1. Unit I - new drug discovery and development.

B. Pharm. Final Year,
Sem-VIII, BP804 ET: PHARMACEUTICAL REGULATORY SCIENCE (Theory).
Unit-I Chapter 1. New Drug Discovery and development

1. Unit-I Chapter 1. New Drug Discovery and development Represented By, Mr. Audumbar Mali. (Assistant Professor) Sahyadri College of Pharmacy Methwade BP804 ET: PHARMACEUTICAL REGULATORY SCIENCE (Theory)

2. STAGES OF DRUG DISCOVERY AND DEVELOPMENT PROCESS: 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.

3. 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 divide into three main components- drug discovery, P re - clinical evaluation and clinical trials.

4. STAGES OF DRUG DISCOVERY AND DEVELOPMENT PROCESS: 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.

5. STAGES OF DRUG DEVELOPMENT: Discovery, Product Characterization, Formulation , Delivery, Packaging Development, Pharmacokinetics and Drug Disposition, Preclinical Toxicology Testing and IND Application, Bioanalytical Testing and Clinical Trials

6. Preclinical synthesis and physiochemical analysis Preliminary biological evaluation Secondary and specific biological evaluation Rang finding toxicological studies Target organ toxicological studies Acute and subacute toxicological studies Metabolic studies

7. synthesis and quality control of bulk materials Phase I clinical evaluation Final formulation and final physiochemical analysis Phase 2 clinical evaluation Phase 3 clinical evaluation Phase 4 clinical evaluation

8. Discovery: 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.

9. 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. ( i ) 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. (ii). Target Discovery: This method involves identification of targets that have already established drug targets.

10. (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: (I) It should be feasible to alter the affinity of the drug to the target by modulating the activity of drug molecule. (II) The effect of the drug should or should not be modified by altering the change cell or tissue type. (III) Introducing mutations in to the binding domain of the protein target should result in either modulation or loss of activity of the ligand.

11. (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.

12. 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.

13. 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.

14. 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.

15. 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 humans.

16. (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 expensive and must be planned for early in the pre-clinical testing process.

17. (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.

18.   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.

19. (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).

20. Regulatory Overview: A. Drug Development Process: 1. Filing of Investigational New Drug (IND)Application: After successful pre-clinical studies, the researchers must file an IND application with the respective regulatory authority. This application includes information on the clinical studies, the chemistry of the molecule, pharmacodynamic and toxicological effects. After the filing of the application, the regulatory authority will review the application to assure the benefits foresees the risk on the humans. In addition to this, Institutional Review Board (IRB) must also grant the permission to initiate the trails. Informed Consent process plays a vital role in clinical studies. After thorough review, both the regulatory authority and the IRB grant the consent to initiate the trials. The sponsor must update the results constantly to the authority and IRB on the ongoing studies. Sponsors and the regulators hold the powers to impede the trails at any phase, it found unethical or harmful on the subjects.

21. 2. Phase 0 Clinical Trials: Phase 0 trials are the first clinical trials done among people. They aim to learn how a drug is processed in the body and how it affects the body. In these trials, a very small dose of a drug is given to about 10 to 15 people. 3. Phase I Clinical Trials: During Phase I studies, researchers test a new drug in normal volunteers (healthy people). In most cases, 20 to 80 healthy volunteers participate in Phase I. However, if a new drug is intended for use in cancer patients, researchers conduct Phase I studies in patients with that type of cancer.

22. Phase I studies are closely monitored and gather information about how a drug interacts with the human body. Researchers adjust dosing schemes based on animal data to find out how much of a drug the body can tolerate and what its acute side effects are. As a Phase I trial continues, researchers answer research questions related to how it works in the body, the side effects associated with increased dosage, and early information about how effective it is to determine, how best to administer the drug to limit risks and maximize possible benefits. This is important to the design of Phase II studies. Approximately 70% of drugs move to the next phase. 4. Phase II Clinical Trials: In Phase II studies researchers administer the drug to a group of patients with the disease or condition for which the drug is being developed. Typically involving a few hundred patients, these studies aren't large enough to show whether the drug will be beneficial.

23. Instead, Phase II studies provide researchers with additional safety data. Researchers use these data to refine research questions, develop research methods and design new Phase II research protocols. Approximately 33% of drugs move to the next phase. 5. Phase III Clinical Trials: Researchers design Phase III studies to demonstrate whether or not a product offers a treatment benefit to a specific population. Sometimes known as pivotal studies, these studies involve 300 to 3,000 participants. Phase III studies provide most of the safety data. In previous studies, it is possible that less common side effects might have gone undetected. Because these studies are larger and longer in duration, the results are more likely to show long-term or rare side effects. This enables them to generate the data on safety, efficacy and benefit risk ratio of the drug. Safety and effectiveness of the trials is determined on the basis of this study. In addition, the labeling requirement of the drug is also fulfilled, enabling the adequate instruction in the use of the drug. Approximately 25-30 % of drugs move to the next phase.

24. 6. Filing of New Drug Application (NDA) and its Approval Process: If the drug is found to be safe and effective, the sponsor shall file the NDA application to the respective regulatory authority. The regulatory authority conducts the stringent review on NDA and may approve or reject the application or may ask the sponsor to provide additional information in regard to NDA. After successful approval of the new drug, the sponsor begins the manufacturing of the drug on the large scale abiding the regulations of the regulatory authority. The drug will be manufactured on the basis of ‘Good Manufacturing Practice’. 7. Phase IV Clinical Trials (Post-marketing Monitoring): This phase of testing involves after the product commercialization. As the large number of people use the drug, continuous monitoring is required. The sponsor is obliged to provide annual reports as required by the authority. This may include reporting and investigation of the incidence and severity of rare adverse reactions, cost-effectiveness analyses comparative trials and quality of life studies.

25.   B. Innovator and Generic Drugs: According to FDA, “A generic drug is a medication created to be the same as an existing approved brand-name drug in dosage form, safety, strength, route of administration, quality, and performance characteristics". An innovator drug is the first drugs created containing its specific active ingredient to receive approval for use. It is usually the product for which efficacy, safety and quality have been fully established. When a new drug is first made, drug patent usually will be acquired by the founding company. Most drug patents are protected up to 20 years. During the patent period, other companies cannot make or sell the same drug until the patent expires.

26. C. Concept of Generics: A generic medicine works in the same way and provides the same clinical benefit as its brand-name version. This standard applies to all FDA-approved generic medicines. A generic medicine is the same as a brand-name medicine in dosage safety, effectiveness, strength, stability and quality, as well as in the way it is taken and should be used. The FDA Generic Drugs Program conducts a rigorous review to make sure generic medicines meet these requirements. In addition, FDA conducts 3,590 inspections of manufacturing plants a year, ensuring compliance with the agency’s regulations on good manufacturing practices.

27. FDA requires drug companies to demonstrate that the generic medicine can be effectively substituted and provide the same clinical benefit as the brand-name medicine that it copies. The abbreviated new drug application (ANDA) submitted by drug companies must show the generic medicine is the same as the brand-name version in the following ways: The active ingredient in the generic medicine is the same as in the brand-name drug/innovator drug. The generic medicine has the same strength, use indications, form (such as: a tablet or an injectable), and route of administration (such as; oral or topical). The inactive ingredients of the generic medicine are acceptable. The generic medicine is manufactured under the same strict standards as; the brand name medicine. The container in which the medicine will be shipped and sold is appropriate, and the label is the same as the brand-name medicine's label.

28. D. Generic Drug Development: After the patent expiry of innovator products, generic company can file for Abbreviated New Drug Application (ANDA). The filing process does not require the data pertaining to the clinical trials; rather it necessitates the applicant to provide data on bioequivalence studies, which demonstrates the therapeutic equivalence of generic drugs with innovator drugs. In addition, the generic drugs must prove its pharmaceutical equivalence with branded drugs. Two pharmaceutical products are said to be bioequivalent if they are pharmaceutically equivalent or pharmaceutical alternatives, and their bioavailability, in terms of rate (Cmax and tmax) and extent of absorption (area under the curve), after administration of the same molar dose under the same conditions, are similar to such a degree that their effects can be expected to be essentially the same. The “Drug Price Competition and Patent Term Restoration Act of 1984,” also known as the Hatch-Waxman Amendments, established the approval pathway for generic drug products, under which applicants can submit an abbreviated new drug application. The Hatch-Waxman Amendments include provisions that involve patents and exclusivities related to new drug applications, and 180-day exclusivity for certain ANDA applicants. *******

29. References: 1. A textbook of Pharmaceutical Regulatory Science, By, Dr. R. Narayana Charyulu , Dr. Jobin Jose. Nirali Prakashan, Page No. 1.1-1.8. 2. A textbook of Pharmaceutical Regulatory Science, By, Dr. Ashok Hajare . Nirali Prakashan, Page No. 1.1-1.36. 3. www.google.com.