Peter Attia MD: The video explains the phases of drug development and the costs and timelines involved.
Peter Attia MD: The video discusses the complexities and costs of drug development, emphasizing the importance of clinical trial phases and the challenges in drug pricing and accessibility.
Peter Attia MD - How a Drug Gets Approved: Safety, Trials, and Funding | Susan Desmond-Hellmann M.D., M.P.H
The discussion focuses on the different phases of drug development, explaining the purpose and process of each phase. Phase one is primarily concerned with safety, determining if a drug is safe for human use, both in single and multiple doses. This phase typically lasts about a year and costs tens of millions of dollars. Phase two aims to prepare for phase three by establishing dosage, schedule, patient selection criteria, and forming a hypothesis for the drug's effectiveness. Costs increase significantly in this phase, reaching into the 20s to 40s of millions. An example is given of a drug tested for colon cancer, which successfully moved from phase two to phase three, focusing on median survival rather than overall survival. The video highlights the complexity and expense of bringing a drug to market, which can take a decade and cost a billion dollars.
Key Points:
- Phase one focuses on safety, determining if a drug is safe for human use.
- Phase two prepares for phase three by establishing dosage and patient criteria.
- Drug development can take a decade and cost a billion dollars.
- Phase one costs tens of millions, while phase two costs 20-40 million.
- Example of a drug for colon cancer moving from phase two to phase three.
Details:
1. 🔬💰 The Complexity and Cost of Drug Development
1.1. Preclinical Studies
1.2. Phase 1 Clinical Trials
1.3. Phase 2 Clinical Trials
1.4. Phase 3 Clinical Trials
1.5. Financial Implications
2. 🧪 Preclinical to Phase One: Ensuring Safety
- Identifying the best method to target molecules, whether through small molecules or antibodies, is crucial for drug development.
- The FDA plays a critical role in questioning and ensuring a method's efficacy and safety through rigorous approval processes, ensuring that only the safest and most effective drugs proceed to human trials.
3. 📊 Phase Two: Paving the Way for Phase Three
- Phase One is dedicated to establishing the safety of a molecule for human use, assessing safety in single and multiple administrations.
- Preclinical packages and IND submissions are crucial for a seamless Phase One, typically lasting around one year.
- Phase One costs range in the tens of millions, while Phase Two expenses escalate into the 20s to 40s of millions, contingent on the trial's scale and complexity.
4. 🏁 Phase Three and Cancer Research Case Study
- Phase two prepares for phase three by establishing dose, schedule, patient selection, and hypothesis.
- After establishing the dose and schedule in phase two, a phase three study in colon cancer research included a comparison of treatments with and without Avastin.
- The phase three colon cancer study showed an 8-month increase in median survival for stage four colon cancer patients with the addition of Avastin.
- This study marked the first significant advancement in colon cancer treatment in years, creating excitement in the field.
Peter Attia MD - How a Drug Gets Approved: Safety, Trials, and Funding | Susan Desmond-Hellmann M.D., M.P.H
The discussion highlights the intricate process of drug development, explaining the different phases of clinical trials: Phase 1 focuses on safety, Phase 2 on determining the right dose and patient selection, and Phase 3 on confirming efficacy and safety in larger populations. The speaker emphasizes the importance of preclinical work, including toxicology and safety plans, and the challenges of producing biologics like antibodies. The conversation also touches on the economic aspects of drug development, particularly the high costs and pricing strategies, using the example of Avastin, a drug that extended median survival in colon cancer but faced criticism for its high cost relative to the benefit. The speaker reflects on the ethical considerations of drug pricing and the company's efforts to ensure patient access despite financial barriers.
Key Points:
- Understanding clinical trial phases is crucial for drug development success.
- Preclinical work, including toxicology, is essential for FDA approval.
- Choosing between small molecules and antibodies impacts drug design and safety.
- Drug pricing strategies must balance cost, accessibility, and company sustainability.
- Economic and ethical considerations are vital in drug development and distribution.
Details:
1. 🔍 Understanding Clinical Trials
- Clinical trials are structured in phases: Phase 1 focuses on safety and dosage, Phase 2 on efficacy and side effects, and Phase 3 on confirming effectiveness and monitoring adverse reactions in larger populations.
- Preclinical studies, taking place before human trials, are vital for assessing a drug's safety and biological activity, serving as a precursor to clinical phases.
- The drug development process can cost over a billion dollars and take up to 10 years, emphasizing the need for strategic planning and execution.
- Key decisions in experimental design, patient selection, and trial execution can significantly impact the trial's success, highlighting the importance of precision and alignment in these areas.
- The analogy of 'lining up Swiss cheese holes' illustrates the precision and alignment needed to successfully navigate through clinical trials.
2. 🔬 Targeting in Oncology
- Targeting in oncology involves identifying specific molecules like VEGF and determining effective methods to inhibit their function.
- A key decision point is choosing between small molecules and antibodies. Small molecules are typically easier to manufacture and can penetrate cells to act on intracellular targets, while antibodies are larger, more specific, and work well for extracellular targets.
- Understanding the differences between these approaches is crucial for developing effective cancer therapies.
- Examples include the use of small molecule inhibitors like Imatinib for intracellular targets and monoclonal antibodies like Bevacizumab for extracellular targets.
3. 🧪 Small Molecules vs. Antibodies
3.1. Mechanisms and Characteristics of Small Molecules
3.2. Mechanisms and Characteristics of Antibodies
4. 💉 Drug Development and Preclinical Work
4.1. Statin Drugs and PCSK9 Inhibitors
4.2. Transition to Injectable Drugs
4.3. Manufacturing Challenges in Biotech
5. 📊 Preclinical Safety and Diagnostics
- Animal models, such as mice and larger animals, are used to test the efficacy and safety of interventions like blocking VEF, though these models have limitations compared to biological targets.
- Preclinical work prioritizes addressing toxicology and safety concerns, which are primary inquiries by regulatory bodies like the FDA.
- Key safety concerns include potential bleeding and allergic reactions to antibodies, necessitating comprehensive preclinical safety plans.
- Diagnosis of allergies to antibodies is crucial, ensuring these are identified and managed before clinical trials.
- Regular monitoring of patients for adverse reactions is integral to preclinical safety.
- Specific methodologies, such as ELISA tests and in vivo imaging, are employed to detect and manage adverse reactions.
- Regulatory guidelines necessitate rigorous safety protocols and diagnostic accuracy in preclinical studies.
6. 📝 IND Application Process
- In modern oncology, integrating diagnostics with targeted therapy is essential; for example, therapies like Herceptin required a companion diagnostic assay during clinical trials.
- The timeline for filing an IND typically spans two to three years, largely due to the need for conducting comprehensive animal model studies.
7. 🔄 Phase One Clinical Trials
- Phase one clinical trials focus on the safety assessment of new drugs or treatments in humans, determining their safety for single or multiple administrations.
- The process starts with applying for Investigational New Drug (IND) status, which is necessary to legally ship an unapproved drug across state lines for trials.
- A successful phase one trial hinges on a robust pre-clinical package and a comprehensive IND application, aiming for a smooth and uneventful progression through the trial phases.
- Trials utilize an escalating dose methodology, where initial doses are based on extrapolations from previous toxicity studies in different organisms, recognizing that these studies may not directly translate to humans.
- Dosing is frequently reassessed, as initial estimates from other organisms often require adjustments for human trials to ensure safety.
- While primarily focused on safety, these trials also observe potential responses in oncology patients, though efficacy observations are limited due to the typically advanced stage of patients’ conditions.
- Challenges include patient recruitment, ethical considerations, and navigating regulatory landscapes.
8. 🧠 Phase Two Clinical Trials
- Phase Two clinical trials generally incur costs ranging from tens to potentially over forty million dollars, depending on scale.
- The trials primarily aim to determine the optimal drug dose, schedule, and patient population, essential for transitioning to Phase Three.
- These trials are crucial for hypothesis formation regarding drug efficacy, establishing criteria for dose, schedule, and patient selection.
- In oncology, some companies may seek approval based solely on Phase Two results, with regulatory confidence, especially for targeted therapies.
- An illustrative case is the anti-VEGF trial in breast cancer, where Phase Two served as an approvable study due to a lack of alternatives for patients.
- Challenges in Phase Two can include balancing financial constraints with the need for comprehensive data collection and dealing with the complexities of patient selection.
- Strategic success in Phase Two involves not only identifying optimal doses and patient populations but also efficiently managing costs and regulatory expectations.
9. 🎯 Phase Three and Economic Considerations
- The breast cancer study failed, highlighting the need for better drugs in this area as Herceptin was not effective for 75% of patients.
- The stock value dropped significantly after the breast cancer study failure, reflecting the high expectations for Avastin.
- In contrast, a successful Phase Three study in colon cancer was conducted, showing an 8-month improvement in median survival for stage four patients when treated with Avastin.
- The treatment with Avastin was priced at $100,000, which raised discussions on its economic viability, particularly as the UK NHS decided against its use despite the survival benefits.
