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Drug: A chemical substance of known structure, other than a nutrient or an essential dietary ingredient, which, when administered to a living organism, produces a biological effect.

Discovery phase: Identification of a new chemical entity as a potential therapeutic agent.

Development phase: Compound is tested for safety and efficacy for one or more clinical indications, and in suitable formulations and dosage form.

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HISTORY OF DRUG DISCOVERY�

In the early days therapeutic drugs were created from the derivative of medicinal plants.

Drug serendipity.

Classical pharmacology in drug discovery.

Reverse pharmacology in drug discovery.

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DRUG SERENDIPITY : -�

Accidental discovery.

Led to introduction of many useful drugs in therapeutics.

Alexander Fleming discovered penicillin while observing mould contamination in culture.

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Stages of the New drug synthesis: �

Drug discovery: Candidate molecules arechosen on the basis of their pharmacological properties.

Preclinical development: Non-human studies (e.g. toxicity testing, pharmacokinetic analysis and formulation) are performed.

Clinical development: The selected compound is tested for efficacy, side effects and potential dangers in volunteers and patients.

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Steps involving drug discovery :

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Drug discovery �

Usual time duration: 2-5 years

Usual no. of projects: 100

It consists of following components:

1 Target selection and validation.
2 Lead-finding or Lead generation.
3 Lead optimization.

Pharmacological profiling

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Target Validation �

Target validation is a series of activities, which aim to build confidence that a drug which acts by modifying the function of the target will deliver the efficiancy and safety required.
Degree of target validation varies, depending upon the nature of the disease, type of target etc.
A target is never fully validated until a drug acting on it worlds in patients.

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TARGET SELECTION �

Target is generally a naturally existing cellular or molecular structure involved in some diseases process.
Potential drug targets are not necessarily disease causing but must by definition be disease modifying.
Design molecule which can interact with target and might be helpfuI in the treatment of disease.

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Hit Discovery Process

After target validation, compound screening assays are developed.

Assay Development and Screening

Drug discovery assay development is a critical component of the drug discovery workflow. Assays are test systems that assess the efficacy of new drug candidates at the cellular, molecular, and biochemical levels.

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High Throughput Screening�

High Throughput Screening (HTS) uses robotics, data processing/control software, fluid handling equipment, and sensitive detectors to screen millions of pharmacological, chemical, and Rapidly perform genetic tests and eliminate hours of tedious testing by scientists. HTS identifies drugs, genes, or antibodies that affect human molecules.

Hit to Lead In the Hit to Lead (H2L) process, small molecule hits are evaluated by HTS and optimized to lead compounds in a limited range. These connections go into the lead optimization proces

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Lead Optimization�

In the Lead Optimization (LO) process, leads discovered in the H2L process are synthesized and modified to improve potency and reduce side effects. Lead optimization uses animal efficacy models and the ADMET tool to perform experimental testing and develop drug candidates.

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Active Pharmaceutical Ingredients�

An active pharmaceutical ingredient (API) is a biologically active ingredient in a drug candidate that produces a desired effect. All medicinal products consist of APIs or APIs and excipients. Excipients are inert substances that release drugs into the human system. High Potency Active Pharmaceutical Ingredients (HP APIs) are molecules that are effective at much lower doses than standard APIs. They are classified based on toxicity, pharmacological potency, and occupational exposure limits (OELs) and are used in complex drug development involving 10 or more steps.

Accelerates drug discovery process once drug candidate leads are identified and the drug development process begins

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Preclinical Trials

Once a lead compound is identified, the preclinical stage of drug development begins with in vivo studies to determine drug efficacy and safety.

Absorption, Distribution, Metabolism, Excretion Information
Potential Benefits and Mechanisms of Action
Optimal Dosages and Routes of Administration
Side Effects/Side Effects
Gender, Race and Ethnicity Effects
Interactions with Other Treatments
Efficacy Comparison with similar drug

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Clinical Drug Development Process

Once preclinical research is complete, researchers move on to clinical drug development, including clinical trials and volunteer studies to finetune the drug for human use.

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Complexity of Study Design, Associated Costs and Implementation Issues
Clinical Trials - Dose Escalation, Single and Multiple Dose Studies
Phase I - Studies in Healthy Volunteers

First Time fewer than 100 volunteers will help investigators assess safety and pharmacokinetics, effects on body absorption, metabolism, excretion, and side effects in a safe dose range.

Phase II and Phase III Trials in a Patient Population to assess the safety and efficacy of Optimal dose intensity analysis helps create schedules while recording adverse events and risks. Phase III will enroll between 1,000 and 5,000 patients, enabling drug labeling and proper drug use instructions. Phase III trials require extensive cooperation, organization, and coordination and regulation by an independent ethics committee (IEC) or an institutional review board (IRB) in anticipation of large-scale post-market production.

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Biological Sample Collection, Storage and Transport
Pharmacodynamic (PD) Biomarkers
Pharmacokinetic Analysis
Bioanalytical Method Development and Validation
Drugs in Biological Samples : Biological samples used in clinical trials include blood, plasma, urine and feces to Determine and analyze various properties and effects on humans of its metabolites.
Patient Protection – GCP, HIPAA, Adverse Event Reporting

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FDA REVIEW

Once a new drug is formulated for maximum efficacy and safety and has clinical trial results, it is submitted for comprehensive FDA review. At this point, the FDA will review and approve or not approve the drug application submitted by the drug development company.
Regulatory Approval Timelines : Regulatory approval timelines for new medicines can be Standard, Accelerated, Breakthrough, Expedited or Priority Review, depending on the application and patient needs. If standard or priority review is required, the approval period is up to 1 year. Faster, breakthrough, or expedited approvals may occur sooner.
IND Applications : IND applications are submitted to the FDA prior to initiation of clinical trials. When the drug is ready to conduct clinical trials and the FDA has not responded negatively to the drug, the developer can begin testing.

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NDA/ANDA/BLA Submissions : An NDA (abbreviated New Drug Application (ANDA), or BLA) is submitted to the FDA after a drug has been demonstrated in clinical trials to be safe and effective. FDA reviews research data to determine whether to grant approval. Additional research or a panel of experts may be required before a final decision is made
Orphan Drugs : Orphan drugs are designed to treat diseases that are so rare that funders do not wish to develop them under standard commercial conditions. These drugs may not be approved immediately or may not be approved at all.
Priority Approval