The Drug Development Process – From Conception to Market

The Drug Development Process –From Conception to Market


Drug development encompasses the entire process of bringing a new drug to market. The drug discovery journey starts with the identification of a disease or disease area with an unmet medical need and ends with regulatory submissions and market launch.

This article explores the process of drug development from discovery through the stages of development up to approval and product launch.

Stage 1: Early drug discovery program

Companies start with the pre-discovery phase by uncovering the molecular basis of the disease. Researchers study the mechanisms at the tissue and subcellular levels. Based on the underlying disease mechanism, suitable animal disease models and assay platforms are developed.

The next step is target identification. A "target" is an entity (gene/protein) whose chemical modulation may lead to a desired therapeutic effect. Target validation is the process of demonstrating the relevance of the selected target for a specific biological pathway, process or disease.

After target identification and validation, follows the hit identification and lead discovery phase. Hits are molecules that can bind to the target and modify its function. Some of the screening methods available to identify hit molecules include high throughput screening, focused or knowledge-based screening, fragment screening, virtual screen and physiological screen.

During lead discovery, an in-depth search results in the identification of a drug candidate that is progressed through preclinical studies, and if successful, into clinical development and ultimately launched in the market.

Stage 2: Preclinical Research

Preclinical research involves all activities that link drug discovery in the lab to the initiation of trials inhumans. The ultimate goal of preclinical phase is to predict the biological effect of a drug accurately.

Preclinical studies are required by all the regulatory authorities. Preclinical phase helps predict the treatment outcome and identify and characterise all toxicities associated with the drug. Pharmacology studies to evaluate the pharmacokinetics and pharmacodynamics studies to assess the mechanisms of action of the drugs on the body are also conducted. Preclinical studies are conducted using in-vitro/in-vivo models, animal models or in-silico model.

Stage 3: Preparing for Regulatory approval

An investigational new drug (IND) is defined as a new substance, chemical or biological entity that has not been approved by any regulatory authorities for marketing as a drug in any country. An investigational drug is often known as a "study drug" or "experimental drug".

In India, the approval of manufacture/import of Investigational New Drugs for marketing in the country is given by the Central Licensing Authority (CLA).Permission to conduct clinical trials of new drugs, including Investigational New Drugs, is also provided by CLA.The IND application must ideally contain information in three broad areas:⎯Animal Pharmacology and Toxicology Studies⎯Manufacturing Information⎯Clinical Protocols and Investigator Information

Stage 4: Clinical Trials

The efficacy, safety, dosing, and tolerability of new drug molecules is established through carefully designed and executed clinical trials. Clinical trial for a new drug progresses through a series of steps called phases during which vital information regarding the new drug is generated.

Clinical trials of drugs developed in India have to undergo all four phases of trials.

⎯Phase I or "first in man" study

-Phase I trials evaluate the safety and tolerability profile of an investigational new drug in humans. Phase I trials are conducted in healthy subjects or specific groups of patients.

⎯Phase II or exploratory trials-Phase II trials evaluate the drug's effectiveness for a particular disease/condition in patients. This phase help identify the common short-term side-effects and other risks associated with the drug. The dose and regimen of the drug for Phase III trials are also decided.

⎯Phase III or confirmatory trials

-Phase III or confirmatory trials confirms the drug safety and efficacy in a larger number of patients, usually between 1000-3000 subjects. In phase III, the drug may be compared with a standard drug and/or a placebo. If the phase III trial results are favourable, the data is presented to the regulatory authorities for a commercial license to market the drug.

⎯Phase IV or post-marketing trial

-Phase IV or post-marketing trial of new drugs are performed after the drug's approval.

Stage 5: New Drug Application

-New Drug Application (NDA) is an application made by the sponsor to the regulatory authorities for approval to sell and market a new drug in different countries.

NDA includes enough information for the regulatory authorities to determine whether the new drug is safe and effective, whether the drug's benefits outweigh its risks, whether the proposed drug label (package insert) is appropriate, and whether the drug manufacturing standards are adequate.NDA can be broadly divided into different steps⎯The submission of application to conduct clinical trials⎯Conducting clinical trial⎯Application to marketing authorisation of drug by submitting the data collected from the clinical trials⎯Post-marketing surveillance

Stage 6: Product Launch

Once the drug receives approval from the licensing authority, several activities are initiated to prepare for the product's market launch. Some of the key activities during this stage include:

    ⎯ Production and scale-up activities
    ⎯ Packaging and labelling activities
    ⎯ Storage and distribution
    ⎯ Developing market access strategies

Stage 7: Post-marketing Safety Surveillance        

Post-marketing safety surveillance is the identification and collection of information regarding the drug product after its approval.Periodic safety update reports (PSUR) are pharmacovigilance documents that allow regular assessment of the drug product's risk-benefit balance after it is marketed. The primary purpose of the PSUR is to identify new or emerging safety information as a means of determining changes in the benefit-risk profile of the authorised drug.As per the New Drugs and Clinical Trials Rules, 2019, the companies should furnish PSURs every six months for the first two years after drug approval. For the subsequent two years, the PSURs need to be submitted annually.

References

  1. Bermúdez-Crespo J, López JL. A better understanding of molecular mechanisms underlying human disease.Proteomics Clin Appl. 2007;1(9):983-1003.
  2. Schenone M, Dančík V, Wagner BK, Clemons PA. Target identification and mechanism of action in chemical biology and drug discovery.Nat Chem Biol. 2013;9(4):232-240.
  3. Targum SD, Milbauer AJ. The process of getting new drugs to market.Psychiatry (Edgmont). 2008;5(8):57-60.
  4. Polson AG, Fuji RN. The successes and limitations of preclinical studies in predicting the pharmacodynamics and safety of cell-surface-targeted biological agents in patients.Br J Pharmacol. 2012;166(5):1600-1602.
  5. Hughes JP, Rees S, Kalindjian SB, Philpott KL. Principles of early drug discovery.Br J Pharmacol. 2011;162(6):1239-1249.
  6. Saxena P, Saxena R. Clinical trials: changing regulations in India.Indian J Community Med. 2014;39(4):197-202.
  7. New Drugs and Clinical Trials Rules, 2019, Ministry of Health & Fam. Welfare, Notification, G.S.R. 227(E), (March 19, 2019).



Frequently Asked Questions

What is an “orphan drug” as per the New Drugs and Clinical Trial Rules, 2019?

“Orphan drug” means a drug intended to treat a condition which affects not more than five lakh persons in India.

The extrapolation of the safety and efficacy data of a particular clinical indication (for which clinical studies has been done) of a similar biologic to other clinical indications may be possible if following conditions are met: Similarity with respect to quality has been proven to reference biologic Similarity with respect to preclinical assessment has been proven to reference biologic Clinical safety and efficacy is proven in one indication Mechanism of action is same for other clinical indications Involved receptor(s) are same for other clinical indications New indication not mentioned by innovator will be covered by a separate application.

The permission to initiate clinical trial granted in Form CT-06 or automatic approval in Form CT 4A shall remain valid for a period of 2 years from the date of its issue, unless extended by the CLA.

Yes. Before enrolment of first participant in any clinical trial, registration in CTRI is mandatory

The three tier mechanism comprises the following authorities: 1. Institutional Biosafety Committee (IBSC) at the Institute/ company – To ensure biosafety on-site 2. Review Committee on Genetic Manipulation (RCGM) in the Department of Biotechnology - Managed genetically engineered cell banks 3. Genetic Engineering Appraisal Committee (GEAC) in the Ministry of Environment & Forests (MoE&F)- for genetically modified organisms/ living modified organisms

Any person or institution or organisation having permanent establishment in India who intends to conduct clinical trial of a biological product can submit application for clinical trial.

After obtaining permission in CT-11 or CT-14 or CT-15 as the case may be, the person, who intends to manufacture the biological product for CT, shall make an application for grant of license to manufacture the biological product by the respective State Licensing Authority (SLA) in accordance with the provisions of the Act and the Drugs and Cosmetics Rules, 1945.

No. For biological product and substances discovered or developed in countries other than India, Phase I data should be submitted along with the application. After submission of Phase I data generated outside India to the Central Licensing Authority, permission may be granted to repeat Phase I trials or to conduct Phase II trials and subsequently Phase III trial concurrently with other global trials for that biological product.

“New drug” means, (i) a drug, including active pharmaceutical ingredient or phytopharmaceutical drug, which has not been used in the country to any significant extent, except in accordance with the provisions of the Act and the rules made thereunder, as per conditions specified in the labelling thereof and has not been approved as safe and efficacious by the Central Licencing Authority with respect to its claims; or (ii) a drug approved by the Central Licencing Authority for certain claims and proposed to be marketed with modified or new claims including indication, route of administration, dosage and dosage form; or (iii) a fixed dose combination of two or more drugs, approved separately for certain claims and proposed to be combined for the first time in a fixed ratio, or where the ratio of ingredients in an approved combination is proposed to be changed with certain claims including indication, route of administration, dosage and dosage form; or (iv) a modified or sustained release form of a drug or novel drug delivery system of any drug approved by the Central Licencing Authority; or (v) a vaccine, recombinant Deoxyribonucleic Acid (r-DNA) derived product, living modified organism, monoclonal anti-body, stem cell derived product, gene therapeutic product or xenografts, intended to be used as drug; Explanation: The drugs, other than drugs referred to in sub-clauses (iv) and (v), shall continue to be new drugs for a period of four years from the date of their permission granted by the Central Licencing Authority and the drugs referred to in sub-clauses (iv) and (v) shall always be deemed to be new drugs;

In India, genetically modified organisms (GMOs) and the products thereof are regulated under the “Rules for the manufacture, use, import, export & storage of hazardous microorganisms, genetically engineered organisms or cells, 1989” (referred to as Rules, 1989) notified under the Environment (Protection) Act, 1986.

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