OR WAIT null SECS
Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
Orphan and cancer drugs continue to lead, but treatments for many common diseases were also approved in 2018.
Editor's note: An abbreviated version of this article appeared in the January 2019 issue of Pharmaceutical Technology.
FDA had a very active year in 2018. The agency investigated ways to improve the drug approval process, increase the efficiency of drug development and better incorporate patient voices in the process, increase access for the public to less expensive generics, and develop solutions for the prevention of drug shortages.
In June 2018, FDA Commissioner Scott Gottlieb issued a statement about a proposal to modernize the agency’s drug review office (1). The proposed changes at the Office of New Drugs in the Center for Drug Evaluation and Research (CDER) were intended to provide its “clinicians and scientists more time, better tools, and greater support to advance the clinical and regulatory principles that the FDA uses to evaluate new drugs for safety and efficacy.”
Also in June, FDA issued the first of four draft guidance documents intended to inform patients and product developers about rigorous approaches for obtaining and incorporating patient input in product development and how the agency will incorporate this information into its regulatory decision-making (2).
To speed drug development, FDA announced in October 2018 that the agency is developing technology- and disease-specific regulatory frameworks for innovations that may not have previously had a clear development pathway, including modernization of the agency’s approach to clinical trial design (3). It also issued several guidance documents for newer trial designs and the development of next-generation therapies.
These changes may have helped-or certainly not hindered-the ability of the agency to review new drug applications. In 2018, CDER had approved 59 novel drugs (4), 13 more than approved in 2017 (5). The following information was sourced from press releases issued by FDA and the drug license holders. A list of 2018 novel drug approvals can be found on the FDA website.
Based on information in FDA and company press releases, approximately half of the new drugs were approved under an expedited review process-Fast Track, Breakthrough Therapy, Priority Review, Accelerated Review-or orphan drug status. These results suggest that both pharma companies and FDA remain committed to leveraging the shorter approval pathways made possible in the 2012 Food and Drug Administration Safety Innovations Act.
Nearly one-third of the new drugs were granted orphan drug designation, clearly reflecting the shift taking place in the industry away from the development of blockbuster drugs to the development of therapies for rare diseases.
Despite all of the hype about and investment in biologic drugs, only one quarter of medicines approved in 2018 by FDA were biologic-based drugs.
In response to concerns about the growing prevalence of drug-resistant bacteria and the ongoing need for medications to treat a variety of infections, FDA has placed an emphasis on approving new antibiotics and antivirals.
Paratek Pharmaceuticals received approval for its modernized tetracycline antibiotic Nuzyra (omadacycline) for the treatment of adults with community-acquired bacterial pneumonia and acute skin and skin structure infections (6). Nuzyra is specifically designed to overcome tetracycline resistance and exhibits broad-spectrum activity. It is also the first and only once-daily intravenous (IV) and oral antibiotic approved for the treatment of both types of infections. Its use enables physicians to transition patients from IV to oral treatment and potentially reduce hospitalizations. Xerava (eravacycline) from Tetraphase Pharmaceuticals is a novel, broad-spectrum antibiotic approved for the treatment of complicated intra-abdominal infections, the most common infection site in intensive care units (7).
New antiviral medications approved in 2018 include Shionogi’s Xofluza (baloxavir marboxil) for the treatment of acute uncomplicated influenza (flu), the first new antiviral flu treatment with a novel mechanism of action approved by FDA in nearly 20 years (8); and Tpoxx (tecovirimat), the first drug approved for the treatment of smallpox (9). Tpoxx was developed by SIGA Technologies in conjunction with the US Department of Health and Human Services’ Biomedical Advanced Research and Development Authority (BARDA); SIGA received a Material Threat Medical Countermeasure Priority Review Voucher.
Four new treatments for HIV patients were also approved by FDA in 2018. Biktarvy (bictegravir 50mg/emtricitabine 200mg/tenofovir alafenamide 25mg, BIC/FTC/TAF) from Gilead Sciences is a once-daily single tablet regimen for the treatment of HIV-1 infection (10); Trogarzo (ibalizumab-uiyk) from TaiMed Biologics is the first drug in a new class of antiretroviral medications that can provide significant benefit to patients who have run out of HIV treatment options (11). Merck’s Delstrigo (doravirine/lamivudine/tenofovir disoproxil fumarate) is a once-daily fixed-dose combination tablet, and Pifeltro (doravirine) is a new non-nucleoside reverse transcriptase inhibitor; both were developed for the treatment of HIV-1 infection in adult patients with no prior antiretroviral treatment experience (12).
Treatments for rare genetic diseases, all with the orphan drug designation, received approval by FDA. Onpattro (patisiran) infusion from Alnylam Pharmaceuticals is the first FDA-approved treatment for patients with polyneuropathy caused by hATTR and is the first in a new class of drugs referred to as small interfering ribonucleic acid treatments (13). Akcea Therapeutics’ Tegsedi (inotersen), also for the treatment of the polyneuropathy of hereditary transthyretin-mediated amyloidosis in adults, is the first RNA-targeting therapeutic designed to reduce the production of human transthyretin protein (14).
Takhzyro (lanadelumab) from Shire is a plasma kallikrein inhibitor and the first monocloncal antibody (mAb) approved in the United States to treat patients 12 years and older with types I and II hereditary angioedema, a rare and serious genetic disease that leads to unpredictable episodes of severe swelling in different areas of the body (15). Dompé farmaceutici’s Oxervate (cenegermin) is the first drug approved by FDA for the treatment of neurotrophic keratitis, a rare disease affecting the cornea, providing an alternative to surgical intervention (16).
Galafold (migalastat) from Amicus Therapeutics is the first oral medication for the treatment of adults with Fabry disease and specifically for patients who have a genetic mutation determined to be responsive to treatment with Galafold based on laboratory data (17). Unlike enzyme replacement therapy, this drug increases the activity of the body’s deficient enzyme.
Crysvita (burosumab-twza) is the first drug approved for the treatment of x-linked hypophosphatemia, a rare, inherited form of rickets that does not respond to vitamin D therapy (18); Ultragenyx Pharmaceutical received the 14th Rare Pediatric Disease Priority Review Voucher awarded by FDA. Palynziq (pegvaliase-pqpz) from BioMarin Pharmaceutical is a novel enzyme therapy approved for the treatment of adult patients with phenylketonuria, a rare genetic disease, who have uncontrolled concentrations of phenylalanine in their blood even on current treatment (19).
Treatments for both common and rare cancers were approved by FDA in 2018, including Regeneron Pharmaceuticals’ PD-1 checkpoint inhibitor Libtayo (cemiplimab-rwlc) injection, the first approved treatment for metastatic or locally advanced cutaneous squamous cell carcinoma, the second most common skin cancer (20). Lumoxiti (moxetumomab pasudotox-tdfk) injection from AstraZeneca Pharmaceuticals is the first CD22-directed cytotoxin approved for the treatment of adult patients with relapsed or refractory hairy cell leukemia who have received at least two prior systemic therapies, including treatment with a purine nucleoside analog (21). Kyowa Kirin’s Poteligeo (mogamulizumab-kpkc) injection is the first drug approved by FDA for the treatment of Sézary syndrome, a rare and hard-to-treat type of non-Hodgkin lymphoma (22).
Erleada (apalutamide) from Janssen Pharmaceutical Companies is the first FDA-approved treatment for non-metastatic, castration-resistant prostate cancer (23). The approval was the first to use the endpoint of metastasis-free survival, measuring the length of time that tumors did not spread to other parts of the body or that death occurred after starting treatment. It was the first participant in FDA’s Clinical Data Summary Pilot Program, an effort to provide stakeholders with more usable information on the clinical evidence supporting drug product approvals.
Lutathera (lutetium Lu 177 dotatate) from Advanced Accelerator Applications (since acquired by Novartis) is the first radiotherapy approved for the treatment of gastroenteropancreatic neuroendocrine tumors, which affect the pancreas or gastrointestinal tract (24). The drug binds to the somatostatin receptors of tumor cells, enabling its entry and their ultimate destruction.
In late November, FDA approved Vitrakvi (larotrectinib) from Loxo Oncology for the treatment of adult and pediatric cancer patients with a specific genetic feature, or biomarker, on their tumors. The approval marks the second time FDA has approved a cancer treatment based on a common biomarker across different types of tumors rather than the location in the body where the tumor originated.
Several other firsts were achieved by FDA in 2018. Approval of the first non-opioid treatment for the management of opioid withdrawal symptoms went to US WorldMeds’ Lucemyra (lofexidine hydrochloride), an oral, selective alpha 2-adrenergic receptor agonist that reduces the release of norepinephrine (25). Epidiolex (cannabidiol) from GW Research for the treatment of seizures associated with Lennox-Gastaut syndrome and Dravet syndrome, two rare and severe forms of epilepsy, is the first FDA-approved drug that contains a purified drug substance derived from marijuana and the first drug approved for the treatment of patients with Dravet syndrome (26).
AbbVie’s Orilissa (elagolix) is the first FDA-approved oral treatment for the management of moderate to severe pain associated with endometriosis in over a decade and the only oral gonadotropin-releasing hormone antagonist specifically developed for women with moderate to severe endometriosis pain (27).
FDA also approved new medications for the prevention of migraines. Aimovig (erenumab-aooe) from Amgen is a once-monthly self-injection and the first FDA-approved preventive migraine treatment in a new class of drugs that work by blocking the activity of calcitonin gene-related peptide (28). Teva Pharmaceutical Industries’ Ajovy (fremanezumab-vfrm) injection is the first and only anti-CGRP treatment for the prevention of migraine with quarterly and monthly dosing options (29). Eli Lilly’s Emgality (galcanezumab-gnlm) also received approval.
Several drugs that received FDA approval in 2018 were targeted therapies, and some were even approved with specific diagnostic tests. Pfizer’s Talzenna (talazoparib), a poly (ADP-ribose) polymerase (PARP) inhibitor, was approved for the treatment of for patients with deleterious or suspected deleterious germline BRCA-mutated, HER2ânegative locally advanced or metastatic breast cancer (30). The BRACAnalysis CDx test from Myriad Genetic Laboratories, Inc. was also approved to identify patients who are eligible for the new drug.
Agios Pharmaceuticals received approval for Tibsovo (ivosidenib), the first isocitrate dehydrogenase-1 inhibitor, for the treatment of adult patients with relapsed or refractory acute myeloid leukemia (AML) who have a specific genetic mutation (31). Patients must be identified using the FDA-approved RealTime IDH1 Assay from Abbott Laboratories.
The combination of BRAFTOVI (encorafenib) and MEKTOVI (binimetinib) from Array BioPharma was approved for the treatment of for patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation (32). The mutation must be detected using the FDA-approved THxID BRAF Kit from bioMérieux.
One interesting trend is the development of new drugs by non-profit organizations, sometimes in collaboration with pharmaceutical companies. Two drugs approved to treat tropical diseases were developed using this approach. The not-for-profit company Medicines Development for Global Health (MDGH), in collaboration with the World Health Organization Special Program for Research and Training in Tropical Diseases, received FDA approval for moxidectin 8 mg oral for the treatment of river blindness, which is caused by the parasite Onchocerca volvulus (33). It is the first new drug approved for the treatment of river blindness in 20 years. MDGH received a priority review voucher (PRV), a saleable item that enables the owner to receive accelerated review of a new drug application (NDA)-the first not-for-profit company to do so under the tropical disease PRV program.
Similarly, GlaxoSmithKline (GSK) received a tropical disease PRV for its part in the development of the first new treatment for Plasmodium vivax (P. vivax) malaria in more than 60 years (34). Single-dose Krintafel (tafenoquine) was developed in collaboration with Medicines for Malaria Venture and received FDA approval for the radical cure (prevention of relapse) of P. vivax malaria in patients aged 16 years and older who are receiving appropriate antimalarial therapy for acute P. vivax infection.
Two other interesting examples are the first approval of a vaginal ring contraceptive: the Population Council’s Annovera (segesterone acetate and ethinyl estradiol vaginal system) (35); and Omegaven, a fat emulsion manufactured by Fresenius Kabi and demonstrated by researchers at Boston Children’s Hospital to be effective for preventing liver disease associated with parenteral nutrition in children (36).
Most of the drugs on FDA’s approval docket through early 2019 include treatments for many common conditions, including heart disease, immune deficiency, diabetes, and influenza (37). There are also several treatments for neurological and psychology disorders, such as Parkinson’s disease and depression. Several drugs for pain management are under review, as are treatments for skin infections, glaucoma, breast cancer, and erectile dysfunction. Several new drugs for the treatment of rare cancers are also awaiting FDA decisions.
Digital health became an increasingly important focus area for FDA in 2018. After launching the Digital Health Innovation Action Plan in 2017, which is seeking to modify the agency’s approach to digital health products (38), FDA formed the internal data science incubator the Information Exchange and Data Transformation (INFORMED) in 2018. The agency has also proposed to create a Center of Excellence for Digital Health in its Fiscal Year 2019 Budget.
Also in 2018, FDA approved the first medical device that combined a special camera and artificial intelligence to detect greater than a mild level diabetic retinopathy in adults who have diabetes in a primary care setting (39) and permitted the marketing of an artificial intelligence algorithm for aiding providers in detecting wrist fractures (40). Most recently, FDA awarded de novo clearance to Apple’s Series 4 model of the Apple Watch (41).
FDA Commissioner Scott Gottlieb has indicated that digital technology requires “a reimagination of healthcare delivery” (38). The agency is committed to fostering, not hindering, innovation in digital health technology. Gottlieb hopes the new Center of Excellence will “help establish more efficient regulatory paradigms, consider building new capacity to evaluate and recognize third-party certifiers, and support a cybersecurity unit to complement the advances in software-based devices.”
From artificial intelligence technologies such as deep learning and natural language processing to smart devices and advances software and apps, digital technologies will clearly play an increasing role in drug and medical device development going forward.
1. FDA, “Statement from FDA Commissioner Scott Gottlieb, M.D., on Proposed Modernization of FDA’s Drug Review Office,” Statement, June 4, 2018.
2. FDA, “Statement from FDA Commissioner Scott Gottlieb, M.D., on New Agency Efforts to Advance the Patient Voice in Medical Product Development and FDA Regulatory Decision-Making,” Statement, June 12, 2018.
3. FDA, “Statement by FDA Commissioner Scott Gottlieb, M.D., on FDA’s New Steps to Modernize Drug Development, Improve Efficiency and Promote Innovation of Targeted Therapies,” Statement, Oct. 15, 2018.
4. FDA, “Novel Drug Approvals for 2018.
5. FDA, “Novel Drug Approvals for 2017.
6. Paratek Pharmaceuticals, “Paratek Announces FDA Approval of NUZYRA (Omadacycline),” Press Release, Oct. 2, 2018.
7. Tetraphase Pharmaceuticals, “Tetraphase Pharmaceuticals Announces FDA Approval of XERAVA (Eravacycline) for Complicated Intra-Abdominal Infections (cIAI),” Press Release, Aug. 27, 2018.
8. FDA, “FDA Approves New Drug to Treat Influenza,” Press Release, October 24, 2018.
9. FDA, “FDA Approves the First Drug with an Indication for Treatment of Smallpox,” Press Release, July 13, 2018.
10. Gilead Sciences, “US Food and Drug Administration Approves Gilead’s Biktarvy (Bictegravir, Emtricitabine, Tenofovir Alafenamide) for Treatment of HIV-1 Infection,” Press Release, Feb. 7, 2018.
11. FDA, “FDA Approves New HIV Treatment for Patients Who Have Limited Treatment Options,” Press Release, March 6, 2018.
12. Merck, “FDA Approves Merck’s Delstrigo and Pifeltro to Treat HIV,” Press Release, Aug. 30, 2018.
13. FDA, “FDA Approves First-Of-Its Kind Targeted RNA-Based Therapy to Treat a Rare Disease,” Press Release, Aug.10, 2018.
14. Akcea Therapeutics, Inc., “Akcea and Ionis Receive FDA Approval of TEGSEDI™ (inotersen) for the Treatment of the Polyneuropathy of Hereditary Transthyretin-Mediated Amyloidosis in Adults,” Press Release, Oct. 5, 2018.
15. FDA, “FDA Approves New Treatment for Rare Hereditary Disease,” Statement, Aug. 23, 2018.
16. FDA, “FDA Approves First Drug for Neurotrophic Keratitis, a Rare Eye Disease,” Press Release, August 22, 2018.
17. FDA, “FDA Approves New Treatment for a Rare Genetic Disorder, Fabry Disease,” Press Release, August 10, 2018.
18. FDA, “FDA Approves First Therapy for Rare Inherited Form of Rickets, X-Linked Hypophosphatemia,” Press Release, April 17, 2018.
19. FDA, “FDA Approves a New Treatment For PKU, a Rare and Serious Genetic Disease,” Press Release, May 24, 2018.
20. FDA, “FDA Approves First Treatment for Advanced Form of the Second Most Common Skin Cancer,” Press Release, September 28, 2018.
21. FDA, “FDA Approves New Kind of Treatment for Hairy Cell Leukemia,” Sept. 13, 2018.
22. FDA, “FDA Approves Treatment for Two Rare Types of Non-Hodgkin Lymphoma,” Press Release.
23. FDA, “FDA Approves New Treatment For a Certain Type of Prostate Cancer Using Novel Clinical Trial Endpoint,” Press Release, Feb. 14, 2018.
24. FDA, “FDA Approves New Treatment for Certain Digestive Tract Cancer,” Press Release, Jan. 26, 2018.
25. FDA, “FDA Approves the First Non-Opioid Treatment for Management of Opioid Withdrawal Symptoms in Adults,” Press Release, May 16, 2018.
26. FDA, “FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy,” Press Release, June 25, 2018.
27. Abbvie, “AbbVie Receives US FDA Approval of ORILISSA (elagolix) for the Management of Moderate to Severe Pain Associated with Endometriosis,” Press Release, July 24, 2018.
28. FDA, “FDA approves novel preventive treatment for migraine,” Press Release, May 17, 2018.
29. Teva Pharmaceutical Industries Ltd., “Teva Announces US Approval of AJOVY (fremanezumab-vfrm) Injection, the First and Only Anti-CGRP Treatment with Both Quarterly and Monthly Dosing for the Preventive Treatment of Migraine in Adults,” Press Release, Sep. 14, 2018.
30. FDA, “FDA Approves Talazoparib for gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer,” Statement, October 16, 2018.
31. FDA, “FDA Approves First Targeted Treatment for Patients with Relapsed or Refractory Acute Myeloid Leukemia Who Have a Certain Genetic Mutation,” Press Release, July 20, 2018.
32. FDA, “FDA Approves Encorafenib and Binimetinib in Combination for Unresectable or Metastatic Melanoma with BRAF Mutations,” Statement, June 27, 2018.
33. Medicines Development for Global Health, “US FDA Approves Moxidectin for the Treatment of River Blindness,” Press Release, June 13, 2018.
34. GSK, “US FDA Approves Krintafel (tafenoquine) for the Radical Cure of P. vivax Malaria,” Press Release, July 20, 2018.
35. FDA, “FDA Approves New Vaginal Ring for One Year of Birth Control,” Press Release, Aug. 10, 2018.
36. Nancy Fliesl, “A Life-Saving Adjustment in IV Nutrition Cleared by the FDA,” Aug.13, 2018.
37. RTT News, “FDA Calendar.”
38. Scott Gottlieb, “Statement from FDA Commissioner Scott Gottlieb, MD, and Center for Devices and Radiological Health Director Jeff Shuren, MD, JD, on Agency Efforts to Work with Tech Industry to Spur Innovation in Digital Health,” FDA Statement, Sept. 12, 2018.
39. FDA, “FDA Permits Marketing of Artificial Intelligence-Based Device to Detect Certain Diabetes-Related Eye Problems,” Press Release, April 11, 2018. .
40. FDA, “FDA Permits Marketing of Artificial Intelligence Algorithm for Aiding Providers in Detecting Wrist Fractures,” Press Release, May 24, 2018. .
41. Conor Hale, “New Apple Watch Receives FDA Clearance for Built-in ECG,” FierceBiotech, September 12, 2018.
Vol. 43, No. 1
When referring to this article, please cite it as C. Challener, “FDA Marks Record Year for New Drug Approvals," Pharmaceutical Technology 43 (1) 2019.