Contents:

Chapter 1: Healthcare delivery in the 21st century

– Challenges, societal expectations and the economic context
?X Preliminary definition of a drug
How do drugs differ from other consumer products?
o Basic properties
?X Efficacy, selectivity, safety
?X Small molecules versus biologics
?X Costs, generics, ethical drugs
o Availability/marketing
?X The ideal patient
Pays extra taxes to consume tobacco and alcohol and dies early – pays for the system but is not around long enough to use it.
?X The population explosion and the aging of the population
Sustainability of economic growth models
Less workers more retirees – who pays?
Drugs and vaccines have prolonged life –
Entitlement versus compassion
– Health care cannot be considered as a commodity
?X Federal versus private insurance
Affordable Care Act/NHS
– The players
?X Physicians and hospitals – primary and secondary healthcare provision
?X Insurance/federal plans for health care provision and prioritization
?X Pharmaceuticals– the role of drugs, vaccines and biologics
– Costs, preemptive cost savings, efficiencies and bureaucracies
?X The ethical drug consumer of drugs is infrequently the payer.
The consumer = patient
The purchaser = healthcare providers
The decision marker = the physician
?X Drug co–pays in an era of iTune downloads
?X Prophylactic drug treatment versus surgery/hospitalization
Ulcer treatment – antibiotic + H2 blocker = pennies per day versus invasive surgery
?X More money is spent on the mechanics of healthcare provision that healthcare itself.
?X Independent Payment Advisory Board concept
Politically adept, scientifically and medically suspect
Common sense or rationing?
?X The free market model of drug delivery
A health imperative – preventative medicine
Healthcare versus the food, tobacco and alcohol industries
o Improving lifestyles
?X The imperative for new drugs
Cost benefit analysis of new drugs
o Reduced burden on health care provision
o Unmet medical need versus:
?X Pharma "disease mongering"
?X Life style drugs
o The $100,000 plus a year drug regimens – e.g., Provenge
Comparative effectiveness research, NICE, etc.
Gawande′s "Cost Conundrum" and procedural cost reductions (New Yorker)
Billions wasted on insurance billing (Emanuel, NYT 11/11)
Le Fanu′s clinician perspective on the genomic revolution – The Rise And Fall Of Modern Medicine

Chapter 2; Pharmaceuticals in healthcare delivery.

– What is a drug?
?X Magic bullet concept
?X Drug properties
Small molecules
Biologics
?X Life style versus acute versus chronic drugs?
?X The drug R & D process – research, clinical trials
?X Drug approval – FDA. EMEA, etc oversight
?X Drug costs – proportion of the health care dollar.
?X Drug cost reimbursement
?X Generics
?X Me–too drugs
?X How producing a drug differs from producing a car
– Societal expectations
?X Biomedical research and the public good
?X Are drugs too expensive?
?X Expectations from genomics
?X Personalized medicine – fact, fantasy and/or unaffordable reality?
Disease causality
o Genetics
o Epigenetics
Biomarkers and diagnosis
o Personalized medicine
Niche disease states

Chapter 3: Historical Perspective of Drug Discovery

– Eras
?X Empirical
Natural products and serendipity, Aryudevic, Kampo, traditional Chinese, other folk medicine systems.
Coming of age
o Claude Bernard
o US Civil War
o German dyestuffs industry
o Conflict – WWI and WW2
o Mechanistic
?X Early efforts in receptors and mechanisms – 1900s
?X Biochemical pharmacology – 1948
?X Molecular Pharmacology – 1976
?X Molecular/genomic – 1985
?X Undercurrent of industrialization – eliminating innovation – a numbers game replacing the intellectual process – 1980s – present
o The process of drug discovery
?X Timelines compared with other industries
?X Discovery process
Disease diagnosis
Disease mechanisms
Target identification
GWAS
screening libraries
small molecule or biological target interactions,
iterations to improve selectivity, novelty, efficacy, safety and drug like properties including delivery and target residence
Translational medicine agendas
o CTSAs, European Advanced Translational Research Infrastructure in Medicine Network – EATRIS and the UK National Institute for Health Research.
– The clinical trial and approval process. Attrition metrics and history
?X IND
?X NDA
?X Patient recruitment
?X Trial endpoints
Lessons from the computer industry? The Grove dictum (2011)
?X Trial size, length and cost
?X The pitfalls of conducting trials cheaply
Dimebon
– ?? Case studies – aspirin, morphine, propranolol, the statins, benzodiazepines, SSRIs, biologics, TNF antibodies, kinase inhibitors

Chapter 4: Origins, evolution and status of the ethical pharmaceutical industry

?X Origins
German dyestuffs industry
Evolution of the European, American industries
Early blockbuster drugs and the cultural shift from applied science to politics and profits
The biotech/venture capitalist revolution
Emergence of the Asian axis – China and India
?X Models of drug discovery and commercialization
Internal discovery
o Organizational structures for drug discovery. The scientist as drug hunter. The roles of basic and applied research.
Collaborations
Acquisition
o The R& D versus the S & D model – the non–sustainability of in licensing as a strategy.
?X Public perceptions of the role and contributions of the pharmaceutical industry – equating applied drug discovery enterprises with the tobacco industry and Wall Street

Chapter 5: The culture ands ethos of biomedical research in the 21st Century

– The biomedical/pharma research complex
o NIH/MRC/Max Planck etc
o Pharma
o Biotech
o Not for profits/foundations
o Academic drug discovery
o CRO role
– The disconnect between biomedical research and the patient (Horrabin)
– Innovation and intuition versus the industrial technology approach
– Patenting biomedical discoveries
o Patenting of the human genome. Implications for a scientific anti–commons– BRCA1 and BRCA2 patents. SIBIA patent #629
o Corruption of the biomedical enterprise by the patent system and the search for individual reward.
?X Extramural NIH funding and university spin out companies – impact of Bayh–Dole.
?X Biomedical science as a subsidiary of Wall Street
?X Biotech versus big pharma
– Translational medicine
o T1 and T2
o The valley of death between the lab and the clinic
o Animal model shortcomings
o Systems biology, biomarkers and omics.
o NCATS
– Science in the 21st century
o The information explosion
o Reductionism and failure to appreciate biological complexity
o Qualitative versus quantitative science
o Meritocracy versus mediocrity
o The ethics of science
o US research enterprise in crisis mode
?X Shift in the scientific enterprise to India, Qatar and China
o Scientist training and education
?X FDA White paper 2004 – need for training of basic and clinical pharmacologists
?X NIH funding to circumvent the postdoctoral process.
?X The perpetual postdoc
o Data replication issues
o Science in sound bytes
o Fraud and data selection
o The scientific poseur/hype merchant, cronyism, greed

Chapter 6: Productivity issues in drug discovery

– Productivity 1992 – 2011
?X Increased cost with decreased output
?X Low hanging fruit issues – targets more difficult
?X Incessant restructuring
?X Business overriding science
?X Consensus as an asset or liability?
?X Paradigms for increasing productivity, six sigma, just in term

o The decline and dissolution of big pharma
?X Pharma′s Detroit moment
GSK turning to McLaren to reinvent its culture – next step Apple?
Management consultants
?X 300,000 jobs lost in past decade
o Where did pharma go wrong?
?X Too big and bureaucratic due to mergers
?X Turning innovation into an SOP
?X Intrusion of business into scientific decisions
?X Blockbuster drug model
?X George W. Merck (1950) – "We try never to forget that medicine is for the people. It is not for the profits. The profits follow, and if we have remembered that, they have never failed to appear. The better we have remembered it, the larger they have been."
o Biotech as a viable alternative or just another Ponzi scheme? (Pisano HBR book)
?X Drug assets being developed irrespective of value – shuffling junk and bottom feeding
?X Primary responsibility to share holders not pateients
o The role of academic medicine
?X NCATS
?X NIH Roadmap
?X Universities
o Emulation of pharma model perfect description of stupidity
o Alternative models
?X Pharma as venture fund source
?X Partnerships
?X Biotech
?X Non–profits/disease foundations
?X NIH
?X M.D. Anderson Institute for Applied Cancer Research
o The FDA regulatory debate

Chapter 7: The pharmaceutical imperative in the healthcare equation

– Premises
?X Innovative new drugs and their effective and timely delivery to health care systems offer the best means to contain health care costs and improve individual quality of life and life expectancy.
?X Patient care and insurance companies consume 85% of the healthcare dollar.
?X The pharma/biotech enterprise
should be rewarded for providing the means for improved health care – drugs – not profits
needs to retool to improve its obligations to the patient and to society
?X Biomedical science and Wall Street entrepreneurship are ill suited as partners and
?X The biomedical research enterprise

Chapter 8: Options for a paradigm change

?X Why haven′t we harnessed the explosion in biomedical research knowledge?
Greater than 50% of academic research in the biomedical arena cannot be replicated.
Increase in fraud
Motivation by money not science
Shortcomings in translational research
Need to reassess and redesign clinical trials.
?X Where will new drugs come from?
?X What will those drugs look like and what will they do?
?X The challenges
Improving the image of the industry and its value to society
Addressing emergence of chronic disease states
Societal conflicts in improving health need to be addressed
o Explosion in diabetes and obesity the result of pressures for increased food consumption
o Lung disease, cancer via smoking
o Cancer via environmental pollution
Inefficiencies and waste in health care administration
Societal entitlement – an increasing population with diminishing productivity
o Universal coverage versus rationing
o Quality of life versus quantity
o Decline in resources
o Global warming
o Pharmaceutical pollution from body excretions
o Third world needs

?X Possible solutions
Translational medicine a shared, prioritized process with oversight from scientists and clinicians from academia, IOM, FDA and industry to chose the best compound(s) and design trials and endpoints – based on collaborative research models along lines of Michael J. Fox and Gates foundations and NIH review panel for Alzheimer′s Disease (Kolata, NYT 2010)
o Pros and cons
Federally funded or incentivized by tax breaks through Phase II proof of concept
o Pros and cons
Improving quality of science and scientific decision making
o Society challenge
For chronic disease states with no effective treatment options – AD, type I diabetes, obesity – institution of new shared R & D mechanisms along the lines of a Manhattan–type WWII project/NASA (Critical Pathway Institute) need to be developed by academia and the pharmaceutical industry to prioritization and execute research and development on devastating disease states like Alzheimer′s to avoid bankrupting healthcare systems worldwide that are already in a precarious financial state.

Index