lunes, 13 de marzo de 2017

FDA Law Blog: Orphan Drugs: The Current Firestorm, a Real Evergreening Issue, and a Possible Solution

FDA Law Blog: Orphan Drugs: The Current Firestorm, a Real Evergreening Issue, and a Possible Solution



Posted: 10 Mar 2017 04:46 AM PST
By Kurt R. Karst –

Periodically, legislators and others become concerned about reports citing the high price of some orphan drugs, including drugs that achieve blockbuster status (earning more than $1 billion a year). Several proposals have been introduced in response to such concerns.  In 1990, Congress passed legislation that would have limited market exclusivity in some circumstances, but the President vetoed it.

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Critics in Congress and in the pharmaceutical industry and patient groups say that while the [Orphan Drug Act] has generally worked, it has proved to be a bonanza for the makers of some very big drugs, allowing them to charge higher prices than there would have been with competition.
With all of the recent hubbub around orphan drugs and pricing, you might think the two quotes above were ripped from recent stories. In fact, the first quote is taken from a 2010 Institute of Medicine report, titled “Rare Diseases and Orphan Products: Accelerating Research and Development” (see our previous post here).  The second quote is from an April 1990 article in the New York Times, titled “Orphan Drug Law Spurs Debate.”  The fact that you likely could not identify the age of the quotes above means that we’re in the midst of another one of those “periods” referred to in the IOM report, where legislators take a look at the Orphan Drug Act to decide whether or not changes need to me made to the law.

The latest round of interest started perhaps within the past two years, as legislators began consideration of legislation – the “Orphan Product Extensions Now Act,” or “OPEN Act” – to amend the FDC Act to provide a 6-month extension of exclusivity periods for companies that obtain approval of a previously approved drug for a new, rare condition. (By the by, the OPEN Act was reintroduced in February as H.R. 1223, the “Orphan Product Extensions Now Accelerating Cures and Treatments Act.”)  Then there was an article in the American Journal of Clinical Oncology, titled “The Orphan Drug Act: Restoring the Mission to Rare Diseases,” alleging that companies are “gaming” the orphan drug system established by the Orphan Drug Act “to use the law for mainstream drugs.”  A report from Public Citizen on the OPEN Act, titled “House Orphan Drug Proposal: A Windfall for Pharma, False ‘Cure’ for Patients” (see our previous post here), followed.  Then things calmed down a bit . . . .  until recently.

In January 2017, the Kaiser Family Foundation published a report, titled “The Orphan Drug Machine: Drugmakers Manipulate Orphan Drug Rules To Create Prized Monopolies.”  That report caught the attention of Senator Chuck Grassley (R-IA), who stated  that he would explore possible misuses of the orphan drug program.  Then last week, Sen. Grassley (along with Senators Orrin Hatch (R-UT) and Tom Cotton (R-AR)) sent a letter to the Government Accountability Office (“GAO”) requesting certain information (much of which is already publicly available) and an investigation into “whether the [Orphan Drug Act] is still incentivizing product development for diseases with fewer than 200,000 affected individuals, as intended, and provide any regulatory or legislative changes that may be needed in order to preserve the intent of this vital law.”  The letter to GAO states the Senators’ general concern: so-called “evergreening” of orphan drug exclusivity.

While few will argue against the importance of the development of [orphan] drugs, several recent press reports suggest that some pharmaceutical manufacturers might be taking advantage of the multiple designation allowance in the orphan drug approval process.
A review of FDA’s Orphan Drug Designations and Approvals Database shows that there are many, many drugs and biological products with multiple orphan drug designations and/or approvals.  In some cases, there are just a couple of entries on the list for the same drug.  In other cases, such as with Imatinib and Ibrutinib, there are quite a few entries.

In most cases, a single period of 7-year orphan drug exclusivity extends from a single orphan drug designation granted by FDA’s Office of Orphan Products Development. Each designation covers a different orphan disease or condition.  And once the first period of orphan drug exclusivity expires, FDA may be able to approve an ANDA for a generic version of the drug product with labeling that omits information on a subsequent use protected by orphan drug exclusivity.  This carve-out option has been affirmed by FDA in various Letter Decisions and Citizen Petition response, and by the courts – see, e.g.Sigma-Tau Pharmaceuticals, Inc. v. Schwetz, 288 F.3d 141 (4th Cir. 2002) (here).

If the reference in the letter to the GAO to “multiple designation allowance” that “some pharmaceutical manufacturers might be taking advantage of” is merely a concern with multiple orphan drug designations that lead to separate grants of orphan drug exclusivity for separate diseases or conditions, then this blogger does not see a particular need for concern. It’s not an evergreening issue at all!  The Orphan Drug Act is working exactly as intended, and generic competition is generally not thwarted because of the ability of an ANDA applicant to carve-out of its labeling (and thus avoid) a period of unexpired orphan drug exclusivity on the brand-name Reference Listed Drug.

But there may be a real evergreening issue that’s probably been overlooked by most folks. In some cases, a single orphan drug designation can result in multiple periods of orphan drug exclusivity.  (A table of examples is provided at the end of this post.)  FDA explained this concept in the preamble to the Agency’s October 2011 proposed orphan drug regulations:

The scope of orphan exclusive approval for a designated drug is limited to the approved indication or use, even if the underlying orphan designation is broader. If the sponsor who originally obtained orphan exclusive approval of the drug for only a subset of the orphan disease or condition for which the drug was designated subsequently obtains approval of the drug for one or more additional subsets of that orphan disease or condition, FDA will recognize orphan-drug exclusive approval, as appropriate, for those additional subsets from the date of such additional marketing approval(s).  Before obtaining such additional marketing approval(s), the sponsor in this instance would not need to have obtained additional orphan designation for the additional subset(s) of the orphan disease or condition. [(Emphasis added)]
In most instances, multiple and staggered periods of orphan drug exclusivity stemming from the same designation do not stymie generic competition. For example, if FDA grants an orphan drug designation for Drug X for Disease Y and the sponsor first obtains approval of the drug for use in adults with Disease Y and then later for the same drug for use in children with Disease Y, FDA would grant two separate periods of orphan drug exclusivity – one for each approval.  An ANDA applicant may obtain approval of the drug for the adult population indication once the initial period of orphan drug exclusivity expires, and then later for the pediatric population indication once that second period of orphan drug exclusivity expires.

But not all cases are as easy as the one above. You see, indications, like Pokémon, can evolve into something new.  There appear to be a growing number of cases where FDA has granted multiple periods of orphan drug exclusivity based on the same original orphan drug designation, and where the drug’s indication evolves into something new, shedding and subsuming the previous indication statement.  This could occur, for example, as different disease stages or different lines of therapy are approved.  (Some possible examples of this might be in the cases of Ibrutinib, Cinacalcet, Bortezomib, and Bevacizumab.)  As the old labeling is shed, the new labeling may not allow for an ANDA (or biosimilar) applicant to easily (if at all) omit information protected by a new 7-year period of orphan drug exclusivity.

But is the solution to what may be a real evergreening problem opening up the Orphan Drug Act? This blogger thinks that there could be a better solution.  If the issue preventing a carve-out is the text of the brand-name drug labeling, then one remedy is to have better communication between the Office of New Drugs (“OND”) and the Office of Generic Drugs (“OGD”) during the course of brand-name drug labeling reviews and drafting.  OGD’s experience with labeling reviews and carve-outs should not be overlooked, and can lead to labeling that does not cause carve-out controversies years down the road.  Another possible remedy is for OGD to take a broader view of permissible labeling changes.  That is, considering so-called labeling “carve-ins” that clarify the omission of other labeling information (and effectively return an indication to its previous state).  It’s a topic FDA raised a few years back (see our previous post here), but that the Agency ultimately decided not to address.

Multiple Orphan Drug Exclusivity Periods Based on a Single Orphan Drug Designation 
Generic Name (Trade Name)Designation (Designation Date)Approved IndicationMarketing Approval Date (Exclusivity End Date)
adalimumab (Humira)Treatment of juvenile rheumatoid arthritis (3/21/2005)Reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 4 years of age and older. 02/21/2008 (02/21/2015)
adalimumab (Humira)Treatment of juvenile rheumatoid arthritis (3/21/2005)Reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in patients 2 years to 4 years of age. 09/30/2014  (09/30/2021)
bevacizumab (Avastin)Treatment of fallopian tube carcinoma (11/23/2010)Either in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine, followed by Avastin as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. 12/06/2016  (12/06/2023)
bevacizumab (Avastin)Treatment of fallopian tube carcinoma (11/23/2010)In combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for treatment of patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who have received no more than 2 prior chemotherapy regimens. 11/14/2014  (11/14/2021)
bevacizumab (Avastin)Treatment of primary peritoneal carcinoma (11/2/2010)Either in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine, followed by Avastin as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. 12/06/2016  (12/06/2023)
bevacizumab (Avastin)Treatment of primary peritoneal carcinoma (11/2/2010)In combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for treatment of patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens 11/14/2014  (11/14/2021)
bevacizumab (Avastin)Therapeutic treatment of patients with ovarian cancer (2/9/2006)Either in combination with carboplatin and paclitaxel or in combination with carboplatin and gemcitabine, followed by Avastin as a single agent, is indicated for the treatment of patients with platinum-sensitive recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer. 12/06/2016  (12/06/2023)
bevacizumab (Avastin)Therapeutic treatment of patients with ovarian cancer (2/9/2006)In combination with paclitaxel, pegylated liposomal doxorubicin, or topotecan for treatment of patients with platinum-resistant, recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who received no more than 2 prior chemotherapy regimens 11/14/2014  (11/14/2021)
bortezomib (Velcade)Treatment of multiple myeloma (1/15/2003)First-line therapy of multiple myeloma. 06/20/2008  (06/20/2015)
bortezomib (Velcade)Treatment of multiple myeloma (1/15/2003)Treatment of multiple myeloma patients who have received at least one prior therapy 03/25/2005  (03/25/2012)
bortezomib (Velcade)Treatment of multiple myeloma (1/15/2003)Treatment of multiple myeloma patients who have received at least two prior therapies and have demonstrated disease progression on the last therapy 05/13/2003  (05/13/2010)
bortezomib (Velcade)Treatment of mantle cell lymphoma (5/30/2012)Treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. 12/08/2006  (12/08/2013)
bortezomib (Velcade)Treatment of mantle cell lymphoma (5/30/2012)Treatment of patients with mantle cell lymphoma who have not received at least 1 prior therapy 10/08/2014  (10/08/2021)
brentuximab vedotin (Adcetris)Treatment of Hodgkin's lymphoma (1/30/2007)Treatment of patients with classical Hodgkin lymphoma at high risk of relapse or progression as post-autologous hematopoietic stem cell transplantation (auto-HSCT). 08/17/2015  (08/17/2022)
brentuximab vedotin (Adcetris)Treatment of Hodgkin's lymphoma (1/30/2007)The treatment of patients with Hodgkin lymphoma after failure of autologous stem cell transplant (ASCT) or after failure of at least two prior multi-agent chemotherapy regimens in patients who are not ASCT candidates 08/19/2011  (08/19/2018)
cinacalcet (Sensipar)Treatment of hypercalcemia in patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo surgery (4/30/2010)Treatment of hypercalcemia in adult patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo parathyroidectomy. 11/21/2014  (11/21/2021)
cinacalcet (Sensipar)Treatment of hypercalcemia in patients with primary hyperparathyroidism for whom parathyroidectomy would be indicated on the basis of serum calcium levels, but who are unable to undergo surgery (4/30/2010)Treatment of severe hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy 02/25/2011  (02/25/2018)
cysteamine enteric coated (Procysbi)Treatment of cystinosis (10/24/2006)For management of nephropathic cystinosis in adults and children ages 6 years and older 04/30/2013  (04/30/2020)
cysteamine enteric coated (Procysbi)Treatment of cystinosis (10/24/2006)To expand the indication to pediatric patients 2-6 years of age with nephropathic cystinosis 08/14/2015  (08/14/2022)
daratumumab (Darzalex)Treatment of multiple myeloma (5/6/2013)For the treatment of patients with multiple myeloma who have received at least 3 prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or are double refractory to a proteasome inhibitor and an immunomodulatory agent 11/16/2015  (11/16/2022)
daratumumab (Darzalex)Treatment of multiple myeloma (5/6/2013)DARZALEX in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. 11/21/2016  (11/21/2023)
ecallantide (Kalbitor)Treatment of angioedema (2/4/2003)Treatment of acute attacks of hereditary angioedema in patients 16 years of age and older 12/01/2009  (12/01/2016)
ecallantide (Kalbitor)Treatment of angioedema (2/4/2003)Treatment of acute attacks of hereditary angioedema (HAE) in patients 12 years of age and older 03/28/2014  (03/28/2021)
everolimus (Afinitor)Treatment of neuroendocrine tumors (2/14/2008)Treatment of adult patients with progressive, well-differentiated, non-functional, neuroendocrine tumors (NET) of gastrointestinal (GI) or lung origin, (excluding pancreatic) with unresectable, locally advanced or metastatic disease. 02/26/2016  (02/26/2023)
everolimus (Afinitor)Treatment of neuroendocrine tumors (2/14/2008)Treatment of progressive neuroendocrine tumors of pancreatic origin (PNET) in patients with unresectable, locally advanced or metastatic disease 05/05/2011  (05/05/2018)
factor XIII concentrate (human) (Corifact)Treatment of congenital factor XIII deficiency (1/16/1985)For the routine prophylactic treatment of congenital factor XIII deficiency 02/17/2011  (02/17/2018)
factor XIII concentrate (human) (Corifact)Treatment of congenital factor XIII deficiency (1/16/1985)Peri-operative management of surgical bleeding in adult and pediatric patients with congenital Factor XIII deficiency. 01/24/2013  (01/24/2020)
Fomepizole (Antizole)Treatment of methanol or ethylene glycol poisoning (12/22/1988)Use for suspected or confirmed methanol poisoning, either alone or in combination with hemodialysis 12/08/2000  (12/08/2007)
Fomepizole (Antizole)Treatment of methanol or ethylene glycol poisoning (12/22/1988)As an antidote to ethylene glycol (antifreeze) poisoning, or for use in suspected ethylene glycol ingestion. 12/04/1997  (12/04/2004)
ibrutinib (Imbruvica)Treatment of nodal marginal zone lymphoma (2/5/2015)Treatment of patients with Marginal Zone Lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy. 01/18/2017  (01/18/2024)
ibrutinib (Imbruvica)Treatment of splenic marginal zone lymphoma (2/5/2015)Treatment of patients with Marginal Zone Lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy. 01/18/2017  (01/18/2024)
ibrutinib (Imbruvica)Treatment of chronic lymphocytic leukemia (CLL) (4/6/2012)Treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy 02/12/2014  (02/12/2021)
ibrutinib (Imbruvica)Treatment of chronic lymphocytic leukemia (CLL) (4/6/2012)Treatment of patients with chronic lymphocytic leukemia with 17p deletion who have not received at least one prior therapy 07/28/2014  (07/28/2021)
ibrutinib (Imbruvica)Treatment of chronic lymphocytic leukemia (CLL) (4/6/2012)Indicated for the treatment of patients with chronic lymphocytic leukemia without 17p deletion who have not received at least one prior therapy (first line therapy). 03/04/2016  (03/04/2023)
infliximab (Remicade)Treatment of pediatric (0 to 16 years of age) ulcerative colitis (11/12/2003)For reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients 6 years of age and older with moderately to severely active ulcerative colitis who have had an inadequate response to conventional therapy 09/23/2011  (09/23/2018)
infliximab (Remicade)Treatment of pediatric (0 to 16 years of age) Crohn's Disease (11/12/2003)For reducing signs and symptoms and inducing and maintaining clinical remission in pediatric patients with moderately to severely active Crohn's disease who have had an inadequate response to conventional therapy 05/19/2006  (05/19/2013)
Iobenguane I 123 (Adreview)For the diagnosis of pheochromocytomas (12/1/2006)To be used in the detection of primary or metastatic pheochromocytomas or neuroblastomas as an adjunct to other diagnostic tests 09/19/2008  (09/19/2015)
Iobenguane I 123 (Adreview)For the diagnosis of neuroblastomas (12/1/2006)To be used in the detection of primary or metastatic pheochromocytomas or neuroblastomas as an adjunct to other diagnostic tests 09/19/2008 (09/19/2015) 
ipilimumab (Yervoy)Treatment of high risk Stage II, Stage III, and Stage IV melanoma (6/3/2004)For the adjuvant treatment of patients with cutaneous melanoma with pathologic involvement of regional lymph nodes of more than 1 mm, who have undergone complete resection including total lymphadenectomy. 10/28/2015  (10/28/2022)
ipilimumab (Yervoy)Treatment of high risk Stage II, Stage III, and Stage IV melanoma (6/3/2004)Treatment of unresectable or metastatic melanoma 03/25/2011  (03/25/2018)
lenalidomide (Revlimid)Treatment of multiple myeloma (9/20/2001)Treatment of multiple myeloma (MM), as maintenance following autologous hematopoietic stem cell transplantation (auto-HSCT) 02/22/2017  (02/22/2024)
lenalidomide (Revlimid)Treatment of multiple myeloma (9/20/2001)For use in combination with dexamethasone for the treatment of patients with multiple myeloma who have not received at least one prior therapy (first line treatment) 02/17/2015  (02/17/2022)
lenalidomide (Revlimid)Treatment of multiple myeloma (9/20/2001)For use in combination with dexamethasone for the treatment of multiple myeloma patients who have received at least one prior therapy 06/29/2006  (06/29/2013)
lumacaftor/ivacaftor (Orkambi)Treatment of cystic fibrosis (6/30/2014)Treatment of cystic fibrosis (CF) in patients age 6-11 year old who are homozygous for the F508del mutation in the CFTR gene 09/28/2016  (09/28/2023)
lumacaftor/ivacaftor (Orkambi)Treatment of cystic fibrosis (6/30/2014)Treatment of cystic fibrosis in patients age 12 years and older who are homozygous for F508del mutation in the CFTR gene 07/02/2015  (07/02/2022)
mefloquine HCL (Lariam)For use in the treatment of acute malaria due to Plasmodium falciparum and Plasmodium vivax, and for the prophylaxis of Plasmodium falciparum malaria which is resistant to other available drugs (4/13/1988)Treatment of acute malaria due to Plasmodium falciparum and Plasmodium vivax 05/02/1989 (05/02/1996) 
mefloquine HCL (Lariam)For use in the treatment of acute malaria due to Plasmodium falciparum and Plasmodium vivax, and for the prophylaxis of Plasmodium falciparum malaria which is resistant to other available drugs (4/13/1988)Prophylaxis of Plasmodium falciparum malaria which is resistant to other available drugs 05/03/1989  (05/03/1996)
Mitoxantrone (Novantrone)Treatment of secondary-progressive multiple sclerosis (8/13/1999)Reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly adnormal between relapses). 10/13/2000  (10/13/2007)
Mitoxantrone (Novantrone)Treatment of progressive-relapsing multiple sclerosis (8/13/1999)Reducing neurologic disability and/or the frequency of clinical relapses in patients with secondary (chronic) progressive, progressive relapsing, or worsening relapsing-remitting multiple sclerosis (i.e., patients whose neurologic status is significantly adnormal between relapses). 10/13/2000  (10/13/2007)
Nitisinone (Orfadin)Treatment of tyrosinemia type 1 (5/16/1995)Treatment of hereditary tyrosinemia type 1 in combination with dietary restriction of tyrosine and phenylalanine. 04/22/2016 (04/22/2023) 
Nitisinone (Orfadin)Treatment of tyrosinemia type 1 (5/16/1995)Adjunctive therapy to dietary restriction of tyrosine and phenylalanine in the treatment of hereditary tyrosinemia type 1 01/18/2002  (01/18/2009)
Octreotide (Sandostatin Lar)Treatment of severe diarrhea and flushing associated with malignant carcinoid tumors (8/24/1998)Supression of severe diarrhea and flushing associated with malignant carcinoid syndrome. 11/25/1998  (11/25/2005)
Octreotide (Sandostatin Lar)Treatment of acromegaly (8/24/1998)Reduction of growth hormone and IGF-1 (somatomedin C) in acromegaly. 11/25/1998  (11/25/2005)
Octreotide (Sandostatin Lar)Treatment of diarrhea associated with vasoactive intestinal peptide tumors (VIPoma) (8/24/1998)Treatment of profuse watery diarrhea associated with VIPoma. 11/25/1998  (11/25/2005)
ofatumumab (Arzerra)Treatment of chronic lymphocytic leukemia (3/10/2009)Arzerra in combination with fludarabine and cyclophosphamide for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL). 08/30/2016  (08/30/2023)
ofatumumab (Arzerra)Treatment of chronic lymphocytic leukemia (3/10/2009)Treatment of chronic lymphocytic leukemia (CLL) refractory to alemtuzumab and fludarabine 10/26/2009  (10/26/2016)
ofatumumab (Arzerra)Treatment of chronic lymphocytic leukemia (3/10/2009)Ofatumumab in combination with chlorambucil, for the treatment of previously untreated patients with chronic lymphocytic leukemia (CLL) for whom fludarabine-based therapy is considered inappropriate. 04/17/2014  (04/17/2021)
ofatumumab (Arzerra)Treatment of chronic lymphocytic leukemia (3/10/2009)For extended treatment of patients who are in complete or partial response after at least two lines of therapy for recurrent or progressive CLL. 01/19/2016  (01/19/2023)
oxybate (Xyrem)Treatment of narcolepsy (11/7/1994)Treatment of excessive daytime sleepiness in patients with narcolepsy 11/18/2005  (11/18/2012)
oxybate (Xyrem)Treatment of narcolepsy (11/7/1994)Treatment of cataplexy associated with narcolepsy 07/17/2002  (07/17/2009)
pembrolizumab (Keytruda)Treatment of Stage IIB through IV malignant melanoma (11/19/2012)Treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. 09/04/2014  (09/04/2021)
pembrolizumab (Keytruda)Treatment of Stage IIB through IV malignant melanoma (11/19/2012)Treatment of patients with unresectable or metastatic melanoma. 12/18/2015  (12/18/2022)
polifeprosan 20 with carmustine (Gliadel)Treatment of malignant glioma (12/13/1989)Expanding the indication to include patients with malignant glioma undergoing primary surgical resection. 02/25/2003  (02/25/2010)
polifeprosan 20 with carmustine (Gliadel)Treatment of malignant glioma (12/13/1989)As an adjunct to surgery to prolong survival in patients with recurrent glioblastoma multiforme for whom surgical resection is indicated 09/23/1996  (09/23/2003)
ponatinib (Iclusig)Treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) (11/20/2009)Treatment of adult patients with Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. 12/14/2012  (12/14/2019)
ponatinib (Iclusig)Treatment of chronic myeloid leukemia (11/20/2009)Treatment of adult patients with chronic phase, accelerated phase, or blast phase chronic myeloid leukemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy. 12/14/2012  (12/14/2019)
prothrombin complex concentrate (human) (Kcentra)Treatment of patients needing urgent reversal of Vitamin K antagonist therapy for treatment of major bleeding and/or surgical procedures (12/27/2012)Urgent reversal of acquired coagulation factor deficiency induced by vitamin K antagonist therapy (VKA, e.g., warfarin) in adult patients with the need for urgent surgery/invasive procedure. 12/13/2013  (12/13/2020)
prothrombin complex concentrate (human) (Kcentra)Treatment of patients needing urgent reversal of Vitamin K antagonist therapy for treatment of major bleeding and/or surgical procedures (12/27/2012)Urgent reversal of acquired coagulation factor deficiency induced by Vitamin K antagonist (VKA, e.g., warfarin) therapy in adult patients with acute major bleeding. 04/29/2013  (04/29/2020)
ramucirumab (Cyramza)Treatment of gastric cancer (2/16/2012)Treatment of advanced gastric cancer or gastro-esophageal junction adenocarcinoma, as a single-agent after prior fluoropyrimidine-or platinum-containing therapy. 04/21/2014  (04/21/2021)
ramucirumab (Cyramza)Treatment of gastric cancer (2/16/2012)Treatment of advanced gastric or gastro-esophageal junction adenocarcinoma, as a single agent or in combination with paclitaxel, after prior fluoropyrimidine- or platinium-containing chemotherapy. 11/05/2014  (11/05/2021)
riociguat (Adempas)Treatment of chronic thromboembolic pulmonary hypertension (9/19/2013)Treatment of adults with persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) WHO Group 4, after surgical treatment, or inoperable CTEPH, to improve exercise capacity and WHO functional class 10/08/2013  (10/08/2020)
riociguat (Adempas)Treatment of pulmonary arterial hypertension (9/19/2013)Treatment of adults with pulmonary arterial hypertension (PAH) WHO Group 1, to improve exercise capacity, WHO functional class and to delay clinical worsening. 10/08/2013  (10/08/2020)
romidepsin (Istodax)Treatment of non-Hodgkin T-cell lymphomas (9/30/2004)Treatment of peripheral T-cell lymphoma (PTCL) in patients who have received at least one prior therapy 06/16/2011  (06/16/2018)
romidepsin (Istodax)Treatment of non-Hodgkin T-cell lymphomas (9/30/2004)Treatment of cutaneous T-cell lymphoma (CTCL) in patients who have received at least one prior systemic therapy 11/05/2009  (11/05/2016)
temozolomide (Temodar)Treatment of recurrent malignant glioma (10/5/1998)Treatment of adult patients with newly diagnosed glioblastoma multiforme concomitatly with radiotherapy and then as maintenance treatment 03/15/2005  (03/15/2012)
temozolomide (Temodar)Treatment of recurrent malignant glioma (10/5/1998)Treatment of adult patients with refractory anaplastic astrocytoma, i.e., patients at first relapse who have experienced disease progression on a drug regimen containing a nitrosourea and procarbazine 08/11/1999 (08/11/2006) 
trametinib and dabrafenib (Mekinist And Tafinlar)Treatment of Stage IIb through IV melanoma (9/20/2012)TAFINLAR (dabrafenib) in combination with trametinib for treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for TAFINLAR in combination with trametinib. 01/09/2014  (01/09/2021)
trametinib and dabrafenib (Mekinist And Tafinlar)Treatment of Stage IIb through IV melanoma (9/20/2012)MEKINIST (trametinib) in combination with dabrafenib for treatment of patients with unresectable or metastatic melanoma with BRAF V600E or V600K mutations as detected by an FDA-approved test. This indication is based on the demonstration of durable response rate. Improvement in disease-related symptoms or overall survival has not been demonstrated for MEKINIST in combination with dabrafenib. 01/08/2014  (01/08/2021)