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Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
FDA looks to achieve near-record level of new drug approvals following slowdown in 2016.
The small number of new drug approvals in 2016-only 22 (1)-may have been an anomaly. As of Nov. 14, 2017, FDA’s Center for Drug Evaluation and Research (CDER) has approved 38 new drugs (2) and is on track to achieve numbers similar to the 41 approvals in 2014 (3) and 45 approvals in 2015 (4). The approved drugs include a number of firsts in terms of both drugs for untreated diseases and new modes of action. Nearly two-thirds were approved under one or more accelerated pathways and just over one-third were designated as orphan drugs.
Given the return to record-level FDA approvals, it is not surprising that most industry analysts predict strong growth in the market for APIs. Markets and Markets, for instance, predicts the global API market, including chemical and biologic branded and generic-drug substances, will expand at a compound annual growth rate of 6.3% from $157.95 billion in 2016 to $213.97 billion in 2021 (5). Market research firm Grand View Research predicts the value of the global API market will reach $239.8 billion by 2025 (6).
Growth is attributed to the aging of the world population with a concomitant rise in age-related diseases and an increase in lifestyle-induced conditions and cancer. Small-molecule APIs account for the greatest share of the market (6), which reflects the rate of approvals for drugs based on chemical and biologic APIs; in 2017 nearly 75% of the approved drugs as of November 14 were formulated with small-molecule APIs (2). Captive manufacturers held the greatest market share, but due to increased outsourcing of API manufacturing, contract manufacturers are expected to expand their share more rapidly in the coming years. Demand for generic APIs is also increasing rapidly (6).
Manufacturers continue to leverage the four expedited review and approval programs-Fast Track and Breakthrough Therapy Designations and Accelerated Approval and Priority Review processes-made possible with passage of the FDA Safety and Innovation Act (FDASIA) in 2012. FDA under Commissioner Scott Gottlieb is also committed to accelerating the approval of new drugs (7). Nearly two-thirds (24 out of 38, 63.2%) of the drugs approved in 2017 through mid-November were filed under at least one of these four programs. Of those 24 drugs, just over one-third qualified for two programs, and nearly 16% for three. Of the four programs, 22 drugs were approved under Priority Review, 14 as Breakthrough Therapies, eight with the Fast Track designation, and six with Accelerated Approval.
The Orphan Drug Act (ODA) was passed in January 1983 to encourage the development of drugs to treat rare diseases. Drugs intended to prevent, treat, or diagnose a disease/condition that occurs in less than 200,000 patients in the United States may be designated as an orphan drug. Developers also can receive tax credits for clinical research expenses and seven years of marketing exclusivity upon FDA approval. In the 10 years prior to passage of the ODA, the pharma industry commercialized only 10 products for rare diseases; since 1983, more than 450 orphan drug products have been approved for more than 600 indications (8). In addition, 60% of the 87 Breakthrough Therapies approved from January 2013 to Sept. 15, 2017 are indicated for rare diseases and accounted for 25% of the orphan drug approvals. Nearly 75% of orphan drugs received Priority Review.
In 2017, 13 of the 38 new drugs approved through November 14, or 34%, were classified as orphan drugs.
Of the types of diseases targeted by the 38 new drugs approved by FDA in 2017 through November 14, cancer accounted for the largest proportion. Drugs were approved for leukemia (9-11), urothelial carcinoma (12), mantle cell lymphoma (13), and lung (14), skin (15), breast (16-18), follicular lymphoma (19), and epithelial ovarian, fallopian tube, and primary peritoneal (20) cancers. Seven of these drugs are kinase inhibitors.
Nerlynx (neratinib maleate) is the first extended adjuvant therapy, a form of therapy that is taken after an initial treatment to further lower the risk of breast cancer returning. Two of the drugs were approved for treatment of acute myeloid leukemia (AML) with companion diagnostics. Idhifa (enasidenib), which is for treatment of adult patients with relapsed or refractory AML who have mutations in the IDH2 gene, was approved for use with the RealTime IDH2 Assay (9). Rydapt (midostaurin) from Novartis, a treatment for adult patients with newly diagnosed AML that have the FLT3 gene mutation, was approved for use with the LeukoStrat CDx FLT3 Mutation Assay (10).
Bavencia (avelumab), a monoclonal antibody (mAb), is the first treatment for metastatic Merkel cell carcinoma (MCC), a rare aggressive form of skin cancer (15).
A number of the new drugs approved in 2017 through November 14 are firsts in the treatment of rare diseases. Benznidazole is the first drug approved in the US for the treatment of Chagas disease, or American trypanosomiasis, a parasitic infection caused by Trypanosoma cruzi that can lead to serious heart illnesses and affect swallowing and digestion (21). Radicava (edaravone) is the first new treatment approved in the US in many years for the treatment of myotrophic lateral sclerosis (ALS), commonly referred to as Lou Gehrig’s disease (22).
Two drugs received the ninth and tenth rare pediatric disease priority review vouchers issued by FDA. Emflaza (deflazacort) is a corticosteroid for the treatment of Duchenne muscular dystrophy (DMD), a rare genetic disorder that causes progressive muscle deterioration and weakness and the first treatment approved for a wide range of patients with DMD (23). Brineura (cerliponase alfa), an enzyme replacement therapy, is the first FDA-approved treatment to slow loss of walking ability in symptomatic pediatric patients three years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase-1 (TPP1) deficiency and a form of Batten disease (24).
The mAb Ocrevus (ocrelizumab), which acts as a direct factor Xa inhibitor, is the first treatment approved for primary progressive multiple sclerosis (25). Bevyxxa (betrixaban) is the first treatment to prevent the development of deep vein thrombosis and pulmonary embolism blood clots in adults hospitalized with acute illnesses for extended periods of time (26). Ingrezza (valbenazine) is the first drug approved by FDA for the treatment of tardive dyskinesia a neurological disorder characterized by repetitive involuntary movements, usually of the jaw, lips, and tongue that is seen in patients that have been taking antipsychotic medications for schizophrenia, bipolar disorder, and depression for long durations (27).
In many cases, the new drugs approved in 2017 are the first treatments commercialized for diseases in 10 or more years. Tymlos (abaloparatide) is the first new bone building agent for postmenopausal women with osteoporosis in the US in nearly 15 years (28). Prevymis (letermovir) is the first new medicine for the prevention of cytomegalovirus infection and disease in adults receiving allogeneic hematopoietic stem cell transplants to be approved in 15 years (29). Austedo (deutetrabenazine) is the first new treatment option in nearly a decade for chorea associated with Huntington’s disease, a rare and fatal neurodegenerative disorder (30). Parsabiv (etelcalcetide) is the first therapy approved for the treatment of secondary hyperparathyroidism in adult patients with chronic kidney disease on hemodialysis in 12 years and the only calcimimetic that can be administered intravenously by the dialysis healthcare team at the end of the hemodialysis session (31).
Two of the approved drugs operate by new mechanisms of action. Vyzulta (latanoprostene bunod ophthalmic solution, 0.024%) is the first prostaglandin analog with nitric oxide as a metabolite to be approved for the reduction of intraocular pressure in patients with open-angle glaucoma or ocular hypertension (32). Solosec (secnidazole) is a next-generation 5-nitroimidazole antibiotic and the first and only single-dose oral therapy for bacterial vaginosis in adult women (compared to twice-per-day dosing for seven days) (33).
Although not approved by CDER and thus not appearing on its list of novel approved drugs (2), FDA, through the Center for Biologics Evaluation and Research, has approved gene therapies for the first time in 2017.
The first, Kymriah (tisagenlecleucel) from Novartis, was approved in August and is a chimeric antigen receptor (CAR) T-cell immunotherapy for the treatment of patients up to age 25 years with B-cell precursor acute lymphoblastic leukemia (34). Kymriah was approved under Priority Review with the Breakthrough Therapy designation.
At the same time, FDA expanded the approval of Actemra (tocilizumab) from Genentech for the treatment of patients two years of age or older with cytokine release syndrome that occurs with CAR T-cell therapy. Because of the risk cytokine release syndrome (CRS) and neurological events, Kymriah is being approved with a risk evaluation and mitigation strategy (REMS), which includes elements to assure safe use (ETASU). FDA is requiring that hospitals and their associated clinics that dispense Kymriah be specially certified and trained to recognize and manage CRS and neurological events.
The second, Yescarta (axicabtagene ciloleucel), is also a CAR T-cell therapy, but for the treatment of adult patients with certain types of large B-cell lymphoma who have not responded to or who have relapsed after at least two other kinds of treatment (35). Yescarta was approved under Priority Review and had both Breakthrough Therapy and Orphan Drug designations. Yecarta was approved with a similar REMS.
Other diseases targeted by novel drugs approved by FDA in 2017 include chronic hepatitis C virus (two different products), complicated urinary tract infections, acute bacterial skin and skin structure infections caused by gram-positive and gram-negative pathogens, eczema, plaque psoriasis (two products), Parkinson’s disease, carcinoid syndrome diarrhea, chronic idiopathic constipation, opioid-induced constipation, rheumatoid arthritis, and asthma.
FDA approved a record number of abbreviated new drug applications (ANDAs)--763 approvals and 174 tentative approvals--in fiscal year 2017 (36), compared with 639 ANDA approvals and 183 tentative approvals in fiscal year 2016 (37). Not only were more ANDAs approved in 2017 compared to 2016, a much higher number of ANDAs was received as well.
In addition, as of Nov. 28, 2017, FDA had approved 65 first generics (38)-or products that are the first generic competitors to their branded counterparts--and looks to be on track to meet or exceed last year’s figure of 73. The increased rate of approvals is attributed to an increase in FDA personnel by nearly 1000 as a result of funds collected through the Generic Drug User Fee Amendments. FDA has also prioritized the approval of generics to help reduce drug costs.
1. FDA, “Novel Drug Approvals for 2016.”
2. FDA, “Novel Drug Approvals for 2017.”
3. J. Jenkins, “CDER Approved Many Innovative Drugs in 2014,” FDA Voice, Jan. 14, 2015.
4. FDA, “Novel Drug Approvals for 2015.”
5. Markets and Markets, Active Pharmaceutical Ingredients/API Market by Type (Innovative, Generic), Manufacturer (Captive, Merchant), Synthesis (Synthetic, Biotech), Product (mAb, Hormone) Drug (OTC, Rx), Therapy (Diabetes, Oncology, CNS, CVD) - Global Forecast to 2021, January 2017.
6. Grand View Research, “API Market Size Worth USD 239.8 Billion By 2025,” Press Release, January 2017.
7. B. Norman, S. Karlin-Smith, and B. Griffiths, “Gottlieb Signals Priorities for FDA, Including Drug Pricing,” Politico, May 30, 2017.
8. M. Lanthier, “Insights into Rare Disease Drug Approval: Trends and Recent Developments,” presented at the NORD Rare Diseases & Orphan Products Breakthrough Summit, Oct. 17, 2017.
9. FDA, “FDA Approves New Targeted Treatment for Relapsed or Refractory Acute Myeloid Leukemia,” Press Release (Silver Spring, MD, Aug. 1, 2017).
10. FDA, “FDA Approves New Combination Treatment for Acute Myeloid Leukemia,” Press Release (Silver Spring, MD, April 28, 2017).
11. FDA, “FDA Approves New Treatment for Adults with Relapsed Or Refractory Acute Lymphoblastic Leukemia,” Press Release (Silver Spring, MD, Aug. 17, 2017).
12. FDA, “Durvalumab (Imfinzi),” www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm555930.htm.
13. FDA, “FDA Approves New Treatment for Adults with Mantle Cell Lymphoma,” Press Release (Silver Spring, MD, Oct. 31, 2017).
14. Takeda Pharmaceutical Company, “Takeda Announces FDA Accelerated Approval of ALUNBRIG (brigatinib),” Press Release (Cambridge, MA, April 28, 2017).
15. FDA, “FDA Approves First Treatment for Rare Form of Skin Cancer,” Press Release (Silver Spring, MD, March 23, 2017).
16. Novartis, “Novartis Kisqali (ribociclib, LEE011) Receives FDA Approval as First-Line Treatment for HR+/HER2- Metastatic Breast Cancer in Combination with Any Aromatase Inhibitor,” Press Release (March 13, 2017).
17. FDA, “FDA Approves New Treatment for Certain Advanced Or Metastatic Breast Cancers,” Press Release (Silver Spring, MD, Sept. 28, 2017).
18. FDA, “FDA Approves New Treatment to Reduce the Risk of Breast Cancer Returning,” Press Release (Silver Spring, MD, July 17, 2017).
19. FDA, “FDA Approves New Treatment for Adults with Relapsed Follicular Lymphoma,” Press Release (Silver Spring, MD, Sept. 14, 2017).
20. FDA, “FDA Approves Maintenance Treatment for Recurrent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancers,” Press Release (Silver Spring, MD, March 27, 2017).
21. FDA, “FDA Approves First US Treatment for Chagas Disease,” Press Release (Silver Spring, MD, Aug. 29, 2017).
22. FDA, “FDA Approves Drug to Treat ALS,” Press Release (Silver Spring, MD, May 5, 2017).
23. FDA, “FDA Approves Drug to Treat Duchenne Muscular Dystrophy,” Press Release (Silver Spring, MD, Feb. 9, 2017).
24. FDA, “FDA Approves First Treatment for a Form of Batten Disease,” Press Release (Silver Spring, MD, April 27, 2017).
25. FDA, “FDA Approves New Drug to Treat Multiple Sclerosis,” Press Release (Silver Spring, MD, March 29, 2017).
26. Portola Pharmaceuticals, “US FDA Approves Bevyxxa (betrixaban) First and Only Anticoagulant for Hospital and Extended Duration Prevention of Venous Thromboembolism (VTE) in Acutely Ill Medical Patients,” Press Release (South San Francisco, June 23, 2017).
27. FDA, “FDA Approves First Drug to Treat Tardive Dyskinesia,” Press Release (Silver Spring, MD, April 11, 2017).
28. Radius Health, “FDA Approves Radius Health’s TYMLOS (abaloparatide), a Bone Building Agent for the Treatment of Postmenopausal Women with Osteoporosis at High Risk for Fracture,” Press Release (Waltham, MA, April 28, 2017).
29. Merck & Co., “Merck Receives FDA Approval of PREVYMIS (letermovir) for Prevention of Cytomegalovirus (CMV) Infection and Disease in Adult Allogeneic Stem Cell Transplant Patients,” Press Release (Kenilworth, NJ, Nov. 9, 2017).
30. Teva Pharmaceuticals, “Teva Announces FDA Approval of AUSTEDO (deutetrabenazine) Tablets for the Treatment of Chorea Associated with Huntington’s Disease,” Press Release (Jerusalem, Israel, April 3, 2017).
31. Amgen, “FDA Approves Amgen’s Parsabiv (Etelcalcetide), First New Treatment in More Than a Decade for Secondary Hyperparathyroidism in Adult Patients on Hemodialysis,” Press Release, Feb. 7, 2017.
32. Valenat Pharmaceuticals, “Bausch + Lomb and Nicox Announce FDA Approval of VYZULTA (Latanoprostene Bunod Ophthalmic Solution), 0.024%,” Press Release (Thousand Oaks, CA, Nov. 2, 2017).
33. Symbiomix Therapeutics, “FDA Approves Symbiomix Therapeutics’ Solose (secnidazole) Oral Granules for the Treatment of Bacterial Vaginosis in Adult Women,” Press Release (Newark, NJ, Sept. 18, 2017.
34. FDA, “FDA Approves tisagenlecleucel for B-cell ALL and Tocilizumab for Cytokine Release Syndrome,” Press Release (Silver Spring, MD, Aug. 30 2017).
35. FDA, “FDA Approves CAR-T Cell Therapy to Treat Adults with Certain Types of Large B-cell lymphoma,” Press Release (Silver Spring, MD, Oct. 18, 2017).
36. FDA, “Activities Report of the Generic Drug Program (FY 2017)”
37. FDA Office of Generic Drugs, 2016 OGD Annual Report.
38. FDA, “First Generic Drug Approvals”
Vol. 42, No. 1
When referring to this article, please cite it as C. Challener, " FDA Ramped up Approval Rate in 2017," Pharmaceutical Technology 42 (1) 2018.