colchicine, benzyl alcohol
DESCRIPTION
5e année Industrie - Projet de groupe: "Colchicine, benzyl alcohol approvals...rethinking innovation?"TRANSCRIPT
COLCHICINE, BENZYL ALCOHOL APPROVALS… RETHINKING
INNOVATION
Samia Thara
Sarah Merlen
Matthieu Boulenger
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
Benzyl Alcohol & NME
2
3
FDA website
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
Wikipedia website
4
5
A toxic compound
Pre-term neonates weighing 2500 gms:
• had central intravascular catheters
flushed periodically each day with bacteriostatic normal saline solution 0.9 % + benzyl alcohol
In the early 1980’s, FDA reported 16 neonatal deaths due to a gasping syndrome associated with use of Benzyl Alcohol
The metabolic pathway of benzyl alcohol may not be well developed in premature infant.
How to explain these deaths?
6The FDA has recommended that intravascular flush solutions containing benzyl alcohol not be used for
newbornshttp://www.cdc.gov/mmwr/preview/mmwrhtml/00001109.htm
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.
7
The applicant submitted one study (SU-01-2007) to evaluate the systemic exposure
of benzylalcohol in patients 6 months of age and
older with head lice infestation
Full-blown NDA
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
oDate of approval : April 4th, 2009
o Indication : 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 Chemical Entity
o FDA’ conclusion: the treatment does not expose subjects to elevated systemic levels of benzyl alcohol
9
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
1938
1962
2006
Safety
Safety and Effectiveness
Unapproved Drugs Initiative
USA Drug Approval Timeline
3400 products
1906 Purity Dosage
Prescription drugs Wrap-Up
1984
The original Federal Food and Drugs Act first brought drug regulation under federal law,
prohibiting the sale of adulterated or misbranded
drugs.
Safety was required only for new drugs : the law was not
retroactive
DESI Amendment - Congress amends The Act to require new drugs to prove effectiveness and safety before being
granted approval
Evaluation of the effectiveness of more than 3,400 products approved only for
safety between 1938 and 1962
E-FerolDrugs which entered the
market before 1938 have never been evaluated for both safety and effectiveness. They were declared
as illegally marketed
FDA finalized its guidance in a formal document
entitled “Compliance Policy Guide” (CPG), which aim is to bring unapproved
marketed drugs into the approval process.
11
E-Ferol tragedy
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.
AP IMPACT: “Gov’t Pays for Risky Unapproved Drugs,” R. Alonzo-Zaldivar, F. Bass (Nov. 23, 2008)
12 FAMILARITY WITH THE UNAPPROVED DRUGS
PRICE BENEFITS VS FDA APPROVED DRUGS
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
• Since the Compliance Policy Guide was published (2006), FDA has removed numerous unapproved drug products from the market.
• FDA announced its intention to take enforcement action against unapproved drug products containing :
UNAPPROVED DRUGS INDICATIONS
Balanced salt solution solutions used during surgical procedures on the eye
Carbinoxamine sedating antihistamine
Codeine sulfate tablet opioid analgesic
Colchicine tablets gout
Ergotamine migraine headaches
Guaifenesine expectorant
Hydrocodone analgesic and antitussif semi-synthetic opioid
Narcotics containing morphine sulfate,hydromorphone,oxycodon
opioid
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
Trimethobenzamide hydrochloride suppositories
treat nausea and vomiting 14
FDA website
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 containing quinine
15
FDA press release (Dec. 11, 2006)
16
• 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
Only one Quinine product on the market :FDA’s approved QUALAQUIN® (URL Pharma)
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 ?
18
A LOT OF NAMES FOR A SAME PLANT
« Ephemeron »
« Spalax »
« Bulbus »« Hermodactylus »
« Suringam »
« Naked lady »« Ephemeron »
« Tue chiens » « Mort-chiens »
«Safran des prés »
« Safran bâtard »
« Crocus »
« Iris sauvage »
« Colchicum autumnale »
• 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)
FROM COLCHICUM TO COLCHICINE
19
Federal Register / Vol. 75, No. 190 / Friday, October 1, 2010 / Notices
• 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
Qualitest Pharmaceuticals
SINCE THE DISCOVERY OF COLCHICINE…
20
21
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
TRADITIONNAL USE OF COLCHICINE
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.
URL PHARMA WILLS
Richard Roberts, MD, president, chair, and CEO of URL Pharma:
“We looked at the universe of unapproveddrugs, searching for medications presenting safety risks or where we had a chance toimprove 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.” 23In 2007, URL pharma organized studies testing its
own version of colchicineThe 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, pre-dating
the GLP
Dose levels used : effects, not safety
Unknown quality of colchicine used
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 »
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
Center for Drug Evaluation and Research , NDA 22-351 Summary review
26
First target: an orphan disease FAMILIAL
MEDITERREAN FEVER
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
FAMILIAL MEDITERRANEAN FEVER:EPIDEMIOLOGY
Turkish people: 1 / 1000
Armenian persons: 1 / 500
Arabic people: 1 / 2600
Ashkenazi Jewish people: 1 / 73,000
Sephardic Jewish people: 1 / 250-100028
http://asso.orpha.net/CEREMAI/seminaire/doc/MAI_pratiques_Hentgen_FMF.pdf
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
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
31
Second target :
TREATMENT OF GOUT
32
GOUT
« the king of diseases and the disease of kings »
Affects 3 to 5 million Americans, most commonly adult men
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
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
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
MECHANISM OF COLCHICINE
Anti-inflammatory mechanism of colchicine, European Heart Journal (2009) 30, 532–539 doi:10.1093/eurheartj/ehn608
36
Study MCP-004-06-00 :
• a multicenter• randomized• double-blind
• placebo-controlled• parallel group
• 1 week
CLINICAL EFFICACY: ACUTE GOUT FLARES
dose comparison study to evaluate the efficacy, safety and tolerability of colchicine in subjects
with an acute gout flare.
37
Center for Drug Evaluation and Research , NDA 22-351 Summary review
Study design:
38
Center for Drug Evaluation and Research , NDA 22-351 Summary review
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
Efficacy results
a greater proportion of patients receiving low-dose colchicine experienced a response
compared to standard dose (p = 0.005)40
Center for Drug Evaluation and Research , NDA 22-351 Summary review
Safety
Colcrys.com
« 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
CINICAL EFFICACY : PROPHYLAXIS OF GOUT FLARES
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.
Maximum dose 1.2 mg/day.
derived from the published literature
42
Center for Drug Evaluation and Research , NDA 22-353 Summary review
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
• October, 16, 2009 : prophylaxis of gout flares43
44
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 »
45
• 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 agency believes could encourage voluntary compliance with the drug-
approval process
URL pharma brought a lawsuit to remove any other versions of colchicine from the market.
• 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.
Enforcement action
CONSEQUENCES
46
Federal Register / Vol. 75, No. 190 / Friday, October 1, 2010 / Notices
Colchicine price increased from $0.09 per pill to $4.85 per pill (NEJM)
“The FDA was not prepared for the unintended consequences” Doctor Stanley Cohen, president of the American College of Rheumatology (arthritistoday.org , 4/20/10)
47
CONSEQUENCES FOR PATIENTS
48
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?
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.URL Pharma set up a Patient Assistance Program
50
Strengths
• Safety
• Effectiveness
• Part of studies based on litterature
• Market exclusivity
Weaknesses
• Bad corporate image
• Not exclusivity for prophylaxis
Opportunities
• Dominate the market during the next 3 years
• A well-established communication with the FDA useful for the future
• Potential Goldmine
Threats
• Developpment of parallel markets
• New manufacturers for the indication of Prophylaxis
OUR OWN OPINION
51
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
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
AND WHAT ABOUT IN EU?
53
53
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
MEDICINAL HERBAL PRODUCTS
55
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
CONFUSIONS IN PEOPLE‘S MIND
56
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
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)
Aristolochic acid
Toxic for kidneys, mutagenic and carcinogenic
57
Afssaps website
EUROPEAN DIRECTIVE ON TRADITIONNAL HERBAL MEDICINAL PRODUCTS
58
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 the EU)
DIRECTIVE 2004/24/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 31 March 2004
59
Positive effects
Negative effects
EXPECTED CONSEQUENCES
60FOR YOUR ATTENTION