Emerging Trends in US Oncological Approvals: A 13-Year Review (1999-2011)

Abstract

Background: Advances in medicine, clinical trial design, and statistical methods affect product approvals. Over the last decade, there were many breakthroughs in the development of novel cancer therapies, including the wide application of biomarkers in drug development. Understanding trends and patterns of trial design and data submissions that lead to the approval of these novel agents assists oncologists, investigators, and regulatory personnel. Methods: All new molecular entity (NME) therapeutic oncological agents approved for the first time within the past 13 years (January 1, 1999 to December 31, 2011) were analyzed for product features, approved indications, regulatory metrics, and clinical trial design. Patterns and trends were reviewed. July 2005 marked the midpoint of this review, concurrent with the FDA establishing the Office of Oncology Drug Products (OODP). Regulatory metrics before and after the establishment of the OODP were compared and analyzed. The Fisher exact test was applied for statistical analyses. Results: A total of 47 new oncological approvals were identified, 2 to 7 approvals per year (median, 3.0), with 6.0-month median reviews. Comparing the pre- and post-OODP period, there was trending towards more approvals (4.3/year vs 2.9/year) along with more targeted agent approvals (50% vs 21%) in the post-OODP period, although these metrics did not reach statistical significance due to relatively small numbers and large variances. There were also numerically fewer orphan designations (36% vs 53%) and accelerated approvals (32% vs 37%) in the post-OODP period. Approvals were for small molecule targeted agents, 38% (frequently kinase inhibitors); monoclonal antibodies, 17%; conventional cytotoxics, 28%; hormonal agents, 13%; and miscellaneous agents, 4%. Two 2011 approvals were associated with companion diagnostics. First-line indications accounted for only 36%; 62% were parenterally administered. Multinational, multicenter, randomized phase II or III trials utilizing overall survival or progression-free survival endpoints were common pivotal trial features in solid tumors. Hematological malignancy trials involved multiple small, single-arm phase II studies measuring mainly response rate, commonly resulting in accelerated approval. Placebo controls (19%) and blinding (24%) were both seldom employed. Conclusions: Over the last 13 years, 55% of NME approvals were targeted agents or monoclonal antibodies, most not for first-line use. Most applications relied upon a single pivotal study for approval. Randomized trials supported most solid tumor approvals, whereas single-arm phase II studies supported (mostly accelerated) approvals in hematological malignancies. After establishment of the OODP, there were trends towards more approvals and less orphan designations.

Keywords

cancer drugs FDA approval NDA BLA trends biomarkers companion diagnostic targeted agents

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References

Dar

Shokat

. The evolution of protein kinase inhibitors from antagonists to agonists of cellular signaling. Annu Rev Biochem. 2011;80:769–795.

Rodon

Perez

Kurzrock

. Combining targeted therapies: practical issues to consider at the bench and bedside. Oncologist. 2010;15(1):37–50.

Lorusso

Eder

. Therapeutic potential of novel selective-spectrum kinase inhibitors in oncology. Expert Opin Investig Drugs. 2008;17(7):1013–1028.

Gutierrez

Kummar

Giaccone

. Next generation oncology drug development: opportunities and challenges. Nat Rev Clin Oncol. 2009;6(5):259–265.

Nair

. Personalized medicine: striding from genes to medicines. Perspect Clin Res. 2010;1(4):146–150.

Pircher

Hilbe

Heidegger

Drevs

Tichelli

Medinger

. Biomarkers in tumor angiogenesis and anti-angiogenic therapy. Int J Mol Sci. 2011;12(10):7077–7099.

Roberts

Stinchcombe

Der

Socinski

. Personalized medicine in non-small-cell lung cancer: is KRAS a useful marker in selecting patients for epidermal growth factor receptor-targeted therapy? J Clin Oncol. 2010;28(31):4769–4777.

Ross

. Cancer biomarkers, companion diagnostics and personalized oncology. Biomark Med. 2011;5(3):277–279.

Dimou

Harrington

Syrigos

. From the bench to bedside: biological and methodology considerations for the future of companion diagnostics in nonsmall cell lung cancer. Patholog Res Int. 2011;2011:312346.

10.

Jing

Greshock

Holbrook

Comprehensive predictive biomarker analysis for MEK inhibitor GSK1120212. Mol Cancer Ther. 2012;11(3):720–729.

11.

Tan

Thomas

Garrett

Biomarker-driven early clinical trials in oncology: a paradigm shift in drug development. Cancer J. 2009;15(5):406–420.

12.

Fine

Amler

. Predictive biomarkers in the development of oncology drugs: a therapeutic industry perspective. Clin Pharmacol Ther. 2009;85(5):535–538.

13.

Brannath

Zuber

Branson

Confirmatory adaptive designs with Bayesian decision tools for a targeted therapy in oncology. Stat Med. 2009;28(10):1445–1463.

14.

Lee

Liu

. Bayesian adaptive randomization designs for targeted agent development. Clin Trials. 2010;7(5):584–596.

15.

Berry

. Adaptive clinical trials: the promise and the caution. J Clin Oncol. 2011;29(6):606–609.

16.

Wang

Hung

O’Neill

. Adaptive patient enrichment designs in therapeutic trials. Biom J. 2009;51(2):358–374.

17.

Korn

Freidlin

Abrams

Halabi

. Design issues in randomized phase II/III trials. J Clin Oncol . 2012;30(6):667–671.

18.

Renfro

Carlin

Sargent

. Bayesian adaptive trial design for a newly validated surrogate endpoint. Biometrics. 2012;68(1):258–267.

19.

Pazdur

. The FDA’s new oncology office. Clin Adv Hematol Oncol. 2005;3(8):612–613.

20.

Faunce

Townsend

McEwan

. The Vioxx pharmaceutical scandal. J Law Med. 2010;18(1):38–49.

21.

Scheen

. Suspension of the commercialization of sibutramine and rosiglitazone in Europe. Rev Med Liege. 2010;65(10):574–579.

22.

Barden

Weaver

. The rise of micropharma. Drug Discov Today. 2010;15(3-4):84–87.

23.

Hober

. Biotech reviews: keeping up with current developments. Biotechnol J. 2011;6(9):1031.

24.

Anonymous. Biotech industry highlights. Biotechnol J. 2011;6(12):1433–1434.

25.

Heinzelmann

. Biotech research: bringing better therapies to the people. Chimia (Aarau). 2010;64(1-2):91–93.

26.

Azare

. From cancer alley to biotech: the importance of mentors. J Cancer Educ. 2009;24(Suppl 2):S71–S72.

27.

Ledford

. Monoclonal antibodies come of age. Nature. 2008;455(7212):437.

28.

Food and Drug Administration. NME drug and new biologic approvals. Available at: http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/ucm121136.htm. Accessed January 2, 2012.

29.

Food and Drug Administration. What’s new from the Office of Oncology Drug Products. Available at: http://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm093885.htm. Accessed January 2, 2012.

30.

Johnson

Ning

Farrell

Justice

Keegan

Pazdur

. Accelerated approval of oncology products: the Food and Drug Administration experience. J Natl Cancer Inst. 2011;103(8):636–644.

31.

Sridhara

Johnson

Justice

Keegan

Chakravarty

Pazdur

. Review of oncology and hematology drug product approvals at the US FDA between July 2005 and December 2007. J Natl Cancer Inst. 2010;102(4):230–243.

32.

Center Watch. FDA approved drugs for oncology. Available at: http://www.centerwatch.com/drug-information/fda-approvals/drug-areas.aspx?AreaID=12. Accessed January 2, 2012.

33.

The Pink Sheet Web site. http://thepinksheet.elsevierbi.com. Accessed January 2, 2012.

34.

Food and Drug Administration. Class labeling changes to anti-EGFR monoclonal antibodies, cetuximab (Erbitux) and panitumumab (Vectibix): KRAS mutations. Available at: http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm172905.htm. Accessed January 2, 2012.

35.

Bokemeyer

Bondarenko

Makhson

Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27(5):663–671.

36.

Van Cutsem

Köhne

Hitre

Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Eng J Med. 2009;360(14):1408–1417.

37.

Barton

Starling

Swanton

. Predictive molecular markers of response to epidermal growth factor receptor(EGFR) family-targeted therapies. Curr Cancer Drug Targets. 2010;10(8):799–812.

38.

Clinical Trials. Cediranib maleate and cilengitide in treating patients with progressive or recurrent glioblastoma. Available at: http://clinicaltrials.gov/ct2/show/NCT00979862?term=cilengitide+biomarker&rank=1. Accessed January 2, 2012.

39.

Clinical Trials. Temsirolimus plus neratinib for patients with metastatic HER2-amplified or triple negative breast cancer. Available at: http://clinicaltrials.gov/ct2/show/NCT01111825?term=HKI272&recr=Open&rank=3. Accessed January 2, 2012.

40.

Clinical Trials. A study of GSK2118436 in BRAF mutant metastatic melanoma to the brain. Available at: http://clinicaltrials.gov/ct2/show/NCT01266967? term=GSK2118436+biomarker&rank=2. Accessed January 2, 2012.

41.

Personalized Medicine Coalition. Policy. Available at: http://www.personalizedmedicinecoalition.org/policy. Accessed January 2, 2012.

42.

Code of Federal Regulations. 2010, Title 21, Volume 5, Part 314. Applications for FDA approval to market a new drug, subpart D: FDA action on applications and abbreviated applications. Sec. 314.126: adequate and well-controlled studies (21CFR314.126). Available at: http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=314.126. Accessed January 2, 2012.

43.

European Medicines Agency. ICH topic E9: statistical principles for clinical trials (1998). Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500002928.pdf. Accessed January 2, 2012.

44.

Pazdur

. Endpoints for assessing drug activity in clinical trials. Oncologist. 2008;13(Suppl 2):19–21.

45.

McKee

Farrell

Pazdur

Woodcock

The role of the U.S. Food and Drug Administration review process: clinical trial endpoints in oncology. Oncologist. 2010;15(Suppl 1):13–18.

46.

Chow

Chang

. Adaptive design methods in clinical trials: a review. Orphanet J Rare Dis. 2008;3:11.

47.

Coffey

Kairalla

. Adaptive clinical trials: progress and challenges. Drugs R D. 2008;9(4):229–242.

48.

Food and Drug Administration. Guidance for industry: adaptive clinical trials design for drugs and biologics. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm201790.pdf. Accessed January 2, 2012.

49.

Wang

Bretz

. From adaptive design to modern protocol design for drug development, part I: editorial and summary of Adaptive Designs Session at the Third FDA/DIA Statistics Forum. Drug Info J. 2010;44:325–331.

50.

Hsu

Gupta

An overview of the FDA draft guidance on adaptive design clinical trials. Available at: http://www.fda.gov/downloads/BiologicsBloodVaccines/…/UCM209179.pdf. Accessed January 2, 2012.

51.

Wang

SJ.

The role of adaptive design in clinical development program. Available at: http://stat.rutgers.edu/iob/bioconf10/slides/SueJaneW.pdf. Accessed January 2, 2012.

52.

Wiederrecht

Hill

Beer

. Partnership between small biotech and big pharma. IDrugs. 2006;9(8):560–564.

53.

Moore

Walker

. Deal-making trends in oncology. Nat Rev Drug Discov. 2009;8(8):604.