Last year witnessed a new high in the number of US Food and Drug Administration (FDA) approvals of new pharmaceuticals, including new molecular entities (NMEs) and new Biologic License Applications (BLAs), amounting to a total of 45 NMEs and BLAs in all disease states compared with 41 approved in 2014 and much fewer (27) in 2013.1
Of these 45 NMEs and BLAs entering the market last year, 16 were novel therapies for cancer,2 providing patients new hope through novel treatment options and new mechanisms of action. New trends in oncology drug development are reflected in the increasing use of biotechnology in the development of anticancer drugs, including immunotherapies or monoclonal antibodies, adoptive-cell therapies, and new vaccines.3
Innovation continues to be a much sought-after quality by the FDA in its approval of new drugs to improve patient outcomes, which is reflected in the agency’s close work with the pharmaceutical industry. According to the FDA, “Innovation drives progress. When it comes to innovation in the development of new drugs and therapeutic biological products, FDA’s Center for Drug Evaluation and Research (CDER) supports the pharmaceutical industry at every step of the process.”2
Introducing the FDA’s summary of its drug approvals in 2015, Janet Woodcock, MD, Director of the FDA’s CDER, said, “Each year, CDER approves hundreds of new medications, most of which are variations of previously existing products….However, products in a small subset of these new approvals, that we refer to as novel drugs, are among the more truly innovative products that often help advance clinical care to another level.”1
Of the 16 new oncolytics approved by the FDA in 2015, the report highlights 9 drugs that were considered truly innovative: “Noteworthy cancer treatments include Darzalex, Empliciti, Farydak, and Ninlaro, to treat patients with multiple myeloma…, Alecensa and Tagrisso, to treat certain patients with non-small cell lung cancer, Cotellic, to treat certain patients with metastatic melanoma…, Lonsurf, for the treatment of certain patients with metastatic colorectal cancer, and, Yondelis, for treatment of soft tissue carcinoma” [emphasis in the original].1
These drugs highlight the innovative trends that have characterized the oncology pipeline in recent years, manifested by the many first-in-class drugs entering the market last year and continuing into 2016, and by the drugs representing the first pharmaceuticals approved by the FDA for a specific tumor type. So the oncology pipeline is not showing any signs of slowing down for now. Indeed, according to the new report from the IMS Institute for Healthcare Informatics, the oncology pipeline has expanded by 63% over the past 10 years.4
In 2015, the IMS Institute described innovation in the oncology pipeline on June 1, 2016, it further highlights innovation, saying that “The surge of innovation in cancer treatments is catching the attention of health system stakeholders and participants around the world….The focus on oncology will continue over at least the next five years, driven by unmet needs that remain high, a bulging pipeline of oncology drugs in clinical development, and limited availability in most countries.”4
Current Trends in the Oncology Pipeline
Clearly, innovation tops the trends in the current oncology pipeline. Another prominent trend is the high cost of cancer drugs, with new drugs entering the market carrying ever-greater costs, as reflected by financial support services offered by many drug manufacturers concomitant to the release of new drugs, in the attempt to mitigate the considerable economic burden on patients who are facing increasing out-of-pocket costs. According to the IMS Institute, the global costs associated with oncology drugs and supportive care medicines increased by 11.5% in 2015, currently reaching $107 billion, projecting that by 2020, global costs for oncology drugs will exceed $150 billion.5
This trend in part reflects the high costs of immunotherapies and targeted therapies, which continue to dominate the oncology pipeline, as well as the increasing competition for those drugs among new biotechnology companies that have recently joined the drug development scene, motivated by the increasing success of specialty drugs, which characterize the majority of new oncology drugs in the pipeline. Oral drugs are yet another growing trend that is much more common than even 5 years ago, and oral drugs are increasingly making up a larger proportion of the oncology drug costs.5
To address the growing concerns surrounding the cost of cancer drugs, various proposals have been made by different experts and other concerned bodies as a means to assess the value of new oncology drugs, by weighing their clinical benefit and contribution to the patient’s quality of life versus their costs. Several new value assessment tools were released last year by different organizations, including the American Society of Clinical Oncology’s value framework, which was updated in May 2016,6 and the National Co
as focused on combination therapies, biomarkers, and drugs developed for cancer types that have few treatment options.5 In its new report releasedmprehensive Cancer Network’s Evidence Blocks.7
Other attempts to control drug costs involve proposals to link the cost of a drug to a specific indication, or to the performance of the drug in the real world, but these proposals must be further elucidated and clearly applied to specific therapies or methodologies; it is too soon to assess their value in clinical practice and to the healthcare market as a whole.
The other key trends in the oncology pipeline include expediting the FDA approval using its various pathways, such as priority review and accelerated approval; breakthrough therapy designation (attributed to a drug designed to treat a serious or life-threatening condition); and orphan drug designation (assigned to a drug being developed for a rare type of cancer with <200,000 patients), designations designed to help expedite the development and availability of the drug.
Oncology Drugs Approved Through Late May 2016
Early signs from the first half of 2016 suggest that innovation continues to lead drug development in oncology. By the end of May 2016, the FDA approved 4 novel drugs and 13 new indications in oncology, some of which represent first-in-class therapies (Table 1).
The 4 novel drugs include defribotide sodium (Defitelio), the first treatment approved by the FDA for severe hepatic veno-occlusive disease; venetoclax (Venclexta), the first BCL-2 inhibitor to receive FDA approval for chronic lymphocytic leukemia with chromosome 17p deletion; cabozantinib (Cabometyx), a tyrosine kinase inhibitor, approved for advanced renal-cell carcinoma (RCC); and atezolizumab (Tecentriq), the first monoclonal antibody PD-1 ligand 1 inhibitor approved by the FDA for metastatic urothelial bladder cancer (Table 1), a cancer that has not seen a new drug approved by the FDA for more than a decade.
The 2016 Oncology Pipeline
According to the Pharmaceutical Research and Manufacturers of America (PhRMA), as many as 836 drugs and vaccines are currently in various stages of development for cancer; these are either in clinical trials or are awaiting review by the FDA.8 Of the 836 drugs and vaccines for cancer8:
- 123 are for lung cancer (still the leading cause of cancer-related death in the United States)
- 106 for leukemia
- 92 for lymphoma (including non-Hodgkin lymphoma)
- 82 for breast cancer (the leading cancer in US women)
- 58 for brain tumors
- 53 for skin cancer (including melanoma).
Furthermore, approximately 80% of cancer drugs in the current pipeline are potentially first-in-class therapies, and 73% can potentially be classified as personalized medicine, because they target a specific genomic aspect of the tumor, according to PhRMA.8
It is not surprising that lung cancer is leading the way in drug development, considering that it remains the leading cause of cancer-related death,9 despite considerable progress in new therapies. The tumor types leading the pipeline in the number (≥3) of drugs expecting approval in 2016 or are in late-stage development are breast cancer, leukemia, lung cancer, and ovarian cancer (Table 2). As shown in Table 2, the majority of these drugs have already received a breakthrough therapy designation, an orphan drug designation, or both, and many are being reviewed under the FDA’s various accelerated approval pathways.
Breakthrough therapies and orphan drugs are clearly 2 of the leading trends in the 2016 oncology pipeline, reflecting the continuing efforts of the FDA to encourage the development of potentially life-saving medications to meet unmet needs for specific patient populations.2 Other promising drugs in late-stage development include drugs for bladder cancer, RCC and other kidney cancers, melanoma, pancreatic cancer, soft-tissue sarcoma, and myelofibrosis (Table 3). Although some of these tumor types, especially melanoma, have seen many new drugs approved recently, other tumors, including bladder and brain cancer, have had few or no new drugs in the recent past. As is the case in other tumor types, many of the drugs listed in Table 3 have also received a breakthrough therapy or an orphan drug designation, and are expected to be approved under the FDA’s accelerated approval pathways.
Biosimilars: The Future Is Here
The most recent trend in the oncology pipeline involves biosimilars, introduced last year with the FDA approval of filgrastim-sndz (Zarxio), the first biosimilar to receive approval in the United States. This opened the floodgate to a new type of biologic products, which potentially may help control the escalating costs of biologic drugs. As can be expected, the number of biosimilars awaiting approval in 2016 is growing. A BLA was filed by the manufacturers of the 4 oncology biosimilars currently in line to receive FDA approval, and 3 of those applications have been accepted by the FDA (Table 4).
The FDA has issued several guidance documents outlining the process of approval of biosimilars and the exact nature of biosimilarity (as opposed to interchangeability), but lack of clarity about this new drug category remains. In March 2016, the FDA released its most recent guidance, titled “Labeling for Biosimilar Products,” which provides additional clarity. “The goal of a biosimilar product development program is to demonstrate biosimilarity between the proposed product and the reference product, not to independently establish safety and effectiveness of the proposed product. A demonstration of biosimilarity means, among other things, that FDA has determined that there are no clinically meaningful differences between the proposed product and the reference product in terms of safety, purity, and potency,” the guidance states.10
Furthermore, the label of a biosimilar should not include any data from clinical trials related to the biosimilar, because such studies are not designed to demonstrate efficacy and safety but rather biosimilarity to the reference drug, that is, to “support a demonstration that there are no clinically meaningful differences between the proposed biosimilar product and the reference product for the approved indications.”10 For this reason, the drug label should include information from the clinical trials of the reference drug.10 At the end of this guidance, the FDA advises it will provide further clarification on interchangeability of a biosimilar in a future guidance.
Conclusion: Are We Closer to a Cure?
Talk about a cure for cancer is in the air, but the evidence remains elusive. Despite President Obama’s Moonshot to cancer last year, and despite the enormous progress in cancer drug development and the actual cure available for some cancers, cancer-related deaths are still the second leading cause of death in this country.9 Neverless, the intense rate of innovation in cancer drugs gives one hope that a major breakthrough is not too far away.
A potential turning point in drug development, if not in cancer care itself, may be the introduction, by several pharmaceutical companies, of patient-reported outcomes and patient input as a new component in drug development, with the goal of producing more user-friendly medicines that deliver reduced toxicity and increased convenience, which can improve adherence and outcomes. Could including the patient’s voice in drug development, and potentially in drug approval, help to change the drug development paradigm toward a cure? Innovation in the oncology pipeline is thriving, and new scientific discoveries abound. The risk for cancer has no boundaries of any sort. Therefore, the incentive for cure cannot be measured only by financial rewards.
1. US Food and Drug Administration. Novel drugs 2015 summary. January 2016. www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/DrugIn
novation/UCM485053.pdf. Accessed May 15, 2016.
2. US Food and Drug Administration. Novel drug approvals 2015. www.fda.gov/drugs/developmentapprovalprocess/druginnovation/ucm430302.htm. Accessed May 15, 2016.
3. von Ranke NL, Fierro IM, Antunes AM. Trends in biotechnological drugs for cancer treatment. Recent Pat Anticancer Drug Discovery. 2016;11:112-120.
4. IMS Institute for Healthcare Informatics. Global Oncology Trend Report: A Review of 2015 and Outlook to 2020. June 2016. www.imshealth.com/en/thought-leadership/ims-institute/reports/global-oncology-trend-report-a-review-of-2015-and-outlook-to-2020. Accessed June 3, 2016.
5. IMS Institute for Healthcare Informatics. Developments in Cancer Treatment, Market Dynamics, Patient Access and Value: Global Oncology Trend Report 2015. May 2015. www.imshealth.com/en/thought-leadership/ims-institute/reports/global-oncology-trend-2015#survival-rates-have-steadily-improved-over-the-past-20-years. Accessed May 15, 2016.
6. Schnipper LE, Davidson NE, Wollins DS, et al. Updating the American Society of Clinical Oncology Value Framework: revisions and reflections in response to comments received. J Clin Oncol. 2016 May 31. Epub ahead of print.
7. Carlson RW, Jonasch E. NCCN Evidence Blocks. J Natl Compr Canc Netw. 2016;14(5 suppl):616-619.
8. Pharmaceutical Research and Manufacturers of America. Medicines in Development for Cancer: From Hope to Cure. 2015 Report. http://phrma.org/sites/default/files/pdf/oncology-report-2015.pdf. Accessed May 15, 2016.
9. American Cancer Society. Cancer Facts & Figures 2016. www.cancer.org/acs/groups/content/@research/documents/document/acspc-047079.pdf. Accessed June 3, 2016.
10. US Food and Drug Administration. Labeling for biosimilar products: guidance for industry. March 2016. www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm493439.pdf. Accessed June 3, 2016.