase II trials are performed on larger groups (100-300) and are designed to assess how well the drug works, as well as to continue Phase I safety assessments in a larger group of volunteers and patients. Genetic testing is common, particularly when there is evidence of variation in metabolic rate. When the development process for a new drug fails, this usually occurs during Phase II trials when the drug is discovered not to work as planned, or to have toxic effects.
Phase IIa is specifically designed to assess dosing requirements.
Phase IIb is specifically designed to study efficacy.
Phase III
This phase is designed to assess the effectiveness of the new intervention and, thereby, its value in clinical practice. Phase III studies are randomized controlled multi-center trials on large patient groups (300–3,000 or more depending upon the disease/medical condition studied) and are aimed at being the definitive assessment of how effective the drug is, in comparison with current ‘gold standard’ treatment.
Phase III trials are the most expensive, time-consuming and difficult trials to design and run, especially in therapies for chronic conditions determined as “pre-marketing phase” as it measures consumer response to the drug.
In addition, trials are performed for “label expansion” to obtain additional safety data, or to support marketing claims for the drug that can be designated as “Phase IIIB studies.”
During the clinical development of an investigational drug, periodic analysis of safety information is crucial to the ongoing assessment of risk and the comprehensive evaluation of safety information, exploring new safety issues and management of potential risks should be submitted as DSUR to assure regulators that safety profile is adequately monitored.
Stage 4 :Regulatory Review & Market Approval
Health Authorities review and regulate products and supervises the associated clinical trials, marketing approval, and risk management processes with the main objectives to promote public health, assess the safety and efficacy of therapeutic products, and collaborate with experts to enhance product development.
The Authority perspective will be initiated when a sponsor starts a clinical trial to test a new chemical in Humans.
Once a Sponsor files an application for clinical trial, can precede further after a stipulated time to hear a response from authority in-case any conditions of hold or termination will be met.
As soon a drug has proved satisfactory after Phase III trials, the trial results along with the comprehensive description of animal studies, methods and manufacturing procedures, formulation details, and shelf life information makes up the “regulatory submission” that is submitted for review to the appropriate regulatory authorities to review, and give the approval to market the drug.
The agency will determine the adequacy of the submission for completeness as per requirements and accepts the application which otherwise can be rejected.
The Application contents will be sent to appropriate sub divisions within the authority for review that determine that the drug meets statutory standards for safety, efficacy. If they found any discrepancies, thy can be communicated to sponsor through various channels for modifications and if satisfied with all requirements, the authority will approve the drugs to be released in to interstate commerce.
Stage 5: Post Marketing Surveillance
Phase IV
Phase IV trial is also known as post-marketing surveillance Trial. Phase IV trials involve the safety surveillance (pharmacovigilance) and ongoing technical support of a drug after it receives permission to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive or other reasons. 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.
The minimum time period mandatory for Post Marketing Surveillance (Phase IV trials) is 2 years.
A comprehensive, concise, and critical analysis of new or emerging information on the risks of the medicinal product, and on its benefit in approved indications, to enable an appraisal of the product’s overall benefit-risk profile should be submitted in the form of a PBRER.
The main focus of each PBRER is the evaluation of relevant new safety information from the available data sources, placed within the context of any pertinent efficacy/effectiveness information.