2. Benzyl Alcohol & NME
o Every year, in the USA , is published a board summarizing New
Molecular Entities approved by the FDA.
In 2009
next to important molecules such as Everolimus (treatment of
advanced renal cell carcinoma)…
…it came to a surprise to find Benzyl Alcohol
2
4. Benzyl alcohol : a new
molecule?
• First synthesis : in 1853 by Cannizaro
• Applications :
Industry :
solvent for inks, paints, lacquer
precursor of esters used in the soap, perfume and flavor industries
Health care :
bacteriostatic preservative at low concentration in intravenous
medications
excipient in a variety of topical drugs
4
Wikipedia website
6. A toxic compound
In the early 1980‟s, FDA reported 16 neonatal deaths due to a
gasping syndrome associated with use of Benzyl Alcohol
Pre-term neonates weighing 2500 gms:
• had central intravascular catheters
flushed periodically each day with bacteriostatic
normal saline solution 0.9 % + benzyl alcohol
How to explain these deaths?
The metabolic pathway of benzyl alcohol may not be well
developed in premature infant.
The FDA has recommended that intravascular flush solutions
6
containing benzyl alcohol not be used for newborns
http://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm
7. EXCIPIENT BECOMING API
Although benzyl alcohol is present in other products as an excipient, it
has not previously been approved as a new drug.
Sciele Pharma decided to make studies proving effectiveness and
safety of a 5% benzyl alcohol lotion against head lice.
Moreover, for safety reasons (refering to the tragedy of the catheter
flushs in the 1980‟s) conducting biopharmaceutics studies was
essential.
Full-blown NDA
The applicant submitted one study (SU-01-2007) to
evaluate the systemic exposure of benzyl
alcohol in patients 6 months of age and older 7
with head lice infestation
8. RESULTS
Major plasma concentrations were below the limit of
quantification…
…except for a few subjects with elevated systemic exposure to
benzyl alcohol.
FDA REFUSED TO GIVE THE APPROVAL …
… and asked Sciele Pharma for a clarification
Investigation : catheters used to take samples of blood were flushed
with NaCl + benzyl alcohol
Second bioavailability study in which any catheter flush used was
free of benzyl alcohol
8
Satisfying results Ulesfia® summary review
9. oFDA‟ conclusion: the treatment does not expose subjects to elevated
systemic levels of benzyl alcohol
oDate of approval : April 4th, 2009
oIndication : topical treatment of head lice
infestation in patients 6 months of age and
older.
Distinct from the population with a risk of
gasping syndrome
• ULESFIA was granted with a « 5 years Exclusivity » as a New 9
Chemical Entity
10. o So, we can be astonished that Benzyl alcohol was officially
recognised as a new molecule in 2009,
although it was known since the 19th…
but more astonishing…
For a variety of historical reasons,
some drugs,
mostly older products,
continue to be manufactured,marketed, distribued,
prescribed and dispensed…
…in the USA without required FDA approval !
10
11. USA Drug Approval Timeline
Unapproved Drugs
Prescription drugs Initiative
Wrap-Up
2006
E-Ferol tragedy 1984
1962 Safety and
3400 products Effectiveness
FDA finalized its guidance in a formal document
The original Federal Foodthe market
Drugs which entered and Drugs
entitledAmendment - Policy Guide” (CPG), which
“Compliance
E-Ferol 1938 Safety DESIfirst 1938 the drug regulationnew The Act
Evaluationwashave Congressfor of moredrugs
Safety of required only amends
Actis to bring unapproved marketed than
before brought effectiveness evaluated
aim never been under
federalinto law approvaltheto prove
3,400to the prohibiting retroactive
drugs productsnewnot process. safety
: require was drugsonly forThey
for bothlaw,the and effectiveness. of
safety approved sale
Purity adulterated or misbrandedbefore being
effectiveness and safety 1962
were declared as 1938 andmarketed
between illegally drugs.
1906 granted approval
Dosage
11
12. Marketed unapproved drugs : a rare
situation?
o 2% of all prescriptions drugs on the market
o = nearly 72 million prescriptions per year
o Medicaid paid at least $200 million from 2004 to 2007 for more than
100 unapproved drugs
WHY?
LACK OF AWARENESS
2006:nationwide study of 500 pharmacists:
91% of them thought all of the products they dispense are FDA approved.
FAMILARITY WITH THE UNAPPROVED DRUGS
12
PRICE BENEFITS VS FDA APPROVED DRUGS
AP IMPACT: “Gov‟t Pays for Risky Unapproved Drugs,” R. Alonzo-Zaldivar, F. Bass (Nov. 23, 2008)
13. However, this use may place patients at:
•Unnecessary risk from drug-drug interactions
•Lack of standardized dosing guidance
•Potential overdose among special populations requiring dosing
adjustements
•Drug purity problems associated with lack of FDA-approved
adjustements
•Too much or too little active ingredient
FDA : “it
is a priority of the agency to remove
from the market unapproved products that
expose consumers to potentially unsafe,
ineffective or poor quality drugs”
13
Unapproved drugs in America : an avoidable public health threat, Salvatore Giorgiani, BSc, PharmD
14. UNAPPROVED DRUGS INDICATIONS
•Since the Compliance Policy Guide was published (2006), FDA has removed
Balanced salt solution
numerous unapproved drug products solutions used during surgical procedures
from the market.
on the eye
•FDA announced its intention to take enforcement action against unapproved
Carbinoxamine sedating antihistamine
drug products containing :
Codeine sulfate tablet opioid analgesic
Colchicine tablets gout
Ergotamine migraine headaches
Guaifenesine expectorant
Hydrocodone analgesic and antitussif semi-synthetic
opioid
Narcotics containing morphine opioid
sulfate,hydromorphone,oxycodon
Nitroglycerin sublingual tablets relieve chest pain once it starts, and to
prevent an acute attack
Topical drugs containing papain removal of dead or contaminated tissue in
acute and chronic lesions
Quinine sulfate malaria and leg cramps
14
Trimethobenzamide hydrochloride treat nausea and vomiting
suppositories
FDA website
15. Example of the Quinine
• A lot of products containing quinine are marketed without approved
applications for malaria and are also used to treat and/or prevent
nocturnal leg muscle cramps
DANGER:
•Linked to 93 deaths, according to FDA
•Serious adverse effects
•Has been shown to cause long QT syndrome
•Narrow margin between an effective dose and a toxic dose
FDA has ordered all firms to
cease manufacturing
unapproved products 15
containing quinine
FDA press release (Dec. 11, 2006)
16. Only one Quinine product on the market :
FDA‟s approved QUALAQUIN® (URL Pharma)
• Approved as an Orphan Drug for the treatment of malaria in August 2005.
7 years of Market Exclusivity
•URL Pharma is now conducting new Clinical Studies to get a new approval
for the indication : muscle cramps
16
URL Pharma website
17. THE CURIOUS STORY OF COLCRYS®
(COLCHICINE) APPROVAL
July 2009: Colcrys® (URL pharma) received approvals from FDA for the
treatment of FMF and acute gout flares.
October 2009: approval for the prophylaxis of gout flares.
FDA orders the other manufacturers to remove any other versions of
colchicine from the market.
Then, URL Pharma raised the price by a factor of 50, from $0,09 to $4,85
per pill.
What happened ?
17
18. A LOT OF NAMES FOR A SAME PLANT
« Bulbus » « Ephemeron »
« Hermodactylus »
« Suringam »
« Spalax »
« Tue chiens »
« Mort-chiens »
« Naked lady »
« Ephemeron »
«Safran des prés »
« Crocus »
« Safran bâtard » « Iris sauvage » 18
« Colchicum autumnale »
19. FROM COLCHICUM TO COLCHICINE
•Papyrus 1500 before JC : use of « crocus » to treat articular pains
•Colchicum was described in the 1st century by Dioscorides in the Materia
Medica.
•Medical use of colchicum for gout pain dates back to the 6th century
•But the use of colchicum in the treatment of gout substantially declined by
the 15thcentury because of its toxicity
•Colchicum was reintroduced as a treatment for acute gout beginning in
1763.
•Colchicine was first isolated from colchicum in 1820 (Pelletier and
Caventou)
19
Federal Register / Vol. 75, No. 190 / Friday, October 1, 2010 / Notices
20. SINCE THE DISCOVERY OF
COLCHICINE…
•Colchicine used around the world to allay sicks of gout
•A lot of drugs containing colchicine were sold in the US since the XIXth
century
« Colchicine has been used by healthcare practitioners for many years to
treat gout but had not been approved by the FDA ».(FDA)
•Examples of manufacturers selling unapproved oral colchicine in the US
before 2009:
Excellium Pharmaceutical Inc.
Vision Pharma LLC
Watson pharmaceuticals Inc
West-Ward Pharmaceutical
20
Qualitest Pharmaceuticals
21. TRADITIONNAL USE OF COLCHICINE
Treatment of acute gout flare:
1 or 1.3 mg initial dose,
followed by 0.5 to 0.65 mg every 1 to 2 hours
until the pain is relieved or nausea and diarrhea appear.
Prophylaxis of recurrent gout:
0.5 mg to 0.65 mg once weekly or up to three times daily, depending on the
frequency of prior acute attack
o Signs of toxicity :
0 to 0.5 mg/kg : gastro-intestinal symptoms
0.5 to 0.8 mg/kg : + bone marrow aplesia and alopecia
> 0.8 mg/kg : + circulatory failure 21
22. Then, it‟s not a « without dangers » drug
• every year : cases of overdoses entraining intoxications and death:
751 reports of adverse events including 169 deaths, through June 2007
However, the use of colchicine was only based on its old
history.
22
23. URL PHARMA WILLS
Richard Roberts, MD, president, chair, and CEO of URL Pharma:
“We looked at the universe of unapproved
drugs, searching for medications presenting
safety risks or where we had a chance to
improve efficacy.
As a physician, I was shocked that colchicine,
with all of the toxicities taught to every doctor since
medical school,
was not an approved medication.”
In 2007, URL pharma organized studies testing its own version 23
of colchicine
The rheumatologist, May 2010
24. NONCLINICAL TOXICOLOGY
URL Pharma has relied almost entirely on the published literature to
support the nonclinical aspects of the application.
But some limitations were noticed:
Old studies, Dose levels used : Unknown quality of
pre-dating effects, not safety colchicine used
the GLP
Nevertheless, FDA said :
« The well-understood clinical toxicity of long-term colchicine administration,
precludes the need to provide modern, GLP-compliant chronic toxicology
studies in animals for support of the application »
24
Center for Drug Evaluation and Research , NDA 22-351 Summary review
25. CLINICAL PHARMACOKINETIC STUDIES
14 studies were conducted to define classic parameters
Absorption
Distribution
Metabolism
Elimination/Excretion
What we learnt from these studies:
• Colchicine crosses the placenta and distributes into breast milk
• 2 primary metabolites involving CYP3A4
• biliary and urinary excretion 25
Center for Drug Evaluation and Research , NDA 22-351 Summary review
27. FAMILIAL MEDITERRANEAN FEVER
Orphan disease in the USA (< 200,000 patients)
Hereditary inflammatory disorder
Recurrent episodes of diffuse inflammation
Beginning before 10 years old
Typical acute crisis:
fever, increasing rapidly
inflammation affecting the serosal surfaces: peritoneal
o Free interval between crisis
27
29. FAMILIAL MEDITERRANEAN
FEVER:TREATMENT
Colchicine : first intention
Posology : 0,5 to 2,5mg / day
Prevent attacks
Prevent secondary amylodoisis
Curative treatment of attacks
AINS, corticoïdes
Noramidopyrine
Anti IL1 : Anakinra in patients with colchicine-resistant FMF
29
http://asso.orpha.net/CEREMAI/seminaire/doc/MAI_pratiques_Hentgen_FMF.pdf
30. CLINICAL EFFICACY : FMF
The evidence for the efficacy of colchicine in patients with FMF is derived from
the published literature
Three randomized, placebo-controlled studies were identified
30
Proven efficacy of colchicine in the treatment of febrile
episodes of FMF
Center for Drug Evaluation and Research , NDA 22-352 Summary review
32. GOUT
« the king of diseases and the disease of kings »
Affects 3 to 5 million Americans, most commonly adult men
32
33. 33
Faculty: N. Lawrence Edwards, MD; H. Ralph Schumacher, MD; Arthur L. Weaver, MD, MS, FACP, MACR; Marc
D. Cohen, MD; Alvin F. Wells, MD, PhD
34. 34
Faculty: N. Lawrence Edwards, MD; H. Ralph Schumacher, MD; Arthur L. Weaver, MD,
MS, FACP, MACR; Marc D. Cohen, MD; Alvin F. Wells, MD, PhD
35. TREATMENTS
Anti-inflammatory drugs :
Colchicine
Corticosteroids
NSAIDs: ibuprofen, naproxen, indomethacin
Control uric acid concentration:
Xanthine oxidase inhibitors: allopurinol and febuxostat
Medication that improves uric acid removal: probenecid
Non of these medications are harmless, and
several side effects exist…
35
36. MECHANISM OF COLCHICINE
36
Anti-inflammatory mechanism of colchicine, European Heart Journal (2009) 30, 532–539 doi:10.1093/eurheartj/ehn608
37. CLINICAL EFFICACY: ACUTE
GOUT FLARES
dose comparison study to evaluate the efficacy, safety
and tolerability of colchicine in subjects with an acute gout
flare.
Study MCP-004-06-00 :
•a multicenter
•randomized
•double-blind
•placebo-controlled
•parallel group
•1 week
37
Center for Drug Evaluation and Research , NDA 22-351 Summary review
38. Study design:
38
Center for Drug Evaluation and Research , NDA 22-351 Summary review
39. Efficacy measure:
• based on response to treatment in the target joint
Patient self-assessment of pain with the 11-point Likert scale
Responder = at least a 50% reduction in pain score at the 24-
hour post-dose assessment relative to the pre-treatment score
39
40. Efficacy results
a greater proportion of patients receiving low-dose
colchicine experienced a response compared to 40
standard dose (p = 0.005)
Center for Drug Evaluation and Research , NDA 22-351 Summary review
41. Safety
« The efficacy of high-dose colchicine with fewer
AEs » 41
Dosage : 1.2 mg (2 tablets) at the first sign of a gout flare followed by 0.6 mg
(1 tablet) one hour later
Colcrys.com
42. CINICAL EFFICACY : PROPHYLAXIS
OF GOUT FLARES
derived from the published literature
Two randomized clinical trials:
In both trials,
treatment with colchicine decreased the
frequency of gout flares.
Dosage : 0.6 mg once or twice daily in adults and adolescents older
than 16 years of age.
42
Maximum dose 1.2 mg/day.
Center for Drug Evaluation and Research , NDA 22-353 Summary review
43. Conclusion
Colcrys ® received 3 approvals :
• July, 29, 2009 : treatment for FMF
7 years of Market exclusivity (under the Orphan Drug Act)
• July 30, 2009 : treatment of gout flares
3 years of Market exclusivity
43
• October, 16, 2009 : prophylaxis of gout flares
45. BUT COLCRYS® : A REAL
INNOVATION?
New labelling information rather than a real innovation:
• A lower dosage for a same efficacy and fewer AEs
• New drug-drug interactions information
The only patents for COLCRYS® are:
« Methods for concomitant administration of
colchicine and a second active agent »
• Dialysis was not an appropriate treatment for overdose
• Colcrys purity and uniformity confirmed by the FDA (unlike the
unapproved versions of Colchicine)
Market exclusivity is an incentive that the
45
agency believes could encourage voluntary
compliance with the drug-approval process
46. CONSEQUENCES
URL pharma brought a lawsuit to remove any other versions of
colchicine from the market.
Enforcement action
• against any currently marketed unapproved single-
ingredient oral colchicine products:
• that are manufactured on or after November 15, 2010,
• or that are shipped on or after December 30, 2010.
46
Federal Register / Vol. 75, No. 190 / Friday, October 1, 2010 / Notices
47. “The FDA was not prepared for the
unintended consequences” Doctor Stanley
Cohen, president of the American College of
Rheumatology (arthritistoday.org , 4/20/10)
Colchicine price increased from $0.09 per pill to $4.85 per pill 47
(NEJM)
48. CONSEQUENCES FOR
PATIENTS
A financial burden
• The price increase will put the drug out-of-reach of many
patients:
ex : treatment for gout prophylaxis
from $6 to $300 / month !!!
• Medicaid programs, in 2007 (NEJM)
paid about $1 million for the drug $50 million now?
48
49. oDoctors‟ reaction :
• Criticism about the trials
• “with responsible prescribing, non-approved colchicine is safe
and effective”
oFDA „s response:
• No statutory authority to control the prices for marketed drugs
in the U.S.
•The marketing exclusivity does not apply to the large market
of gout prophylaxis
oURL PHARMA‟s response:
•“In our society, people are rewarded for making advancements”
• unapproved drugs cost to patients and the healthcare system.
49
URL Pharma set up a Patient Assistance Program
50. Strengths Weaknesses
• Safety • Bad corporate image
• Effectiveness • Not exclusivity for
prophylaxis
• Part of studies based on
litterature
• Market exclusivity
Opportunities Threats
• Dominate the market • Developpment of parallel
during the next 3 years markets
• A well-established • New manufacturers for the
communication with the indication of Prophylaxis
FDA useful for the future
50
• Potential Goldmine
51. OUR OWN OPINION
FDA‟ s « Unapproved drugs initiative » was necessary.
We cannot take the risk to let unsafe or ineffective drugs
on the market
URL Pharma was the only firm to take the initiative to drive clinical
studies and to submit an approval
Their exclusivity reward was well-justified
Increasing the price by 50 is unreasonable
51
52. As a comparison, for Nitroglycerin pills :
Pfizer makes the only FDA-approved brand Nitrostat®.
FDA has moved against firms manufacturing unapproved versions of the
drug.
Pfizer was also beneficiary with higher prices, but more
reasonably.
The cash price for a pack of 100 tablets:
$22 Vs $20 for the banned-drugs before.
52
Bnet website : How the FDA‟s Crackdown on Unapproved Drugs Could Create New Monopolies
54. CASE OF COLCHICINE
The situation is not the same with colchicine
For example, in France, two branded-drugs on the market:
Colchicine opocoalcium 1 mg ( colchicine)
Colchimax ( colchicine+thiemonium+opium)
Prescribed too for the treatment of acute gout and
prophylaxie, for FMF and Behcet disease
AMM are evaluated at least every 5 years
54
55. MEDICINAL HERBAL PRODUCTS
In the EU, we can find traditionnal herbal
products on the market
But are they all safe?
a significant number of herbal medecinal
products, despite their long tradition do
not fullfil the requirement of a well-
established:
•Efficacy
•Safety
•Quality
55
56. CONFUSIONS IN PEOPLE„S MIND
For most people, drugs coming from plants are safe because « natural »
But we must not forget that a lot of compounds in plants are toxic:
Atropine ,Codeine, Strychnine…
DRUGS OR NOT DRUGS?
YES NO
•Active substances •Regulation less severe
•Indication, adverse effects •Not reserved to chemists
•Used in a determinate dose •Efficacy based on
experience
56
57. EXAMPLE OF TOXICITY
A lot of health public problems have been proved with the use of
these traditional products:
Nephropathies and chinese plants:
90‟s: 100 cases of terminal renal failure in Belgium were observed
in patients taking two plants to lose weights:
Magnolia officinalis and Stephania tetandra.
INVESTIGATION:
Substitution of Stephania tetandra for Aristolochia fangchi
(because they have chinese names very close)
Toxic for kidneys,
Aristolochic acid mutagenic and 57
carcinogenic
Afssaps website
58. EUROPEAN DIRECTIVE ON TRADITIONNAL
HERBAL MEDICINAL PRODUCTS
April 30,2004: standardizing regulation across Europe
Before April 30 , 2011(transposition in the member states)
Herbal medicines already on the market must apply for a simplified
registration:
• no clinical or pre-clinical trials…
• … but the authority can ask for all safety data
• and quality of the product must be demonstrated
Conditions for the simplified registration :
The product must have been used throughout a period
of at least 30 years (including at least 15 years within 58
the EU)
DIRECTIVE 2004/24/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 31 March 2004
