Prelim 1 Flashcards
pharmaceutical contributions to improvements in health and welfare
- surfactant and premature baby survival
- anesthesia and surgery
- vaccines and contagious diseases
- oral contraceptives and women’s education/work experience
- pharmaceutical companies have huge expenditures on marketing/administration and the prices charged are way more than cost of production
- only a few handful of drugs have been significant
- “new” drugs are just variations of existing ones
- dependent on government-granted monopolies
Marcia Angell Opinion on Pharmaceutical Industry
- approval of Alzheimer’s drug with weak scientific support
- operation warp speed sent $20 to Pharma firms to pre-buy covid vax
recent favorable/generous actions of US gov for Pharma
- new law in Aug 2022 that will cut drug prices in Medicare by requiring price negotiations, capping drug price increases, and reducing out-of-pocket costs
recent unfavorable actions of US gov for pharma
what phases are in the first 3-6 years of drug development?
drug discovery and preclinical testing
when is the IND submitted?
after preclinical testing
when do the clinical trials occur in drug development timeline?
6-7 years
how many volunteers are in phase 1 clinical trial?
20-100
how many volunteers are in phase 2 clinical trial?
100-500
how many volunteers are in phase 3 clinical trial?
1,000-5,000
when is an NDA submitted?
after phase 3 clinical trial
how long is the FDA review?
0.5-2 years
- understand how a disease affects the body
- hypothesize how a drug might intervene in the disease process
- identify candidate drugs
drug discovery
compounds that have favorable properties, likely to be effective, but not likely to be (too) toxic
candidate drugs
- gene regulator protein is active in early embryonic development to allow cells to move around the embryo, but then it becomes dormant
- cancer tumor cells reactivate and “hijack” its process to move cancer cells around the body
- a drug that could prevent the reactivation could, in theory, prevent some cancers from metastasizing
- no company “owns” this theory/hypothesis
drug discovery - twist protein
- hypothesis created on how a drug could stop the reactivation
- researchers prove how this theory works in cells
- pre-clinical (before human) phase with computer-based simulation and test compounds in vitro/in vivo
- narrow focus to fewer compounds
steps for twist protein drug discovery
- before human subjects
- identify compounds likely to work
- computer based simulation, molecular modelings nd combinatorial chemistry help choose a successful compound
- test compound(s) in vitro (cells in lab) and in vivo (animals with disease)
- narrow to fewer compounds
pre-clinical trial
human epidermal growth factor receptor 2: part of a family of genes that produces a protein that regulates the growth and development of cells
HER2
- 1985: researchers discovered that an over expression of HER2 causes cells to multiply rapidly
- 1987: researchers linked HER2 to breast cancer (an over expression was found in 25-30% of cancers)
- 1998: FDA approved this drug for patients with favorable genetic makeup (I.e. patients with HER2+)
Herceptin case study
Trastuzumab binds to excess HER2 protein and attracts cells that destroy these proteins
Herceptin
Is Herceptin a pharmaceutical or a biologic?
biologic
- small MW (<1,000)
- made by chemical synthesis by chemists
- generally oral solids because they’re stable enough to digest
- pharmacy benefit
- generic law: HW act
- ex, lipitor for cholesterol
pharmaceutical
- large MW (>10,000)
- made from cultures of living cells
- often injected or infused (not stable for digestion)
- often medical benefit
- Generic law: biologics price competition and innovation act of 2010
- ex, Herceptin for breast cancer
biologic
- microbiology, genetics, and the human genome project
- recombinant proteins - understand how to make proteins from a gene sequence
- monoclonal antibodies (-mab).- lab created antibodies that bind to a target
- biologic drugs created from living organisms
scientific breakthroughs for pharmaceutical industry
How much does biologics account for in US Pharmaceutical sales?
43%
- greater growth rate than pharmaceuticals
- market grows faster than pharmaceuticals
- increasing over the past 20 years (~13% increase)
biologics spending
what type of drug are vaccines?
biologic
now a rising share of FDA approvals
biologic approvals
effect for an aggressive breast cancer especially those recently diagnosed, however, even those 5 years from diagnosis had a 23.4% probability of survival
Herceptin and survivability
where does a drug discovery happen?
usually at a university funded by the NIH
Who owns the intellectual property for a drug discovery?
the scientist
allowed inventors and grantees keep intellectual property offering incentives for researchers to relicense
bayh-dole act of 1980
federal government had accumulated thousands of patents on commercializable technology, but hadn’t relicensed them
motivation for bayh-dole act of 1980
- a never-used “back door” in bayh-dole act
- NIH can “march in” and reassert ownership of IP if holder isn’t developing the technology or if it is not satisfying “health and safety needs”
- NIH recently denied 6 petitions to exercise these rights
“march-in rights”
why do researchers work with pharmaceutical companies on top of NIH and universities?
funding, but now pharma firm owns most of IP
why would the drug development project be over if the pharma firm decides to not go forward?
pharm firm owns the IP
genentech is ______, as slamon is __________
record label; band
why does Genetech get to decide whether and when to do the moss protein test rather than Dr. Slamon?
the pharma firm needs a successful test for an IND before phase 1 and Slamon might be biased
understand compound, side effects, develop evidence for IND approval
pre-clinical testing
government regulation starts at this early stage before any human testing (pre-clinical) to show FDA why they [pharma firm] think the drug is safe, worthy of clinical trial, and manufacturing consistency
investigational new drug
What was the unintentional Rx that came out of testing _____ which was originally intended to lower BP?
viagra
- preclinical phase
- IND
- Phase 1 clinical trial - safety, dosing, 10s of subjects
FDA consult
- Phase 2 - safety, early evidence of effectiveness, hundreds of subject
FDA consult
- Phase 3 - safety, effectiveness, thousands of subjects
- Approval if safe, effective, and produced reliably
FDA involvement in drug development and trials
formulation and mechanism of action,
evidence for investigational new drug approval
example: Herceptin (trastuzumab; active pharmaceutical ingredient (API)) is a humanized IgG1 kappa monoclonal antibody that selectively binds with high affinity to the extracellular domain of the human epidermal growth factor receptor 2 protein, HER2. Trastuzumab is produced by recombinant DNA technology in a mammalian cell (chinese hamster ovary) culture contain the antibiotic gentamicin (manufacturing process)
drug formulation
example: The HER2 (or c-erbB2) proto-oncogene encodes a transmembrane receptor protein of 185 kDa, which is structurally related to the epidermal growth factor receptor. Herceptin has been shown, in both in vitro assays and in animals, to inhibit the proliferation of human tumor cells that overexpress HER2
mechanism of action
what does the mechanism of action provide the FDA?
why you should let us do this and why it might be effective
- serum concentrations
- pharmacokinetics
- half-life
- dose-dependent
- clearance
- safety
phase 1 trial considerations
why are multiple doses of drugs tested in phase 1?
safety, pharmacokinetics, and optimal dosing
concentration (of active portion) in blood
serum concentration
time of absorption, distribution, metabolism, and execution (ADME)
pharmacokinetics
time for half of API to become inactive
half-life
larger dose –> predictable increases in time of ADME
dose-dependent
rate at which wastes are cleared
clearance
2 oz. of alcohol will clear renal 0.06 L/h, sweat 0.02 L/h, breath 0.00007 L/h
~5 hours to clear BAC to 0.00
pharmacokinetic of ethanol
assemble preliminary evidence on safety and efficacy
phase 2 clinical trial goal
why would the FDA not approve a drug based on phase 2?
too small subject size to demonstrate safety and efficacy
- presence of common side effects
- whether biomarkers in the body are reacting as expected (target HER-2?)
- whether the disease reacted as expected (tumor growth affected?)
- sometimes experimentation with dosage
phase 2 clinical trial
- What type of patients (and how many) to enroll in clinical trial?
- Primary health endpoint that will be measured and how it will be measured?
- What treatment will the experimental and control patients receive?
pharmaceutical drug development decisions
- multicenter, randomized, controlled clinical trial
- 469 subjects with metastatic breast cancer who had no previous chemotherapy treatment and whose tumors overexpress HER-2
- subjects eligible if they had 2+ or 3+ levels of over expression of HER2
- randomized to receive chemotherapy alone or in combination with Herceptin (testing against SOC)
Herceptin clinical trial design
many physicians throughout the US sign-up their own patients for trial
multicenter
phase 3 clinical trial was only aimed at high-HER2 patients so FDA will only approve its indication for high-HER2 (even if it would be beneficial for low-HER2 there is no evidence)
on-label indication for Herceptin
How would low-HER2 patients receive Herceptin?
off-label prescription
how does the clinical trial design impact labeling and approval?
FDA will only approve an indication for the specific type of subjects that were tested in the clinical trial even if it would be beneficial to all subjects with condition
- how the drug can be marketed
- whether health insurers choose to pay for it and how much
- the types of patients who are prescribed the drug
drug label impact
true or false: FDA controls prescribing
false
allows a drug to be sold in the US and allows drug firms to market the drug, but has no influence on prescribing - left up to physicians and insurer
FDA approval
- physicians can prescribe any FDA approved drug either as on-label or off-label treatment
- insurer may not pay for it
- medical licensing and malpractice will restrict prescribing
physicians and insurers on prescribing
how many prescriptions are uses as off-label?
21%
how many off-label prescriptions are not supported by evidence of clinical efficacy?
70%
what is the most common development delay?
difficulty recruiting appropriate patients for clinical trials
allowing patient to receive an experimental drug even if they are not enrolled in its clinical trial
compassionate access
- Genentech was preparing to test bevacizumab in a phase 3 colorectal cancer trial
- mechanism of action: “chokes off” the blood supply of cancerous cells
- VEGF-A is a chemical signal that stimulates to its receptors (Fat-1 and KDR) on the surface of endothelial cells
- administration of bevacizumab to xenotransplant models of colon cancer in mice caused reduction of microvascular growth and inhibition of metastatic disease progression
Avastin case study
- subject consideration:
—- stage 1 subjects: cancer is localized so it hasn’t spread to nearby lymph nodes or distant sites
—– stage IV subjects would be more difficult because cancer has spread beyond the initial site
—– 2.5x more stage IV colorectal cancer pt receive drug treatment in US than stage II/III - look at comparator drug to see what control group should get: brand and generic chemo
- audiences for clinical trial
- trial length (choose an outcome that won’t take years to happen)
Avastin clinical trial design considerations
wants clear evidence of safety and efficacy in clinical trial
FDA
- will be the ones prescribing
- want to know whether Avastin is really better than current alternatives
- want patients to recover or at least survive
physicians
- randomized controlled trial
- subjects were patients with stage IV colon cancer
- treatment: 402 subjects given Avastin and generic chemo (5-Fu)
- control: 411 subjects given irinotecan (brand) + 5-FU
- primary endpoint: median survival
- secondary endpoint: response rate and time to progression
- side effects: abdominal pain, diarrhea, and nausea
Avastin clinical trial design
why were stage IV patients chosen over stage I/II for Avastin?
because median survival wouldn’t have been applicable and this is better to prove clinical benefits. if stage I/II were chosen response rate would have to be the primary endpoint which isn’t as strong
based on phase 3 RCT for Avastin…
- physicians will be too cautious to prescribe off-label until later studies test the efficacy
- physicians will try on a small number of early stage pt and evaluate efficacy in own practice
- physicians will infer Avastin will work better for stage II pt than any existing alternative
predicting physician behavior
developed for other health conditions and patient populations
Feb 2004: FDA approved 1st line metastatic colorectal cancer
June 2006: FDA approved 2nd line metastatic colorectal cancer
June 2006: Lucentis (a lower dose of Avastin) approved for macular degeneration of the eye
Oct 2006: approved for lung cancer
Feb 2008: Accelerated approval for metastatic breast cancer (met its secondary rather than primary endpoint)
May and July 2009: approved for glioblastoma (brain) and renal cell carcinoma
Dec 2011: FDA rescinds approval for metastatic breast cancer because it failed to meet its primary endpoint
Genentech continued drug development for Avastin
generally, the most important outcome for patient and the FDA’s focus in its approval decisions
primary endpoint
a cause or consequences of primary endpoints; side effects, convenience, “nice to haves”
secondary endpoint
- AM-pharma was a startup with no approved drugs who wanted to target kidney failure after a sepsis diagnosis
- found recombinant alkaline phosphatase protects organs
- two potential endpoints: kidney function (primary) or mortality (secondary)
RecAP case study
- Results in March 2018: no effect on short term kidney function, but 40% reduction in all-cause mortality
- However, since primary endpoint was not achieved, interpreted as bad news
- Pfizer, who had bought an option to acquire AM-Pharma, declined to acquire
- AM-Pharma got other investors and continued
AM-Pharma Phase 2 trial
- 1400 subjects
- Relatively small number of patients and short follow-up
$163 M is cheap for a phase III trial - Primary endpoint: 28-day mortality
- Secondary endpoints: 90- and 120-day kidney function and quality of life
- Results: no reductions in 28-day mortality (primary)
Improvements in kidney functions (secondary) - Because 28-day mortality is primary endpoint, FDA is unlikely to approve based on these results
- AM-pharma now faces a difficult decision: raise yet more money for a further trial or give up
AM-Pharma Phase 3 trial
- prevalence/incidence
- greatest clinical benefit
- differentiation
- approval probability
- off-label prescribing
optimal phase 3 trial design
what stage of the disease do most of the patients have (e.g. stage I/II vs. Stage IV cancer)?
prevalence (optimal phase 3)
where can a drug add the most value?
- For colorectal cancer, stage I and II patients have a very good chance to survive after surgery without drugs
- For stage IV and III, the drug treatment can make a big difference
- For other diseases, a drug might provide the greatest health benefit for relatively healthy/robust patients
greatest clinical benefit (optimal phase 3)
in what type of patients can your drug best differentiate itself from competitor drugs?
differentiation (optimal phase 3)
what type of patients will maximize the approval probability and/or minimize the cost of running the trial?
approval probability (optimal phase 3)
will the trial facilitate off-label prescribing?
off-label prescribing (optimal phase 3)
two large, randomized, double-blind trials comparing an experimental drug to an existing drug
89% of approved drugs had randomized trials
80% had double-blind
32% compared experimental to an active ingredient in an existing drug
55% compared to a placebo
13% compared to none
Number of patients: median 760 across both arms of trial
Length of trial: 34% followed patients for 6 months or longer
Number of trials: 63% ran two separate phase III, or pivotal, trials
scientific gold standard for phase 3
- are there health benefits (actual vs. expected) vs. the control group?
- if so, do the health benefits outweigh the possible side effects or safety issues?
FDA decisions rule
The FDA often mandates post-marketing studies as a condition for approval, to explore whether safety issues in a RCT persist in a broader patient population
phase 4 studies
true or false: the FDA considers the drug’s potential price and European regulatory bodies
false
What does the FDA consider when deciding to approve a drug?
availability, efficacy, and side effects of existing clinical alternatives
balance protecting the public from unsafe or ineffective products and speed access to important new products
role of the FDA
Late 1800s-early 1900s: ineffective and sometimes dangerous “patient medicines” were heavily advertised
1902: biologics control act
1906: pure food and drug act
1938: Food, drug and cosmetic act
1962: Kefauver-harris amendment
history of FDA drug regulation
established standards for safety, purity, and potency of vaccines
biologics control act (1902)
creation of the FDA, accurate labeling required
pure food and drug act (1906)
- triggered by sulfanilamide disaster
- drugs must be proven safe before being marketed
- companies must notify FDA before products are sold
food, drug, and cosmetic act (1928)
- triggered by thalidomide incidents
- drugs must be formally approved by FDA
- required “substantial evidence” of efficacy for drugs
- companies must report adverse events on ongoing basis
Kefauver-harris amendment (1962)
- pharmacist dissolved it in diethylene glycol (antifreeze) to make a liquid
- sold as an effective streptococcal treatment in solid form
- a woman wrote to President Roosevelt describing the death of her daughter, urging him to prevent the sale of these drugs
- resulted in food, drug, and cosmetics act of 1983
sulfanilamide disaster
- treatment for morning sickness (anti-nausea)
- became very popular in Europe where there was no FDA
- US FDA blocked its use in America
- found to cause birth defects and FDA was seen as a hero
- resulted in Kefauver-harris amendments (1962)
thalidomide incidents
- Marketed for teething and colicky babies…contained morphine
- Cocaine toothache drops
- Aspirin and heroin ads
- Claimed to cure many ailments. Contained arsenic, opium, and insect parts
“patent” medicines of early 20th century
- key policy tradeoff: greater protection means less innovation
- “The FDA is responsible for protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, medical devices, our nation’s food supply, cosmetics, and products that emit radiation, and by regulating the manufacture, marketing, and distribution of tobacco products”
“The FDA is also responsible for advancing the public health by helping to speed innovations that make medicines and foods more effective, safer, and more affordable; and helping the public get the accurate science-based information they need to use medicines and foods, and to reduce tobacco use to improve health”
FDA mission statement
- slow response from medical community
- galvanized LGBT activism
- model of disease-specific activism
- even after successful clinical trial, FDA approval might take 2 years
- individuals will rare disease have a group representing them to FDA and congress
treatment of HIV/AIDs
drug is not safe, yet FDA approves; approves a drug that is later found to have harmful side effects
type 1 error
