FDA Regulation of New Drugs and Medical Devices

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Lecture 22

• FDA Regulation of New Drugs and Medical Devices

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Overview

• Drug and Device Regulation
• Reaction to Disaster, Tragedy and Misfortune
• 1906
• First federal regulation of drugs
• Burden on FDA to PROVE it is UNSAFE
• 1938
• Food, Drug and Cosmetic Act
• Pre-market NOTIFICATION
• 1962
• Drug amendments to FDC Act
• Pre-market APPROVAL
• 1976
• Medical Device Amendments to FDC Act

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Using Gold to Detect Cancer
How long do you think it will be before we can
test this in patients?
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Using Gold to Feel Better

• http//www.alchemistsworkshop.com/
• http//www.cnn.com/2002/ALLPOLITICS/10/02/offbeat.
  blue.candidate/

How long do you think it will be before we can
test this in patients?
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Vitamin-, Mineral-, Herbal-Supplements

• Thousands sold in the US
• Remarkably little is known about most
• http//www.gnc.com/products/
• 6 out of 10 Americans take one or more
  supplements a day
• Multi-vitamins
• Amino acids
• Weight-loss cures
• Herbal tonics
• Americans spent 19 billion on dietary
  supplements in 2003

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Zantrex-3

• One of the most popular weight loss supplements
  currently sold in the US
• One months supply 50
• Millions of bottles sold
• Hit US market in March, 2003
• Sold at
• GNC, CVS, RiteAid, Wal-Mart, internet, eBay
• Contains
• Caffeine
• Green tea
• Three common South American herbs that act as
  stimulants

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http//1800patches.com/zantrex/combo.html?siteidi
a_cT7QKpQM-fHD1gG4hCzyoEaxIXjDS5g
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Zantrex Marketing

• Don Atkinson
• VP of Sales for Basic Research
• Company that distributes Zantrex-3
• When I train salespeople, I say to them, Do you
  know what people are calling you for? It isnt
  the pill. They are calling you for hope. That
  is really what they want from you.
• I love my job. And do you know why? Because
  when I get up in the morning I know somebodys
  life is better because we are here. Somebody
  today got some hope.

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1994 Dietary Supplement Health Education Act

• Congress deregulated supplement industry
• Companies are not required to prove products are
  effective or even safe before marketing them
• Companies CANNOT
• Blatantly lie
• Claim to have a cure for a specific disease
  (cancer, diabetes, AIDS)
• Companies CAN say (without evidence)
• Product is designed to support a healthy heart
• CardiAll
• Protect cells from damage
• Liverite
• Improve function of compromised immune system
• Resist
• Almost no standards that regulate how pills are
  made
• Not tested once they are made

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Benefits of Supplements

• Vitamin C to prevent scurvy
• Mid-18th century
• Scurvy killed more British sailors than war
• Folic acid to prevent neural tube defects
• Calcium to prevent osteoporosis
• Vitamin B12 to prevent dementia

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History of Supplements

• 1793
• Patent legislation that permitted manufacturers
  to protect their formulations
• Did not require that they work
• Early 1800s
• Number of newspapers in US published increased
  dramatically
• Early 1900s
• Patent-medicine business accounted for more
  newspaper ads than any other kind of product

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Lydia Pinkhams Vegetable Compound

• A Positive Cure for all those Painful
  Complaints and Weaknesses so common to our female
  population
• 1914 AMA analyzed Pinkhams compound
• 20 pure alcohol
• 80 pure vegetable extracts
• Many supplements laced with
• Cocaine
• Caffeine
• Opium
• Morphine

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History of Supplements

• 1906
• Pure Food and Drug Act
• Reaction to The Jungle by Upton Sinclair
• Permitted Bureau of Chemistry to insure that
  labels contained no false or misleading
  advertising

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History of Supplements

• 1937
• Sulfanilimide, antibiotic for streptococcal
  infections, used safely as a pill for years
• Most children cant swallow pills
• One company in Tennessee found they could
  dissolve drug in ethylene glycol (antifreeze)
• Tested for flavor, appearance, fragrance, NOT for
  toxicity
• Shipped it all over the country
• Within weeks, scores of children were dead

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Sulfanilimide

• 137 children died
• Severe abdominal pain, nausea, vomiting,
  convulsions
• Even the memory of her is mixed with sorrow for
  we can see her little body tossing to and fro and
  hear that little voice screaming with pain and it
  seems as though it would drive me insane.
• Letter to FDR, from woman describing the death of
  her child

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History of Supplements

• 1938
• Food, Drug and Cosmetic Act
• Gave FDA authority it needed to regulate such
  products

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History of Supplements

• 1940s-1960s
• Line between foods and drugs was fairly clear
• If manufacturers made a disease related claim for
  a supplement, FDA would go after them
• 1970s
• Government started telling Americans to alter
  diets if they wanted to have longer, healthier
  lives
• Heart disease, diabetes, cancers ? eat less salt,
  fat add fiber, eat more fruits vegetables

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Kelloggs All Bran

• 1984
• Launched campaign with NCI
• All-Bran cereal illustrated how low-fat,
  high-fiber diet might reduce risk of certain
  cancers
• http//www.kelloggs.com/brand/allbran/

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Today

• CANNOT mention disease
• CAN make claims that food can affect structure of
  function of body
• Examples
• CANNOT say that a product reduced cholesterol but
  CAN say it maintains healthy cholesterol levels
• CANNOT say echinacea cures disease, but CAN say
  it has natural antibiotic activities and is
  considered an excellent herb for infections of
  all kinds

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Echinacea

• One of the most commonly used cold remedies in US
• Clinical Trial
• 400 children with common colds over 4 months
• Compared placebo to echinacea
• Placebo worked just as well
• Children taking echinacea were more likely to
  develop a rash

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Ephedra

• Was most popular supplement in US
• Brought in more than 1B/year
• 10 of supplement industry annual sales
• Risks of ephedra use (when used with caffeine)
• Increased risk of heart attack, stroke,
  palpitations, anxiety, psychosis, death
• Steve Belcher
• 23 year old pitcher for Baltimore Orioles
• Died February, 2003 of heatstroke following
  taking an over-the-counter product that contained
  ephedra
• http//www.cnn.com/2003/HEALTH/12/30/cnna.thompson
  /

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Today

• Congress
• Considering a bill that would modify 1994 law so
  that many unregulated botanical supplements would
  be treated more like drugs than like foods
• Supplement manufacturers
• Assault on first amendment
• We put disclaimers in our ads, and we give
  people the results of the studies and a
  money-back guarantee. What more could you want?
  Dont prevent people from using their judgment.
  Let them try it. If it doesnt work, they can
  return it. Thats whats fair. Thats whats
  American.

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Misfortune, disaster, tragedy

• Lead to reforms in drug and device regulation

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FDA

• Regulates products whose annual sales account for
  ¼ of consumer spending in US
• Responsible for ensuring SAFETY and EFFICACY of
  CHEMICAL, BIOLOGICAL agents and sophisticated
  medical DEVICES
• Safe
• Probable benefits to health for intended use
  outweigh any probable risk of harm
• Effective
• Device does what it is supposed to do in a
  reliable fashion

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History of Regulation

• 1906
• First federal regulation of drugs
• Food and Drugs Act
• 1938
• Food, Drug and Cosmetic Act
• 1962
• Drug amendments to FDC Act
• 1976
• Medical Device Amendments to FDC Act

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1906

• Food and Drug Act
• Label could not contain any statement regarding
  therapeutic effect which is false and fraudulent
• FDA could act only after drugs were marketed
• Was not enough to show that product did not work
• Had to show that seller knew the claims it made
  were false

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1938

• Food, Drug and Cosmetic Act
• New Drugs
• Could not be marketed without first notifying the
  FDA and allowing agency time to assess safety
• Beginning of era in which it is illegal to market
  a new drug without FDA approval
• Sellers belief regarding products value was no
  longer relevant
• Issue does the product really work?

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1962

• Drug Amendments to FDC Act
• FDA must review evidence of drug safety and
  effectiveness
• Converted pre-market notification system into
  pre-market approval system
• Evidence of safety and efficacy must come from
  well-controlled investigations by qualified
  experts
• FDA has the authority to prevent harm before it
  occurs

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Drug Approval Process

• Pre-clinical testing (cell, animal) occurs first
• Assess toxicity
• Investigational New Drug (IND)
• Human clinical trials allowed with IND
• Phase 1, 2, 3 clinical trials
• Manufacturer files NDA (New Drug Application) for
  permission to market new drug

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Phases of Clinical Trials

• Phase 1
• Goal safety of compound
• Low doses administered to small group of healthy
  volunteers
• 20-100 volunteers
• Phase 2
• Goal effectiveness of compound
• 100-300 patients who suffer from condition
• Phase 3
• Final step before seeking FDA approval
• Randomized clinical trial

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Post-Market Surveillance

• Phase 4
• Study longer term effects of drug exposure
• Report adverse effects to FDA

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Not Many Drugs Make It

• For every 5,000-10,000 drugs that enter
  pre-clinical testing
• ONE makes it to market
• Cost of developing one new drug
• 360 million-500 million

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Regulation of Medical Devices

• FDA did not regulate devices before 1938
• 1938
• FDA could only challenge sale of products it
  believed were unsafe
• Could only remove them from the market after
  patient injuries
• 1960s
• Rapid innovation in medical technology
• Tried to regulate many as drugs contact lenses,
  IUDs
• Catastrophic failures of heart valves and
  pacemakers
• 1970s
• Broad recognition that different rules were
  needed to regulate devices

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1976

• Device amendments to FDC Act
• No single policy would work for all devices
• Tongue depressor
• Artificial heart

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1976 Device amendments to FDC Act

• Three classes of devices
• Class I
• Pose least risk to patient
• Not life sustaining
• GMP, proper record keeping required
• 30 of devices
• X-ray film, tongue depressors, stethoscopes
• Class II
• Not life sustaining, but must meet performance
  standards
• Blood pressure monitors, Catheter guide wires
• 60 of devices
• Class III
• Pose greatest risk to patient
• For use in supporting or sustaining human life
• 10 of devices
• Stents, heart valves, LVADs
• Require GMP, failure modes analysis, animal
  tests, human clinical studies under IDE

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Role of CDRH

• Ensure that products coming to market have more
  benefit than risk
• Ensure that products are labeled so that
  practitioners and patients know what to expect
  from their use
• Regulates 1,700 types of devices
• 23,000 registered manufacturers
• 1996 received 20,236 device related submissions

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Device Approval Process

• Device intended use considered together
• Manufacturer submits request for marketing
  approval
• Advisory panel
• One consumer representative (non-voting)
• One industry representative (non-voting)
• Physicians and scientists
• FDA not required to follow recommendations of
  panel, although they usually do

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IDE

• Investigational Device Exemption
• Enables experimental use of high risk device
• Must have positive engineering and animal data
• First give approval for feasibility studies with
  small number of patients
• Then proceed to multi-center trials
• Larger data sets frequently show results from
  small sample sets are not true

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Humanitarian Use Exemption

• Device designed to treat or diagnose condition
  that affects lt4,000 patients/year
• Device would not otherwise be available without
  exemption
• No comparable device is available
• Patients will not be exposed to unreasonable or
  significant risk of injury or illness by device

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Medical Device Reporting

• System to detect device related problems in a
  timely manner
• Serious injuries or deaths that may have been
  caused by or related to a a medical device must
  be reported to the manufacturer of the device
  within 10 days
• Must be reported to the FDA within 10 days

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400-500 million to develop one drug
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Recently Approved Devices

• http//www.accessdata.fda.gov/scripts/cdrh/cfdocs/
  cfTopic/MDA/mda-list.cfm?list1
• NIRflex Stent System
• http//www.fda.gov/cdrh/mda/docs/p020040.html
• http//www.medinol.com/nirflex.html
• http//www.fda.gov/cdrh/PDF2/P020040a.pdf
• http//www.fda.gov/cdrh/PDF2/P020040.html

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Pancreatic Cancer

• Pancreas
• Functions as two separate glands
• Some cells in gland make pancreatic juice that
  contains enzymes to break down fats and proteins
  in food
• Smaller number of cells in the pancreas are
  endocrine cells arranged in clusters called
  islets. Islets make hormones (such as insulin)
  that help control the amount of sugar in the blood

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Pancreatic Cancer

• Incidence
• 31,860 people in the US will be found to have
  pancreatic cancer in 2004
• Mortality
• 31,270 will die of the disease in 2004
• Fourth leading cause of cancer death in men and
  women
• Survival
• One year survival 15-20
• Five year survival few percent

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Detection of Pancreatic Cancer

• Early detection is difficult
• Pancreas is deep inside the body, cannot see or
  feel tumors during a routine physical exam
• No blood tests or other tests that can find this
  cancer early in people without symptoms
• By the time a person has symptoms, the tumor has
  often reached a large size and cancer may have
  spread to other organs
• Late symptoms
• Jaundice
• Pain
• Weight Loss
• Digestive Problems

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Treating Pancreatic Cancer

• 3 main types of treatment for cancer of the
  pancreas
• Surgery
• Radiation therapy
• Chemotherapy
• Depending on the stage of the cancer, 2 or even 3
  of these types of treatment could be given --
  either at the same time or one after the other.

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New Chemotherapy - Vinblastine

• Phase I clinical trials 10 patients
• One year survival
• 5 lived one year with new drug
• 20 for historical controls
• Immediate treatment related mortality
• 2 patients had short-term fatal drug reaction
  with Vinblastine

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New Chemotherapy - Vinblastine

• Phase II clinical trials 100 patients
• One year survival
• 45 with new drug
• Age-matched controls, standard treatment 17
• Immediate treatment related mortality
• 13 of patients had near-term fatal drug reaction
  to new drug
• 2 of patients had near-term fatal drug reaction
  to standard treatment

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New Chemotherapy - Vinblastine

• Randomized Phase III clinical trials 300
  patients
• One year survival
• 42 with new drug
• 18 with standard treatment
• Immediate treatment related mortality
• 10 of patients had immediate fatal drug reaction
  to new drug
• 1 of patient had immediate fatal reaction to
  standard treatment

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FDA Panel Meeting - Vinblastine

• Cast of Characters
• Panel MDs
• Panel Pharmacologists
• Pancreatic Cancer Patient
• Family member of patient who suffered fatal drug
  reaction in phase III clinical trial
• Drug company representative
• FDA Officer

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Real FDA Decision

• http//www.cnn.com/HEALTH/9903/26/rezulin.review.0
  2/
• Rezulin
• Drug to treat adult onset type 2 diabetes
• Sensitizes body to insulin
• Often given when patients fail other therapies
• Taken by more than 750,000 Americans
• Associated with liver failure and death
• Taken off the market in Britain

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Real FDA Decision

• http//www.usatoday.com/news/health/2001-11-19-dis
  puted-drug.htm
• Intergel
• Intended to reduce adhesions following
  gynecologic surgery, internal scar tissue that
  can cause chronic pain or intestinal obstruction
• 281 women
• 5.6 of Intergel recipients suffered infection at
  surgical site
• 2.9 of women who received standard surgical
  treatment suffered an infection

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Nanoparticle-Laser Robotic Surgery

• Phase I clinical trials 10 patients
• One year survival
• 5 lived one year with new surgery
• 20 for historical controls
• Immediate treatment related mortality
• 1 patient died due to surgical complications with
  new system

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Nanoparticle-Laser Robotic Surgery

• Phase II clinical trials 100 patients
• One year survival
• 46 with new surgical system
• Age-matched controls, standard treatment 17
• Immediate treatment related mortality
• 13 of patients died on the table due to surgical
  complications with new system
• 2 of patients had near term fatal drug reaction
  to standard treatment

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Nanoparticle-Laser Robotic Surgery

• Randomized Phase III clinical trials 300
  patients
• One year survival
• 48 with new surgical system
• 18 with standard treatment
• Immediate treatment related mortality
• 12 of patients died on the table due to surgical
  complications with new system
• 2 of patient had immediate fatal reaction to
  standard treatment

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FDA Panel Meeting Nanoparticle Robotic Surgery

• Cast of Characters
• Panel MDs
• Panel Biomedical Engineers
• Pancreatic Cancer Patient
• Family member of patient who suffered fatal
  complication in phase III clinical trial
• Medical device company representative
• FDA Officer

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Summary

• Drug and Device Regulation
• Reaction to Disaster, Tragedy and Misfortune
• 1906
• First federal regulation of drugs
• Burden on FDA to PROVE it is UNSAFE
• 1938
• Food, Drug and Cosmetic Act
• Pre-market NOTIFICATION
• 1962
• Drug amendments to FDC Act
• Pre-market APPROVAL
• 1976
• Medical Device Amendments to FDC Act

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Due Dates

• Tuesday, November 23rd
• Exam Three
• Wednesday, November 24th
• Project Due (e-mail url)
• Thursday, December 2nd
• Presentation of top 6 projects