`
`The Return of
`Thalidomide:
`New Uses and
`Renewed
`Concerns
`Dr V Pannikar, Medical
`Officer, Communicable
`Diseases (Leprosy
`Group), WHO
`
`History
`α-(N-
`or
`Thalidomide
`phthalimido) glutarimide was
`marketed in 1957 for morning
`sickness and nausea and soon
`became the ‘drug of choice to
`help pregnant women’. It went
`into general use by the following
`year and was widely prescribed
`in Europe, Australia, Asia, Africa
`and the Americas1. Allegedly, the
`drug was harmless and a lethal
`dose
`could not even be
`established2. However, in the
`early 1960s, in what might be
`described as the worst case of
`pharmaceutical oversight, the
`drug was found to be associated
`with a congenital abnormality
`causing severe birth defects in
`children born of women who had
`been prescribed this drug during
`pregnancy. More than 10, 000
`cases of birth defects were
`reported in over 46 nations
`following thalidomide exposure.
`Children were born with missing
`(amelia)
`or
`abnormal
`(phocomelia) legs, arms, feet
`and hands; spinal cord defects;
`cleft lip or palate; absent or
`abnormal external ears; heart,
`kidney,
`and
`genital
`abnormalities; and abnormal
`formation of
`the digestive
`system. It is estimated that 40%
`of
`thalidomide victims died
`within a year of birth3. Today
`there are approximately 5000
`survivors1.
`thalidomide
`The
`‘thalidomide syndrome’
`trig-
`gered a world wide response.
`Safety monitoring systems were
`set up to prevent this tragedy
`ever happening again and the
`drug was taken off the market in
`many countries in 1961.
`
`Thalidomide in Leprosy
`A few years later, however, the
`drug
`thalidomide
`was
`reintroduced as treatment for a
`complication of leprosy called
`erythema nodosum
`leprosum
`(ENL). Although the evidence
`was not fully established, very
`soon the drug was heralded as
`the drug of choice for the
`management of ENL reactions in
`leprosy
`and
`regulatory
`authorities granted exemption
`from licensing requirements to
`enable doctors to obtain limited
`supplies of thalidomide under
`strictly controlled circumstances
`for use
`in named patients.
`Thalidomide's effectiveness in
`minimizing symptoms of ENL was
`mainly due to its antipyretic
`action. Its effectiveness in
`controlling neuritis, the major
`cause of permanent disabilities in
`leprosy, was limited.
`
`Several controlled studies
`done
`in
`the
`70's
`have
`that predni-
`demonstrated
`solone is more effective in
`controlling ENL and associated
`neuritis4-6. In addition, it was
`demonstrated that clofazimine,
`an anti-leprosy drug introduced
`on a small scale in the early 60's
`had anti-inflammatory action7,8.
`Studies showed that clofazimine
`is the drug of choice for the
`management
`of
`chronic,
`recurrent ENL reactions, as it
`had both anti-reaction and anti-
`leprosy effect. Moreover, while
`almost
`all
`patients
`given
`thalidomide
`relapsed
`after
`discontinuation of the drug, none
`of the patients treated with
`clofazimine for ENL reactions
`relapsed9-11.
`The
`drug
`clofazimine is now a component
`of the multidrug therapy (MDT),
`introduced by WHO in 1981 as
`the standard
`treatment
`for
`leprosy.
` The presence of
`clofazimine in the combination
`has significantly reduced the
`frequency and severity of ENL
`reactions world-wide12,13.
`
`Today ENL reaction is a rare
`complication, limited to a small
`proportion
`of multibacillary
`patients. Most of the ENL
`reactions are mild in nature and
`
`do not require any specific
`treatment except with some
`analgesics/antipyretics. In those
`suffering ENL associated neuritis,
`the
`drug
`of
`choice
`is
`prednisolone.
`For
`chronic
`recurrent reactions the drug of
`choice is clofazimine.
`Thalidomide in other
`indications
`clearly
`points
`The
`above
`demonstrate that there is no
`place for thalidomide in leprosy.
`But very often this disease is
`used as an entry point to
`reintroduce thalidomide for a
`multitude of other indications.
`Millions of treatments are being
`prescribed annually and almost
`all of
`it
`is
`for non-leprosy
`conditions
`including
`cancer
`treatment and use in HIV. There
`are limited trials demonstrating
`the efficacy of thalidomide in
`conditions14,15.
`Each
`other
`condition must be evaluated in
`its own right and there must be
`put in place stringent restrictions
`on its availability. In addition
`there must be a monitoring
`system in place. There is no
`justification in extrapolating data
`from monitoring systems for
`leprosy to other conditions. The
`medical community that support
`the use of thalidomide for other
`conditions should make their
`own case for the drug. They
`cannot base it on the leprosy
`studies which are anything but
`exhaustive.
`In conclusion
`Today, a
`large number of
`thalidomide babies continue to
`be born each year16-18 possibly
`reflecting regulatory insufficiency
`and widespread use under
`inadequate supervision. In Brazil,
`which has more than 1000
`registered thalidomide victims,
`the last officially known case was
`in 199519,20. There
`is
`born
`evidence that second generation
`babies with similar deformities
`are being born to thalidomide
`victims21,22. In the US, Celgene
`Corporation has had
`FDA
`approval to market the drug
`since 1998 for the cutaneous
`manifestations of moderate to
`
`Page 1 of 2
`
`CELGENE EXHIBIT 2002
`Coalition for Affordable Drugs VI LLC (Petitioner) v. Celgene Corporation (Patent Owner)
`Case IPR2015-01096
`
`
`
`
`
`
`FEATURE
`
`cases. Bull World Health Org
`1971, 45: 719.
`10. Iyer CG, Ramu G. An open trial
`with clofazimine in the
`management of recurrent lepra
`reaction using thalidomide as a
`control drug. Leprosy in India,
`1976, 48: 690.
`11. Ramanujam K, Iyer CG, Ramu
`G. Open trial with clofazimine in
`the management of recurrent
`lepra reaction and of sulphone
`sensitive cases: A preliminary
`report. Leprosy Review, 1975,
`46 (supplement): 117.
`12. Becx-Bluemink M, Berhe D.
`Occurrence of reactions, their
`diagnosis and management in
`leprosy patients treated with
`multidrug therapy; experience
`in the Leprosy Control
`Programme of All Africa Leprosy
`and Rehabilitation Training
`Centre (ALERT) in Ethiopia.
`International Journal of Leprosy
`and Other Mycobacterial
`Diseases, 1992, 60(2): 173.
`13. Willcox, M.L. The impact of
`multidrug therapy on leprosy
`disabilities. Leprosy Review,
`1997, 68: 350.
`14. Wines, N.Y., Cooper, A.J. and
`Wines, M.P. Thalidomide in
`dermatology. Australian Journal
`of Dermatology, 2002, 43(4):
`229.
`15. Gaspari A. Thalidomide
`neurotoxicity in dermatological
`patients: The next “STEP”. The
`Journal of Investigative
`Dermatology, 2002, 119: 987.
`16. FDA tries to plug risky drug
`loopholes. The Associated Press,
`ABCNEWS.com, December 9,
`2002. Available:
`http://www.boston.com/globe
`17. Kranish, M. New use is found for
`thalidomide: Fighting cancer.
`Boston Globe Online, October
`20, 2002
`18. 40 years after the thalidomide
`holocaust. Available:
`www.thalidomide.org/FfdN/Grun
`en/Grunthl.html
`19. Castilla EE et al. Thalidomide, a
`current teratogen in South
`America. Teratology1996, 54:
`273.
`20. Communication from CEATOX -
`Centro de Assistência
`Toxicológica, Instituto da
`Criança Prof. Pedro de
`Alcantara, Hospital das Clinicas
`da Faculdade de Medicina da
`U.S.P, Brazil.
`21. "Second generation"
`Thalidomide claims. BBC News,
`Health, October 2, 2000.
`22. A curse on my baby. Sunday
`Times Focus, July 20, 1997.
`
`nodosum
`erythema
`severe
`leprosum. In Europe, the US
`company Pharmion Corp and
`French rival Laphal have both
`secured orphan drug status for
`thalidomide and have applied to
`market the drug as a therapy for
`multiple myeloma and for ENL in
`the EU. The EU is currently
`holding discussions on the re-
`launch of thalidomide. Whatever
`the
`outcome
`of
`the EU
`discussions, it cannot be over
`emphasized that any potential
`benefit with thalidomide must be
`balanced with the known toxicity
`and the accompanying ethical
`and legal constraints on its use.
`Experience has shown that it is
`virtually impossible to develop
`and
`implement a
`fool-proof
`surveillance mechanism
`to
`combat misuse of thalidomide.
`
`References:
`1. What is Thalidomide? TVAC:
`Thalidomide Victims Association
`of Canada, September 01,
`1999. Available:
`http://www.thalidomide.ca
`2. James JS. (ATN) Thalidomide
`and HIV: Background. AIDS
`Treatment News Issue #179,
`July 23, 1993. Available :
`http://www.aegis.com/pubs/atn
`/1993/ATN17902.html
`3. Lenz W. The History of
`Thalidomide. TVAC: Thalidomide
`Victims Association of Canada,
`September 01, 1999. Available:
`http://www.thalidomide.ca
`4. Dharmendra. Leprosy Volume 1,
`1978, Kothari Medical Publishing
`House, Bombay, India.
`5. WHO. The final push strategy to
`eliminate leprosy a public health
`problem, questions & answers,
`second edition, 2003, WHO,
`Geneva.
`6. Ramu G and Iyer CG. Treatment
`of reactions in leprosy. In : A
`window on leprosy, 1978. Edited
`by Chatterjee BR., published by
`Gandhi Memorial Leprosy
`Foundation
`7. Browne SG. B 663 - possible
`anti-inflammatory action in
`lepromatous leprosy. Leprosy
`Review, 1965, 36: 9.
`8. Waters MFR. Transactions of the
`Ninth International Leprosy
`Congress, International Journal
`of Leprosy, 1968, 36: 560.
`9. Iyer CG et al. WHO coordinated
`short term double blind trial
`with thalidomide on the
`treatment of acute lepra
`reactions in male lepromatous
`
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