Original Article
`
`Trends in FDA drug approvals over last 2 decades: An
`observational study
`Angelika Batta1, Bhupinder Singh Kalra1, Raj Khirasaria2
`1Department of Pharmacology, Maulana Azad Medical College, 2Medical Affairs, Sanofi Genzyme India, Saket District Center,
`Saket, New Delhi, India
`
`AbstrAct
`Introduction: The discovery of novel drugs is critical for pharmaceutical research and development as well as for patient treatment.
`Repurposing existing drugs that may have anticipated effects as potential candidate is one way to meet this important goal. Systematic
`investigation and comprehensive analysis of approved drugs could provide valuable insights into trends in the discovery and may
`contribute to further discovery of newer drugs systematically. Food and drug administration (FDA’s) Center for Drug Evaluation and
`Research (CDER) every year summarizes novel drugs, some of which are truly innovative and help in advancing clinical care. This
`study was conducted to find a trend in drug approvals by FDA in the last 2 decades. Awareness of these new drugs amongst the
`primary care physicians is also crucial as they have been prescribing these agents in the past. Methodology: In this cross‑sectional
`study, we collected, surveyed, and analyzed drugs approved by U.S. Food and Drug Administration (USFDA) from the year 2000 till
`2017 identified from ClinicalTrials.gov and online database of FDA. Drugs approved every year were assessed for total number, class
`of drug, indication, and category of approval. Type of accelerated regulatory pathways and reasons for speedy approvals every year
`were also studied. Microsoft Office Excel 2007 was used for tabulation and analysis. Results: Total 209 were approved from 2000
`to 2008. Out of these 9.09% were indicated for cardiovascular disorders and 12.91% for neurological disorders. Antibiotics (5.26%)
`and antivirals (5.74%) were least contributed, whereas anticancer drugs (11.96%) and biologics (7.17%) approval remained constant.
`Whereas, out of three hundred and two drugs approved during 2009‑‑2017, 5.29% were for cardiovascular disorders, 9.93% for
`neurological disorders. Antibiotics (5.29%) and antivirals (5.96%) were least in number, whereas anticancer drugs (17.54%) and
`biologics (15.56%) approval took a steep rise in these years. Also, a wide variation in the number and category of approval was
`observed over a period of years. The use of fast track, accelerated approval, and priority review programs have also been steadily
`increasing since 2000. Conclusion: There has been a steady rate of introduction of new drugs by CDER over the last two decades.
`Expedited approval of anticancer and biologics is seen as recent trend in drug development. Relatively, slow progress in approval of
`drugs for neurological disorders (depression, psychosis, multiple sclerosis, etc.) and lifestyle diseases like obesity, atherosclerosis,
`diabetes, etc., were seen. These findings reflect more emphasis being laid down in research for anticancer drugs and biologics.
`
`Keywords: Drug approval, drug discovery and development, USFDA
`
`History and Introduction
`
`Since its inception as a Food and Drug Administration (FDA)
`in 1930, FDA is serving as a gatekeeper for promoting safe and
`effective drugs. After 1962 Amendments to the federal Food
`
`Address for correspondence: Dr. Bhupinder Singh Kalra,
`Department of Pharmacology, Maulana Azad Medical College,
`Bahadur Shah Zafar Marg, New Delhi ‑ 110 002, India.
`E‑mail: drbskalra@gmail.com
`Revised: 14‑11‑2019
`Received: 23‑07‑2019
`
`Accepted: 18‑11‑2019
`Published: 28‑01‑2020
`
`Access this article online
`Quick Response Code:
`
`Website:
`www.jfmpc.com
`
`Drug and Cosmetic Act (FD and C), well‑controlled trial became
`standard of evidence which contributed to evaluation of new
`drugs in terms of efficacy and safety.[1,2]
`
`First federal drug law was passed by Congress in 1906 which
`prohibited misbranded and adulterated drugs apart from foods
`and drinks.[1] Then in 1938, Congress passed the federal which
`ensures that drug is safe before entering the market.[1] After
`Kefauver‑‑Harris Drug Amendment in 1962, not only safety,
`
`This is an open access journal, and articles are distributed under the terms of the Creative
`Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to
`remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is
`given and the new creations are licensed under the identical terms.
`
`For reprints contact: reprints@medknow.com
`
`DOI:
`10.4103/jfmpc.jfmpc_578_19
`
`How to cite this article: Batta A, Kalra BS, Khirasaria R. Trends in FDA
`drug approvals over last 2 decades: An observational study. J Family
`Med Prim Care 2020;9:105-14.
`
`© 2020 Journal of Family Medicine and Primary Care | Published by Wolters Kluwer - Medknow
`
`105
`
`Mylan Exhibit 1155
`Mylan v. Regeneron, IPR2021-00881
`Page 1
`
`

`

`but efficacy also became an important parameter before market
`authorization.[3] In 1966, the drug division of FDA mentioned in
`FD and C Act was reorganized to office of new drugs which started
`reviewing new drug applications.[2] In 1982, bureau of biologics
`was merged with it. In 1987, two different entities Center for Drug
`Evaluation and Research (CDER) and Centre for Biologics and
`Evaluation Research (CBER) were formed.[4] Originally; CDER was
`composed of six offices, now CDER is comprised of 13 offices.
`Today, CDER is serving as a consumer watchdog for thousands of
`drugs available in the market by supporting innovation and thereby
`improving treatment for patients.
`
`Other notable milestones was Orphan drug Act, 1983 which
`encourages research and development of drugs for rare
`diseases.[1] This act also offers financial incentive, tax credits for
`clinical research cost for 7 years of marketing exclusivity. Access
`to generic prescribing became an important area to cut down
`the cost for common man. The 1984 act (Hatch‑‑Waxman Act)
`encourages production of generics while protecting rights of brand
`name manufacturers.[2] In 1999, Clinical Trials.gov was formed to
`give information of recent clinical research to patients regarding
`ongoing promising therapies.[2] In 2004, “Innovation or Stagnation:
`Challenge and Opportunity on the Critical Path to New Medical
`Products” was released by FDA which highlighted collective action
`needed to transform the development, evaluation, and manufacture
`of medical products.[1,2] Since then, consistent reformations have
`been incorporated as per requirements and patient safety.
`
`Seeing rapid drug approvals in the recent years, we planned to
`study the trends in novel drug approvals by FDA over the past
`18 years and evaluate reasons for the same. Also, knowledge of
`these novel agents is prudent for primary care physicians who
`under the influence of key opinion leaders are adopting and
`prescribing these drugs.
`
`Methodology
`
`Data for the study were collected from online database of FDA
`under the category of novel drug approvals from the year 2000 till
`2017. CDER issues an annual report which gives a list of all new
`drugs approved during a particular year. Also, any new indication
`of an already FDA approved drug is mentioned.
`
`All the drugs listed in the drug summary of respective year
`were segregated for parameters: Number of drug approved
`per year, pharmaceutical class of drug, indication for use in
`patient population, and type of approval received or combined
`expedited approvals.
`
`Also, literature search was conducted in electronic databases
`like PubMed, clinicaltrials.gov, Google scholar, and Cochrane
`database to corroborate evidence which led to approval of drugs.
`
`Statistical analysis
`Data were entered in MS Excel sheet 2007 for tabulation and
`analysis. Descriptive statistics was used for analysis.
`
`Results
`
`Trends in drug approval in last 18 years are as
`follows
`2000‑‑2008: A total number of drugs approved were 209. Out
`of these, 9.09% of drugs like fondaparinux, ranolazine, etc.,
`were indicated for cardiovascular disorders. 12.91% of drugs
`were approved for neurological disorders namely rivastigmine,
`aripiprazole, etc., Antibiotics (5.26%) and antivirals (5.74%)
`were least contributed, anticancer drugs (11.96%) and
`biologics (7.17%) approval remained constant during these
`years.[5] These results reflect that less number of Investigational
`New Drug Applications (INDA) are being filed pertaining to
`antibiotic/antiviral category. It could be because of research and
`developments of pharmaceutical giants are focused on other
`categories of drugs or failure of New Chemical Entity (NCE)
`during development. Some landmark drugs during this period
`are mentioned in Table 1.
`
`2009‑‑2017: Total number of drugs approved was 302. Out of
`these, 5.29% of drugs like prasugrel, rivaroxaban, etc., were
`indicated for cardiovascular disorders. This is relatively less as
`compared to previous years, i.e. a fall of 4% approximately.
`9.93% of drugs were indicated for neurological disorders namely
`perampanel, pimavanserine, etc. In neurological indications,
`again a fall of 3% approximately is observed as compared
`to previous years. Antibiotics (5.29%) and antivirals (5.96%)
`were least contributed, whereas anticancer drugs (17.54%) and
`biologics (15.56%) approval took a steep rise. Some important
`drugs approved during these years are highlighted in Table 2. We
`observed that limited numbers of drugs are being approved for
`lifestyle disorders like diabetes, obesity, cardiovascular disorders,
`etc., Presently, more number of anticancer drugs and biologics
`are being approved compared to drugs required for lifestyle
`diseases, antibiotics, respiratory disorders, etc.
`
`Is it discovery‑driven or market‑driven approach?? The answer
`to this query is difficult to decipher. Number of new cancer
`patients will rise to 23.6 million by 2030. In 2018 alone, estimated
`1,735,350 new cancer patients were diagnosed in U.S. and 609,640
`people have died.[6] Diabetes is not behind in the race. There will
`be 54% rise in number of diabetic patients in America by 2030
`and total deaths due to diabetes will be increased by 38%. Annual
`and societal costs will reach to $622 billion by 2030.[7] Table 3, 4
`and 5 highlights list of anticancer drugs, biologics, and antiviral
`drugs approved, respectively.
`
`The driving force to this increase in new drug approvals can be
`attributed to a number of factors:
`
`1. Increased New Drug Applications
`The number of New Drug Applications (NDA’s)/Biologic
`License Applications (BLA’s) filed per year has increased slightly
`over the past decade. Between 2000 and 2010, an average of 23
`approvals was made per year, compared with 35 approvals in
`2011, 39 in 2012, 45 in 2015, and 46 in 2017. 59 novel agents
`
`Journal of Family Medicine and Primary Care
`
`106
`
`Volume 9 : Issue 1 : January 2020
`
`Batta, et al.: FDA approvals
`
`Mylan Exhibit 1155
`Mylan v. Regeneron, IPR2021-00881
`Page 2
`
`

`

`Year Drug
`2000 Linezolid
`
`Insulin glargine
`Insulin aspart
`Bivalirudin
`
`Oxcarbazepine
`Rivastigmine tartarate
`2001 Fondaparinux sodium
`Ziprasidone HCL
`2002 Voriconazole
`Fulvestrant
`
`Oxaliplatin
`
`Ezetimibe
`
`Aripiprazole
`2003 Gefitinib
`
`Bortezomib
`Aprepitant
`Rosuvastatin calcium
`
`Memantine HCL
`
`Azacitidine
`
`Cetuximab
`Bevacizumab
`
`Insulin detemir
`2005
`2006 Decitabine
`
`Review type
`P
`
`S
`S
`S
`
`S
`S
`P
`S
`S
`S
`
`P
`
`S
`
`S
`P
`
`P, O
`P
`S
`
`S
`
`P, O
`
`P, O
`
`P
`P
`
`S
`S, O
`
`Table 1: List of some landmark drugs between 2000 and
`2010
`Indication
`Skin and skin structure
`infections
`DM‑1
`DM‑1
`Unstable angina in
`patients undergoing
`PTCA
`Partial seizures
`Alzheimer’s dementia
`Prophylaxis of DVT
`Schizophrenia
`Invasive aspergillosis
`Metastatic breast
`carcinoma
`Metastatic carcinoma of
`colon or rectum
`Primary
`hypercholesterolemia
`Schizophrenia
`Metastatic nonsmall cell
`lung carcinoma
`Multiple myeloma
`CINV
`Primary
`hypercholesterolemia
`Alzheimer’s type
`dementia
`2004 Pemetrexed Disodium Malignant pleural
`mesothelioma
`Myelodysplastic
`syndrome and CML
`Colorectal carcinoma
`Metastatic carcinoma of
`the colon and rectum
`DM‑1&2
`Myelodysplastic
`syndrome
`Smoking cessation
`Chronic angina
`Hypertension
`ITP
`BHP
`Malaria
`
`P
`S
`S
`P, O
`S
`P, O
`
`Varenicline
`Ranolazine
`2007 Nebivolol
`2008 Romiplostim
`Silodosin
`2009 Artemether 20 mg
`lumefantrine 120 mg
`Stroke in patients of
`2010 Dabigatran etexilate
`atrial fibrillation
`mesylate
`# P ‑ Priority review, S ‑ Standard review, O ‑ Orphan designation. Standard Review ‑Products that do
`not qualify for priority review
`
`P
`
`have been approved in 2018.[8] (An application may have been
`filed in 1 year and approved in another). An increase in the
`number of new drug filings could potentially affect the number
`of approvals in a given year. Figure 1 depicts the total number
`of new drugs approved every year.
`
`2. First in Class and Orphan Approvals
`In recent years, there has also been a shift in the types of new
`drugs that are submitted to the FDA for approval: CDER had
`
`Year Drug
`2011 Rivaroxaban
`
`Table 2: List of some landmark drugs between 2011 and
`2018
`Indication
`To decrease PE, DVT
`following knee or hip
`replacement surgery
`Hypertension
`Azilsartanmedoxomil
`Restless legs syndrome
`Gabapentin enacarbil
`2014 Ceftolozane/tazobactam Intraabdominal infections
`and UTI
`Unresectable melanoma O, B, P, A
`Pembrolizumab
`Hepatitis‑C
`F, P
`2015 Daclatasvir
`For high cholesterol
`O
`Evolocumab
`Hepatitis‑C
`F, B, P
`2016 Sofusbuvir; Velpatasvir
`2017 L‑glutamine oral powder Sickle cell disease
`# P ‑ Priority review, S ‑ Standard review, O ‑ Orphan designation, F‑ Fast track
`
`Review type
`S
`
`S
`S
`F, P
`
`Figure 1: Year-wise new drug approvals
`
`20 first in class approvals (agents with a unique mechanism
`of action) in 2012, 16 in 2015, and 15 in 2017. Those are
`relatively high numbers; between 1987 and 2011, FDA first
`in class approvals was fairly steady and ranged from roughly
`3 to 15 agents per year (note that these ranges are for new
`molecular entities (NMEs) only, not NMEs and biologics).
`CDER had 18 orphan approvals in 2017, 9 in 2016, and 21
`orphan approvals in 2015 as compared to 5 orphan approvals
`on an average from 2000 to 2010. Those are some of the
`highest numbers in recent years; hence, the number of FDA
`orphan approvals has been steadily increasing since 2000. So,
`the unique and new qualities of the drugs submitted to the
`FDA in 2017 and 2015 may have contributed to the increase
`in CDER approvals. Figure 2 shows number of orphan drugs
`approved each year.
`
`3. Increase in first cycle approvals:
`From 2011 to 2016, CDER approved 204 novel drugs, of which
`166 (81%) were approved on the first cycle. In 2017, 39 of the
`46 novel drugs (85%) were under “first cycle” of review.[9] The
`rate for 2017 is consistent with this average. This high proportion
`of first cycle approval reflects the extensive discussions between
`CDER staff and drug developers that go on during drug
`
`Journal of Family Medicine and Primary Care
`
`107
`
`Volume 9 : Issue 1 : January 2020
`
`Batta, et al.: FDA approvals
`
`Mylan Exhibit 1155
`Mylan v. Regeneron, IPR2021-00881
`Page 3
`
`

`

`Year‑wise
`2000
`
`No:
`2
`
`2001
`2002
`
`2003
`
`2004
`
`2005
`
`2006
`
`2007
`
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`
`1
`2
`
`3
`
`4
`
`2
`
`4
`
`4
`
`3
`
`4
`
`2
`
`6
`
`9
`
`7
`
`Table 3: List of anticancer agents approved in last 2 decades
`Anticancer agents
`Indication
`Advanced prostate cancer
`Acute promyelocytic leukemia
`CML
`Metastatic cancer of colon or rectum
`Meta breast cancer
`Meta nonsmall cell lung cancer
`Multiple myeloma
`Advanced prostate cancer
`Malignant pleural mesothelioma
`Myelodysplastic syndrome and CML
`Nonsmall‑cell lung cancer
`Relapsed or refractory ALL
`T‑cell ALL
`Advanced RCC
`Gastrointestinal stromal tumor
`MDS
`CML
`Cutaneous T‑cell lymphoma
`Breast cancer
`RCC
`Meta breast cancer
`CML
`CLL
`Pheochromocytoma
`Prostate cancer
`Advanced RCC
`Relapsed or refractory peripheral t‑cell lymphoma
`Advanced RCC
`Cutaneous T‑cell lymphoma
`Prostate cancer
`Metastatic breast cancer
`Hodgkin’s lymphoma and ALCL
`Meta medullary thyroid cancer
`metastatic breast cancer
`Nonsmall cell lung caner
`Metastatic melanoma
`Prostate cancer
`Basal cell carcinoma
`Multiple myeloma
`Cancer chemotherapy‑induced severe neutropenia
`Prostate cancer
`CML
`Colorectal cancer
`CML
`Medullary thyroid cancer
`CML
`Multiple myeloma
`Metastatic breast cancer
`Metastatic prostate cancer
`Melanoma
`Melanoma
`Metastatic nonsmall cell lung cancer
`Mantle cell lymphoma
`
`Drug
`Triptorelin pamoate
`Arsenic trioxide
`Imatinib mesylate
`Oxaliplatin
`Fulvestrant
`Gefitinib
`Bortezomib
`Abarelix
`Pemetrexed disodium
`Azacitidine
`Erlotinib HCl
`Clofarabine
`Nelarabine
`Sorafenib tosylate
`Sunitinib malate
`Decitabine
`Dasatinib
`Vorinostat
`Lapatinib
`Tesirolimus
`Ixabepilone
`Nilotinib
`Bendamustine hydrochloride
`Iobenuane
`Degarelix
`Everolimus
`Pralatrexate injection
`Pazopanib tablet
`Romidepsin for infusion
`Cabazitaxel
`eribulin mesylate
`Brentuximab vedotin
`Vandetanib
`Eribulin mesylate
`Crizotinib
`Vemuranfenib
`Abiraterone acetate
`Vismodegib
`Carfilzomib
`TBO‑filgrastim
`Enzalutamide
`Bosutinib
`Regorafenib
`Omacetaxine mepesuccinate
`Cabozantinib
`Ponatinib
`Pomalidomide
`Ado‑trastuzumab emtansine
`Radium Ra 223 dichloride
`Dabrafenib
`Trametinib
`Afatinib
`Ibrutinib
`
`Review type
`
`S
`P, O
`P, O
`P
`S
`P
`P, O
`P
`P, O
`P, O
`P
`P, O
`P, O
`P, O
`P
`S, O
`P, O
`P, O
`P
`P, O
`P
`S, O
`P, O
`P, O
`S
`P
`P, O
`S
`S
`P
`P
`P, O
`P, O
`P, O
`P, O
`P, O
`P
`P
`O, F, A
`
`F, P
`O
`F, P
`O, A
`O, F, P
`F, O, P, A
`O, F, A
`F, P
`F, P
`O, F
`O, F
`O, F, P
`O, F, B, P, A
`
`Contd...
`
`Journal of Family Medicine and Primary Care
`
`108
`
`Volume 9 : Issue 1 : January 2020
`
`Batta, et al.: FDA approvals
`
`Mylan Exhibit 1155
`Mylan v. Regeneron, IPR2021-00881
`Page 4
`
`

`

`Year‑wise
`2014
`
`2015
`
`No:
`4
`
`10
`
`Table 3: Contd...
`Anticancer agents
`Indication
`Drug
`Advanced ovarian cancer.
`Olaparib
`Blood cancer
`Idelalisib
`peripheral T‑cell lymphoma
`Belinostat
`Nonsmall cell lung cancer
`Ceritinib
`ALK‑positive lung cancer
`Alectinib
`Multiple myeloma
`Ixazomib
`Nonsmall cell lung cancer
`Osimertinib
`Advanced melanoma
`Cobimetinib
`Soft tissue sarcomas
`Trabectedin
`Advanced colorectal cancer
`Trifluridine and tipiracil
`BCC
`Sonidegib
`Multiple myeloma
`Panobinostat
`Refractory thyroid cancer
`Lenvatinib
`Metastatic breast cancer
`Palbociclib
`Lymphocytic leukemia
`Venetoclax
`Ovarian cancer
`Rucaparib
`Mantle cell lymphoma
`Acalabrutinib
`Metastatic breast cancers
`Abemaciclib
`Relapsed follicular lymphoma
`Copanlisib
`Refractory AML
`Enasidenib
`Reduce the risk of breast cancer returning
`Neratinib maleate
`AML
`Midostaurin
`(ALK)‑positive nonsmall cell lung cancer
`Brigatinib
`recurrent epithelial ovarian, fallopian tube, peritoneal cancer
`Niraparib
`advanced breast cancer
`Ribociclib
`# P ‑ Priority review, S ‑ Standard review, O ‑ Orphan designation, F‑ Fast track, A‑ Accelerated review, B‑ Break through review
`
`2016
`
`2017
`
`2
`
`9
`
`Review type
`
`O, P A
`O, F, B, P, A
`O, F, P, A
`O, B, P, A
`O, B, P, A
`P, O
`P, O
`P, O
`P, O
`S
`S
`P, O
`P, O
`P
`P, O
`P, O
`P, O
`P
`P, O
`P, O
`S
`P, O
`P, O
`P, O
`P
`
`sclerosis, valbenazine for tardive dyskinesia etc.; 17 (37%) were
`designated as breakthrough therapies like ribociclib for breast
`cancer, niraparib for ovarian cancer, etc.; 28 (61%) were given
`priority review, e.g. dupilumab for atopic dermatitis, midostaurin
`for acute myeloid leukemia, etc.; and 6 (13%) received accelerated
`approval like benznidazole for Chagas disease. Use of these
`expedited programs has been steadily increasing since the year
`2000.
`
`The breakthrough therapy designation was created in 2012, so it
`has only recently begun to take effect. But use of the designation
`is increasing: there were 17 approvals in 2017 as compared to 3
`approvals in 2013. In other words, expedited programs increase
`the speed at which new drugs are developed and reviewed, which
`could contribute to the number of CDER approvals in recent
`years. Accelerated regulatory pathways for the development of
`new drugs in the U.S., Europe, and Japan intend to bring novel
`treatments to patients more quickly. These have multiplied in the
`recent years, offering opportunities, benefits, and challenges for
`developers, patients, regulators, and payers.[11]
`
`4. Therapeutic Area
`Between 2000 and 2017, cancer therapeutics generated more
`fast track, accelerated, and priority approvals than any other
`therapeutic area.[12‑14] This fact is particularly interesting because
`in 2015, oncology was the single largest therapeutic area for which
`new drugs were approved. Again there is a hike in 2017, 12 out
`
`Figure 2: Number of orphan drugs approved over a period of years
`
`development. Hence, it is important that an application contains
`all the relevant information which the CDER needs to know
`and fully review.
`
`Current FDA Expedited Approval Programs: Additionally,
`the manner in which the FDA works with industry on new
`drug development programs has been evolving. The FDA now
`offers four paths for expedited development and/or review,
`which can be used singly or in conjunction with each other:
`fast track, breakthrough therapy, priority review, and accelerated
`approval.[10] In 2017, 18 of the 46 approved novel drugs (39%)
`had fast track designation namely ocrelizumab for multiple
`
`Journal of Family Medicine and Primary Care
`
`109
`
`Volume 9 : Issue 1 : January 2020
`
`Batta, et al.: FDA approvals
`
`Mylan Exhibit 1155
`Mylan v. Regeneron, IPR2021-00881
`Page 5
`
`

`

`Table 4: List of biologics approved in last 2 decades
`Biologics
`
`Year‑wise No: Drug
`2000
`1
`GemtuzumabOzogamicin
`2001
`0
`2002
`0
`2003
`0
`2004
`5
`
`2005
`
`2006
`
`2007
`2008
`
`2009
`
`2010
`
`2011
`
`2012
`
`2013
`2014
`
`2015
`
`2016
`
`2
`
`4
`
`1
`2
`
`4
`
`2
`
`3
`
`3
`
`1
`7
`
`9
`
`7
`
`Cetuximab
`Bevacizumab
`Technetium 99m Tc scintigraphicimagingFanolesomab
`Natalizumab
`Palifermin
`Galsulfase
`Abatacept
`Alglucosidase alfa
`Ranibizumab
`Idursulfase
`Panitumumab
`Eculizumab
`Rilonacept
`Certolizumab pegol
`Golimumab
`Canakinumab
`Ustekinumab
`Ofatumumab
`Denosumab to
`tocilizumab
`Belimumab
`Ipilimumab
`Belatacept
`Pertuzumab
`Ziv‑aflibercept
`Raxibacumab
`Obinutuzumab
`Blinatumomab
`Nivolumab
`Pembrolizumab
`Peginterferon beta‑1a
`Vedolizumab
`Siltuximab
`Ramucirumab
`Elotuzumab
`Necitumumab
`Daratumumab
`Mepolizumab
`Idarucizumab
`Evolocumab
`Alirocumab
`Dinutuximab
`Secukinumab
`Obiltoxaximab
`Ixekizumab
`Reslizumab
`Atezolizumab
`Daclizumab
`Olaratumab
`Bezlotoxumab
`
`Indication
`AML
`
`Colorectal cancer
`Metastatic cancer of the colon and rectum
`Scintigraphic imaging
`Multiple sclerosis
`Hematologic malignancies
`Mucopolysaccharidosis VI
`RA
`Pompe disease
`Neovascular (wet) ARMD
`Mucopolysaccharidosis II
`EGFR‑expressing meta colorectal cancer
`PNH
`CAPS
`Crohn’s disease
`RA, psoriatic arthritis
`Cryopyrin‑associated periodic syndrome
`Psoriasis
`CLL
`Osteoporosis in postmenopausal women
`Severe RA
`Autoantibody‑positive lupus
`Metastatic melanoma
`Prevent organ rejection
`metastatic breast cancer
`Colorectal cancer
`Inhalational anthrax
`CLL
`B‑cell ALL
`Metastatic melanoma
`Unresectable melanoma
`Multiple sclerosis
`Ulcerative colitis and Cr D
`Castleman’s disease
`Stomach cancer
`Multiple myeloma
`squamous non‑small cell lung cancer
`Multiple myeloma
`Asthma
`Reverse dabigatran’s effects
`High cholesterol
`High cholesterol
`Neuroblastoma
`Plaque psoriasis
`Inhalational anthrax
`Moderate‑to‑severe plaque psoriasis
`Severe asthma
`Urothelial carcinoma,
`Multiple sclerosis
`Soft tissue sarcoma
`Clostridium difficile infection
`
`Review type
`
`P, O
`
`P
`P
`S
`P
`P
`P, O
`P
`P, O
`P
`P, O
`P
`P, O
`P, O
`S
`S
`P, O
`S
`P, O
`S
`S
`P
`P, O
`S, O
`P
`P
`O, F, P
`O, B, P
`O, B, P, A
`O, F, B, P, A
`O, B, P, A
`
`F, P
`O, P
`O, F, P
`O, P, B
`O, F
`O, F, B, P, A
`
`O, B, P, A
`O
`
`O, P
`S
`S, O
`S
`S
`P
`S
`P, O
`P
`
`Contd...
`
`Journal of Family Medicine and Primary Care
`
`110
`
`Volume 9 : Issue 1 : January 2020
`
`Batta, et al.: FDA approvals
`
`Mylan Exhibit 1155
`Mylan v. Regeneron, IPR2021-00881
`Page 6
`
`

`

`Table 4: Contd...
`Biologics
`
`Review type
`
`Indication
`Year‑wise No: Drug
`bleeding episodes in patients with hemophilia A
`2017
`11
`Emicizumab
`mucopolysaccharidosis type VII (MPS VII)
`Vestronidase alfa
`asthma with an eosinophilic phenotype
`Benralizumab
`Refractory ALL
`Inotuzumabozogamicin
`Mod to severe plaque psoriasis
`Guselkumab
`RA
`Sarilumab
`Metastatic urothelial cancer
`Durvalumab
`Multiple sclerosis
`Ocrelizumab
`atopic dermatitis
`Dupilumab
`Merkel cell cancer
`Avelumab
`Moderate‑to‑severe plaque psoriasis
`Brodalumab
`# P ‑ Priority review, S ‑ Standard review, O ‑ Orphan designation, F‑ Fast track, A‑ Accelerated review, B‑ Break through review
`
`P, O
`P, O
`S
`P, O
`P
`S
`P
`P
`P
`P, O
`S
`
`Figure 3: Trend in anticancer drug approval over a period of years
`
`of 46 drugs are anticancer agents. Perhaps in 2018, 23 out of 55
`are anticancer drugs.[5] The constant need for cancer therapeutics,
`coupled with their proven track record for obtaining accelerated
`approval (based on surrogate endpoints), may have contributed
`to their approval rate in recent years. Table 3 highlights list of
`approved anticancer drugs. Figure 3 depicts trend of the same.
`
`Various categories in drug approval process are as follows:
`
`First-in-class
`A drug with, first of its kind mechanism of action and totally
`different from already available set of drugs for a medical
`condition belongs to first in Class drug approval process. Some
`notable approvals in this category include ocrelizumab for
`multiple sclerosis (2017), palbociclib (2015) for metastatic breast
`cancer, etc.
`
`Drugs for rare diseases (orphan drugs)
`Drugs approved for a small population of patients, i.e. less
`than 200,000 people are known as orphan drugs. Rare disease
`patients have very limited options for their treatment. Examples
`of orphan drugs are mentioned in Tables 1, 3, and 4.
`
`Figure 4: Drug designation summary overview from 2011 to 2017
`
`First cycle approval
`Drug approval process which consists of only one cycle of review
`belongs to this category. Maximum numbers of drugs get approval
`under this designation, e.g. Deflazacort (2017) for Duchenne
`muscular dystrophy, evolocumab (2015) for hypercholesteremia.
`
`Combined expedited approval methods: CDER applies
`innovative regulatory approval methods like fast track,
`accelerated approval, priority review, breakthrough approval
`and expanded access programs [Table 6].[10,15] Many times,
`NMEs require more than one drug approval process from the
`above‑mentioned categories. These help in expediting timelines
`from research and development to availability in the market.
`Examples of drugs approved under more than one category
`are mentioned in Tables 3, 4, and 5. Figure 4 gives an overview
`of drug designation summary from 2011 to 2017. In March
`2017, the US FDA has also introduced the new Regenerative
`Medicine Advanced Therapy (RMAT) which is a new program to
`facilitate and expedite development and review of regenerative
`medicines.[16]
`
`Discussion
`
`CDER and pharmaceutical industry work together in bringing
`innovation in research and development of new drugs. Starting
`
`Journal of Family Medicine and Primary Care
`
`111
`
`Volume 9 : Issue 1 : January 2020
`
`Batta, et al.: FDA approvals
`
`Mylan Exhibit 1155
`Mylan v. Regeneron, IPR2021-00881
`Page 7
`
`

`

`Table 5: List of antiviral agents approved in last 2
`decades
`Antiviral agents
`
`Review
`type
`Indication
`P
`HIV‑1
`P
`HIV‑1
`Ch Hep B P
`HIV‑1
`P
`HIV‑1
`P
`HIV‑1
`S
`
`P
`HIV‑1
`Ch Hep B P
`HIV
`P
`Chr Hep B S
`HIV‑1
`P
`HIV‑1
`P
`HIV‑1
`P
`
`HIV‑1
`HCV
`HCV
`HIV‑1
`
`S
`P
`P
`F
`
`F, P
`HIV‑1
`Simeprevir F, P
`Sofosbuvir F, B, P
`HCV
`F, B, P
`HCV
`F, B, P
`
`Year No: Drug
`2000
`1 Lopinavir, ritonavir
`2001
`1 Tenofovir disoproxil fumarate
`2002
`1 Adefovir dipivoxil
`2003
`3 Enfuvirtide
`Atazanavir
`Emtricitabine
`
`2004
`2005
`
`2006
`
`2007
`
`2008
`2009
`2010
`2011
`
`2012
`
`2013
`
`2014
`
`0
`2 Tipranavir
`Entecavir
`2 Darunavir
`Telbivudine
`2 Maraviroc
`Raltegravir potassium
`1 Etravirine
`0
`0
`3 Rilpivirine
`Telaprevir
`Boceprevir
`1 Elvitegravir, cobicistat, emtricitabine,
`tenofovir disoproxil, fumarate
`3 Dolutegravir
`HCV
`HCV
`3 Ledipasvir/sofosbuvir
`Ombitasvir, paritaprevir, and ritonavir
`tablets copackaged with dasabuvir
`tablets
`Peramivir
`
`2015
`
`2016
`
`2017
`
`2 A fixed‑dose combination tablet
`containing elvitegravir, cobicistat,
`emtricitabine and tenofovir
`alafenamide
`Daclatasvir
`2 Elbasvir; grazoprevir
`sofosbuvir; velpatasvir
`2 Glecaprevir and pibrentasvir
`Sofosbuvir, velpatasvir and
`voxilaprevir
`# P ‑ Priority review, S ‑ Standard review, O ‑ Orphan designation, F‑ Fast track, A‑ Accelerated review,
`B‑ Break through review
`
`influenza
`infection
`HIV‑1
`
`HCV
`HCV
`HCV
`Ch HCV
`Ch HCV
`
`F
`
`S
`
`P
`P
`P
`P
`P
`
`Table 6: Expedited drug approval methods
`Fast track approval
`Drugs with the potential to address unmet medical needs. Fast track
`speeds new drug development and review, either
`by increasing the level of communication to drug developers
`or reviewing portions of a drug application ahead of the submission of
`the complete application
`Breakthrough approval
`Drugs with preliminary clinical evidence demonstrating that it may
`result in substantial improvement on at least one clinically significant
`endpoint (i.e., study result) over other available therapies for serious
`conditions.
`A breakthrough therapy designation includes all of the fast track
`program features, as well as more intensive FDA guidance on an
`efficient drug development program.
`Shorten the development time of a potential new therapy
`Priority review
`Drug could potentially provide a significant advance in medical care and
`set a target to review the drug within six months instead of the standard
`10 months.
`
`Accelerated approval
`Early approval of a drug for a serious or life‑threatening illness that
`offers a benefit over current treatments based on a “surrogate endpoint”
`(e.g., a laboratory measure) or other clinical measure that is considered
`reasonably likely to predict a clinical benefit of the drug. But, after
`approval, the drug must undergo additional testing to confirm that
`benefit. (Phase‑IV)
`
`knowledge from basic research and unmet medical needs are
`likely to provide market for pharmaceuticals. Right to Try Act,
`2017 may compromise patient’s safety in a hurry by giving
`access to new drugs.[18]
`
`Since the year 2000, there has been a steady rate of introduction
`of new drugs by CDER, out of which expedited approval
`of anticancer and biologics is seen as recent trend in drug
`development. But stringent norms have been followed in this
`process, i.e. without compromising the safety and quality which
`has indeed led to efficacious drugs coming up in the market.
`On the contrary, slow progress in approval of antiviral drugs
`especially anti HIV/Hepatitis C virus (HCV) and lifestyle diseases
`was seen. A total of 59 novel molecules have been approved in
`2018. Also, in 2019, due to expedited drug approval programs,
`trends are likely to remain the same. Is it because of change in
`prevalence of disease pattern or market‑driven profitability?
`There is a need to conduct studies to get some insight into
`changing trends in approvals over last 2 decades by FDA.
`
`from testing and manufacturing process to understanding of
`science of the disease, FDA provides complete guidance through
`CDER.
`
`CDER plays a crucial role in bringing innovation to drug
`development process approving new drugs and biological
`products. These include both new class of drug or drugs
`belonging to same class with few addition or deletions in
`the molecular structure.[17] FDA approval of a new drug is
`extremely challenging. Rate of drug approval is much higher
`than previous years. We also observed that medical needs
`and disease pattern are usually not changing drastically but
`
`This trend in drug approvals by U.S. Food and Drug
`Administration (USFDA) sooner or later will come in India as
`well, since there are no innovations from our side. However,
`considering the disease burden of our nation, which mostly
`comprises of infectious diseases like tuberculosis, malaria
`apart from cancer, diabetes, hypertension: novel agents being
`approved by USFDA every year do not suffice the unmet need
`of our country.
`
`Journal of Family Medicine and Primary Care
`
`112
`
`Volume 9 : Issue 1 : January 2020
`
`Batta, et al.: FDA approvals
`
`Mylan Exhibit 1155
`Mylan v. Regeneron, IPR2021-00881
`Page 8
`
`

`

`Nowadays, primary care is increasingly being promoted, by
`government sector and health funders worldwide, as the
`preferred setting for most health care for various reasons,
`such as increasing need, to stabilize health‑care costs, and to
`accommodate patient’s preference for care close to home.[19] So,
`it is prudent that primary care physicians should be well versed
`with new drug approval and its clinical applications. At the same
`time, it is difficult for them to keep track on such large number
`of drugs being approved by the USFDA every year. But among
`these drugs, certain drugs have clear cut indications in primary
`care like eluxadoline use in diarrhe