Colchicine, Benzyl Alcohol

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

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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

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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.

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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

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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 !

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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.

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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”

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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

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FDA press release (Dec. 11, 2006)

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• 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

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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 ?

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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

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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…

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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

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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

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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

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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


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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

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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

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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


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Second target :

TREATMENT OF GOUT

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GOUT

« the king of diseases and the disease of kings »

Affects 3 to 5 million Americans, most commonly adult men

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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

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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…

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MECHANISM OF COLCHICINE

Anti-inflammatory mechanism of colchicine, European Heart Journal (2009) 30, 532–539 doi:10.1093/eurheartj/ehn608

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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.

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Study design:

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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


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

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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

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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 »

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• 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

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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)

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CONSEQUENCES FOR PATIENTS

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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?

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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

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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

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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.

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Bnet website : How the FDA’s Crackdown on Unapproved Drugs Could Create New Monopolies

AND WHAT ABOUT IN EU?

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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

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MEDICINAL HERBAL PRODUCTS

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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

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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

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Afssaps website

EUROPEAN DIRECTIVE ON TRADITIONNAL HERBAL MEDICINAL PRODUCTS

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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

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Positive effects

Negative effects

EXPECTED CONSEQUENCES

60FOR YOUR ATTENTION

Documents

Colchicine, Benzyl Alcohol