FEATURE
`
`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
`
`CELGENE EXHIBIT 2002
`Coalition for Affordable Drugs VI LLC (Petitioner) v. Celgene Corporation (Patent Owner)
`Case IPR2015-01103
`
`Page 1 of 2
`
`
`
`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
`
`CELGENE EXHIBIT 2002
`Coalition for Affordable Drugs VI LLC (Petitioner) v. Celgene Corporation (Patent Owner)
`Case IPR2015-01103
`
`Page 1 of 2
`
`
`
`
`
`
`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
`
`Page 2 of 2
Accessing this document will incur an additional charge of $.
After purchase, you can access this document again without charge.
Accept $ Charge
Still Working On It
This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.
Give it another minute or two to complete, and then try the refresh button.
A few More Minutes ... Still Working
It can take up to 5 minutes for us to download a document if the court servers are running slowly.
Thank you for your continued patience.
This document could not be displayed.
We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.
Your account does not support viewing this document.
You need a Paid Account to view this document. Click here to change your account type.
Your account does not support viewing this document.
Set your membership
status to view this document.
With a Docket Alarm membership, you'll
get a whole lot more, including:
- Up-to-date information for this case.
- Email alerts whenever there is an update.
- Full text search for other cases.
- Get email alerts whenever a new case matches your search.
One Moment Please
The filing “” is large (MB) and is being downloaded.
Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.
Your document is on its way!
If you do not receive the document in five minutes, contact support at support@docketalarm.com.
Sealed Document
We are unable to display this document, it may be under a court ordered seal.
If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.
Access Government Site
