Stages of drug discovery, drug development process
Unit I New Drug Discovery and development
BP804 ET: Pharmaceutical Regulatory Science
Drug discovery is defined as the process of designing and developing new chemical moieties for the treatment of diseases. The association of chemistry, biology and pharmacology has worked miracles in the field of medicines.
The discovery of new molecules hails back from the olden times that include extraction of medicinal components from natural sources. The discovery of the drugs blooms with the pre-discovery phase, where scientist discovers the root of disease.
Their study involves understanding how the proteins are altered, how the altered proteins affect the cells and tissues and how these transformed proteins affect the patients health.
In ancient time most of the drug used in the treatment of disease were derived from naturally occurring substances of plant origin, e.g. Opium from poppy, Quinine from cinchona, digitalis from foxglove .
Presently, the majority of new therapeutics agent are synthetic in nature.
Drug discovery and development is complex, time-consuming, costly process which carries commercial risk.
Drug discovery and development is broadly divided into three main components-
- drug discovery,
- Pre-clinical evaluation and
- clinical trials.
STAGES OF DRUG DISCOVERY AND DEVELOPMENT PROCESS
2. Product Characterization,
3. Formulation, Delivery, Packaging Development,
4. Pharmacokinetics and Drug Disposition,
5. Preclinical Toxicology Testing and IND Application,
6. Bioanalytical Testing and
Phases of drug discovery are as follows:
(a) Target Identification:
Identification of Target for the Drug: Drug can be therapeutically efficient after it binds to the body proteins. Hence, it is essential to determine the binding target of the drug. These targets include gene or a protein that is responsible for the particular disease. However, it is pivotal, for the researchers to select an appropriate target that will interact with drug molecule and produce the therapeutic effect.
Identification of drug targets can be done by following means: The important means of identifying the drug targets is via scientific literature. In addition, the two prominent methods include target deconvolution and target discovery.
- Target Deconvolution: This method involves phenotypic approach of identification. The method involves identification of specific target by exposing the cells, tissues and small molecules that exert the required effects. It is done by various methods like; affinity chromatography, protein array, expression cloning and biochemical suppression.
- Target Discovery: This method involves identification of targets that have already established drug targets.
(b) Target Validation:
Confirm the Role of Target on the Disease: After the selection of target, the researchers must confirm that the targets are the potential cause of disease. This stage is considered essential as it saves the times and avoids unproductive results. Target validation can be done by following steps: Reproducibility: The targets can be identified by literature review or by specific technique. However, it is considered almost essential to repeat the experiments again to confirm the targets are the cause of disease. Creating Variation to Ligand Target Environment:
- It should be feasible to alter the affinity of the drug to the target by modulating the activity of drug molecule.
- The effect of the drug should or should not be modified by altering the change cell or tissue type.
- Introducing mutations in to the binding domain of the protein target should result in either modulation or loss of activity of the ligand.
(c) Lead Compound Identification:
Lead compounds are the ones with desired pharmacological and the therapeutic effect. After ensuring the target, the scientist and researchers work on selecting the compound that can bind to the desired target. The sources of lead compound include: Natural Sources: Nature has been source of lead compound from earlier days. Although it is difficult to extract the desired compound from natural resources, however it motivates the researchers to replicate the similar structure and produce the lead compound. Natural products include; plants, animals and microorganisms. Chemical Libraries: Chemical libraries contain large number of compounds with varying sizes from hundreds to millions. These libraries are developed via combinatorial chemistry. The molecules in libraries are screened through high throughput screening methods to identify the lead compound.
Computational Medicinal Chemistry: It includes Computer Aided Drug Discovery and Designing. The 3D structure of the target protein is resolved by X- ray crystallography, and the binding site of the compound is determined.
(d) Lead Optimization:
After the identification of lead compound, efforts have been made to increase the potency, binding and pharmacokinetic properties of the drug followed by decreasing the toxicity. This phase involves the analysis of Structure Activity Relationship (SAR) and various analogues are developed. The developed analogues are tested by the biologics and the chemists. The biologics are concerned about the effect of analogues on the biological systems,
(e) Preclinical Testing:
Safety of the drug is determined by testing on lab animals. Scientist carries out in-vitro and in-vivo tests to estimate its safety. This phase involves first scale up process as the researchers analyses the techniques for making large scale production of the drugs from the small scale. The suitable five to six molecules will be selected as an appropriate molecule to be studied in clinical studies.
2. Product Characterization:
When the candidate molecule shows promise as a therapeutic, it must be characterized according to the molecules size, shape, strengths and weaknesses, preferred conditions for maintaining function, toxicity, bioactivity and bioavailability must be determined. Characterization studies will undergo analytical method development and validation.
Early-stage pharmacology studies help to characterize the underlying mechanism of action of the compound.
3 Formulation, Delivery and Packaging Development:
Drug developers must devise a formulation that ensures the proper drug delivery parameters. It is critical to begin looking ahead to clinical trials at this phase of the drug development process. Drug formulation and delivery may be refined continuously until, and even after, the drug’s Final approval. Scientists determine the drug’s stability in the formulation itself, and for all the parameters involved with storage and shipment such as; heat, light and time.
The formulation must remain potent and sterile; and it must also remain safe (non-toxic). It may also be necessary to perform leachable and extractable studies on containers or packaging.
4 Pharmacokinetics and Drug Disposition:
Pharmacokinetic (PK) and ADME (Absorption/Distribution/Metabolism/Excretion) studies provide useful feedback for formulation scientists. PK studies yield parameters such as;
- AUC (Area Under the Curve),
- Cmax (maximum concentration of the Drug in Blood), and
- Tmax (Time at which Cmax is reached).
Later on, this data from animal PK studies is compared to data from early stage clinical trials to check the predictive power of animal models.
5. Preclinical Toxicology Testing and IND Application:
Pre-clinical testing analyses the bioactivity, safety and efficacy of the formulated product. This testing is critical to a drug’s eventual success and as such, is scrutinized by many regulatory entities. During the preclinical stage of the development process, plans for clinical trials and an Investigative New Drug (IND) application are prepared. Studies taking place during the preclinical stage should be designed to support the clinical studies that will follow.
The main stages of pre-clinical toxicology testing are:
(a) Acute Studies:
Acute toxicity studies look at the effects of one or more doses administered over a period of up to 24 hours. The goal is to determine toxic dose levels and observe clinical indications of toxicity. Usually, at least two mammalian species are tested. Data from acute toxicity studies helps to determine doses for repeated dose studies in animals and Phase 1 studies in
(b) Repeated Dose Studies:
Depending on the duration of the studies, repeated dose, studies may be referred to as sub acute, sub chronic or chronic. The specific duration should anticipate the length of the clinical trial that will be conducted on the new drug. Again, two species are typically required.
(c) Genetic Toxicity Studies:
These studies assess the likelihood that the drug compound is mutagenic or carcinogenic. Procedures such as: the Ames test (conducted in bacteria) detect genetic changes DNA damage is assessed in tests using mammalian cells such as: the Mouse Micronucleus Test. The Chromosomal Aberration Test and similar procedures detect damage at the chromosomal level.
(d) Reproductive Toxicity Studies:
Segment I reproductive toxicity studies look at the effects of the drug on fertility. Segment II and III studies detect effects on embryonic and post-natal development. In general, reproductive toxicity studies must be completed before a drug can be administered to women of child-bearing age.
(e) Carcinogenicity Studies:
Carcinogenicity studies are usually needed only for drugs intended for chronic or recurring conditions. They are time consuming and
(f) Toxicokinetic Studies:
These are typically similar in design to PK/ADME studies except that they use much higher dose levels. They examine the effects of toxic doses of the drug and help estimate the clinical margin of safety. There an numerous FDA and ICH guidelines that give a wealth of detail on the different types of pre-clinical toxicology studies and the appropriate timing for them relative to IND and NDA or BLA filings.
6. Bioanalytical Testing:
Bioanalytical laboratory work and bioanalytical method development supports most of the other activities in the drug development process. The bioanalytical work is key to proper characterization of the molecule, assay development, developing optimal methods for cell culture or fermentation, determining process yields and providing quality assurance and quality control for the entire development process.
It is also critical for supporting pre-clinical toxicology/pharmacology testing and clinical trials.
7. Clinical Trials:
The Clinical studies are grouped according to their objective into three types or phases:
(a) Phase I Clinical Development (Human Pharmacology):
Thirty days after a biopharmaceutical company has filed its IND, it may begin a small-scale Phase I clinical trial unless the FDA places a hold on the study. Phase I studies are used to evaluate pharmacokinetic parameters and tolerance, generally in healthy volunteers. These studies include initial single-dose studies, dose escalation and short-term repeated dose studies.
(b) Phase II Clinical Development (Therapeutic Exploratory):
Phase II clinical studies are small-scale trials to evaluate a drug’s preliminary efficacy and side-effect profile in 100 to 250 patients. Additional safety and clinical pharmacology studies are also included in this category.
(C) Phase III Clinical Development (Therapeutic Confirmatory):
Phase III studies are large-scale clinical trials for safety and efficacy in large patient populations. While phase III studies are in progress, preparations are made for submitting the Biologics License Application (BLA) or the New Drug Application (NDA). BLAs are currently reviewed by the FDA’s Center for Biologics Evaluation and Research (CBER). NDAs are reviewed b the Center for Drug Evaluation and Research (CDER).
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