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Lecture 1/2 Slide Notes, Case studies, Other Questions, History of Drug…

- - - - Chemical synthesis
      - Oral solids
      - Pharmacy benefit
      - Generic Law: 1984 Hatch Waxman
      - Small <1000
    - - Large >10,000
      - Cultures of living cells
      - Often injected or infused
      - Medical benefit
      - Generic Law: biologics price competition and innovation act of 2010
  - - - Micropiology, geneetics, hman genome
      - recombinant proteins
      - Monoclonal antibodies
      - Biologic Drugs
    - - 46% of US pharma sales
  - - - Why: Federal govt accumulated thousands of patent but hadn't relicensed them
      - March In Rights
        
        NIH can reassert ownership fo IP if holder isn't developing technology or not satisfying health ands afety needs
  - - - Why they expect the drug is safe
      - Why they thiknk the drug is worthy of clinical trials
      - Drug can be manufactured consistantly
    - - Formulation: active pharmaceutical ingredient
      - Mechanism: how it works
  - - - Goal: Assemble preliminary evidence on safety and efficacy
      - companies learn common side effects and if biomarkers in body are reacting as expected
      - Key drug development decisions:
        
        type of patients and # to enroll; health conditions + stage + patients treated before
        
        Primary Health endpoint that will be measured
        
        What treatment will the expreimental and control patients receive
    - - serum concentrations, absorption, metabolism, excretion; half life; dose-dependent; clearance
    - - Approval indicated for specific patients that were included in the phase 3 trial
      - Indirect restrictions: insurer may not pay for it; medical licensign and malpractice can curb it
      - 70% of off label prescriptions not supported by evidence
      - Type I and II Errors in drug approval
        
        Type I: drug is not safe; fda approves
        
        Type II: Drug is safe; FDA rejects
      - Reducing approval times
        
        Fast track: drug treats serious condition and potential to address unmet medical need
        
        Breakthrough therapy: subset ot fast track due to substantial improvements
        
        Accelerated approval: accept improvement ons econary endpoint because of serious condition and unmet medical need
        
        Priority review: FDA will try to review in six months
        
        PDUFA: Prescription Drug User Fee Act: goal is to review new drug applications faster
        
        most applications reviewed within set timeframe; industry provides 52% of FDA evaluation funding; firms pay fees per NDA to help FDA hire staff;
    - - Primary: most important outcome for patients; FDA priority
      - Secondary: trail success even if this metric fails; conveniences, nice to haves
    - - prevalence/incidence; 2. greatest clinical benefit; 3. differentiation; 4. approval probability; 5. off-label prescribing
      - Characteristics of phase 3 trials for all drugs approved: two large, randomized, double blind trials comparing experimental drug to existing drug
    - - Are there health benefits vs control group
      - do health benefits outweigh side effects
      - Phase 4: post marketing studies to explore safety issues
      - does NOT consider prices
- - - - Encourages FDA to accept real world evidence
        
        drug company submit evidence from actual patients
        
        externally controlled: compare to patients not taking the drug
        
        likely application: drugs used off label for certain indications will try to use data from off-label uses
        
        Pros: actual patient populations, cheaper to obtain approval for off label inidcations
        
        cons: easier to data mine or find a population with good outcomes
      - Encourages FDA to accept secondary endpoints as primary endpoints; ex. tumor progression
    - - approve and wait and see- encourage further study
        
        Expanded access: provision of unapproved drug; compassionate use
        
        Both FDA and drug firm must approve (life threatening)
        
        Three pathways
        
        inndiivudal access: physician determines benefit > risk
        
        intermeidate size use: collection of individuals
        
        Widespread use: between phase 3 and approval
        
        Drug firms denying expanded access
        
        direct costs not covered by insurance; far less than retail price
        
        deters clinical trial enrollment; documented cases fo patients withdrawing from phase III and applying for expanded acces
        
        liability exposure
      - approve after considering alternatives
      - approve and label
        
        use Black Box Warning for potential fatal risks
        
        approve for sub population where safety and efficacy was clearest
      - deny
      - Libertarian Perspective: approve all drugs that provide health benefit to control treatment; provide substantial information to physicians and patients regarding safety ; allow them to make decisions
  - - - patents
      - Patents allow a firm to recover R&D costs; expiration triggers fierce competition
    - - bioequivalent competitors
      - patent pricing; allows charge price above cost producing
      - competitive pricing: competitors allow drug prices to fall to production costs
      - Generic protection: protection from generic
    - - patent definition: limited grant from US gov giving inventor right to exclude others from the making of the drug
      - Patent limitations: can only exclude others from practicing the invention for limited period of time
    - - Branded drugs make money after FDA approval and before entry of generics
      - generics can enter for small molecules when there are no patents and market exclusivity has expired
    - - Active ingredient: defines molecule (strongest legally)
      - Method of Use: Unique application of drug (Method of Use)
      - Drug Product Patent: defines formulation, dose, or manufacturing process (Weakest Legally)
    - - useful; novel; non obvious; sufficiently described/enabled
      - Why may a patent be overturned:
        
        patented invention is not new
        
        obvious
        
        no useful purpose
        
        patent not sufficiently descriptive
    - - temporary monopoly on a compound not health condition
        
        Why imperfect monopolt
        
        same disease competition
        
        alternative treatment choices
        
        international enforcement
    - - Prior 1984
        
        Generic Clinical Trials: generics had to run their own trials
        
        small molecule: applies to small molecule drugs, not biologics
        
        Many patents: drug firms obtained many patents
        
        Market exclusivity: 5 year exclusivity
      - After 1984
        
        Branded Firm negatives
        
        Generic exclusivity
        
        ANDAs: sufficient to prove bioequivalence to existing drug
        
        Bioequivalence research: can do before patents expire without violating patents
        
        Branded Firms Positive
        
        patent restoration: branded drugs get up to 5 years patent restoration for time spent in clinical trials under FDA review
        
        Patent extension: .5-year patent extension for testing drug on children
        
        Market Exclusivity: 5 years exclusivity; no ANDA can be approved in first 5 years
        
        Paragraph IV Challenges: legal suit brought by generic manufacturer stating that a relevant patent should not preclude generic entry
        
        What effects timing of generic entry?
        
        New indiication market exclusivity: branded firms receive additional 3 years of exclusivity if an already approved drug is approve dfor new indication
        
        Orphan Drug Act: provides 7 years of exclusivity for drugs taht address rare disease
        
        What is market exclusivity?
        
        FDA will not approve an anda; UNREALTED TO PATENTS
        
        Length of market exclusivity: generic won't be approved before 5 years from date of FDA approval; 5.5 years if pediatric dosing
        
        what are the steps in the paragraph IV challenge
        
        01: Generic company files an ANDA
        
        patent holding files patent infringement suit in federal court
        
        federal court decides whether patent is invalid or infringed
        
        generic launch: if generic compnay wins then first filer generic can launch and recieve 180 day generic exclusivity
        
        What are the possible outcomes?
        
        patent overturned
        
        patent upheld
        
        settlement ; brand pays generic firm to delay its entry to 6 months before patent expires; firm enjoys monpoloy durign delay period
        
        challenges by generic firms reduce market life by 3.5 years
- - - - created legal pathway to biosimilars
      - created biologic market exclusivity of 12 years
    - - no active ingredient
      - many biosimilars obtain FDA approval first
- - - - PBM sets formulary, copay tiering, discounts, utilization management,
  - - - drug reduces medical costs, insurer will want to ensure patients take it
      - if those averted medical costs happen off in the future current insurer may not care
      - if drug has large value to patients with no close substitues, drug firm will not have to offer a discount
  - - - small drug co payments