Novel Therapies: What Are the Ethical, Legal, and ...€¦ · R & D Efficiency Declining (Inflation...
Transcript of Novel Therapies: What Are the Ethical, Legal, and ...€¦ · R & D Efficiency Declining (Inflation...
Christian Tomaszewski, MD, MS, FACEP, FACMT, FIFEM
Novel Therapies: What Are the Ethical, Legal, and Regulatory Issues?
“On the internet, nobody knows you are in Puerto Rico having a Mojito.”
Objectives Issues in New Drugs/Applications
• New drug approval process
• Pricing of new drugs • Off-label drug use
Fairy Tale
Three Stories
Ethics
Regu-latory
Law
Brief History of Drug Development
• Problem • “I have a headache”
• Solution • 2000 BC- Here, eat this root • 1000 AD- That root is heathen, say this prayer • 1850 AD- That prayer is superstition, drink this
potion • 1940 AD- That potion is snake oil, swallow this pill • 1950 AD- That pill is ineffective, take this
prescription drug • 2010 AD- That drug is too expensive take this
generic
Medicinal “Nuts” • 67 y/o female with non-resectable carcinoma of the bowel
ground up 12 bitter almonds given to her by friend to increase protein intake. Within 30 minutes she developed crampy abdominal pain and then collapsed.
• VS – 128 20 138/90 afebrile • HEENT – PERRL 4 mm, unusual breath odor • Lungs – clear lung fields • Cor – Regular tachycardia without murmurs • Abd – occasional BS, soft and NT • ABG 7.17/CO2 25/O2 56 • Lactate 14 meq/L
Shragg TA. West J Med 1982;136:65-69
What is the Toxin?
Cyanide
“Poison Pill” • Amygdalin
• Emulsin (β-glucosidase)
What Antidote did they give?
Hydroxocobalamin
Drug Development & Approval Process
R & D Efficiency Declining (Inflation Adjusted)
Diagnosing the decline in pharmaceutical R&D efficiency Jack W. Scannell, Alex Blanckley, Helen Boldon & Brian Warrington Nature Reviews Drug Discovery 11, 191-200 (March 2012)
Key Elements of Drug Development
Discovery
Medical Will the drug work? How well? In what
indications?
Chemistry Can we manufacture
it? Safely? With consistent quality?
Pharmacology / Toxicology
How does it work? What are the toxic
effects in the body?
Transition probabilities 1993-2002
DiMasi and Grabowski (2007a)
NDAs are Filed Electronically and Can Consist of as Many as 15 Different Sections:
• Index • Summary • Chemistry, Manufacturing, and Control (CMC) • Samples, Methods Validation Package, and Labeling • Nonclinical Pharmacology and Toxicology • Human Pharmacokinetics and Bioavailability • Microbiology (for anti-microbial drugs only) • Clinical Data • Safety Update Report (typically submitted 120 days after the
NDA's submission) • Statistical • Case Report Tabulations and Case Report Forms • Patent Information and Patent Certification • Other Information
FDA Pain Points in Drug Development
• Bureaucratic & slow
• Not creative • Risk averse
especially to innovative technologies
Orphan Drug Act • Orphan Drug Act:
• Enacted by US Congress in 1983 • Rewards for developing drugs for
patient population fewer than 200,000 • Reward:
• 7 year monopoly • 50% tax credit for clinical trials
• Consequence: other similar drugs cannot compete unless they can demonstrate higher efficacy
Animal Efficacy Rule June 30, 2002 • Drugs and biologics intended to reduce
serious and life-threatening conditions • May be approved for marketing based on:
• Effectiveness from animal studies • Human efficacy studies are not ethical
or feasible • Aim is to protect public from disabling
toxic substances and organisms • Need pharmaco-kinetic data to gauge
dose
21 CFR Parts 314 and 601
Animal Rule: Examples • Pyridostigmine bromide 2003
• Prophylaxis for soman exposure • Hydroxocobalamin 2006
• Treatment of cyanide poisoning • Levofloxacin 2012
• Treatment of pneumonic plague • Raxibacumab 2012
• Treatment of inhalational anthrax
Prescription Drug User Fee Act V – effective Oct 1st 2012 • FDA pledges to review 90% of NDAs within
12 months • Expectation is that this increases # of first
cycle approvals • Mid cycle and late-cycle review meetings
with sponsors • Increased communication & transparency
• Pre-submission meeting to ensure NDA/BLA completeness
• User fees increase: • Application now $ 1.96 million (6.3% inc)
Cyanide Antidotes • Sodium Thiosulfate 250mg/ml 50ml
$77 • Sodium Nitrite 30mg/ml 10ml $77 • Nithiodote ( sodium nitrite/
thiosulfate) 30-250mg/ml $150 • Cyanokit ( hydroxocobalamin) 5gm
$ 715/kit
Cyanide Treatment: $300 Antidote
Standards in Drug Development • GLP – Good Laboratory Practice • GCP – Good Clinical Practice • GMP or cGMP – (current) Good
Manufacturing Practice • 21 CFR - Title 21 CFR Part 11 of the Code of Federal Regulations
Why are Drugs Regulated? Answer is obvious, but, as with most regulations, the rules are often written, or tightened after the “event”, in response to one or more health disasters:
• 1907 - Introduction of arsphenamine (anti-syphilitic organic arsenical) • UK- Therapeutic Substances Act (1925)
• 1937 - Elixir of Sulfanilamide - USA • Food and Drugs Act (1938)
• 1957 - Introduction of Thalidomide (ex USA) • FDA introduced tightened approval requirements, regulation of
advertising, and GMP inspections (1962)
• UK Committee on Safety of Drugs (1963)
• European Medicines Directive (1965)
• UK Medicines Act (1968)
Regulation of Medical Products Other public health problems that caused changes in regulatory control of medical products:
• Viral/HIV contamination of blood & blood products • Tylenol contamination • CJD and prions in blood products • Counterfeit products – GMP • Heparin & melamine contamination – FDA overseas • Leaking breast implants • Malfunctioning medical devices • Fungal infections at compounding pharmacies?
Marcie Edmonds, 52, was stung in her abdomen last June at her Ahwatukee Foothills home in Phoenix.
Eculizumab (Soliris) • Treatment for paroxysmal nocturnal
hemoglobinuria • Most expensive drug in the world
High Visibility & Political Pressure
Average Cost of Drug Development
Mestre-Ferrandiz J: The R&D Cost of a New Medicine . Dec 2012. Office of Health Economics based on Center for Medicines Research
INTERVAL Spending ($m)
Time to Core
Launch
Capitalized Spend/
Successful Med ($m)
1- Pre-1 tox dose 76.5 9.6 207.4
2- 1st tox dose to 1st human dose 86.8 7.2 184.1
3- 1st human dose to 1st patient dose
149.5 6.2 284.0
4- 1st patient dose to 1st pivotal dose
316.9 4.4 501.6
5 – 1st pivotal dose to 1st core submission
235.9 2.1 293.8
6 – 1st core submission to 1st core launch
33.3 0.5 34.9
TOTAL 899 1,506
0.00%
5.00%
10.00%
15.00%
$0
$500,000
$1,000,000
$1,500,000
$2,000,000
$2,500,000
$3,000,000
$3,500,000
$4,000,000
$4,500,000
$5,000,000 19
82
1983
19
84
1985
19
86
1987
19
88
1989
19
90
1991
19
92
1993
19
94
1995
19
96
1997
19
98
1999
20
00
2001
20
02
2003
20
04
2005
20
06
2007
20
08
2009
20
10
2011
20
12
2013
20
14
2015
20
16
2017
20
18
2019
20
20
Health Expenditures Prescription Drugs
US Growth in Health Expenditures
Source: CMS, Office of the Actuary, National Health Statistics Group.
Mill
ions
%
of Total Health E
xpenditure
Projection
0.0
5.0
10.0
15.0
20.0
25.0 19
60
1962
19
64
1966
19
68
1970
19
72
1974
19
76
1978
19
80
1982
19
84
1986
19
88
1990
19
92
1994
19
96
1998
20
00
2002
20
04
2006
20
08
2010
20
12
2014
20
16
2018
20
20
National Health Expenditures as a Share of Gross Domestic Product (GDP) to 2008
Projection
% o
f GD
P
Sou
rce:
CM
S, O
ffice
of t
he A
ctua
ry, N
atio
nal H
ealth
Sta
tistic
s G
roup
.
The Value Decision
Change in effects C
hang
e in
cos
ts
The “Easy No” (More
expensive and less effective)
Standard of care
The Challenge (More expensive
and more effective)
The “Easy Yes” (Less
expensive and more effective)
The Dilemma (Less expensive
and less effective)
Value Threshold
Attractive
Unattractive
The Pricing Channel: Cost vs. Clinical Value
Clinical Value
Cos
t per
Cou
rse
of T
hera
py
Trend Line
90% confidence limits
Ref.:&Easton&Associates,&LLC&
Analysis Type Cost Consequence
Cost Minimization $ Equal (no denominator)
Cost Effectiveness $ Natural Units
Cost Benefit $ $
Cost Utility $ QALYs
46
Pharmacoeconomic Analyses
What is a life worth? • People are willing to accept a risk of
0.000002 of death to save 7 min of walking : $1,170,000
• For each 0.0001 increase in risk of death, there is a $240 increase in annual salary: $2,400,000
• Each smoke detector reduces death risk by 0.000036 for a cost of $30: $400,000
• Willingness to pay for hypothetical auto safety feature: $1,600,000
Michael W. Jones-Lee, 1989
Pressure on Healthcare Decision Making
Affordability Upward pressure
Downward pressure
Medical Need Value
Dr. Gleason Promoted Xyrem
• He was making as much as $3,000/day off Jazz • $450 for a face-to-face
meeting in a doctor's office, • $750 to speak at a
luncheon, • $1,500 for a dinner speech.
• “He even gave up his medical practice, in order to devote all his time to "hawking" the $600-a-month drug.”
http://evelynpringle.blogspot.com/2010/07/investigators-zero-in-on-pill-pushing.html
Under the agreement released Thursday by federal prosecutors, Warner-Lambert
(Pfizer) acknowledged spending hundreds of thousands of dollars to promote non-approved uses for the
anti-seizure drug Neurontin through a publication strategy that subsidized
production and dissemination of anecdotal reports.
May 13, 2004
Court Rulings on Off-Label 1983 • “Once a drug product has been approved for
marketing, a physician may, in treating patients, prescribe the drug for uses not included in the drug’s approved labeling.” Proposed New Drug, Antibiotic, and Biologic Drug Regulations, 48 Fed. Reg. 26,720; 26,733 (proposed June 9, 1983).
• The FDA disclaims authority to interfere with a doctor’s judgment to prescribe a drug for an unapproved use. Id. See also 21 C.F.R. § 312.3(d) (exemption from FDA regulations for “the use in the practice of medicine for an unlabeled indication of a new drug product approved” by the Agency”).
• The same is true for medical devices. 21 U.S.C. § 396.
FDA’s Deputy Commissioner for External Affairs 1992 • “…off-label drug use is often essential
to good medical practice, and in some areas—oncology and pediatrics in particular—off-label uses are often considered necessary. In fact, it is on this edge that science and medicine move forward to benefit patients with intractable illness.”
Carol Scheman, Prescription Drug Marketing and Promotion—An FDA Perspective, Address before the PMA Public Affairs Section, Mid-Year Meeting, April 15, 1992.
Cost Substitution: Off Label
• Bevacizumab (Avastin ) • $50/dose • $595/month
• Ranibizumab (Lucentis) • $2,000/dose • $23,400/month
J Med Internet Res. 2011 Jan-Mar; 13(1): e6.
Patient-reported Outcomes as a Source of Evidence in Off-Label Prescribing
• PatientsLikeMe • “web-based community
and research platform where patient members share details about their treatments, symptoms, and conditions, with the intention of improving their outcomes.”
On December 3, 2012, a divided Second Circuit held in United States v. Caronia (“Caronia”) that the misbranding provisions of the Federal Food, Drug, and Cosmetic Act (“FDCA”) do not criminalize “the truthful off-label promotion of FDA-approved prescription drugs.” The two-judge majority based its holding primarily on last year’s Supreme Court decision in Sorrell v. IMS Health, Inc., which held that “[s]peech in aid of pharmaceutical marketing…is a form of expression protected by the Free Speech Clause of the First Amendment.”
http://www.jdsupra.com/legalnews/off-label-marketing-questioned-as-a-viab-49267/
lipidrescue.squarespace.com
Controlled Animal Studies: Effect of IV Lipid Emulsion
DRUG POSITIVE N.S. Bupivacaine 4 3 * Thiopental 2 0 Verapamil 5 1 Nifedipine 0 1 Propranolol 1 2 Atenolol 0 1 Metoprolol 0 1 Amitriptyline 0 1 Clomipramine 5 0
Jamaty C et al: Lipid emulsions in the treatment of acute poisoning. Clin Toxicol 2010; 48:1-27
PATENT RIGHT • The right to
exclude others from making, using or selling the claimed invention
• Patent holder, not government, is responsible for enforcement
Phase II Failures: 2008-2010
John Arrowsmith1 Nature Reviews Drug Discovery 10, 328-329 (May 2011) | doi:10.1038/nrd3439
John P.A. Ioannidis
Date of download: 3/10/2013" Copyright © 2012 American Medical Association. All rights reserved."
From: Comparison of Effect Sizes Associated With Biomarkers Reported in Highly Cited Individual Articles and in Subsequent Meta-analyses!
JAMA. 2011;305(21):2200-2210. doi:10.1001/jama.2011.713"
Conclusion • Most large treatment
effects emerge from small studies, and when additional trials are performed, the effect sizes become typically much smaller.
• Well-validated large effects are uncommon and pertain to nonfatal outcomes.
Hydroxocobalamin: Cost Analysis • Cyanokit $715 a dose
• Save 20% • Spend $3575/life saved
• But Nithiodote is $150 • If equally efficacious:
use this • If better: calculate the
incremental benefit • If a life is worth $ 1 million
Nithiodote would have to be ~ 5% efficacious
Our Baby is Ugly!
We don’t really
need to slay
the dragon…
SUMMARY • Regulatory
• FDA is expediting process • Good manufacturing practices
• Legal • Continue to promote drugs as we see fit • Leverage intellectual property appropriately
• Ethics • Price drugs so that they are affordable • We cannot exaggerate claims of efficacy
FUTURE WINNERS
• Drugs that reduce morbidity and mortality while reducing overall health care costs.