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.