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Drug development process

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Drug development process

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Drug development process

  1. 1. 1 | P a g e DRUG DEVELOPMENT PROCESS: Stages of Drug Development Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery. Any drug development process must proceed through several stages in order to produce a product that is safe, efficacious, and has passed all regulatory requirements. Detailed Stages of Drug Development 1. Discovery and Development 2. Preclinical Research 3. Investigational New Drug (IND) Application Filing 4. Clinical Research i. Clinical Trial Phase Studies  Phase 1  Phase 2  Phase 3 ii. The IND Process iii. FDA IND approval 5. FDA Review i. New Drug Application ii. Review of The New Drug Application iii. FDA Final Approval 6. FDA Post-Market Safety Monitoring Stage 1: DISCOVERY AND DEVELOPMENT Discovery The first step in the drug development process involves discovery work. Discovery often begins with target identification – choosing a biochemical mechanism involved in a disease condition. Drug candidates, discovered in academic and pharmaceutical or biotech research labs, are tested for their interaction with the drug target. Typically, researchers discover new drugs through:  New insights into a disease process that allow researchers to design a product to stop or reverse the effects of the disease.  Many tests of molecular compounds to find possible beneficial effects against any of a large number of diseases.  Existing treatments that have unanticipated effects.  New technologies, such as those that provide new ways to target medical products to specific sites within the body or to manipulate genetic material.
  2. 2. 2 | P a g e At this stage in the process, thousands of compounds may be potential candidates for development as a medical treatment. After early testing, however, only a small number of compounds look promising and call for further study. Development Once researchers identify a promising compound for development, they conduct experiments to gather information on: 1. How it is absorbed, distributed, metabolized, and excreted. 2. Its potential benefits and mechanisms of action. 3. The best dosage form. 4. The best way to give the drug (such as by mouth or injection). 5. Side effects or adverse events that can often be referred to as toxicity. 6. How it affects different groups of people (such as by gender, race, or ethnicity) differently. 7. How it interacts with other drugs and treatments. 8. Its effectiveness as compared with similar drugs. Product Characterization When the candidate molecule looks promise as a therapeutic, it must be characterized—the molecule’s size, shape, strengths and weaknesses, preferred conditions for maintaining function, toxicity, bioactivity, and bioavailability must be
  3. 3. 3 | P a g e determined. Characterization studies undergoes analytical method development and validation. Early stage pharmacology studies help to characterize the underlying mechanism of action of the compound. Stage 2: PRECLINICAL RESEARCH Preclinical research refers to the testing of a new drug, biological procedure or a treatment in animal models before trials may be carried out in humans. Before testing a new drug in people, researchers must find out whether it has the potential to cause serious harm, called toxicity. Preclinical Toxicology Testing Preclinical testing analyzes the bioactivity, safety, and efficacy of the formulated drug 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 purpose of preclinical toxicology testing is: 1. Evaluate acute and short term toxicity in animals (one rodent, one non- rodent). – Dose at increasingly high levels to induce toxicity. – Determine lethal dose. – Dose at normal levels for short and long term. 2. Assess how drug is absorbed, distributed, metabolized, and excreted in animals Stages Of Preclinical Toxicology Testing The main stages of preclinical toxicology testing are: Acute Studies Acute tox 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 tox studies helps determine doses for repeated dose studies in animals and Phase I studies in humans. Repeated Dose Studies Depending on the duration of the studies, repeated dose studies may be referred to as subacute, subchronic, 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.
  4. 4. 4 | P a g e Genertic 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. Reproductive Toxicity Studies Segment I reproductive tox 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 tox studies must be completed before a drug can be administered to women of child-bearing age. 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 preclinical testing process. 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 preclinical toxicology/pharmacology testing and clinical trials. There are two types of preclinical research:  In Vitro  In Vivo In vitro testing examines the drug molecules' interactions in test tubes and within the lab setting. In vivo testing involves testing the drug molecules on animal models and in other living cell cultures. Although efficacy is beginning to be established here, safety is uncertain. This is the stage where only 1 to 5 lead compounds are chosen between thousands of drug molecule candidates. By the time preclinical research has been ended, many years have often passed. However, this study provides detailed information on dosing and toxicity levels of new drug candidate. After preclinical testing, researchers review their findings and decide whether the drug should be tested in people.
  5. 5. 5 | P a g e Stage 3: CLINICAL RESEARCH “Clinical research” refers to studies or trials that are done in human. This stage includes, Designing Clinical Trials Clinical Research Phase Studies The Investigational New Drug (IND) Process Asking for FDA Assistance FDA IND Review Team Approval DESIGNING CLINICAL TRIALS Researchers design clinical trials to answer specific research questions related to a medical product. These trials follow a specific study plan, called a protocol, that is developed by the researcher or manufacturer. Before a clinical trial begins, researchers review prior information about the drug to develop research questions and objectives. Then, they decide: 1. Who qualifies to participate (selection criteria) 2. How many people will be part of the study 3. How long the study will last 4. Whether there will be a control group and other ways to limit research bias 5. How the drug will be given to patients and at what dosage 6. What assessments will be conducted, when, and what data will be collected 7. How the data will be reviewed and analyzed Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late, large- scale, Phase 3 studies. CLINICAL RESEARCH PHASE STUDIES Phase 1 Clinical Development (Human Pharmacology) 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.  Study Participants: 20 to 100 healthy volunteers or people with the disease/condition.  Length of Study: Several months  Purpose: Determining safety and dosage
  6. 6. 6 | P a g e During Phase 1 studies, researchers test a new drug in normal volunteers (healthy people). In most cases, 20 to 80 healthy volunteers or people with the disease/condition participate in Phase 1. However, if a new drug is intended for use in cancer patients, researchers conduct Phase 1 studies in patients with that type of cancer. Phase 1 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 1 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 2 studies. Approximately 70% of drugs move to the next phase. Phase 2 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.  Study Participants: Up to several hundred people with the disease/condition.  Length of Study: Several months to 2 years  Purpose: Evaluate Efficacy/effectiveness, look for side effects In Phase 2 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. Instead, Phase 2 studies provide researchers with additional safety data. Researchers use these data to refine research questions, develop research methods, and design new Phase 3 research protocols. Approximately 33% of drugs move to the next phase.
  7. 7. 7 | P a g e Phase 3 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).  Study Participants: 300 to 3,000 volunteers who have the disease or condition  Length of Study: 1 to 4 years  Purpose: Confirm effectiveness, monitoring of adverse reactions for long term use Researchers design Phase 3 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 3 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. Approximately 25-30% of drugs move to the next phase. Phase 4  Study Participants: Several thousand volunteers who have the disease/condition  Purpose: Safety and efficacy Phase 4 trials are carried out once the drug or device has been approved by FDA during the Post-Market Safety Monitoring The Investigational New Drug (IND) Application Filing Drug developers or sponsors must submit an Investigational New Drug (IND) application file to FDA before beginning human clinical trials. In the IND application, developers must include:  Animal study data and toxicity (side effects that cause great harm) data  Manufacturing information  Clinical protocols (study plans) for studies to be conducted  Data from any prior human research  Information about the investigator
  8. 8. 8 | P a g e FDA will examine the results from the preclinical test report, look at side effects and other safety features of the experimental drug and then, if approved, it can move onto human trials. An IND approval is also the point at which a patented drugs' 20-year exclusivity period begins. Asking for FDA Assistance Drug developers are free to ask for help from FDA at any point in the drug development process, including: Pre-IND application, to review FDA guidance documents and get answers to questions that may help enhance their research. After Phase 2, to obtain guidance on the design of large Phase 3 studies Any time during the process, to obtain an assessment of the IND application Even though FDA offers extensive technical assistance, drug developers are not required to take FDA’s suggestions. As long as clinical trials are thoughtfully designed, reflect what developers know about a product, safeguard participants, and otherwise meet Federal standards, FDA allows wide latitude in clinical trial design. FDA IND Review Team The review team consists of a group of specialists in different scientific fields. Each member has different responsibilities. Project Manager: Coordinates the team’s activities throughout the review process, and is the primary contact for the sponsor. Medical Officer: Reviews all clinical study information and data before, during, and after the trial is complete. Statistician: Interprets clinical trial designs and data, and works closely with the medical officer to evaluate protocols and safety and efficacy data. Pharmacologist: Reviews preclinical studies. Pharmakineticist: Focuses on the drug’s absorption, distribution, metabolism, and excretion processes. Interprets blood-level data at different time intervals from clinical trials, as a way to assess drug dosages and administration schedules. Chemist: Evaluates a drug’s chemical compounds. Analyzes how a drug was made and its stability, quality control, continuity, the presence of impurities, etc. Microbiologist: Reviews the data submitted, if the product is an antimicrobial product, to assess response across different classes of microbes. APPROVAL The FDA review team has 30 days to review the original IND submission. The process protects volunteers who participate in clinical trials from unreasonable and significant risk in clinical trials.
  9. 9. 9 | P a g e FDA responds to IND applications in one of two ways:  Approval to begin clinical trials.  Clinical hold to delay or stop the investigation. FDA can place a clinical hold for specific reasons, including: 1. Participants are exposed to unreasonable or significant risk. 2. Investigators are not qualified. 3. Materials for the volunteer participants are misleading. 4. The IND application does not include enough information about the trial’s risks. A clinical hold is rare; instead, FDA often provides comments intended to improve the quality of a clinical trial. In most cases, if FDA is satisfied that the trial meets Federal standards, the applicant is allowed to proceed with the proposed study. Stage 4: FDA FINAL REVIEW If a drug developer has evidence from its early tests and preclinical and clinical research that a drug is safe and effective for its intended use, the company can file an application to market the drug. The FDA review team thoroughly examines all submitted data on the drug and makes a decision to approve or not to approve it. Find out how the FDA is Speeding Up the Approval Process- New Drug Application A New Drug Application (NDA) tells the full story of a drug. Its purpose is to demonstrate that a drug is safe and effective for its intended use in the population studied. A drug developer must include everything about a drug—from preclinical data to Phase 3 trial data—in an NDA. Developers must include reports on all studies, data, and analyses. Along with clinical results, developers must include: 1. Proposed labeling 2. Safety updates 3. Drug abuse information 4. Patent information 5. Any data from studies that may have been conducted outside the United States 6. Institutional review board compliance information 7. Directions for use
  10. 10. 10 | P a g e FDA Review of The New Drug Application Once FDA receives an NDA, the review team decides if it is complete. If it is not complete, the review team can refuse to file the NDA. If it is complete, the review team has 6 to 10 months to make a decision on whether to approve the drug. The process includes the following: Each member of the review team conducts a full review of his or her section of the application. For example, the medical officer and the statistician review clinical data, while a pharmacologist reviews the data from animal studies. Within each technical discipline represented on the team, there is also a supervisory review. FDA inspectors travel to clinical study sites to conduct a routine inspection. The Agency looks for evidence of fabrication, manipulation, or withholding of data. The project manager assembles all individual reviews and other documents, such as the inspection report, into an “action package.” This document becomes the record for FDA review. The review team issues a recommendation, and a senior FDA official makes a decision. FDA Final Approval In cases where FDA determines that a drug has been shown to be safe and effective for its intended use, it is then necessary to work with the applicant to develop and refine prescribing information. This is referred to as “labeling.” Labeling accurately and objectively describes the basis for approval and how best to use the drug. Often, though, remaining issues need to be resolved before the drug can be approved for marketing. Sometimes FDA requires the developer to address questions based on existing data. In other cases, FDA requires additional studies. At this point, the developer can decide whether or not to continue further development. If a developer disagrees with an FDA decision, there are mechanisms for formal appeal. FDA Advisory Committees Often, the NDA contains sufficient data for FDA to determine the safety and effectiveness of a drug. Sometimes, though, questions arise that require additional consideration. In these cases, FDA may organize a meeting of one of its Advisory Committees to get independent, expert advice and to permit the public to make comments. These Advisory Committees include a Patient Representative that provides input from the patient perspective. Learn more about FDA Advisory Committees.
  11. 11. 11 | P a g e Stage 5: FDA Post-Market Safety Monitoring Even though clinical trials provide important information on a drug’s efficacy and safety, it is impossible to have complete information about the safety of a drug at the time of approval. Despite the rigorous steps in the process of drug development, limitations exist. Therefore, the true picture of a product’s safety actually evolves over the months and even years that make up a product’s lifetime in the marketplace. FDA reviews reports of problems with prescription and over-the-counter drugs, and can decide to add cautions to the dosage or usage information, as well as other measures for more serious issues. Reference: https://www.fda.gov>Approvals>Drugs U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, MD 20993 1-888-INFO-FDA (1-888-463-6332)

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