colchicine, benzyl alcohol...rethinking innovation?


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colchicine, benzyl alcohol...rethinking innovation?

  1. 1. COLCHICINE, BENZYL ALCOHOL APPROVALS… RETHINKINGINNOVATION <br />Samia Thara<br />Sarah Merlen<br />Matthieu Boulenger<br />
  2. 2. BenzylAlcohol & NME<br /><ul><li>Everyyear, in the USA , ispublished a boardsummarizingNew </li></ul>MolecularEntitiesapproved by the FDA.<br />In 2009<br />next to important moleculessuch as Everolimus (treatment of advancedrenalcellcarcinoma)…<br />…it came to a surprise to findBenzylAlcohol<br />2<br />
  3. 3. 3<br />FDA website<br />
  4. 4. Benzylalcohol : a new molecule?<br /><ul><li>First synthesis : in 1853 by Cannizaro
  5. 5. Applications :
  6. 6. Industry :</li></ul>solvent for inks, paints, lacquer<br />precursor of esters used in the soap, perfume andflavor industries<br /><ul><li>Health care : </li></ul>bacteriostatic preservative at low concentration in intravenous medications<br />excipientin a variety of topical drugs<br />Wikipedia website<br />4<br />
  7. 7. A toxic compound<br /> In the early 1980’s, FDA reported 16 neonatal deaths due to a gasping syndromeassociated with use of Benzyl Alcohol<br />Pre-term neonates weighing 2500 gms:<br /><ul><li> had central intravascular catheters </li></ul> flushed periodically each day with bacteriostatic normal saline solution 0.9 % + benzyl alcohol<br />How to explain these deaths?<br /> The metabolic pathway of benzyl alcohol may not be well developed in premature infant.<br />5<br />The FDA has recommended that intravascular flush solutions containing benzyl alcohol not be used for newborns<br /><br />
  8. 8. Excipient becoming API<br />Although benzyl alcohol is present in other products as an excipient, it has not previously been approved as a new drug.<br />Sciele Pharma decided to make studies proving effectiveness and safety of a 5% benzyl alcohol lotion against head lice.<br />Moreover, for safety reasons (refering to the tragedy of the catheter flushs in the 1980’s) conducting biopharmaceutics studies was essential. <br />6<br />Full-blown NDA<br />The applicant submitted one study (SU-01-2007) to evaluate the systemic exposure of benzyl<br />alcohol in patients 6 months of age and older with head lice infestation<br />
  9. 9. RESULTS<br />Major plasma concentrations were below the limit of quantification…<br />…except for a few subjects with elevated systemic exposure to benzyl alcohol.<br />FDA REFUSED TO GIVE THE APPROVAL …<br /> … and asked ScielePharma for a clarification<br />Investigation : catheters used to take samples of blood were flushed with NaCl + benzyl alcohol<br />Second bioavailability study in which any catheter flush used was free of benzyl alcohol<br />7<br />Satisfyingresults<br />Ulesfia® summary review<br />
  10. 10. <ul><li>FDA’ conclusion: the treatment does not expose subjects to elevated systemic levels of benzyl alcohol
  11. 11. Date of approval : April 4th, 2009
  12. 12. Indication : topicaltreatment of head lice </li></ul> infestation in patients 6 months of age and <br />older.<br />Distinct from the population with a risk of gasping syndrome <br /><ul><li> ULESFIA was granted with a « 5 years Exclusivity » as a New Chemical Entity</li></ul>8<br />
  13. 13. <ul><li> So, we can be astonished that Benzyl alcohol was officially recognised as a new molecule in 2009, </li></ul>although it was known since the 19th…<br />but more astonishing…<br />For a variety of historical reasons, <br />some drugs, <br />mostly older products, <br />continue to be manufactured,marketed, distribued, prescribed and dispensed… <br />…in the USA without required FDA approval !<br />9<br />
  14. 14. USA Drug ApprovalTimeline<br />Unapproved Drugs Initiative<br />Prescription drugs Wrap-Up<br />E-Ferol tragedy<br />1984<br />Safety and Effectiveness<br />3400 products<br />FDA finalized its guidance in a formal document <br />entitled “Compliance Policy Guide” (CPG), which aim is to bring unapproved marketed drugs into the approval process.<br />The original Federal Food and Drugs Act first brought drug regulation under federal law, prohibiting the sale of adulterated or misbranded drugs.<br />DESI Amendment - Congress amends The Act to require new drugs to prove <br />effectiveness and safety before being granted approval<br />Evaluation of the effectiveness of more than 3,400 products approved only for safety <br />between 1938 and 1962<br />Safetywasrequiredonly for new drugs : the lawwasnot retroactive<br />Drugswhichentered the marketbefore 1938 have never been evaluated for bothsafety and effectiveness. Theyweredeclared as illegallymarketed<br />Safety<br />E-Ferol<br />1906<br />Purity Dosage<br />10<br />
  15. 15. Marketed unapproved drugs : a rare situation?<br /><ul><li> 2% of all prescriptions drugs on the market
  16. 16. = nearly 72 million prescriptions per year
  17. 17. Medicaid paid at least $200 million from 2004 to 2007 for more than 100 unapproved drugs</li></ul>WHY? <br /><ul><li>LACK OF AWARENESS</li></ul>2006:nationwide study of 500 pharmacists: <br />91% of them thought all of the products they dispense are FDA approved.<br /><ul><li>FAMILARITY WITH THE UNAPPROVED DRUGS
  18. 18. PRICE BENEFITS VS FDA APPROVED DRUGS</li></ul> AP IMPACT: “Gov’t Pays for Risky Unapproved Drugs,” R. Alonzo-Zaldivar, F. Bass (Nov. 23, 2008)<br />11<br />
  19. 19. However, this use may place patients at:<br /><ul><li>Unnecessary risk fromdrug-drug interactions
  20. 20. Lack of standardized dosing guidance
  21. 21. Potential overdose among special populations requiring dosing adjustements
  22. 22. Drug purity problemsassociated with lack of FDA-approved adjustements
  23. 23. Too much or too little active ingredient</li></ul>FDA : “it is a priority of the agency to remove from the market unapproved products that <br />expose consumers to potentially unsafe, ineffective or poor quality drugs”<br />12<br />Unapproved drugs in America : an avoidable public health threat, Salvatore Giorgiani, BSc, PharmD<br />
  24. 24. <ul><li>Since the Compliance Policy Guide was published (2006), FDA has removed numerous unapproved drug products from the market.
  25. 25. FDA announced its intention to take enforcement action against unapproved drug products containing :</li></ul>13<br />FDA website<br />
  26. 26. Example of the Quinine<br /><ul><li>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 </li></ul>DANGER:<br /><ul><li>Linked to 93 deaths, according to FDA
  27. 27. Serious adverse effects
  28. 28. Has been shown to cause long QT syndrome
  29. 29. Narrow margin between an effective dose and a toxic dose</li></ul>FDA has ordered all firms to cease manufacturing unapproved products containing quinine<br />14<br />FDA press release (Dec. 11, 2006)<br />
  30. 30. Only one Quinine product on the market :<br />FDA’sapprovedQUALAQUIN® (URL Pharma)<br /><ul><li> Approved as an Orphan Drug for the treatment of malariain August 2005. </li></ul>7 years of Market Exclusivity <br /><ul><li>URL Pharma is now conducting new Clinical Studies to get a new approval </li></ul> for the indication : muscle cramps<br />15<br />URL Pharma website<br />
  31. 31. THE CURIOUS STORY OF COLCRYS® (COLCHICINE) APPROVAL<br /><ul><li>July 2009: Colcrys® (URL pharma) received approvals from FDA for the treatment of FMF and acute gout flares.
  32. 32. October 2009: approval for the prophylaxis of gout flares.
  33. 33. FDA orders the other manufacturers to remove any other versions of colchicine from the market.
  34. 34. Then, URL Pharma raised the price by a factor of 50, from $0,09 to $4,85 per pill.</li></ul>What happened ?<br />16<br />
  35. 35. A LOT OF NAMES FOR A SAME PLANT <br />« Ephemeron »<br />« Bulbus »<br />« Hermodactylus»<br />« Suringam »<br />« Spalax »<br />« Tue chiens » <br />« Mort-chiens »<br />« Naked lady »<br />« Ephemeron »<br />«Safran des prés »<br />« Crocus »<br />« Safran bâtard » <br />« Iris sauvage » <br />17<br />« Colchicumautumnale » <br />
  36. 36. FROM COLCHICUM TO COLCHICINE<br /><ul><li>Papyrus 1500 before JC : use of « crocus » to treat articular pains
  37. 37. Colchicum was described in the 1st century by Dioscorides in the Materia Medica.
  38. 38. Medical use of colchicum for gout pain dates back to the 6th century
  39. 39. But the use of colchicum in the treatment of gout substantially declined by the 15thcentury because of its toxicity
  40. 40. Colchicum was reintroduced as a treatment for acute gout beginning in</li></ul>1763.<br /><ul><li>Colchicine was first isolated from colchicum in 1820 (Pelletier and Caventou)</li></ul>18<br />Federal Register / Vol. 75, No. 190 / Friday, October 1, 2010 / Notices<br />
  41. 41. SINCE THE DISCOVERY OF COLCHICINE…<br /><ul><li>Colchicineused around the world to allay sicks of gout
  42. 42. A lot of drugs containing colchicine were sold in the US since the XIXth century</li></ul>« Colchicine has been used by healthcare practitioners for many years to treat gout but had not been approved by the FDA ».(FDA)‏<br /><ul><li>Examples of manufacturers selling unapproved oral colchicine in the US before 2009:
  43. 43. Excellium Pharmaceutical Inc.
  44. 44. Vision Pharma LLC
  45. 45. Watson pharmaceuticals Inc
  46. 46. West-Ward Pharmaceutical
  47. 47. Qualitest Pharmaceuticals</li></ul>19<br />
  48. 48. TRADITIONNAL USE OF COLCHICINE<br /><ul><li>Treatment of acute gout flare:
  49. 49. 1 or 1.3 mg initial dose,
  50. 50. followed by 0.5 to 0.65 mg every 1 to 2 hours
  51. 51. until the pain is relieved or nausea and diarrhea appear.
  52. 52. Prophylaxis of recurrent gout:
  53. 53. 0.5 mg to 0.65 mg once weekly or up to three times daily, depending on the frequency of prior acute attack
  54. 54. Signs of toxicity :
  55. 55. 0 to 0.5 mg/kg : gastro-intestinal symptoms
  56. 56. 0.5 to 0.8 mg/kg : + bone marrow aplesia and alopecia
  57. 57. > 0.8 mg/kg : + circulatory failure</li></ul>20<br />
  58. 58. Then, it’s not a « without dangers » drug<br /><ul><li> every year : cases of overdoses entraining intoxications and death:</li></ul>751 reports of adverse eventsincluding 169 deaths, through June 2007<br />However, the use of colchicine was onlybased on its old history.<br />21<br />
  59. 59. URL PHARMA WILLS<br /><ul><li>Richard Roberts, MD, president, chair, and CEO of URL Pharma: </li></ul>“We looked at the universe of unapproved<br />drugs, searching for medications presenting <br />safety risksor where we had a chance to<br />improve efficacy. <br />As a physician, I was shockedthat colchicine, <br />with all of the toxicities taught to every doctor since <br />medical school, <br />was not an approved medication.”<br />22<br />In 2007, URL pharma organizedstudiestestingitsown version of colchicine<br />The rheumatologist, May 2010<br />
  60. 60. NONCLINICALTOXICOLOGY<br />URL Pharma has relied almost entirely on the published literature to support the nonclinical aspects of the application.<br />But some limitations were noticed:<br />Old studies, pre-dating<br />the GLP<br />Dose levels used : effects, not safety<br />Unknown quality of colchicine used<br />Nevertheless, FDA said :<br /> « 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 »<br />23<br />Center for Drug Evaluation and Research , NDA 22-351 Summary review<br />
  61. 61. CLINICAL PHARMACOKINETIC STUDIES<br />14 studies were conducted to define classic parameters<br />Absorption<br />Distribution<br />Metabolism<br />Elimination/Excretion<br />What we learnt from these studies: <br /><ul><li>Colchicine crosses the placenta and distributes into breast milk
  62. 62. 2 primary metabolites involving CYP3A4
  63. 63. biliary and urinary excretion</li></ul>24<br />Center for Drug Evaluation and Research , NDA 22-351 Summary review<br />
  64. 64. 25<br />First target: an orphandisease<br />FAMILIAL MEDITERREAN FEVER<br />
  65. 65. FAMILIAL MEDITERRANEAN FEVER<br /><ul><li>Orphan disease in the USA (< 200,000 patients)
  66. 66. Hereditary inflammatorydisorder
  67. 67. Recurrent episodesof diffuse inflammation
  68. 68. Beginning before 10 years old </li></ul> Typical acute crisis:<br />fever, increasing rapidly<br />inflammation affecting the serosal surfaces: peritoneal +++<br /><ul><li>Free interval between crisis</li></ul>26<br />
  69. 69. FAMILIAL MEDITERRANEAN FEVER:EPIDEMIOLOGY<br />Turkish people: 1 / 1000<br />Arabic people: 1 / 2600<br />Ashkenazi Jewish people: 1 / 73,000<br />Armenian persons: 1 / 500<br />27<br />Sephardic Jewish people: 1 / 250-1000<br /><br />
  70. 70. FAMILIAL MEDITERRANEAN FEVER:TREATEMENT<br /><ul><li>Colchicine : first intention
  71. 71. Posology : 0,5 to 2,5mg / day
  72. 72. Prevent attacks
  73. 73. Prevent secondary amylodoisis
  74. 74. Curative treatement of attacks
  75. 75. AINS, corticoïdes
  76. 76. Noramidopyrine
  77. 77. Anti IL1 : Anakinra in patients with colchicine-resistant FMF </li></ul>28<br /><br />
  78. 78. CLINICAL EFFICACY : FMF<br />The evidence for the efficacy of colchicine in patients with FMF isderivedfrom the publishedliterature<br />Threerandomized, placebo-controlledstudieswereidentified<br />29<br />Provenefficacy of colchicine in the treatment of febrileepisodes of FMF <br />Center for Drug Evaluation and Research , NDA 22-352 Summary review<br />
  79. 79. 30<br />Second target : <br />TREATMENT OF GOUT<br />
  80. 80. GOUT<br />« the king of diseases and the disease of kings »<br />Affects 3 to 5 million American, mostcommonlyadult men<br />31<br />
  81. 81. 32<br />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<br />
  82. 82. 33<br />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<br />
  83. 83. treatments<br />Anti-inflammatory drugs :<br />Colchicine<br />Corticosteroids<br />NSAIDs: ibuprofen, naproxen, indomethacin<br />Control uric acid concentration:<br />Xanthine oxidase inhibitors: allopurinol and febuxostat<br />Medication that improves uric acid removal: probenecid<br />Non of these medications are harmless, and several side effects exist…<br />34<br />
  84. 84. MECHANISM OF COLCHICINE<br />35<br />Anti-inflammatory mechanism of colchicine, European Heart Journal (2009) 30, 532–539 doi:10.1093/eurheartj/ehn608<br />
  85. 85. CLINICAL EFFICACY: ACUTE GOUT FLARES<br />dose comparison study to evaluate the efficacy, safetyand tolerability of colchicine in subjects with an acute gout flare.<br />Study MCP-004-06-00 :<br /><ul><li>a multicenter
  86. 86. randomized
  87. 87. double-blind
  88. 88. placebo-controlled
  89. 89. parallel group
  90. 90. 1 week</li></ul>36<br />Center for Drug Evaluation and Research , NDA 22-351 Summary review<br />
  91. 91. Study design:<br />37<br />Center for Drug Evaluation and Research , NDA 22-351 Summary review<br />
  92. 92. Efficacy measure:<br /><ul><li> based on response to treatment in the target joint </li></ul>Patient self-assessment of pain with the 11-point Likert scale<br />Responder = atleast a 50% reduction in pain score at the 24-hour post-dose assessment relative to the pre-treatment score<br />38<br />
  93. 93. Efficacy results<br /><ul><li> a greater proportion of patients receiving low-dose colchicine experienced a response compared to standard dose (p = 0.005)</li></ul>39<br />Center for Drug Evaluation and Research , NDA 22-351 Summary review<br />
  94. 94. Safety<br />« The efficacy of high-dose colchicine with fewer AEs »<br />40<br />Dosage : 1.2 mg (2 tablets) at the first sign of a gout flarefollowed by 0.6 mg <br />(1 tablet) one hourlater<br /><br />
  95. 95. CINICAL EFFICACY : PROPHYLAXIS OF GOUT FLARES<br />derivedfrom the publishedliterature<br />Tworandomizedclinical trials:<br />In both trials, treatment with colchicine decreased the frequency of gout flares.<br />Dosage : 0.6 mg once or twice daily in adults and adolescents older than 16 years of age.<br />Maximum dose 1.2 mg/day.<br />41<br />Center for Drug Evaluation and Research , NDA 22-353 Summary review<br />
  96. 96. Conclusion<br />Colcrysreceived3 approvals:<br /><ul><li>July, 29, 2009 : treatment for FMF</li></ul>7 years of Marketexclusivity(under the Orphan Drug Act)<br /><ul><li> July 30, 2009 : treatment of gout flares</li></ul>3 years of Marketexclusivity<br /><ul><li>October, 16, 2009 : prophylaxis of gout flares</li></ul>42<br />
  97. 97. 43<br />
  98. 98. BUT COLCRYS : A REAL INNOVATION?<br /> New labelling information rather than a real innovation:<br /><ul><li> A lower dosage for a same efficacy and fewer AEs
  99. 99. New drug-drug interactions information</li></ul> The only patents for COLCRYS are:<br />« Methods for concomitant administration of colchicine and a second active agent »<br />44<br /><ul><li> Dialysis was not an appropriate treatment for overdose
  100. 100. Colcrys purity and uniformity confirmed by the FDA (unlike the unapproved versions of Colchicine)</li></ul>Market exclusivity is an incentive that the agency believes could encourage voluntary compliance with the drug-approval process<br />
  101. 101. CONSEQUENCES<br />URL pharma broughta lawsuit to removeanyother versions of colchicine from the market.<br /><ul><li>Enforcement action
  102. 102. against any currently marketed unapproved single-ingredient oral colchicine products:
  103. 103. that are manufactured on or after November 15, 2010,
  104. 104. or that are shipped on or after December 30, 2010.</li></ul>45<br />Federal Register / Vol. 75, No. 190 / Friday, October 1, 2010 / Notices<br />
  105. 105. “The FDA was not prepared for the unintended consequences” Doctor Stanley Cohen, president of the American College of Rheumatology ( , 4/20/10)‏<br />Colchicine price increased from $0.09 per pill to $4.85 per pill (NEJM)‏<br />46<br />
  106. 106. CONSEQUENCES FOR PATIENTS <br />A financial burden<br /><ul><li> The price increase will put the drug out-of-reach of many patients:</li></ul>ex : treatment for gout prophylaxis <br />from $6 to $300 / month !!! <br /><ul><li> Medicaid programs, in 2007 (NEJM)
  107. 107. paid about $1 million for the drug  $50 million now?</li></ul>47<br />
  108. 108. 48<br /><ul><li>Doctors’ reaction :
  109. 109. Criticism about the trials
  110. 110. “with responsible prescribing, non-approved colchicine is safe and effective”
  111. 111. FDA ‘s response:
  112. 112. No statutory authority to control the prices for marketed drugs in the U.S.
  113. 113. The marketing exclusivitydoes not apply to the large market of gout prophylaxis
  114. 114. URL PHARMA’s response:
  115. 115. “In our society, people are rewarded for making advancements”
  116. 116. unapproved drugs cost to patients and the healthcare system.</li></ul>URL Pharma set up a Patient Assistance Program<br />
  117. 117. 49<br />
  118. 118. OUR OWN OPINION <br />50<br />FDA’ s « Unapproveddrugs initiative » wasnecessary.<br />Wecannottake the riskto let unsafeor ineffective drugson the market<br />URL Pharma was the onlyfirmto take the initiative to drive clinicalstudiesand to submit an approval<br />Theirexclusivityrewardwaswell-justified<br />Increasing the priceby 50 isunreasonable<br />
  119. 119. As a comparison, for Nitroglycerinpills:<br />Pfizer makes the only FDA-approved brand Nitrostat®. <br />FDA has movedagainstfirmsmanufacturingunapproved versions of the drug.<br />Pfizer wasalsobeneficiarywithhigherprices, but more reasonably.<br /> The cash price for a pack of 100 tablets:<br /> $22 Vs $20 for the banned-drugsbefore. <br />51<br />Bnet website : How the FDA’s Crackdown on Unapproved Drugs Could Create New Monopolies<br />
  120. 120. AND WHAT ABOUT IN EU?<br />52<br />52<br />
  121. 121. CASE OF COLCHICINE<br /><ul><li>The situation is not the same with colchicine
  122. 122. For example, in France, two branded-drugs on the market:
  123. 123. Colchicineopocoalcium 1 mg ( colchicine)
  124. 124. Colchimax( colchicine+thiemonium+opium)
  125. 125. Prescribed too for the treatment of acute gout and </li></ul>prophylaxie, for FMF and Behcet disease<br /><ul><li>AMM are evaluated at least every 5 years</li></ul>53<br />
  126. 126. MEDICINAL HERBAL PRODUCTS<br />54<br />In the EU, we can find traditionnal herbal products on the market<br />But are they all safe?<br /><ul><li>a significant number of herbal medecinal products, despite their long tradition do not fullfil the requirement of a well-established:
  127. 127. Efficacy
  128. 128. Safety
  129. 129. Quality</li></li></ul><li>CONFUSIONS IN PEOPLE‘S MIND<br />55<br />For most people, drugscomingfrom plants are safebecause « natural »<br />But we must not forgetthat a lot of compounds in plants are toxic:<br />Atropine ,Codeine, Strychnine… <br />DRUGS OR NOT DRUGS?<br />
  130. 130. EXAMPLES OF TOXICITY<br /><ul><li>A lot of health public problems have been proved with the use of these traditional products:
  131. 131. Nephropathies and chinese plants:</li></ul> 90’s: 100 cases of terminal renal failure in Belgium were observed in patients taking two plants to lose weights:<br />Magnolia officinalis and Stephaniatetandra.<br /> INVESTIGATION:<br /> Substitution of Stephaniatetandrafor Aristolochiafangchi<br /> (because they have chinese names very close) <br />Toxic for kidneys, mutagenicand carcinogenic<br />Aristolochic acid<br />56<br />
  132. 132. EUROPEAN DIRECTIVE ON TRADITIONNAL HERBAL MEDICINAL PRODUCTS<br />57<br /><ul><li>April 30,2004: standardizingregulationacross Europe
  133. 133. Before April 30 , 2011(transposition in the member states) </li></ul>Herbalmedicinesalready on the market must apply for a simplified registration: <br /><ul><li> no clinical or pre-clinical trials…
  134. 134. … but the authoritycanask for all safety data
  135. 135. and quality of the product must bedemonstrated</li></ul>Conditions for the simplified registration :<br /><ul><li>The product must have been usedthroughout a period of at least 30 years (includingat least 15 yearswithin the EU)</li></ul>DIRECTIVE 2004/24/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 31 March 2004<br />
  136. 136. 58<br />EXPECTED CONSEQUENCES<br />
  137. 137. 59<br />FOR YOUR ATTENTION<br />
  138. 138.
  139. 139.  The metabolic pathway of benzyl alcohol may not be well developed in premature infant :<br />Immature Liver<br />Accumulation<br />Metabolic acidosis<br />the FDA recommended that intravascular flush solutions containing benzyl alcohol not be used for newborns and that diluents with this preservative not be used as medications for these infants<br />
  140. 140. 62<br />
  141. 141. BUT!<br />Diet is necessary!!!<br />Guidelines recommended by American Dietetic during a gout attack:<br />Avoid alcohol<br />Eat a moderate amount of protein, preferably from healthy sources, such as low-fat or fat-free dairy, tofu, eggs, and nut butters.<br />Limit your daily intake of meat, fish and poultry to 4 to 6 ounces (114 to 170 grams).<br />…2000 calories per day is enough!<br />
  142. 142. Total of subjects included in the study = 185<br /><ul><li> 4.8 mg colchicine dose = 52 subjects
  143. 143. 1.8 mg colchicine dose = 75 subjects
  144. 144. placebo = 58 subjects </li></ul>64<br />
  145. 145. Efficacy results<br /><ul><li> A greater proportion of patients receiving standard-dose colchicine experienced a response compared to placebo
  146. 146. Similarly, a greater proportion of patients receiving low-dose colchicine experienced a response compared to placebo </li></ul>65<br />
  147. 147. Was Colchicine considered as a NME, such as benzyl alcohol?<br /> Colchicine in dosage oral form was marketed in combinaison with probenecid<br />Probenecid= uricosuric drug that increases uric acid excretion in the urine.<br />Indication: treatment of chronic gouty arthritis when complicated by frequent, recurrent acute attacks of gout. <br />First Approval : Col-Benemid®in july 1961, MERCK<br />Since 1967: a lot of generics have been on the market, legally<br />That’swhy colchicine doesn’tappear on the 2009 NME list.<br />66<br />
  148. 148. MECHANISM OF COLCHICINE IN THE GOUT<br /><ul><li>Not complitely understood
  149. 149. Inhibits the process of microtubule self assembly by binding β-tubulin: formation of tubulin-colchicine complexes
  150. 150. Several cellular functions touched: phagocytosis, degranulation, chemotaxis
  151. 151. Reduction of inflammatory response
  152. 152. Therapeutic effect at low doses</li></ul>67<br />67<br />
  153. 153. CLINICAL PHARMACOLOGY/BIOPHARMACEUTICS<br />14 studies were conducted:<br />Absorption: bioavailability = 45%. <br />Distribution: Binding to serum protein = 39 +/- 5%<br />Colchicine crosses the placenta and distributes into breast milk<br />Metabolism: 2 primary metabolites : CYP3A4 involved<br />Recommendations for Colchicine dosage adjusments with CYP3A4 inhitors<br />Elimination/Excretion : <br /><ul><li>enterohepatic recirculation,
  154. 154. biliary excretion mediated by P-gp,
  155. 155. excreted in the urine by both glomerular filtration and tubular secretion.
  156. 156. not removed by hemodialysis</li></ul>68<br />68<br />
  157. 157. FAMILIAL MEDITERRANEAN FEVER:COMPLICATIONS<br /><ul><li>Secondary amyloidosis :
  158. 158. AA type‏
  159. 159. Worst complication (nephropathy)
  160. 160. 10 à 40 % of patients without treatment
  161. 161. Others complications :
  162. 162. Chronic arthropathy
  163. 163. Infertility (male and female)‏</li></ul>69<br />69<br />
  164. 164. CLINICAL EFFICACY: ACUTE GOUT FLARES<br />Inclusion criteria :<br />Patients with a confirmed diagnosis of crystal-proven gout per the diagnostic criteria set by the American College of Rheumatology:<br /><ul><li> Presence of characteristic urate crystals in the join fluid
  165. 165. And/or tophus proven to contain urate cristals by chemical or polarized light microscopic means</li></ul>70<br />70<br />
  166. 166. HOW DID DOCTORS REACT?<br />Criticism about the trials :<br /><ul><li>Assessment of efficacy ended at 24 hours : how to manage patients still suffering?</li></ul>A 1-week comparison between a low-dose colchicine regimen and a standard NSAID regimen would have been far more clinically relevant<br /><ul><li> « No one treats acute gout with that much colchicine anymore(4.8 mg)»
  167. 167. Use of information provided by “illegal” colchicine </li></ul>“with responsible prescribing, non-approved colchicine is safe and effective” <br />71<br />
  168. 168. FDA’s RESPONSE<br /><ul><li> Our mission : to ensure that every drug on the market is safe and effective
  169. 169. No statutory authority to control the prices for marketed drugs in the U.S.
  170. 170. The marketing exclusivitydoes not apply to the large market of gout prophylaxis
  171. 171. The FDA waits one year after granting an approval before taking action against unapproved products</li></ul>Opportunity for other Colchicine manufacturers to submit their own applications <br /><ul><li>FDA admitsthat Congress wrote laws to encourage innovation, although such regulations sometimes have a broader sweep. The FDA is required to implement the laws as written </li></ul>72<br /><br />72<br />
  172. 172. URL PHARMA’s RESPONSE<br />“In our society, people are rewarded for making advancements” (URL Pharma website)<br /><ul><li> URL Pharma decided to “test the old beliefs, risk the resources, make the discoveries, and save millions of patients from adverse reactions”
  173. 173. Price of a legal drug vs. unapproved drug
  174. 174.  Inadequate labelling of unapproved drugs cost to patients and the healthcare system.
  175. 175. “We want to make sure people get access to Colcrys”</li></ul>URL Pharma set up a Patient Assistance Program in order to help people withlowincomes to benefitfromColcrys.<br />73<br />73<br />
  176. 176. EXAMPLES OF TOXICITY<br /><ul><li>A lot of health public problems have been proved with the use of these traditional products:
  177. 177. Nephropathies and chinese plants:</li></ul>90’s: 100 cases of interstitial nephropathy evolving quickly in terminal renal failure in Belgium were observed in patients taking two plants to lose weights: Magnolia officinalis and Stephania tetandra.<br /> INVESTIGATION:<br />Substitution of Stephania tetandra for Aristolochia fangchi<br /> (because they have chinese names very close) <br />Toxic forkidneys,mutangenic and carcinogenic<br />Aristolochic acid<br />74<br />74<br />
  178. 178. Mechanism of action<br />“Stunning” of the respiratory spiracles of the louse such that they remain open blockage and asphyxiation of louse.<br />Post treatment<br />Control<br />When lice were exposed to ULESFIA® their breathing spiracles remain open liquid materials occlude the breathing apparatus <br />DEATH<br />
  179. 179. FAMILIAL MEDITERRANEAN FEVER:CLINIC<br /><ul><li>Erysipelas-like rashes:
  180. 180. Generally with an articular attack
  181. 181. Favorised by orthostatism
  182. 182. Spontaneous disparition in few days</li></ul>76<br />
  183. 183. FAMILIAL MEDITERRANEAN FEVER:MECHANISM<br /><ul><li>1997: discovery of gene responsible of FMF: Mediterranean fever genen disease
  184. 184. MEFV encodes pyrin called marenostrin
  185. 185. Protein expressed mostly in neutrophils:
  186. 186. Exact function unknown
  187. 187. May function as an inhibitor of chemotactic factor C5a or perhaps of interleukin IL8
  188. 188. A normal pyrin/marenostrin level may have the ability to deactivate the target chemotactic factor when it is produced in response to an inflammatory stimulus
  189. 189. More than 25 mutations in the gene MEFV described.</li></ul>77<br />
  190. 190. Mechanism of action<br />Koné-Paut I, et al. Current data on familial Mediterranean fever. Joint Bone Spine (2010), doi:10.1016/j.jbspin.2010.09.021 <br />
  191. 191. EXAMPLES OF TOXICITY<br /><ul><li>2006: recommandations of EMA about the use of Actaea racemosa:</li></ul>Used for the treatment of troubles of menopause<br />42 cases of hepatic failure: could be associated with the take of<br />actaea but most of people took other drugs witch could explain this<br />failure.<br />Then, only recommandations<br /><ul><li>For patients: to stop taking this medecine
  192. 192. For GP: to ask their patients about the use of medecinals products</li></ul>and to inform EMA if they suspect adverse effects associated with this product<br />79<br />Before 2004, the regulation of herbalproductswas not clearlydefined and was not harmonizedacross the community<br />EMA Website<br />