Drugs, Discovery and Development Final
Health Care System
Lack of access to healthcare by a sizable portion of the population (Access) Runaway costs of healthcare goods and services (Value)
Ethics
Lack of real power and resources from the FDA in the last decade
Patent and IP
"Obviousness" test: In light of known, similar products, processes or designs, would a person of ordinary skill (but not extraordinary skill) working in the field related to the inventor's invention consider the differences between the invention and similar products, processes or designs obvious?
Bio-similar
"Pay to Delay": paying generic companies $$$ not to challenge brand's patent or exclusivity in order to delay potential Who benefits (DM)? Who is hurt if P2D is allowed (PT/INS)? Federal Trade Commission (FTC) is cracking on this practice "Ever-Greening": putting patients on a slightly different (often extended release version) of the original brand (made by the same manufacturer) before generics enter the market (line extension)
Discovery of Drug Targets and Drug Leads 2
"Rational design" -Design new molecules with similar structure De novo or in silico discovery -Requires significant knowledge of the structure of the protein (usually from x-ray crystallography)
Health Care System
-Under a free market, health insurance companies have tried to lessen the impact of adverse selection by excluding people with pre-existing conditions -Alternatively, insurance companies will raise the premiums significantly to cover the expected healthcare expenditures incurred by high risk patients -Both will lead to reduced access to health insurance
Discovery of Drug Targets and Drug Leads 2
Lead: search for 'natural' proteins with critical functions to be supplied when the human body lacks of it (not always need to find targets, they are known)
Manufacturing and Production
2nd Generation Program: R&D focused on a new Lead molecule with new and improved therapeutic profile
Bio-similar
3 key provisions: Establish an expedited pathway for regulatory approval of generic drugs An original brand name drug can receive an extension term on the original patent dependent on the duration of IND and NDA application processes Up to five years of extension (average was close to 3) Authorize the FDA to grant years of market exclusivity to original brand name drugs after drug approval Exclusivity is not added to the patent life. It may expire before or after patent expiry
Discovery of Drug Targets and Drug Leads
A "Hit" is a chemical that interacts with a target, typically at a very early, initial stage of R&D A "Lead" is a chemical that interacts with a target and has been shown to be effective in animals, typically at a more advanced stage of R&D
Discovery of Drug Targets and Drug Leads
A "Target" is a biological molecule (protein) or system (cell) that is believed to be responsible for a disease state
Bio-similar
A biosimilar is expected to produce the same clinical result as the pioneer in any given patient
Bio-similar
A biosimilar product is defined as one that is "highly similar" (NOT IDENTICAL, as in generics) to the pioneer product, despite minor differences in clinically inactive components and where there are no clinically meaningful differences in terms of safety, purity and potency.
Clinical Trials
A clinical drug candidate must meet the following criteria Potency supports target clinical dosing regimen Acceptable therapeutic (safety) window (>10x) In vitro selectivity translates into acceptable in vivo safety margin Pharmacokinetic (PK) profile sufficient to support bioavailability and clinical dosing Improved and optimized in vivo properties (bioavailability, PK, ADME, PD, dosing) Supportive on-target PD profile Sufficient non-GLP safety demonstrated Economical production of sufficient quantity possible For clinical, commercial
Pharmaceutical pricing
A drug formulary is a list of prescription drugs, both generic and brand name, used by practitioners to identify drugs that offer the greatest overall value. A committee of physicians, nurse practitioners, and pharmacists maintain the formulary
Health Care System
A federal and state-government co-sponsored insurance program (financed by both federal and state income tax dollars)
Manufacturing and Production
A generic drug is a product that is comparable to a brand/reference listed drug product in dosage form, strength, route of administration, quality and performance characteristics, and intended use. A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA-approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product.
Bio-similar
A generic drug is identical--or bioequivalent--to a brand name drug in dosage form, safety, strength, route of administration, quality, performance characteristics and intended use. In other words, their pharmacological effects are exactly the same as those of their brand-name counterparts
Clinical Trials2
Clinical endpoint - A measurable outcome that indicates a drug's effectiveness
Discovery of Drug Targets and Drug Leads 2
A screen is a biological assay used to test many potential hit/leads against a biological target or in other biological evaluations
Pharmaceutical pricing
A therapy may do any of the followings: Prolong life, reduce well-being (e.g., due to drug side effects) Prolong life, improve well-being (e.g., less pain from tumors) Not prolong life, but improve well-being (e.g., improves pain, helps patients feel comfortable) So a better measure of effectiveness is called Quality of Life Adjusted Life Years (QALY), and CEA becomes CUA.
Pharmaceutical Research and Development2
Active Pharmaceutical Ingredient (API) - the active chemical compound in the drug Excipients - inactive ingredients in the drug that serve as the delivery vehicle and to provide other useful properties to the drug product
Manufacturing and Production
Additional clinical trials are conducted to expand the use, the claims, and ultimately, the value of the new drug These clinical trials are required by the FDA to comply with "off-label" marketing regulations
Marketing
Adjusting, modifying the plan to fit the new "reality"
Clinical Trials2
Adverse effects, "side effects", are unwanted physiological activity of the drug product
Clinical Trials2
Clinical endpoint: The occurrence of a disease, symptom, sign or laboratory abnormality that constitutes one of the target outcomes of the trial
Health Care System
An entirely publicly financed (by federal tax dollars) and public provided system of healthcare Military veterans only (not dependent family members) Covers ~ 2% Americans Most physicians, nurses, and other personnel in the VA system are federal government employees
Pharmaceutical Research and Development
Any medicinal product extracted from biological sources
Pharmaceutical Research and Development
Attrition: failure of molecules in development Cost of attrition: Poor pharmacokinetic properties during clinical evaluation (typical during 1990-2000) Toxicity (typical in 2000): liver, cardiovascular system, skin, and blood Adverse effects in the clinic
Manufacturing and Production
Back-up Program: R&D focused on a second Lead molecule in case the initial clinical candidate fails
Bio-similar
Big pharma and large biotechnology companies are devoting a significant amount of resources to developing biosimilar products, but NOT generic drugs
Pharmaceutical Research and Development
Biologics can be composed of proteins, nucleic acids, complex combinations of these substances (e.g., monoclonal antibodies, etc.), or living entities such as cells and tissues
Discovery of Drug Targets and Drug Leads 2
Biomarkers: biological molecules in blood, tissue, fluids indicating normal (healthy), or abnormal process (disease)
Marketing
Biopharmaceutical companies spend large sum of money to subsidize continuing medical education (CME) programs attended by physicians, dentists, and other healthcare professionals Most materials about products presented at these venues are subject to FDA review and regulation
Ethics
Business ethics is a form of applied ethics or professional ethics that examines ethical principles and moral or ethical problems that arise in a business environment. It applies to all aspects of business conduct and is relevant to the conduct of individuals and entire organizations
Pharmaceutical pricing
By statute, Medicaid and VA are entitled to the best prices on drugs Medicare is prohibited from directly negotiating with drug firms on prices
Pharmaceutical pricing
CEA = Ratio of Difference in cost and Difference in effectiveness = Price of treatment can be adjusted to result in different CE ratio
Clinical Trials
CMC = Chemistry, Manufacturing, and Controls GMP = Good Manufacturing Practices GLP = Good Laboratory Practices Food and Drug Administration (FDA) has regulations and requires documentation for all parts of the laboratory and manufacturing process going into Clinical Trials
Pharmaceutical pricing
CUA = Ratio of Difference in cost and Difference in utility adjusted effectiveness
Patent and IP
Chakrabarty (a scientist for General Electric) denied patent for genetically engineered bacteria capable of digesting crude oil Chakrabarty (GE) sues USPTO and wins in court Diamond, the USPTO Commissioner takes the case to the Supreme Court Supreme Court decision Patent Granted. Congress intended patentable subject matter to "include anything under the sun that is made by man," even living things (GE bacterium capable of breaking down crude oil)
Manufacturing and Production
Commercialization: from product to therapeutic application to sales
Health Care System
Compared to every other developed economies, the system in the US is disorganized, fragmented, and highly inefficient
Health Care System
Compared with the rest of the developed world, the United States has a very high proportion of its population uninsured The high cost of insurance has been the main reason why people go without coverage.
Patent and IP
Composition of matter = a new chemical invention Structure of API Formulation of API process: A way of producing something new or an inventive way of producing something already known Even if a drug itself is held not to be inventive, the inventor may seek to patent the way in which the drug is produced in the laboratory - the process, rather the product
Pharmaceutical pricing
Cost-effectiveness analysis compares several treatment options for a given condition in terms of the incremental costs per unit of effectiveness gained
Patent and IP
Currently the patent term is 20 years from the filing date Regardless of the time a patent application is prosecuted through the USPTO, which on average takes 2-3 years Pre-clinical and clinical trials, followed by FDA review of NDA can take 5 - 10 years New drugs on average have only 11-12 years of useful or effective patent life remaining
Marketing
DTC- Controversial Means of Promotion Support: Provide information to patients in a more timely fashion Empower patients to be a more active participant in his/her own healthcare decisions Healthcare should be treated like other consumer products—consumers need to know what they are getting Arguments: Healthcare is NOT like other consumer products Greater potential for misleading information DTC tends to under-mention side effects of products Undue burden on providers to explain why patients should not be on that new med Contribute to rising Rx spending US and New Zealand are the only 2 OECD countries that allow DTC of Rx
Marketing
Detailers = pharmaceutical sales reps, who call on physicians in their private offices, hospitals, clinics, etc.
Marketing
Detailing is an almost unregulated activity
Pharmaceutical Research and Development2
Drug development goals: To produce the drug in a marketable form To gain regulatory permission to market the drug for use in the target indication(s) as quickly as possible
Patent and IP
Effective Patent Life = the elapsed time between FDA approval for marketing of a new drug and the expiration of the last patent that effectively protects the original compound from competition from generic products
Discovery of Drug Targets and Drug Leads
Enzyme: A protein target that binds a natural substrate and catalyzes its reaction to form products Substrate: A molecule which is bound by an enzyme and converted into a new product
Patent and IP
Every new prescription drug has 2 names: a generic (nonproprietary) name and a brand name
Health Care System
Extensive and Unrestricted Use of Medical Technology Is an Important Reason for Rising Healthcare Costs
Manufacturing and Production
FDA inspects manufacturers or processors of FDA-regulated products to verify that they comply with relevant regulations.
Pharmaceutical pricing
Factor 2 = Efforts to communicate the objective value A complete and objective communication should include Benefits of product Costs of negative events
Pharmaceutical pricing
Factor 3 = Price of Substitute(s) In the absence of complete information on the objective value, consumers often equate price of substitutes to value of product
Introduction to the global pharmaceutical and biotech industry
First biotech product: human insulin produced in genetically modified bacteria: 1982
Patent and IP
For a limited time = patent life = 20 years Granted by the United States Patent and Trademark Office (USPTO)
Patent and IP
For biopharmaceutical inventions, an applicant can make up to four types of claims in Utility Patent alone: Overlapping patents (product and process + design patent) can allow a company to dominate a particular market for a long time
Health Care System
For people who are poor enough to qualify for social welfare financial support, and do not have health insurance (whether working or not), they may qualify for Medicaid
Pharmaceutical pricing
For these companies: the goal is to minimize overall costs of care, not just costs on pharmaceutical products Important for medicines with high price tags to show cost offsets in other parts of healthcare system
Patent and IP
Four main conditions for patentability Invention must be a "patentable subject matter" Invention must be useful Invention must be novel Invention must not be "obvious"
Marketing
Free samples = free medications provided to physician during an office visit (with/without seen by the physician)
Patent and IP
Frivolous or immoral inventions are not patentable for they have no utility or have negative utility
Bio-similar
Full name=Drug Price Competition and Patent Term Restoration Act of 1984 Objectives: To streamline and simplify the review and approval process for generics in order to encourage more generic drugs to enter the market (pro competition) To restore some patent life on pioneer brand drugs lost during the development and approval process (pro innovation)
Manufacturing and Production
GMP: Good Manufacturing Practices Product specifications, purity, stability, shelf life Quality Assurance and Quality Control processes
Patent and IP
Intellectual property rights are embodied in patents, trade secrets, copyrights, and trademarks.
Introduction to the global pharmaceutical and biotech industry
Genetic engineering enables bacteria to adopt the genes and produce proteins of other organisms, including humans
Discovery of Drug Targets and Drug Leads 2
Genome: the complete set of hereditary instructions for an organism contained in its chromosomes
Discovery of Drug Targets and Drug Leads 2
Genomics applies recombinant DNA, DNA sequencing methods, and bioinformatics to sequence and analyze the function and structure of genomes
Bio-similar
Growth drivers for the generic pharma industry in the US: State and federal government (Medicaid) Employers (through lower insurance premiums on pharmacy benefits) Insurance and other 3rd party payers (Drug formulary) Patients (lower co-pay and out of pocket costs) Discount on the generic products usually increases when the number of generic competitors increases for a given product
Health Care System
HTA refers to the evaluation of new medical technology to determine if it is worth the cost. Objective of HTA is to establish the appropriateness of medical technology.
Health Care System
Health insurance provided/paid by an employer as a fringe benefit; usually also covering the immediate family members of employee Most of the people covered in this system are of working age, and generally healthy
Health Care System
Health insurance: a contract under which a buyer (the insured) agrees to make regular payments, or premiums, in exchange for the seller (the insurance firm) agreeing to pay some or all of the buyer's medical bills
Health Care System
High-tech procedures, equipment, and pharmaceutical products are more readily available in the US than in any other developed country Medicare prohibited by law to negotiate prices directly with drug companies
Pharmaceutical pricing
If final price < perceived value, consumers gain from buying and using this product If final price > perceived value, consumers will not buy If final price = perceived value, consumers are indifferent
Pharmaceutical pricing
If the clinical outcomes from treatment alternatives are considered equivalent, the economic analysis will focus on the costs of each alternative, and rank the preference for each alternative based on the costs
Clinical Trials
Impurity profile (organic and genotoxic impurities) "Biosimilar" = generic Biotech drug
Bio-similar
In the 30 years since the Hatch-Waxman Act, the FDA has repeatedly assessed US generic medicines and determined that they are fully substitutable for the brand product
Health Care System
In the US, there are several subsystems of healthcare: Employment-based subsystem (job-related) Medicare (elderly and some disabled) Veterans Administration Medicaid: system serving the poor The uninsured Self insured (very small number)
Discovery of Drug Targets and Drug Leads
In vitro - in cells In vivo - in animals
Clinical Trials2
Intellectual Property Rights (IPR) & Pharma Patents Preparation of regulatory documents: Drug Master Files (DMF), New Drug Submission (NDS)/Abbreviated New Drug Submission (ANDS)/Common Technical Document (CTD)
Patent and IP
Invention must be different from what had been previously discovered or disclosed
Marketing
It is also about completely conveying a product's attributes, including pricing information and information on side effects
Introduction to the global pharmaceutical and biotech industry
Key discoveries transforming the industry: Hormone insulin in the pancrease to treat diabetes (1923; F. Banting/J. Macleod; University of Toronto; Nobel Prize) Penicillin to treat bacteria infections (1928; Alex Fleming/Ernst Chain/Howard Florey; Nobel Prize)
Manufacturing and Production
Major steps in commercial drug production and manufacturing: API production- Small molecule products: chemical synthesis from cheapest available starting materials but reliable source of starting materials Protein products: fermentation/cell culture Purification- Filtration and precipitation Separation - chromatography Formulation- NCE: API, excipients, blending, pelleting NBE: API, vehicle, stabilizers Packaging - Primary - doses Secondary - package (bubble packs, bottle, package) Testing - Occurs throughout process Quality Control (QC)
Introduction to the global pharmaceutical and biotech industry
Many biotech companies with marketed products have become subsidiaries of pharma
Marketing
Marketing in the modern pharmaceutical industry is not just (not even most) about selling/promotion It is about understanding the market, the customers, the competitors, and the position your (new) product occupies, both in the short term and in the long run
Pharmaceutical Research and Development
Mechanism of action - the biochemical and molecular mechanisms by which a drug produces its effect Dose-response relationship - the relationship between the concentration of a drug and the magnitude of the response to that drug
Marketing
Medical Journey Advertising: Serves an educational purpose as an information tool to inform physicians about new or improved medications Content strictly regulated by FDA
Manufacturing and Production
Medical devices also require regulatory approval by being tested in clinical trials
Health Care System
Medicare is a federal (national) health insurance system for people over 65 (who have worked and paid into the system) and for people with certain chronic/permanent and debilitating disease (e.g., kidney failure)
Bio-similar
Modeled after the 1984 Hatch-Waxman Act establishing a generic pathway for small molecule drugs Provides a new biosimilar pathway for the approval of large molecule (biologic) drugs which are similar to pioneering drugs while providing incentives for pioneering drugs
Introduction to the global pharmaceutical and biotech industry
Modern day biotechnology refers to the use of genetic engineering and recombinant DNA technology in the production of pharmaceutical products
Health Care System
Moral hazard refers to actions people take after entering into a contract, that make the other party of the transaction worse off by their behavior Moral hazard leads to wasteful spending on healthcare
Pharmaceutical pricing
More than patients and providers, payers (e.g., insurance plans) are becoming much more sensitive to rising drug prices and pharmacy expenditures
Discovery of Drug Targets and Drug Leads
NCE - New Chemical Entity - a small molecule (<500 amu) that is ready for clinical trials...."Pharma" NBE - New Biological Entity - a large molecule (>10,000 amu - protein) that is ready for clinical trials.... "Biotech"
Discovery of Drug Targets and Drug Leads
Natural Products are the chemicals produced by plants, microorganisms, marine organisms, and other living things
Patent and IP
New pharmaceutical drugs on average have only 11-12 years of effective patent life remaining Typically biotechnology drugs have longer effective patent life because of the "A method of manufacture claim"
Health Care System
Obamacare mandates that ALL individuals carry insurance, and a preexisting condition won't effect the cost of insurance - non-participation will be fined
Pharmaceutical pricing
Objective value of the product = True Economic Value (TEV) = Benefits that the product delivers to the consumer relative to other products TEV = Cost of the Next Best Alternative + Value of Performance Differential
Bio-similar
On average, the cost of a generic drug is 80 to 85 percent lower than the brand name product. Today, >85% prescriptions filled in the United States are for generic drugs.
Pharmaceutical pricing
Outcomes Analysis A systematic and comparative approach combining both the clinical attributes and economic/financial impact of alternative therapies in the same equation Cost-Minimization Analysis (CMA) Cost-Effectiveness Analysis (CEA) Cost-Utility Analysis (CUA)
Pharmaceutical pricing
Outcomes Research (or HTA) It systematically evaluates among alternative treatments, both the clinical benefits and economic consequences
Manufacturing and Production
Outsourcing is a practice used by companies to reduce costs by transferring portions of work to outside suppliers rather than completing it internally. Outsourcing is an effective cost-saving strategy when used properly.
Pharmaceutical Research and Development
Parallel medicinal chemistry - the simultaneous synthesis of modest collections (100s) of compounds on a single structural scaffold Combinatorial chemistry - the simultaneous synthesis of large collections (1000s) of compounds on many structural scaffolds
Health Care System
Part D covers most FDA approved pharmaceutical products used out-patient
Pharmaceutical pricing
Perceived value is influenced by three key factors: Factor 1 = Objective Value (OV) Factor 2 = Efforts to communicate the objective value Factor 3 = Price of Substitute(s)
Pharmaceutical Research and Development2
Pharmaceutical Formulation: allows delivery of a specific dose of drug by a particular route of administration.
Pharmaceutical Research and Development2
Pharmaceutical chemistry, or pharmaceutics: Field of research and development concerned with the formulation and chemical properties of pharmaceutical products
Pharmaceutical Research and Development
Pharmacokinetics (PK) - The temporal and spatial distribution of a drug in a system Absorption, Distribution, Metabolism, and Excretion (ADME) - Processes that determine the concentration of a drug in body fluids and tissues over time Bioavailability - the fraction of an administered dose of drug that reaches the systemic circulation PD = Pharmacodynamics - what the drug does to the body
Clinical Trials2
Placebo - an identical treatment (tablet, capsule, solution) in every way except for the absence of the API Placebo effect - a positive reported or physical response to a placebo dose Cohorts (or "arms") - groups of patients that will receive the same treatment Randomization - the unbiased and random assignment of patients into different cohorts Controlled - a trial where one cohort receives placebo or current standard of care and another cohort receives the new treatment for comparison Blinded - obscuring knowledge of which cohort a patient is in to avoid biased response due to the placebo effect, or biased reporting, observations, or analysis
Pharmaceutical Research and Development
Pharmacology: the study of drugs and their effects on living organisms
Pharmaceutical Research and Development
Pharmacophore - the description of steric and electronic features of a molecule that is necessary to interact with a biological target and induce a biological response Bioisosteres - chemical substituents or groups with similar physical or chemical properties which produce broadly similar biological properties
Clinical Trials
Phase IA (First-In-Humans - FIH) Single dose Dose-escalation (i.e.: 20, 40, 80, 160, and 320mg) Phase IB (First-In-Humans - FIH) Multiple doses Dose-escalation (i.e.: 2x20, 2x40, 2x80, and 2x160mg) Safety parameters Vital signs Clinical observations Maximum tolerated dose (MTD) Human PK-ADME Bioavailability, t1/2, Cmax, AUC
Clinical Trials2
Phase II trials intend to prove efficacy in Humans "Proof-of-Concept" Trial Single & multiple dose escalation (= Phase 2A) -Dose-escalation: 2x80, 2x160mg -Comparator: Placebo or Standard-of-Care treatment Confirmatory Proof-of-Bioactivity (= Phase 2B) -Safety: 2x80 vs. 2x160mg vs. placebo -Efficacy: 2x80 vs. 2x160mg vs. placebo/comparator Safety parameters: vital signs, laboratory parameters Efficacy: Clinical endpoint(s), observations, and biomarkers What drug levels for best therapeutic ratio? More PK-ADME
Clinical Trials2
Phase III trials focus dosing and clinical endpoint based on knowledge gained in Phase II May be only one or two doses Clinical endpoint may be more specific Larger patient populations provide better statistical power Safety parameters: always vigilant for adverse effects Efficacy: primary clinical endpoint to confirm efficacy
Health Care System
Potential adverse selection in the health insurance market: The people who want health insurance are the ones who are likely to use it because they are sicker.
Pharmaceutical Research and Development2
Preformulation studies: Purity: high purity API (>99%) and impurities and degradation products must be identified (if >0.1%) and quantified Solubility and dissolution rate: to determine the concentration of API in solution and it solubility rate Stability: related to shelf-life with less than 5% decomposition under normal storage conditions or at least 3 years Particle size and morphology: API solid needs to be small, uniformly sized particles, smooth power to be blended with excipients to form tablets or capsules
Marketing
Primary Data: Brand new data collected by pharma marketer in order to inform, assess, and evaluate the market new product faces Advantages- Data relevant and to the point in interpreting the results More credible with FDA Disadvantages- Costs and time in data collection Because of the direct interactions with patients, institutional approval of data collection plan is needed before actual data collection begins (Often) small sample size
Pharmaceutical pricing
Principal Agent problem: demander, payer, and consumer not the same in healthcare market!
Pharmaceutical pricing
Prior Authorization (PA) Requires providers receive authorization from payer prior to prescribing or administering the drug (Price often used as a trigger for PA)
Manufacturing and Production
Process needs to be scalable (under existing CMC) to support sales growth of drug
Manufacturing and Production
Process needs to be scalable (under existing CMC) to support sales growth of drug in initial years
Clinical Trials
Production of the drug product must be increased to supply the demand for material needed as a Lead Compound moves from laboratory to animal and clinical trials
Pharmaceutical pricing
Prospective Payment System (PPS): a prospectively determined fixed-fee for all inpatient services, procedures and drugs defined by the diagnosis-related groups (DRGs) code Under PPS, a hospital is at risk for losing money if expenditures > payment.
Discovery of Drug Targets and Drug Leads 2
Proteome - Entire complement of proteins produced by cells or organism Proteomics - Study of a species' proteome to understand cellular processes
Manufacturing and Production
Quality Assurance (QA) - Guidelines for all operations, processes, and QC procedures to enable operations and end product to be produced within specifications Standard Operating Procedures (SOPs) - Documents detailing exact procedures and operations for each step in the production process Quality Control (QC) - Analytical testing of drug product, intermediates, processes, and equipment to ensure product produced and operations are within specifications
Manufacturing and Production
Recalls are actions taken by a firm to remove a product from the market. Recalls may be conducted on a firm's own initiative, by FDA request, or by FDA order under statutory authority. All recalls (Class I, II, and III) can be found in the FDA Enforcement Report (www.fda.gov). A Warning Letter is informal and advisory.
Discovery of Drug Targets and Drug Leads 2
Receptor Antagonist: a molecule that inhibits the receptor-ligand interaction Receptor Agonist: a molecule that enhances the receptor-ligand interaction
Discovery of Drug Targets and Drug Leads 2
Receptor: A protein target that binds a natural ligand and produces a response Ligand: A molecule which binds to a protein target and elicits a response.
Clinical Trials2
Regulatory Affairs: Interaction with government to obtain regulatory approval to conducting clinical studies and for production of therapeutics
Ethics
Reimbursement system often provides strong incentives for physicians to over-prescribe medicines administered by physicians or nurses in office based settings
Marketing
Remember: off-label promotion (promoting the drug on benefits not yet approved by FDA) is ILLEGAL and strictly enforced Tools Detailing/Sales Representatives Promotional Mailings Free Samples Journal Advertising Sponsorship of Continuing Medical Educational Programs Mass Media/Direct to Consumer Advertising (DTC)
Health Care System
Saving/extending life:Dialysis Bypass surgery Insulin, Antibiotics, Cancer medicines Improving Quality of Life: Hip/knee replacement surgery Ability for daily functioning and activities Reducing costs of care: Drugs keep patients out of hospital (e.g., asthma meds) Drugs reduce probability of disease progressions
Health Care System
Science and engineering applied to the delivery of healthcare
Marketing
Secondary Data: Existing data collected by sources other than the marketer or the market research team in the company Advantages- Database plentiful Sample size huge—good for powerful statistical analysis Often free (public/gov owned) Disadvantages- Lack of relevance: particular variables of interest may not be available Privately owned data can be quite expensive
Health Care System
Standardized, lump sum payment for a medical encounter, instead of individual payment for each service or product
Pharmaceutical pricing
Step Therapy Prohibits reimbursement for a therapy until after alternative, less costly therapies have proven unsuccessful
Patent and IP
Strong patent protection provide firms with the opportunity to recoup R&D investments in new products Temporary monopoly power in pricing Strong patent protection allows the patent-holder to disclose the patented research and science underlying the innovation without losing the financial benefits This leads to "spillover effects" of the scientific knowledge to other firms and even to other industries, further encouraging the innovative process
Pharmaceutical Research and Development2
Systemic drugs: Medicines that circulate in the bloodstream and have an effect throughout the body
Pharmaceutical Research and Development
Target selection and validation: main properties of molecules Molecular profiling: sufficient in vitro potency and selectivity in cellular assays Mechanism of action: activity in vitro (cell-based or cell-free assay) related to a physiological function of the target in a dose-dependent manner Lead identification: by HTS of existing libraries, molecules with particular biophysicochemical properties ('drug-likeness') for effective interaction with target (e.g., Lipinski 5 rules) Lead optimization: compound with specific characteristics: Be a member of a distinct structural series with confirmed structure-activity relationship Show evidence of desired selectivity profile Have activity in cellular systems Have acceptable metabolic stability in vitro Be free of any structural toxicity alerts and no major toxicity issue Have right ADME properties to predict human pharmacokinetics and clinical dose
Patent and IP
The "Patent Bargain": The patentee agrees to disclose his or her invention publicly in exchange for the right to exclude others from making, using, selling, offering to sell, or importing the invention for a limited time
Marketing
The Promotional Strategy is the communication platform. It is what will be said about the product and to whom it will be said
Pharmaceutical Research and Development
The Structure-Activity Relationship (SAR) is the relationship between the chemical or 3D structure of a molecule and its biological activity
Pharmaceutical Research and Development2
The drug or API (Active Pharmaceutical Ingredient) must be formulated to dosage forms to handle, distribute and administer to patients
Health Care System
The lack of public or private restrictions on the use of medical technology despite the high price Extensive insurance coverage with limited patient co-pay reduces price sensitivity (elasticity) for healthcare products and services
Ethics
The negative economic consequence of fraud (if convicted, or settled) is too small compared to the financial gains from committing the fraud
Marketing
The promotional strategy is based in the current state of art, and MUST be consistent with the current product label In most companies, promotional messages are strictly reviewed and must be approved by internal legal and regulatory representatives before dissemination FDA has authority over any and all promotional contents of biopharmaceutical products
Patent and IP
The scope of patentable subject matter has been broadly constructed to "include anything under the sun that is made by man" Abstract ideas, laws of nature, and natural phenomena are not patentable subject matter because they exist without any inventive act
Health Care System
The share of GDP (total economic output measured in $) accounted for by healthcare spending = 17.5%
Ethics
The system which allows off-label usage of medications is being abused In the US, insurance (including Medicare) typically reimburses an approved drug for an off-label usage if a physician prescribes it; esp. when few alternatives are available or when the condition is dire While drug reps are not supposed to initiate discussions on off-label usage, they can provide lots of information when asked by physicians Some companies employ the tactic of getting a drug on the market for the easiest indication, then expanding its usage thru off-label prescriptions without having to do a true RCT for a formal FDA approval
Discovery of Drug Targets and Drug Leads
Therapeutic category - similar to disease, but also defined by the underlying cause and/or mechanism
Discovery of Drug Targets and Drug Leads
Therapeutic concept: decision based on strategy Unmet medical needs, competition (market), government policy (price/reimbursement), patent situation, company strategy (pipeline, technology, franchise), etc. Target selection: related to therapeutic indications Diseases (conventional), genotype (altering gene expression), phenotype (physiological effects through proteins) Target validation: experimentally the potential drug is tested and gives credibility in terms of efficacy and safety (reliable results from pharmacokinetics studies) Lead finding: identification of high-quality lead molecules Lead optimization: identification of a compound that possesses the required properties for preclinical development (pharmacokinetics or ADME, acceptable exposure to target site or receptor, efficacy and safety in vitro and small scale in vivo in animals)
Discovery of Drug Targets and Drug Leads
Therapeutic intervention: therapy to treat a disease/condition, to prevent a disease/condition, and to improve non-disease conditions (e.g., pregnancy, skin wrinkles)
Discovery of Drug Targets and Drug Leads Therapeutic Modalities
Therapeutic modalities: Conventional therapeutic drugs: small-molecule drugs synthetic or natural products Biopharmaceuticals: therapeutic proteins, nucleic acids from recombinant DNA
Discovery of Drug Targets and Drug Leads Therapeutic Outcome
Therapeutic outcome: Pharmacological effect: effect of drugs on cells, organs, tissues, measured in animals and humans (e.g., by blood pressure, plasma cholesterol) Efficacy: ability of the drug to produce the desired effect in patients in clinical trials (under control conditions) Effectiveness: how the drug works in real life with heterogeneous and not randomized patients Benefit: effectiveness in monetary terms
Ethics
There is a very small personal price on the part of CEO and/or other executives for committing a fraud Very difficult for whistle blowers to prevail in court Thin wall and revolving door between government authority and corporate world
Pharmaceutical pricing
Tier System with Different Co-Pay Levels Tier 1: Generics, lowest co-pay; Tier 2: preferred brand name, medium co-pay; Tier 3: non-preferred brand name, highest co-pay
Pharmaceutical Research and Development2
Toxicology is the study of harmful effects of drugs and other chemicals and the mechanisms underlying pathologic changes, disease, and death Most drugs have toxic effects at high enough doses and may have adverse effects at therapeutic doses
Clinical Trials
Trial design Healthy individuals (not disease treatment) Dozens enrolled Dose ranging (escalation) Outcomes Human safety data Observation of adverse effects Maximum tolerated dose (MTD) Human PK-ADME data Bioavailability
Patent and IP
USPTO had granted Myriad's patents on the BRCA1/2 genes and their relationship to breast cancer Isolated DNA sequence is NOT a product of nature "because that DNA molecule does not occur in that isolated form in nature." ACLU, Physician groups sued Myriad Supreme Court ruled that natural, isolated DNA sequences were NOT patentable "We merely hold that genes and the information they encode are not patent eligible under §101 simply because they have been isolated from the surrounding genetic material."
Pharmaceutical pricing
Value-Based Pricing Price set to what the perceived value of the product is How is value determined?
Health Care System
asymmetric information: a situation in which one party (the patient) to an economic transaction (purchasing insurance) has more information than the other (the insurance plan). Two main forms of asymmetric information: Adverse selection: one party elects to take part in the market or not, based on their private information. Moral hazard: after engaging in a transaction, one party chooses different actions knowing that the other will bear some of the cost.
Marketing
new product stategy: This is why many marketing strategy plans in the pharmaceutical industry are co-developed (and certainly have to be approved) by clinical scientists (usually physicians and regulatory experts)
Pharmaceutical pricing
payers primary rely on 3 mechanisms to discourage use of expensive medications : Tier System Prior Authorization Step Therapy
Pharmaceutical pricing
utility = preference for a given health state On a scale of 0 to 1, with 0 indicating death and 1 indicating perfect health, patients assign utility values to different health states, which are then used as weights to calculate QALY.
