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FDA issued approvals for less than half the number of new drugs in 2016 compared with 2015.
Following two years of near-record numbers of new drug approvals by FDA, with 41 in 2014 (1) and 45 in 2015 (2), 2016 appears to be seriously bucking the trend, with only 20 approvals issued as of Dec. 14, 2016 (3). The sharp decline was not expected. What might be the reasons? John Jenkins, director of FDA’s Office of New Drugs, attributed the difference to a decline in the number of submitted applications, more complete response letters in 2016, and the fact that five approvals originally scheduled for 2016 were finalized earlier in 2015 (4). On a positive note, Jenkins reported that the number of applications received by FDA through Dec. 9, 2016 was 36, surpassing the average number (35) of new molecular entity filings for the past decade.
Notably, the decline in approvals does not seem to be having an impact on growth expectations for the global API market. Mordor Intelligence projects the global API market to expand at a compound annual growth rate of 6.5% from $154 billion in 2015 to $225 billion in 2021 (5).
While chemical compounds continue to account for the greatest percentage of APIs, biologic drug substances are growing at the fastest rate. APIs were intended slightly more often for branded drugs compared to generic drugs (43.5%) in 2015, and APIs for cancer treatments are experiencing the fastest growth vs. APIs for other therapies. North America remains the largest market for APIs, but demand is growing most rapidly in Asia-Pacific (5).
The 20 approvals in 2016 included treatments for asthma, type II diabetes, different cancers, hepatitis C, plaque psoriasis, multiple sclerosis, muscular dystrophy, and several rare diseases. Eight of the approvals were for biologics, including seven monoclonal antibodies (mAbs) and one hormone. Two were radioactive diagnostics agents and two were for the treatment of hepatitis C. Merck, Eli Lilly, and Sanofi each received two approvals. Half of the new drugs approved by FDA in 2016 received one or more special designations. Three are considered new classes of drugs, and three are the first-ever treatments for the diseases they target.
With passage of the FDA Safety and Innovation Act (FDASIA) in 2012, FDA was granted authority to implement expedited review and approval programs to accelerate the introduction of novel medications to the market. Four programs are currently in use. Manufacturers can qualify for fast track and breakthrough therapy designations, and accelerated approval and priority review processes depending on the characteristics of their drug candidates. Breakthrough therapies provide substantial improvement over currently available treatments. Fast Track drugs meet unmet medical needs and treat serious conditions. Accelerated approval is available for similar reasons. Priority review is granted to drugs that have improved safety and effectiveness compared to current medicines.
Drug companies are utilizing these pathways. In 2014 and 2015, respectively, 66% and 60% of the 41 and 45 new drugs approved by FDA received one or more special designation or was granted an expedited review of some kind (6,7).
In 2016, five of the newly approved drugs were awarded the breakthrough therapy designation, three received fast track status, five received accelerated approval, and eight underwent priority review. In addition, six of the newly approved treatments were classified as orphan drugs. One product-Exondys 51 (eteplirsen, Sarepta Therapeutics) for the treatment of patients with Duchenne muscular dystrophy (DMD)-received priority review for a rare pediatric disease. Notably, two of the approved drugs in 2016 had a total of five special designations (8).
Several of the newly approved drugs are the first new therapies approved by FDA for the treatment of different diseases. Exondys 51 is the first drug approved to treat patients with DMD that have a confirmed mutation of the dystrophin gene amenable to exon 51 skipping, which affects about 13% of the population with DMD (8).
In addition to receiving the seventh rare pediatric disease priority review voucher issued by FDA since the program began, Exondys 51 was granted fast track and orphan drug designations and was approved under the accelerated approval pathway based on the surrogate endpoint of dystrophin increase in skeletal muscle observed in some Exondys 51-treated patients. FDA is requiring Sarepta Therapeutics to conduct a clinical trial to confirm the drug’s clinical benefit.
Nuplazid (pimavanserin) from Acadia Pharmaceuticals is the first drug approved to treat hallucinations and delusions associated with psychosis experienced by as many as 50% of people with Parkinson’s disease. An estimated 50,000 Americans are diagnosed with Parkinson’s disease each year, according to the National Institutes of Health, and about 1 million Americans have the condition. Nuplazid received priorty review and was designated a breakthrough therapy (9).
Defitelio (defibrotide sodium) marketed by Jazz Pharmaceuticals is the first FDA-approved therapy for the treatment of severe hepatic veno-occlusive disease (VOD), a rare and life-threatening liver condition that can occur in adults and children that receive a stem cell transplant from blood or bone marrow (hematopoietic stem cell transplantation or HSCT). Fewer than 2% of patients develop severe hepatic VOD after HSCT, but as many as 80% of patients who develop severe hepatic VOD do not survive. Defitelio was granted priority review and designated an orphan drug (10).
Epclusa (fixed dose combination of sofosbuvir and velpatasvir) from Gilead Sciences is the first regimen to treat all six major hepatitis C virus (HCV) genotypes and was approved for adult patients with chronic HCV. Velpatasvir is the new drug; sofosbuvir was approved in 2013. Epclusa was granted priority review (11).
Lartruvo from Eli Lilly is the first new therapy approved by the agency for the initial treatment of soft-tissue sarcomas (STS), cancers that develop in muscles, fat, tendons or other soft tissues and cannot be cured with radiation or surgery, since doxorubicin’s approval more than 40 years ago. This platelet-derived growth factor (PDGF) receptor-alpha blocking antibody blocks PDGF receptors that cause tumor growth. The National Cancer Institute estimates that 12,310 new cases of STS and nearly 5000 deaths are likely to occur from the disease in 2016. Lartruvo (olaratumab) with chemotherapy drug doxorubicin was granted accelerated approval and priority review, as well as fast track, breakthrough therapy, and orphan designations (12).
Other drugs approved in 2016 fall into new classes of compounds that act by new pathways. Genentech’s Tecentriq (atezolizumab) is the first FDA-approved PD-L1 inhibitor and the latest in the broader class of PD-1/PD-L1 targeted biologics approved by FDA in the past two years. This mAb was approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma, the most common type of bladder cancer. It blocks PD-1/PD-L1 interactions between the body’s immune cells and some cancer cells, potentially helping the body’s immune system to fight cancer cells. Tecentriq received priority review and accelerated approval and was designated a breakthrough therapy (13).
Venclexta (venetoclax) from AbbVie is the first FDA-approved treatment that targets the B-cell lymphoma 2 (BCL-2) protein, which supports cancer cell growth. The drug is for the treatment of patients with chronic lymphocytic leukemia (CLL) who have a chromosomal abnormality called 17p deletion and who have been treated with at least one prior therapy. According to the National Cancer Institute, CLL is one of the most common types of leukemia in adults, with approximately 15,000 new cases diagnosed each year. The relevant chromosomal abnormality occurs in approximately 10% of patients with untreated CLL and in approximately 20% of patients with relapsed CLL. Venclexta was granted priority review and accelerated approval and designated a breakthrough therapy and orphan drug (14).
Netspot from Advanced Accelerator Applications USA is the first kit for the preparation of gallium Ga 68 dotatate injection, a radioactive diagnostic agent for positron emission tomography imaging. The radioactive probe helps locate tumors in adult and pediatric patients with the rare condition somatostatin receptor positive neuroendocrine tumors by binding to receptors on the tumors, which develop in the hormone-producing cells of the body’s neuroendocrine system. Netspot received priority review and was designated an orphan drug (15).
Several of the approved drugs in 2016 are intended for the treatment of diseases with existing therapies, but in some cases the new drug is of particular interest. For instance, Ocaliva (obeticholic acid) from Intercept Pharmaceuticals is only the second drug approved to treat patients with primary biliary cholangitis. Ursodeoxycholic acid, the only other approved drug, is effective in just over 50% of patients on its own and is not tolerated by many. An oral drug, Ocaliva binds to the farnesoid X receptor, a receptor found in the nucleus of cells in the liver and intestine, reducing bile flow from the liver and suppressing bile acid production in the liver. It received accelerated approval and fast track and orphan drug designations (16).
Merck’s ZINPLAVA (bezlotoxumab) is approved for the reduction of the recurrence of Clostridium difficile infection (CDI) in patients 18 years of age or older who are receiving antibacterial drug treatment for CDI and are at high risk for CDI recurrence. CDI is caused by bacteria that produce toxins, including toxin B. Developed by researchers at the University of Massachusetts Medical School’s MassBiologics Laboratory in conjunction with Medarex (now part of Bristol-Myers Squibb) and licensed to Merck in 2009, Zinplava, a human monoclonal antibody, binds to C. difficile toxin B and neutralizes its effects (17).
Developed by Elusys Therapeutics in cooperation with the US Dept. of Health and Human Services’ Biomedical Advanced Research and Development Authority, Anthim (obiltoxaximab) is a mAb that neutralizes toxins produced by Bacillus anthracis and was approved for the treatment of inhalational anthrax in combination with appropriate antibacterial drugs. Inhalational anthrax is a rare disease that can occur after exposure to infected animals or contaminated animal products, or as a result of an intentional release of anthrax spores. Notably, the drug was approved under FDA’s Animal Rule, which allows efficacy findings from adequate and well-controlled animal studies to support FDA approval when it is not feasible or ethical to conduct efficacy trials in humans (18).
It is also worth noting that FDA’s Center for Drug Evaluation and Research (CDER) approved 72 “first generic drugs” in 2016 as of Nov. 16, 2016 (19). “First generics” are the first approval by FDA that permits a manufacturer to market a generic drug product in the United States and receive prioritized review.
1. FDA, New Molecular Entity and New Therapeutic Biological Product Approvals for 2014, accessed Dec. 14, 2016.
2. FDA, New Molecular Entity and New Therapeutic Biological Product Approvals for 2015, accessed Dec. 14, 2016.
3. FDA, New Molecular Entity and New Therapeutic Biological Product Approvals for 2016, accessed Dec. 14, 2016.
4. J. Jenkins, “CDER New Drug Review: 2016 Update,” presentation at FDA/CMS Summit, Dec. 14, 2016, accessed Dec. 14, 2016.
5. Mordor Intelligence, “Global Active Pharmaceutical Ingredients Market-Growth, Trends & Forecasts (2016-2021),” September 2016, accessed Dec. 14, 2016.
6. FDA, Novel New Drugs 2014. January 2015, accessed Dec. 14, 2016.
7. FDA, Novel Drugs Summary 2015. January 2016, accessed Dec. 14, 2016.
8. FDA, “FDA Grants Accelerated Approval to First Drug for Duchenne Muscular Dystrophy,” Press Release (Silver Spring, MD, Sept. 19, 2016).
9. FDA, “FDA Approves First Drug to Treat Hallucinations and Delusions Associated with Parkinson’s disease,” Press Release (Silver Spring, MD, April 29, 2016).
10. FDA, “FDA Approves First Treatment for Rare Disease in Patients Who Receive Stem Cell Transplant from Blood or Bone Marrow,” Press Release (Silver Spring, MD, March 30, 2016).
11. FDA, “FDA Approves Epclusa for Treatment of Chronic Hepatitis C Virus Infection,” Press Release (Silver Spring, MD, June 28, 2016).
12. FDA, “FDA Grants Accelerated Approval to New Treatment for Advanced Soft Tissue Sarcoma,” Press Release (Silver Spring, MD, Oct. 19, 2016).
13. FDA, “FDA Approves New, Targeted Treatment for Bladder Cancer,” Press Release (Silver Spring, MD, May 18, 2016).
14. FDA, “FDA Approves New Drug for Chronic Lymphocytic Leukemia in Patients with a Specific Chromosomal Abnormality,” Press Release, April 11, 2016.
15. FDA, “FDA Approves New Diagnostic Imaging Agent to Detect Rare Neuroendocrine Tumors,” Press Release, (Silver Spring, MD, June 1, 2016).
16. FDA, “FDA Approves Ocaliva for Rare, Chronic Liver Disease,” Press Release (Silver Spring, MD, May 31, 2016).
17. Merck & Co., “FDA Approves Merck’s ZINPLAVA (bezlotoxumab) to Reduce Recurrence of Clostridium difficile Infection (CDI) in Adult Patients Receiving Antibacterial Drug Treatment for CDI Who Are at High Risk of CDI Recurrence,” Press Release (Silver Spring, MD, Oct. 21, 2016).
18. FDA, “FDA Approves New Treatment for Inhalation Anthrax,” Press Release (Silver Spring, MD, March 21, 2016).
19. FDA, First Generic Drug Approvals, accessed Dec. 14, 2016.