Process of Discovering And Creating New Drug
What is Drug Discovery?
In medicine, pharmacology, and biotechnology, drug discovery is a procedure to discover and design a new drug .In early years, many drugs were discovered by recognizing the active constituent from traditional remedies (for example, morphine, cocaine, digitalis, tubocurarine) or by the serendipitous discovery (for example, penicillin, streptomycin, vinblastine, methotrexate). But in the modern era, a drug has been discovered using a new approach i.e.,firstly to know how disease and infection can be controlled at the molecular and physiological level and to focus specific entities based on thesefacts. The drug development is a time consuming and costly process that takes about 12 years and costs, on average over €1 billion to do all the research and trials. A lot of medicines (around 98%) that entering development processes don’t come in the market, after being developed. So, the development of a medicine is a high risk speculation.
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Process Involved in Drug Discovery
The figure shows the whole process that should be followed by a chemical candidate to become a ‘DRUG.’
The steps followed during drug development can be given as:
Step-1: Drug Discovery and Validation of Target:
The first step in the process of drug development is discovery work.A pharmaceutical company decides which disease to target when designing a new drug in consideration of medical as well as economic factors.This is the matter of market strategies of a company who ensure that they also get an excellent financial return for their investment. The identification of the therapeutic area is following by target identification. A drug target can be a receptor, enzyme, or nucleic acid, depending upon the etiology of a disease. The target identification may be made with the help of numerous tests and new technologies. It is common for drug developers that they have some of promising lead compounds at this stage.These lead molecules for that specific drug can be identified using combinatorial chemistry, molecular docking and in-silico tests, and high throughput screening of chemical libraries.
These lead molecules have to be optimized for development of a promising compound, at the numerous levels like:
1) Target selectivity and specificity between species and within the body
2) Pharmacokinetics and pharmacodynamics
3) The best dosage form and formulation
4) Toxicity profile
5) Drug interaction profile
6) Bioequivalence
Step-2: Preclinical testing or Preclinical Research:
The next step in the drug development process is preclinical testing of lead molecules to check the toxicity profile before these will tested upon people. Preclinical testing can be divided into two subcomponents:
- In-vitrotesting
- In-vivo testing
In-vitro testing often starts with genetically engineered cell cultures to studyinteractionsof the drug molecules in test tubes within the lab where researchers should follow good laboratory practices (GLPs) defined by Food & Drug Agency (FDA) for preclinical testing. In-vivo testing involves testing the drug molecules on transgenic mice or other animal models to examine any effects on cell reproduction and to identify carcinogenicity of the test molecules. Any sign of toxicity and carcinogenicity may prevent the test molecule fromgoing to the next step. Hence preclinical testing would take many years to collect the extensive data on safety as this is the utmost requirement of FDA.
Step-3: Investigational New Drug Application Filing:
Before the commencement of human clinical trials, the next step involves submitting an Investigational New Drug (IND) application to the FDA. This is the step where the FDA will consider pharmacokinetics, pharmacodynamics, toxicity, manufacturing process, and other preclinical data of the applied drug toscrutinize the results from the preclinical testing. A drug or IND can move to clinical studies only after the FDA approval.After this IND approval step, 20-year exclusivity period of patented drugs also begins.
Step-4: Clinical Studies:
After the FDA approval, the tested drug is ready to go to clinical trials. Clinical trialsinvolve testing of the drug on volunteers and patients. Hence, the procedure must be ethical and without any accusation. This step is the extremely expensive, time-taking and also requires hundred to thousand human volunteers. There are four phases of clinical testing.
A) Phase-I Clinical Trials: The first phase involves 20–100 healthy volunteers, and it will take about a year. Phase-I trials provide the preliminary data on absorption, distribution, metabolism, excretion from the body, side effects, and maximum tolerated doses of the drug. Phase-1 clinical studies are also carried out on particular age groups; for example, drug for Alzheimer’s disease are tested on elderly patients. The drugs intended for life-threatening diseases are tested on cancer and AIDS, volunteer patients. Bioequivalence studies are also carried out at this stage because powder-filled capsules are used in this phase, whereas tablets are used in Phase-II and III. The promisingdata of Phase-I studies of the drug opens the door of Phase-II, or mid-stage trials.Almost 70% of drugs go to the Phase-II.
B) Phase-II Clinical Trials: Usually, Phase-II trials may start before Phase-I studies get complete. This phase generally takes about two years. The patient pool extendsa hundred or more than hundred and the patients being treated are the volunteers having disease in question.Phase-II studies can be divided into early (Phase-IIa) and late (Phase-IIb) studies. In early (Phase-IIa) involve a limited number of patients, so see the therapeutic efficacy, the best dose regimen, and any apparent side effects of the drug. If the results are disappointing, further studies may be terminating at this stage.
Phase-IIb involves a larger number of patients. This is a double-blind placebo-controlled study where the patients split into two groups: one group receives the drug, and the other group gets a placebo. Neither the doctor nor the patients know whether a placebo or drug is administered. These studies show the efficacy of drug relative to placebo with different dosing levels. The endpoint of the study is the measurement of successful of the drug. This measurement can be a blood assay, blood pressure, inhibition of pathogen, or any measurable and ethical parameter. The promising data of the experimental drug pave the way of late-stage studies.
C) Phase-III Clinical Trials:This trial takes typically about three years. Phase-III studies also divided into two groups like Phase-II studies: Phase-IIIa and Phase-IIIb clinical studies. The FDA approval on primary endpoint of Phase-II studies is necessary to carry out Phase-III studies.This can be also a double-blind experiment that involves some hundred to thousand patients.A comparative study of patients taking the drug is applied among the patients receiving placebo, and people take another available drug.
Phase-IIIa studies establish actuality efficacy and acquire any side effect that wasn’t previously detected. After passing this trial, the drug will be registered.
After registration, Phase-IIIb studies can be conducted out, but before approval. These studies involve a comparison of the drug with an already established drug. In some cases where drug shows a clear benefit early on, the Phase-III trials can be terminated earlier than planned. This can be also the stage where drug developers will begin to give some thought to how they go to build up production if the Phase-III results are favorable. If the results of phase III studies find promising, the following step is to file for its approval.
Step 5: New Drug Application Filing:
If it is evidenced by preclinical and clinical researchthat a drug is safe and effective, the company can file a New Drug Application (NDA) with the FDAto market the drug. An NDA tells the full story of a drug from preclinical data to Phase-III clinical trials with 100000 or more pages.It is decision of the FDA review team to approve or not to approve a drug who will take his decision after thoroughly examination of all submitted data on the drug.
If the New Drug Application is accepted Prescription Drug User Fee Act, the date is set 10 months by the FDA tomake its decision. Here, the FDA has three choices:
1) It can approve a drug
2) It can absolutely deny a drug or
3) It can appeal supplementary information by referring a complete response letter (CRL).
A CRLis simply a statement about shortcomings and suggestions to remedy the situation. Usually, drug developers carry out additional studies on drug or maymodify their manufacturing process to appease the FDA.If the drug approved by the FDA, the drug turns out to be immediately available for commercial production.
Step-6: Phase-IV Clinical Trials:
Technically, an approved drug is now placed on the market and can be prescribed. But it is still monitored for effectiveness and rare or unexpected side effects as the safety remains the top priority of the FDA. From start to end, the whole drug development process usually spans about ten to fifteen years. Now, the drug developers have around a decade of exclusive patent on branded drugs once they make it to market. This is the reason why prescription drug prices are so high.
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Author
Dr. Shilpi Chauhan
Assistant Professor
Lloyd Institute of Manngement and Technology (Pharm.)
