présentation réalisée dans le cadre du projet scientifique

1. COLCHICINE, BENZYL ALCOHOL APPROVALS… RETHINKINGINNOVATION Samia Thara Sarah Merlen Matthieu Boulenger

3. 3 FDA website

5. Applications :

8. 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. 6 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 with head lice infestation

9. 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 ScielePharma 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 7 Satisfyingresults Ulesfia® summary review

11. Date of approval : April 4th, 2009

14. USA Drug ApprovalTimeline Unapproved Drugs Initiative Prescription drugs Wrap-Up E-Ferol tragedy 1984 Safety and Effectiveness 3400 products 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. The original Federal Food and Drugs Act first brought drug regulation under federal law, prohibiting the sale of adulterated or misbranded drugs. 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 Safetywasrequiredonly for new drugs : the lawwasnot retroactive Drugswhichentered the marketbefore 1938 have never been evaluated for bothsafety and effectiveness. Theyweredeclared as illegallymarketed Safety E-Ferol 1906 Purity Dosage 10

16. = nearly 72 million prescriptions per year

18. PRICE BENEFITS VS FDA APPROVED DRUGS AP IMPACT: “Gov’t Pays for Risky Unapproved Drugs,” R. Alonzo-Zaldivar, F. Bass (Nov. 23, 2008) 11

20. Lack of standardized dosing guidance

21. Potential overdose among special populations requiring dosing adjustements

22. Drug purity problemsassociated with lack of FDA-approved adjustements

23. Too much or too little active ingredientFDA : “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” 12 Unapproved drugs in America : an avoidable public health threat, Salvatore Giorgiani, BSc, PharmD

25. FDA announced its intention to take enforcement action against unapproved drug products containing :13 FDA website

27. Serious adverse effects

28. Has been shown to cause long QT syndrome

29. Narrow margin between an effective dose and a toxic doseFDA has ordered all firms to cease manufacturing unapproved products containing quinine 14 FDA press release (Dec. 11, 2006)

32. October 2009: approval for the prophylaxis of gout flares.

33. FDA orders the other manufacturers to remove any other versions of colchicine from the market.

34. Then, URL Pharma raised the price by a factor of 50, from $0,09 to $4,85 per pill.What happened ? 16

35. A LOT OF NAMES FOR A SAME PLANT « Ephemeron » « Bulbus » « Hermodactylus» « Suringam » « Spalax » « Tue chiens » « Mort-chiens » « Naked lady » « Ephemeron » «Safran des prés » « Crocus » « Safran bâtard » « Iris sauvage » 17 « Colchicumautumnale »

37. Colchicum was described in the 1st century by Dioscorides in the Materia Medica.

38. Medical use of colchicum for gout pain dates back to the 6th century

39. But the use of colchicum in the treatment of gout substantially declined by the 15thcentury because of its toxicity

43. Excellium Pharmaceutical Inc.

44. Vision Pharma LLC

45. Watson pharmaceuticals Inc

46. West-Ward Pharmaceutical

47. Qualitest Pharmaceuticals19

49. 1 or 1.3 mg initial dose,

50. followed by 0.5 to 0.65 mg every 1 to 2 hours

51. until the pain is relieved or nausea and diarrhea appear.

52. Prophylaxis of recurrent gout:

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. Signs of toxicity :

55. 0 to 0.5 mg/kg : gastro-intestinal symptoms

56. 0.5 to 0.8 mg/kg : + bone marrow aplesia and alopecia

57. > 0.8 mg/kg : + circulatory failure20

60. NONCLINICALTOXICOLOGY 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 » 23 Center for Drug Evaluation and Research , NDA 22-351 Summary review

62. 2 primary metabolites involving CYP3A4

63. biliary and urinary excretion24 Center for Drug Evaluation and Research , NDA 22-351 Summary review

64. 25 First target: an orphandisease FAMILIAL MEDITERREAN FEVER

66. Hereditary inflammatorydisorder

67. Recurrent episodesof diffuse inflammation

69. FAMILIAL MEDITERRANEAN FEVER:EPIDEMIOLOGY Turkish people: 1 / 1000 Arabic people: 1 / 2600 Ashkenazi Jewish people: 1 / 73,000 Armenian persons: 1 / 500 27 Sephardic Jewish people: 1 / 250-1000 http://asso.orpha.net/CEREMAI/seminaire/doc/MAI_pratiques_Hentgen_FMF.pdf

71. Posology : 0,5 to 2,5mg / day

72. Prevent attacks

73. Prevent secondary amylodoisis

74. Curative treatement of attacks

75. AINS, corticoïdes

76. Noramidopyrine

77. Anti IL1 : Anakinra in patients with colchicine-resistant FMF 28 http://asso.orpha.net/CEREMAI/seminaire/doc/MAI_pratiques_Hentgen_FMF.pdf

78. CLINICAL EFFICACY : FMF The evidence for the efficacy of colchicine in patients with FMF isderivedfrom the publishedliterature Threerandomized, placebo-controlledstudieswereidentified 29 Provenefficacy of colchicine in the treatment of febrileepisodes of FMF Center for Drug Evaluation and Research , NDA 22-352 Summary review

79. 30 Second target : TREATMENT OF GOUT

80. GOUT « the king of diseases and the disease of kings » Affects 3 to 5 million American, mostcommonlyadult men 31

81. 32 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

82. 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

83. 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… 34

84. MECHANISM OF COLCHICINE 35 Anti-inflammatory mechanism of colchicine, European Heart Journal (2009) 30, 532–539 doi:10.1093/eurheartj/ehn608

86. randomized

87. double-blind

88. placebo-controlled

89. parallel group

90. 1 week36 Center for Drug Evaluation and Research , NDA 22-351 Summary review

91. Study design: 37 Center for Drug Evaluation and Research , NDA 22-351 Summary review

94. Safety « The efficacy of high-dose colchicine with fewer AEs » 40 Dosage : 1.2 mg (2 tablets) at the first sign of a gout flarefollowed by 0.6 mg (1 tablet) one hourlater Colcrys.com

95. CINICAL EFFICACY : PROPHYLAXIS OF GOUT FLARES derivedfrom the publishedliterature Tworandomizedclinical 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. 41 Center for Drug Evaluation and Research , NDA 22-353 Summary review

97. 43

100. 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

102. against any currently marketed unapproved single-ingredient oral colchicine products:

103. that are manufactured on or after November 15, 2010,

104. or that are shipped on or after December 30, 2010.45 Federal Register / Vol. 75, No. 190 / Friday, October 1, 2010 / Notices

105. “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 (NEJM)‏ 46

107. paid about $1 million for the drug  $50 million now?47

109. Criticism about the trials

110. “with responsible prescribing, non-approved colchicine is safe and effective”

111. FDA ‘s response:

112. No statutory authority to control the prices for marketed drugs in the U.S.

113. The marketing exclusivitydoes not apply to the large market of gout prophylaxis

114. URL PHARMA’s response:

115. “In our society, people are rewarded for making advancements”

116. unapproved drugs cost to patients and the healthcare system.URL Pharma set up a Patient Assistance Program

117. 49

118. OUR OWN OPINION 50 FDA’ s « Unapproveddrugs initiative » wasnecessary. Wecannottake the riskto let unsafeor ineffective drugson the market URL Pharma was the onlyfirmto take the initiative to drive clinicalstudiesand to submit an approval Theirexclusivityrewardwaswell-justified Increasing the priceby 50 isunreasonable

119. As a comparison, for Nitroglycerinpills: Pfizer makes the only FDA-approved brand Nitrostat®. FDA has movedagainstfirmsmanufacturingunapproved versions of the drug. Pfizer wasalsobeneficiarywithhigherprices, but more reasonably. The cash price for a pack of 100 tablets: $22 Vs $20 for the banned-drugsbefore. 51 Bnet website : How the FDA’s Crackdown on Unapproved Drugs Could Create New Monopolies

120. AND WHAT ABOUT IN EU? 52 52

122. For example, in France, two branded-drugs on the market:

123. Colchicineopocoalcium 1 mg ( colchicine)

124. Colchimax( colchicine+thiemonium+opium)

127. Efficacy

128. Safety

131. 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 Stephaniatetandra. INVESTIGATION: Substitution of Stephaniatetandrafor Aristolochiafangchi (because they have chinese names very close) Toxic for kidneys, mutagenicand carcinogenic Aristolochic acid 56

134. … but the authoritycanask for all safety data

136. 58 EXPECTED CONSEQUENCES

137. 59 FOR YOUR ATTENTION

139. The metabolic pathway of benzyl alcohol may not be well developed in premature infant : Immature Liver Accumulation Metabolic acidosis 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

140. 62

141. BUT! Diet is necessary!!! Guidelines recommended by American Dietetic during a gout attack: Avoid alcohol Eat a moderate amount of protein, preferably from healthy sources, such as low-fat or fat-free dairy, tofu, eggs, and nut butters. Limit your daily intake of meat, fish and poultry to 4 to 6 ounces (114 to 170 grams). …2000 calories per day is enough!

143. 1.8 mg colchicine dose = 75 subjects

144. placebo = 58 subjects 64

146. Similarly, a greater proportion of patients receiving low-dose colchicine experienced a response compared to placebo 65

147. Was Colchicine considered as a NME, such as benzyl alcohol? Colchicine in dosage oral form was marketed in combinaison with probenecid Probenecid= uricosuric drug that increases uric acid excretion in the urine. Indication: treatment of chronic gouty arthritis when complicated by frequent, recurrent acute attacks of gout. First Approval : Col-Benemid®in july 1961, MERCK Since 1967: a lot of generics have been on the market, legally That’swhy colchicine doesn’tappear on the 2009 NME list. 66

149. Inhibits the process of microtubule self assembly by binding β-tubulin: formation of tubulin-colchicine complexes

150. Several cellular functions touched: phagocytosis, degranulation, chemotaxis

151. Reduction of inflammatory response

152. Therapeutic effect at low doses67 67

154. biliary excretion mediated by P-gp,

155. excreted in the urine by both glomerular filtration and tubular secretion.

156. not removed by hemodialysis68 68

158. AA type‏

159. Worst complication (nephropathy)

160. 10 à 40 % of patients without treatment

161. Others complications :

162. Chronic arthropathy

163. Infertility (male and female)‏69 69

165. And/or tophus proven to contain urate cristals by chemical or polarized light microscopic means70 70

167. Use of information provided by “illegal” colchicine “with responsible prescribing, non-approved colchicine is safe and effective” 71

169. No statutory authority to control the prices for marketed drugs in the U.S.

170. The marketing exclusivitydoes not apply to the large market of gout prophylaxis

173. Price of a legal drug vs. unapproved drug

174. Inadequate labelling of unapproved drugs cost to patients and the healthcare system.

175. “We want to make sure people get access to Colcrys”URL Pharma set up a Patient Assistance Program in order to help people withlowincomes to benefitfromColcrys. 73 73

177. Nephropathies and chinese plants: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. INVESTIGATION: Substitution of Stephania tetandra for Aristolochia fangchi (because they have chinese names very close) Toxic forkidneys,mutangenic and carcinogenic Aristolochic acid 74 74

178. Mechanism of action “Stunning” of the respiratory spiracles of the louse such that they remain open blockage and asphyxiation of louse. Post treatment Control When lice were exposed to ULESFIA® their breathing spiracles remain open liquid materials occlude the breathing apparatus DEATH

180. Generally with an articular attack

181. Favorised by orthostatism

182. Spontaneous disparition in few days76

184. MEFV encodes pyrin called marenostrin

185. Protein expressed mostly in neutrophils:

186. Exact function unknown

187. May function as an inhibitor of chemotactic factor C5a or perhaps of interleukin IL8

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. More than 25 mutations in the gene MEFV described.77

190. Mechanism of action Koné-Paut I, et al. Current data on familial Mediterranean fever. Joint Bone Spine (2010), doi:10.1016/j.jbspin.2010.09.021

192. For GP: to ask their patients about the use of medecinals productsand to inform EMA if they suspect adverse effects associated with this product 79 Before 2004, the regulation of herbalproductswas not clearlydefined and was not harmonizedacross the community EMA Website