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| Modafinil, racemic (diphenylmethyl)sulfinyl-2 acetamide |
For those who are following the Provigil story, here is an itemized history of this non-amphetamine CNS stimulant drug. We present this as an exemplary case study assembled from our drug tracking database, demonstrating how corporations, strategies, patents, markets and legal proceedings mesh over time as an active ingredient is born and ages through its life cycle, finally to face its generic competition. Of course there is almost infinite detail behind this bare-bones chronology.
Note that all factual information is taken from public information for which H.M. Pharma Consultancy accepts no responsibility.
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July 10, 1981 — French regulators approve Olmifon (adrafinil), a liver-metabolized prodrug of modafinil discovered and developed by Laboratoire L. Lafon SA of France, for the treatment of disorders of vigilance, attention, and ideomotor slowing in elderly patients.
September 1985 — Olmifon is launched in France.
1987 — Cephalon, Inc. is established.
1992 — Lafon receives French regulatory approval for modafinil.
January 1993 — Cephalon exclusively licenses modafinil from Lafon for development in the United States and Mexico; agreement amended later that year to include the United Kingdom and Ireland.
1993 — Lafon licenses German and Spanish marketing rights to Merckle GmbH and CEPA Schwarz Pharma SL, respectively.
August 17, 1993 — Cephalon announces initiation of U.S. clinical trials for modafinil to treat daytime sleepiness in narcolepsy.
December 27, 1996 — Cephalon submits New Drug Application to the U.S. Food and Drug Administration (FDA) seeking approval for 100 mg and 200mg strengths of modafinil under the brand name Provigil.
October 1997 — The United Kingdom Medicines Control Agency approves Provigil tablets for the treatment of narcolepsy.
December 22, 1997 — The Acting Assistant Secretary for Health recommends that the U.S. Drug Enforcement Agency put modafinil in Schedule IV of the Controlled Substances Act.
December 1997 — The FDA issues an Approvable Letter for Provigil for the treatment of excessive daytime sleepiness in narcolepsy.
March 4, 1998 — Cephalon launches Provigil in the United Kingdom. Meanwhile, marketing rights have been acquired for Japan and Italy.
May 1998 – The Irish Medicines Board approves Provigil for the treatment of narcolepsy (launched in February 1999).
June 1998 — Cephalon licenses modafinil development and marketing rights to Nippon Shoji Kaisha Ltd. in Japan, and to Dompe SpA in Italy.
November 1998 — Cephalon UK Ltd acquires exclusive rights to promote modafinil in Austria and Switzerland from Merckle.
December 1998 — The U.S. FDA approves Provigil for excessive daytime sleepiness associated with narcolepsy (launched in February 1999). Cephalon estimates U.S. narcolepsy population around 125,000 patients, 30,000 – 45,000 of whom are thought to be seeking treatment.
April 28, 1999 — Cephalon announces initiation of U.S. and UK clinical studies to evaluate Provigil in obstructive sleep apnea, as an adjuvant therapy to continuous nasal positive airway pressure. – The pharma news magazine, SCRIP publishes an article titled “Cephalon’s Success Riding On Provigil.”
September 1999 — Cephalon commences a Phase II clinical trial with Provigil in adults with attention deficit hyperactivity disorder (ADHD), with dextroamphetamine as active comparator.
1999 sales for Provigil were $25 million.
February 2000 — The sleep apnea study yields positive results.
March 2000 — Cephalon obtains marketing rights to Provigil from Lafon for Latin America and several countries in Asia.
July 31, 2000 — Cephalon announces that Provigil has shown no benefit in the adult ADHD study.
September 2000 — Cephalon launches Provigil in Switzerland for the treatment of narcolepsy.
December 4, 2001 — Cephalon announces its intent to acquire Group Lafon. The acquisition is completed on Dec. 28, giving Cephalon worldwide control of modafinil.
May 2001 — Data from two pilot studies show that Provigil reduces fatigue and sleepiness in people who are clinically depressed and who are partial responders to antidepressant therapy.
February 19, 2002 — Cephalon reports Provigil sales of $150.3 million in 2001.
March 28, 2002 — Cephalon files application for obstructive sleep apnea as additional indication in the United Kingdom.
September 2002 — Cephalon discloses positive results from a 4-week placebo-controlled, parallel design study for Provigil in pediatric and adolescent ADHD.
October 23, 2002 — Cephalon announces positive results from a 12-week placebo-controlled clinical study in 209 patients with a confirmed diagnosis of shift work sleep disorder.
December 24, 2002 — Barr Laboratories, Inc. files an Abbreviated New Drug Application (ANDA) with the U.S. FDA for modafinil; Teva Pharmaceuticals USA, Inc., Mylan Pharmaceutical Inc., and Ranbaxy Pharmaceuticals Inc. follow suit.
March 31, 2003 — Cephalon announces a lawsuit against Barr, Teva, Mylan and Ranbaxy for infringement of Cephalon’s U.S. patent RE37,516, precluding the FDA from approving any ANDA for up to 30 months.
October 21, 2003 — Acting on Cephalon’s Supplemental New Drug Application, the U.S. FDA grants a label expansion for Provigil to cover patients who suffer excessive sleepiness associated with shift work sleep disorder and in patients with obstructive sleep apnea.
October 2003 — The Provigil approval is extended to daytime sleepiness from sleep apnea in Germany and Ireland.
In 2003, worldwide sales of Provigil totaled $290 million.
January 4, 2004 — Barr receives tentative FDA approval for generic modafinil tablets.
January 13, 2004 — Cephalon announces the initiation of Phase III trials for the R-isomer of modafinil (armodafinil) in sleepiness from narcolepsy and obstructive sleep apnea.
January 23, 2004 — Cephalon receives formal FDA approval for shift work sleep disorder.
February 20, 2004 — Ranbaxy receives tentative FDA approval for generic modafinil tablets.
April 2004 — The Provigil approval in the United Kingdom is extended to daytime sleepiness from obstructive sleep apnea and moderate to severe chronic shift work sleep disorder.
August 2004 — Cephalon reports preliminary positive results from three 9-week studies of more than 600 children and adolescents with ADHD, says it targets a launch of modafinil for this indication (originally as Attenace, later changed to Sparlon) by early 2006.
December 2004 — Cephalon files a supplemental new drug application with FDA for Sparlon to treat ADHD patients aged 6-17 years.
In 2004, Provigil sales increased 51 percent to $439.7 million.
February 10, 2005 — Mylan receives tentative FDA approval for generic modafinil tablets. – Cephalon announces positive clinical trial results for Nuvigil (armodafinil) in narcolepsy, shift work sleep disorder, and obstructive sleep apnea.
March 31, 2005 — Cephalon files an FDA New Drug Application for Nuvigil.
December 9, 2005 – Cephalon and Teva announce settlement of their U.S. and UK patent dispute and a worldwide agreement for modafinil. Teva’s license in the United States will become effective in October 2011 absent a pediatric extension for Provigil, which would delay the entry date to April 2012. Outside the U.S., the terms generally allow for market entry in October 2012.
December 22, 2005 — Cephalon and Ranbaxy announce settlement of their U.S. patent dispute. Terms are confidential but assumed to be similar to those of the Teva agreement. Ranbaxy will grant to Cephalon a non-exclusive license to its worldwide modafinil patents in exchange for milestone payments. Cephalon will supply modafinil to Ranbaxy. Similar settlements with Barr and Mylan follow but Apotex, which had also made attempts toward generic modafinil, is not part of the deal.
December 24, 2005 — Cephalon’s Orphan Drug exclusivity for Provigil in the U.S. expires.
March 23, 2006 — The U.S. FDA Psychopharmacologic Drugs Advisory Committee votes 12:1 not to recommend approval of Sparlon for pediatric and adolescent ADHD.
June 12, 2006 — Cephalon and Takeda Pharmaceuticals North America, Inc. agree to co-promote Provigil in the United States, starting in July 2006. The agreement extends to Nuvigil once the FDA approves it.
June 15, 2007 — The U.S. FDA approves Nuvigil for the treatment of excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder.
October 24, 2007 — Following an August 2007 labelling update, the FDA and Cephalon notifyhealthcare professionals of updates to the warnings for Provigil regarding serious rash, including Stevens-Johnson Syndrome and hypersensitivity reactions, and psychiatric symptoms.
February 13, 2008 — The U.S. Federal Trade Commission files a complaint against Cephalon asserting anticompetitive conduct that is preventing generic competition to Provigil, based on the “pay-for-delay” settlement agreements with the four generics manufacturers.
July 2010 — The European Medicines Agency recommends use restriction of Provigil to treat only sleepiness associated with narcolepsy.
Provigil generated sales of $1.12 billion in 2010.
April 2011 – European Union antitrust regulators start to investigate Cephalon and Teva for anti-competitive behavior intended to keep modafinil generics out of the EU market.
September 2011 — Cephalon discloses that the U.S. Department of Justice is investigating “certain promotional practices” concerning Provigil and Nuvigil.
October 14, 2011 — Five days after the U.S. Federal Trade Commission granted early termination of waiting period under the Hart-Scott-Rodino Antitrust Act, Teva completes its acquisition of Cephalon, which continues as a Teva subsidiary. Cephalon/Teva are ordered to spin off the generic modafinil business.
October 31, 2011 — In re: Apotex vs. Cephalon, a U.S. District Court invalidatesCephalon’s Orange Book listed patent RE37,516 for modafinil (due to expire in 2014), inter alia on the grounds that the invention had been made by Lafon, was on sale for more than one year prior to the filing date, and for obviousness.
December 2011 — Cephalon discontinues Olmifon (adrafinil).
March 29, 2012 — Teva formally launches its authorized generic of Provigil in the U.S., to be marketed by Cephalon.
April 6, 2012 — Par Pharmaceutical Companies, Inc. assume sales of generic modafinil while Teva/Cephalon continue to sell original Provigil. – Mylan sues the FDA to gain approval and marketing exclusivity for its modafinil generic in the U.S., alleging that Teva did not maintain valid paragraph IV certifications as a result of its acquisition of Cephalon.
To be continued, for sure…