MPP Lecture 4 on Drug Discovery & Development PDF

Outline the timeline of drug discovery and explain the process by which a drug becomes commercially available. a. First 4-7 years i. 1. Discovery/Development ii. 2. Preclinical Research b. 2nd phase: 8 years i. 3. Clinical research c. FDA application: 2 years...

Outline the timeline of drug discovery and explain the process by which a drug becomes commercially available. a. First 4-7 years i. 1. Discovery/Development ii. 2. Preclinical Research b. 2nd phase: 8 years i. 3. Clinical research c. FDA application: 2 years i. 4. Data review d. Post-approval: ongoing i. 5. Post-market monitoring Describe the role of the FDA and examine the impact of key legislation on drug development: 1962 Kefauver-Harris Drug Amendment; 2007 Food and Drug Administration Amendment Act; and 1983 Orphan Drug Act. ii. 1962 Kefauver-Harris Drug Amendment: drug manufacturers required to prove to the FDA the safety and effectiveness of their products before marketing them based on data from thalidomide. iii. 2007 Food and Drug Administration Amendment Act: Enhanced FDA's ability to monitor post-market drug safety and required manufacturers to conduct post-approval studies. Clinical Trials Registration Mandated the registration of most clinical trials and reporting of their results on ClinicalTrials.gov. iv. Orphan Drug Act (ODA) of 1983 mandated the FDA designate a proposed treatment as an "orphan" drug if it is intended to treat a rare disease or condition affecting fewer than 200,000 people in the United States. Identify and discuss barriers to participation and diversity in clinical trials. v. Lack of awareness about available trials vi. Transportation difficulties vii. Time and resource constraints viii.Insufficient compensation for participants ix. Trust issues also hinder participation:  Define and differentiate between the terms safety, efficacy, and effectiveness as they relate to drug development and clinical trials. Safety: Safety is the assessment of the potential risks and adverse effects associated with the investigational intervention (such as a drug, medical device, or treatment) being tested. The evaluation of safety involves monitoring and documenting any adverse events or side effects that participants experience during the trial. The goal is to ensure that the benefits of the intervention outweigh the potential risks and that participants are not subjected to undue harm. Efficacy: Efficacy refers to the extent to which an investigational intervention produces the intended beneficial effects under controlled conditions. In the context of clinical trials, it's about determining whether the intervention achieves its desired therapeutic outcomes. This is typically assessed through predefined endpoints or outcome measures, such as improvements in symptoms, disease progression, or other relevant factors. Efficacy evaluation helps to establish whether the intervention has the potential to provide the intended medical benefits. Effectiveness: Effectiveness refers to the real-world impact of an intervention in a patient population that is more heterogenous and less controlled. It evaluates how well the intervention works in everyday clinical practice, beyond the controlled environment of a clinical trial. Effectiveness is studied in Phase IV and studies often involve larger and more diverse patient groups and consider factors that might not have been well-represented in the trial setting, such as patients with multiple comorbidities or those who may not strictly meet the trial's eligibility criteria. Explain the key components and purposes of each phase in clinical studies: Phase 1; Phase 2; Phase 3; and New Drug Application (NDA) filing with the FDA. Phase 1: Purpose: The primary goal is to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of the drug. This phase aims to determine the drug's effects on the body, how it is absorbed, metabolized, and excreted, and to identify any potential side effects.  Participants: Typically involves 20-100 healthy volunteers or patients (if the drug is intended for a serious condition where testing on healthy volunteers is not ethical). Key Components: ○ Dose escalation: Starts with a low dose, which is gradually increased. ○ Safety assessment: Monitoring for adverse effects. ○ Pharmacokinetics: Measuring how the drug is processed by the body. ○ Pharmacodynamics: Understanding the drug's effects on the body. Phase 2: Purpose: The main focus is on evaluating the drug's efficacy, as well as further assessing its safety. This phase helps determine the optimal dose and treatment regimen. Participants: Involves 100-300 patients who have the condition the drug is intended to treat. Key Components: ○ Efficacy assessment: Dose optimization: Safety monitoring: Phase 3: Purpose: This phase aims to confirm the drug's efficacy, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug to be used safely. Participants: Involves 1,000-3,000 patients, and is typically conducted in multiple sites and sometimes multiple countries. Key Components: ○ Efficacy confirmation: Large-scale studies to confirm the drug's benefit. ○ Comparison: Often compared to a standard treatment or placebo. ○ Safety data collection: Monitoring for adverse events over a longer period and in a larger group. ○ Risk-benefit analysis: Helps determine if the benefits outweigh the risks. New Drug Application (NDA) Filing with the FDA: Purpose: This is the formal proposal submitted to the U.S. Food and Drug Administration (FDA) to approve a new drug for sale and marketing in the U.S. Components of NDA:  e. Preclinical and clinical study data: Includes all data from Phase 1-3 trials. f. Proposed labeling: Information on how the drug should be used, including dosing, administration, and safety information. g. Manufacturing details: Information on the drug's production, quality control, and stability. h. Data supporting the drug's safety and efficacy: Comprehensive review of all collected data. FDA Review: The FDA reviews the NDA to determine whether the drug is safe and effective for its intended use. This can include further requests for information, advisory committee reviews, and the potential for post-marketing studies. Describe the purpose of Phase 4 trials and post-marketing monitoring required by the FDA, including: a) Methods for reporting adverse events to the FDA b) The process of continuous drug monitoring after FDA approval. Phase 4 Trials (Post-Marketing Surveillance): Purpose: Long-term safety and effectiveness: Phase 4 trials occur after a drug has been approved by the FDA and is on the market. These studies are designed to monitor the long-term effects, effectiveness, and safety of the drug in a broader patient population. Detection of rare or long-term adverse events: Since Phase 3 trials involve a limited number of participants and follow them for a relatively short period, Phase 4 helps detect rare side effects, interactions with other medications, or long-term risks that may not have been apparent earlier. Comparative effectiveness: Some Phase 4 studies compare the new drug with other standard treatments to determine its relative effectiveness and safety. Additional indications: Phase 4 trials may also explore the drug's efficacy for other conditions or in different populations (e.g., pediatric or geriatric). Post-Marketing Monitoring Required by the FDA: a) Methods for Reporting Adverse Events to the FDA:  MedWatch Program: ○ Purpose: MedWatch is the FDA’s Safety Information and Adverse Event Reporting Program. It allows healthcare professionals, patients, and consumers to report adverse events, product problems, or medication errors associated with FDA-regulated products, including drugs. Mandatory Reporting by Manufacturers: ○ 21 CFR Part 314: Requires drug manufacturers to report any adverse events or product defects to the FDA as part of their post-marketing obligations. ○ Serious Adverse Event Reporting: Any serious or unexpected adverse event must be reported to the FDA within 15 days of the manufacturer becoming aware of it. b) The Process of Continuous Drug Monitoring After FDA Approval: Periodic Safety Update Reports (PSURs): i. Purpose: Manufacturers must regularly submit safety update reports, which summarize all known safety data, including newly identified risks, adverse events, and the benefit-risk assessment. j. Frequency: These reports are usually required annually for the first few years after approval and then less frequently. FDA’s Adverse Event Reporting System (FAERS): k. Purpose: The FDA maintains a database called FAERS, which contains adverse event reports, medication error reports, and product quality complaints. FAERS is used to monitor for potential safety concerns with drugs post-approval. l. Signal Detection: The FDA uses FAERS to identify "signals" or patterns of adverse events that might suggest a safety issue with a drug. m. Action: If a safety signal is identified, the FDA may take action, such as updating the drug’s labeling with new warnings, issuing communications to healthcare providers, or in some cases, withdrawing the drug from the market. Risk Evaluation and Mitigation Strategies (REMS):  n. Purpose: The FDA may require REMS for certain drugs to ensure that their benefits outweigh their risks. REMS may include restricted distribution, specialized training for prescribers, or other measures to manage specific risks. o. Monitoring Compliance: The FDA monitors compliance with REMS requirements and may take enforcement action if necessary. Post-Marketing Studies: p. Purpose: The FDA may require additional studies or clinical trials after a drug is approved to gather more information on its safety, efficacy, or optimal use. q. Types of Studies: These can include long-term safety studies, studies in specific populations (e.g., children), or studies assessing the drug’s effectiveness in real-world settings. Outline the process and reasons for drug recalls. Class I: A dangerous or defective product that could cause serious health problems or death. Class II: A product that might cause a temporary health problem or pose slight threat of a serious nature. Class III: A products that is unlikely to cause any adverse health reaction, but that violates FDA labeling or manufacturing laws. Discuss the purpose of orphan drugs and explain the incentives provided to pharmaceutical companies for their development. - ODA provides pharmaceutical companies with incentives to increase research efforts focused on treatments for rare diseases.