Drug Development Process PDF

DRUG DEVELOPMENT PROCESS Adopted from: https://www.fda.gov/patients/learn-about-drug- and-device-approvals/drug-development-process  Step 1: Discovery and Development Disease Insight: Cystic fibrosis is caused by mutations in the CFTR gene, leading to dysfunctional chloride...

DRUG DEVELOPMENT PROCESS Adopted from: https://www.fda.gov/patients/learn-about-drug- and-device-approvals/drug-development-process  Step 1: Discovery and Development Disease Insight: Cystic fibrosis is caused by mutations in the CFTR gene, leading to dysfunctional chloride channels. The G551D mutation results in a channel that fails to open properly. Drug Development: Ivacaftor was developed to enhance the opening (gating) of the defective CFTR protein, improving chloride transport. Impact: Ivacaftor significantly improved lung function and quality of life in patients with the G551D mutation. Disease Insight: Research showed that sodium-glucose cotransporter 2 (SGLT2) in the kidneys plays a key role in glucose reabsorption, contributing to hyperglycemia in diabetes. Drug Development: Dapagliflozin, an SGLT2 inhibitor, was developed to block glucose reabsorption, promoting its excretion in urine. Impact: Initially approved for diabetes, SGLT2 inhibitors also showed significant benefits in heart failure and chronic kidney disease.  Step 1: Discovery and Development Discovery Process: Derived from salicin in willow bark, aspirin's mechanism was not initially understood. Researchers systematically tested its effects, leading to its widespread use as an anti- inflammatory, antipyretic, and analgesic agent. Impact: Aspirin remains a cornerstone in pain relief, cardiovascular disease prevention, and inflammatory conditions. Discovery Process: In the 1960s, Barnett Rosenberg and colleagues were testing the effects of electrical currents on bacterial cell growth and observed that platinum-containing compounds inhibited cell division. Systematic testing revealed its efficacy against cancer. Impact: Cisplatin is a cornerstone chemotherapy drug for various cancers, including testicular, ovarian, and lung cancers.  Step 1: Discovery and Development Discovery Process: Derived from salicin in willow bark, aspirin's mechanism was not initially understood. Researchers systematically tested its effects, leading to its widespread use as an anti- inflammatory, antipyretic, and analgesic agent. Impact: Aspirin remains a cornerstone in pain relief, cardiovascular disease prevention, and inflammatory conditions. Discovery Process: In the 1960s, Barnett Rosenberg and colleagues were testing the effects of electrical currents on bacterial cell growth and observed that platinum-containing compounds inhibited cell division. Systematic testing revealed its efficacy against cancer. Impact: Cisplatin is a cornerstone chemotherapy drug for various cancers, including testicular, ovarian, and lung cancers.  Step 1: Discovery and Development Original Use: Developed as a treatment for angina and hypertension. Unanticipated Effect: During clinical trials, participants reported improved erectile function. New Use: Sildenafil was repurposed as the first oral treatment for erectile dysfunction and later for pulmonary arterial hypertension. Original Use: Bimatoprost was developed to lower intraocular pressure in glaucoma patients. Unanticipated Effect: Patients reported increased eyelash growth. New Use: Marketed as a cosmetic treatment to enhance eyelash length, thickness, and darkness.  Step 1: Discovery and Development Technology: RNA interference (RNAi), a mechanism to silence specific genes. Development: Patisiran, the first approved RNAi therapeutic, uses lipid nanoparticles to deliver small interfering RNA (siRNA) to the liver, targeting the transthyretin (TTR) gene in hereditary amyloidosis. Impact: It offers a novel way to manage genetic diseases by reducing the production of harmful proteins. Technology: Messenger RNA (mRNA) platforms for vaccines.(Pfizer-BioNTech COVID-19 Vaccine, Moderna COVID-19 Vaccine) Development: Researchers created lipid nanoparticle-encased mRNA vaccines that encode the spike protein of SARS-CoV-2, triggering an immune response. Impact: These vaccines were developed and deployed at unprecedented speed during the COVID-19 pandemic, demonstrating the potential of mRNA for rapid vaccine development. Step 1: Discovery and Development Step 1: Discovery and Development  Step 1: Discovery and Development Asian patients show higher plasma concentrations of rosuvastatin compared to Caucasians, potentially leading to increased risk of adverse effects like myopathy. Poor metabolizers with CYP2C19 loss-of-function alleles (e.g., CYP2C19 *2/*3) are less responsive to clopidogrel. These alleles are more common in East Asian populations, leading to reduced efficacy in preventing cardiovascular events. Ultra-rapid metabolizers (more common in Middle Eastern and North African populations) convert codeine to morphine quickly, increasing risk of toxicity. Step 2: Preclinical Research  Step 2: Preclinical Research Examples of Discoveries Through In Vivo Studies: Discovery of Insulin Study: Banting and Best demonstrated the role of pancreatic extracts in reducing blood glucose levels in diabetic dogs. Led to the development of insulin therapy for diabetes. Vaccines Study: Edward Jenner used cowpox virus inoculation in humans (in vivo) to develop the first smallpox vaccine. Pioneered immunization strategies. Penicillin’s Efficacy Study: Penicillin was tested in mice infected with bacterial infections, demonstrating its ability to kill bacteria in a living organism. Revolutionized antibiotic therapy. Thalidomide Teratogenicity Study: Animal studies revealed the severe teratogenic effects of thalidomide, which caused birth defects. Strengthened regulations for drug testing in pregnancy.  Step 2: Preclinical Research Examples of Discoveries Through In Vitro Studies: Structure of DNA Study: Watson and Crick used in vitro data from X-ray crystallography (generated by Rosalind Franklin and Maurice Wilkins) to determine the double-helix structure of DNA. Fundamental to modern genetics and molecular biology. Monoclonal Antibodies Study: Kohler and Milstein developed a technique to produce monoclonal antibodies using hybridoma technology in vitro. Revolutionized diagnostic tests and targeted therapies. HIV Drug Discovery Study: Screening of compounds in vitro led to the discovery of reverse transcriptase inhibitors, such as AZT, effective against HIV. Provided the first antiretroviral drugs for AIDS treatment. Step 2: Preclinical Research Step 2: Preclinical Research Investigational New Drug Process FDA IND Review Team FDA IND Review Team IND Approval IND Approval Step 3: Clinical Research Step 3: Clinical Research Step 3: Clinical Research Clinical Research: Phase 1  Clinical Research: Phase 1 Reasons for Failure in Phase 1 Clinical Trials Drugs may fail Phase 1 for several reasons: Toxicity: Unacceptable side effects at even low doses. Pharmacokinetics Issues: Poor bioavailability or rapid clearance. Inefficacy Signals: Lack of desired biological activity (though efficacy is not the primary focus at this stage). Commercial Viability: High production costs or insufficient market potential.  Clinical Research: Phase 1 Examples of Drugs That Did Not Pass Phase 1: 1. TGN1412 (Theralizumab) Type: Immunomodulatory monoclonal antibody. Reason for Failure: Severe adverse effects in a Phase 1 trial in 2006, where six healthy volunteers experienced life- threatening cytokine release syndrome ("cytokine storm"), leading to multiple organ failure. Preclinical animal studies did not predict this outcome due to differences between human and animal immune systems. Outcome: Highlighted the need for cautious dosing in first-in-human trials, particularly with immunotherapies. 2. BIA 10-2474 Type: FAAH inhibitor for pain and neurodegenerative diseases. Reason for Failure: In 2016, a Phase 1 trial in France resulted in severe neurological damage in multiple participants, with one fatality. Toxic effects were linked to off-target activity of the drug at high doses. Outcome: Stressed the importance of comprehensive preclinical testing to uncover potential off-target effects. Clinical Research: Phase 2 Clinical Research: Phase 2 Drugs may fail Phase 2 trials due to: Lack of Efficacy: The drug does not provide a statistically significant therapeutic benefit. Safety Issues: Adverse effects emerge with broader testing. Dose Optimization Challenges: Difficulties in identifying a therapeutic window that balances efficacy and safety. Commercial Viability: High costs, competitive landscape, or insufficient market potential.  Clinical Research: Phase 2 Examples of Drugs That Did Not Pass Phase 2: 1. Torcetrapib (Pfizer) Type: CETP inhibitor for raising HDL ("good cholesterol"). Reason for Failure: Phase 2 trials showed increases in blood pressure and other adverse cardiovascular effects, despite efficacy in raising HDL levels. Subsequent Phase 3 trials confirmed risks, leading to discontinuation. Impact: Raised concerns about off-target effects in drugs targeting lipid metabolism 2. Pimavanserin (Nuplazid) Type: Antipsychotic for schizophrenia. Reason for Failure in Phase 2: Early Phase 2 studies failed to show significant efficacy for schizophrenia, though it was later approved for Parkinson’s disease psychosis. Impact: Demonstrates how drugs may succeed for different indications despite early setbacks. Clinical Research: Phase 3 Clinical Research: Phase 3 Reasons for Failure in Phase 3 Clinical Trials: Lack of Efficacy: Drug fails to demonstrate a significant benefit compared to placebo or standard care. Safety Concerns: Unacceptable side effects or long-term risks emerge. Suboptimal Trial Design: Poor selection of endpoints, patient population, or trial methodology. Economic Factors: Cost-benefit analysis suggests the drug may not be commercially viable. Regulatory Hurdles: Issues with data quality or non-compliance with regulatory requirements.  Clinical Research: Phase 3 Examples of Drugs That Did Not Pass Phase 3: 1. Dalcetrapib (Roche) Type: CETP inhibitor for raising HDL ("good cholesterol"). Reason for Failure: Phase 3 trials showed no significant reduction in cardiovascular events despite raising HDL levels. Impact: Highlighted that improving biomarkers (e.g., HDL) does not always translate to clinical benefits. 2. Rimonabant (Sanofi-Aventis) Type: CB1 receptor antagonist for obesity and metabolic syndrome. Reason for Failure: Although effective in weight loss, Phase 3 trials revealed severe psychiatric side effects, including depression and suicidal ideation. Outcome: Withdrawn from the market in Europe and never approved in the U.S. Clinical Research: Phase 4  Clinical Research: Phase 4 Reasons for Failure in Phase 4 Clinical Trials: Rare Adverse Effects: Serious side effects not observed in earlier phases due to limited sample sizes. Long-Term Safety Concerns: Problems that arise only with prolonged use. Inefficacy in Real-World Settings: Efficacy in controlled trials may not translate to broader, diverse populations. Regulatory Scrutiny: Inadequate post-market surveillance or misleading marketing claims.  Clinical Research: Phase 4 Examples of Drugs That Did Not Pass Phase 4: 1. Rofecoxib (Vioxx, Merck) Type: COX-2 inhibitor for pain and inflammation. Reason for Withdrawal: Post-marketing studies revealed an increased risk of cardiovascular events (e.g., heart attacks and strokes) with long-term use. Linked to tens of thousands of deaths worldwide. Impact: One of the largest drug recalls in history; led to stricter FDA guidelines for cardiovascular risk monitoring. 2. Sibutramine (Meridia, Abbott Laboratories) Type: Weight-loss drug. Reason for Withdrawal: Phase 4 studies revealed an increased risk of heart attack and stroke in patients with cardiovascular disease. Outcome: Withdrawn from global markets in 2010. Step 4: FDA Drug Review Step 4: FDA Drug Review Step 4: FDA Drug Review  FDA 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 Approval 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 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.  Step 5: FDA Post-Market Drug 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.  THANK YOU! Market Withdrawal is a firm’s removal or correction of product that involves minor infraction that does not cause product to be adulterated or misbranded. Black box warnings aka boxed warnings are required by the FDA for certain medications that carry serious safety risks. Often these warnings communicate potential rare but dangerous side effects, or they may be used to communicate important instructions for safe use of the drug.