What is new
Key findings
What this adds to what is known
What is the implication, what should change now
Background
Study characteristics | Characteristics described or analyzed | ||||||||
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(Reference, publication year) | Objective | Health authority | Time period | Approval type | Disease characteristics | Regulatory* | Trials | Endpoints | Effect sizes |
Zeitoun et al. (2018) [28] | To characterize post-marketing trials of cancer drugs | EMA, FDA | 2005–2010 | Original and supplemental | Solid tumors and hematologic malignancies | x | x | x | |
Barnes and Amir (2017) [29] | To describe the efficacy, safety, tolerability, and price of new cancer drugs. | FDA | 2005–2016 | Not described/Unclear | Solid tumors only | x | x | x | |
Booth and Del Paggio (2017) [30] | To evaluate the value of novel drugs using the ESMO Magnitude of Clinical Benefit Scale and ASCO Value Framework. | FDA | 2015–2016 | Not described/Unclear | Selected solid tumors [a] | x | x | ||
Brooks et al. (2017) [31] | To understand the consequences of delaying approval of novel drugs until data on overall survival is available | FDA | 1952–2016 | Original and supplemental | Ten most common solid tumors [b] | x | |||
Davis et al. (2017) [11] | To determine the availability of data on overall survival and quality of life benefits of cancer drugs. | EMA | 2009–2013 | Original and supplemental | Solid tumors and hematologic malignancies | x | x | x | x |
Grossmann et al. (2017) [32] | To investigate the extent of EMA-approved cancer drugs that meet the threshold for “meaningful clinical benefit”, defined by the framework. | EMA | 2011–2016 | Original and supplemental | Solid tumors and hematologic malignancies | x | x | ||
Naci et al. (2017) [33] | To characterize preapproval and confirmatory clinical trials of drugs granted accelerated approval. | FDA | 2009–2013 | Original and supplemental | Solid tumors and hematologic malignancies [c] | x | x | ||
Naci et al. (2017) [9] | To systematically evaluate the timing and characteristics of clinical trials of drugs receiving accelerated approval. | FDA | 2000–2013 | Original only | Any disease or medical condition | x | x | x | |
Pease et al. (2017) [34] | To characterize controlled studies for drugs approved based on limited evidence. | FDA | 2005–2012 | Original only | Any disease or medical condition [d] | x | x | x | |
Salas-Vega et al. (2017) [35] | To evaluate the comparative therapeutic value of all new cancer medicines. | EMA, FDA | 2003–2013 | Original only | Solid tumors and hematologic malignancies | x | x | ||
Smith et al. (2017) [36] | To characterize the primary endpoints used to support FDA approvals for new drug or novel hematologic malignancies indications. | FDA | 2002–2015 | Original and supplemental | hematologic malignancies only | x | x | x | x |
Tibau et al. (2017) [37] | To derive the clinically meaningful benefit for FDA-approved drugs using the ESMO Magnitude of Clinical Benefit Scale. | FDA | 2006–2016 | Original and supplemental | Solid tumors only | x | |||
Grossmann and Wild (2016) [38] | To describe the knowledge about the clinical benefit of new cancer therapies at the time of approval. | EMA | 2009–2016 | Original and supplemental | Solid tumors and hematologic malignancies | x | x | ||
Hoekman et al. (2015) [39] | To describe the marketing authorization of oncology medicines granted based on the conditional marketing authorization pathway | EMA | 2006–2013 | Original only | Solid tumors only | x | x | x | |
Kim and Prasad (2015) [7] | To describe how often cancer drugs are approved based on a surrogate endpoint, whether subsequent studies for these drugs are reported, and whether the drugs improve overall survival. | FDA | 2008–2012 | Not described/Unclear | Solid tumors and hematologic malignancies | x | x | ||
Wang and Kesselheim (2015) [40] | To characterize the types of comparators and endpoints used in efficacy trials for approvals of supplemental indications, compared with the data supporting these drugs’ originally approved indications. | FDA | 2005–2014 | Supplemental only | Any disease or medical condition [e] | x | x | x | |
Winstone et al. (2015) [41] | To characterize the clinical trial evidence of orphan drugs. | EMA | 2006–2014 | Not described/Unclear | Solid tumors and hematologic malignancies[f] | x | x | x | |
Downing et al. (2014) [6] | To characterize pivotal efficacy trials for newly approved novel therapeutic agents. | FDA | 2005–2012 | Original only | Any disease or medical condition [e] | x | x | x | |
Fojo et al. (2014) [42] | To determine the availability of data on overall survival and quality of life benefits of cancer drugs. | FDA | 2002–2014 | Not described/Unclear | Solid tumors only | x | |||
Hartmann et al. (2013) [12] | To review the outcomes of marketing authorization applications for cancer drugs | EMA | 2006–2011 | Original only | Solid tumors and hematologic malignancies | x | x | x | x |
Martell et al. (2013) [43] | To describe approval trends and characteristics. | FDA | 1949–2011 | Original and supplemental | Solid tumors and hematologic malignancies | x | x | x | |
Thomas et al. (2013) [44] | To describe pre- and post-approval availability of published comparative efficacy studies. | FDA | 2000–2010 | Original only | Any disease or medical condition [g] | x | x | ||
Goldberg et al. (2011) [45] | To quantify the availability of comparative efficacy data for new molecular entities. | FDA | 2000–2010 | Original only | Any disease or medical condition | x | x | ||
Johnson et al. (2011) [46] | To provide an overview of the regulatory history of accelerated approved oncology products. | FDA | 1992–2010 | Not described/Unclear | Solid tumors and hematologic malignancies[c] | x | x | ||
Kesselheim et al. (2011) [47] | To define characteristics of orphan cancer drugs and their pivotal clinical trials and to compare these with non-orphan drugs. | FDA | 2004–2010 | Not described/Unclear | Solid tumors and hematologic malignancies[f] | x | x | x | |
Ocana and Tannock (2011) [48] | To determine if a difference in outcome between the experimental and control groups was detected that was equal to or greater than the value predefined in the protocol | FDA | 2000–2010 | Not described/Unclear | Solid tumors only | x | |||
Sridhara et al. (2010) [13] | To conduct an overview of products that were reviewed by the FDA’s Office of Hematology and Oncology Products for marketing approval and the regulatory actions taken during July 2005 to December 2007. | FDA | 2005–2007 | Original and supplemental | Solid tumors and hematologic malignancies | x | x | x | x |
Tsimberidou et al. (2009) [10] | To review the long-term safety and efficacy or cancer drugs approved without evidence from randomized trials. | FDA | 1973–2006 | Original only | Solid tumors and hematologic malignancies[h] | x | x | x | x |
Methods
Data collection
Project organization and database structure
Step 1: Inventory of FDA-approved drugs and acquisition of approval packages
Inventory of FDA-approved drugs
Selection of cancer indications
Extraction of information on drug, indication, and regulatory characteristics
Variable | (Data type), data value or code | Description and further elaboration |
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Drug characteristics | ||
Brand name | (Character string) | As accepted by the US Food and Drug Administration (FDA) and used in the US. |
Generic name | (Character string) | According to US Adopted Names. |
Type of active compound | “NME”; “NBE” | NME (New Molecular Entity, that is, a small molecule) or NBE (New Biologic Entity; that is, a biologic product). |
Date of marketing authorization | (Date) | Format: YYYY-MM-DD. |
Innovation class | “First-in-class”; “Advance-in-class”; “Addition-to-class” | Drug innovation class, following the definitions and categories described by Lanthier et al. [17]. New molecular or new biological entities are categorized as “First-in-class” if they define a new drug class, as “Advance-in-class” if they offer significant therapeutic advance (that is, they were granted priority review by the FDA) over existing drugs in the same class, or “Addition-to-class” in any other case. |
Indication characteristics | ||
FDA-approved indication | (Character string) | Medical condition for which the drug of interest has been approved, according to the first-ever available FDA drug label. |
Line of treatment | “1st”; “2nd”; “3rd”; “4th” | The clinical order the treatment is given |
NDA/BLA number | (Integer) | FDA’s Original New Drug Application (NDA) or Biologics License Application (BLA) number. A unique identifier assigned to each application for approval submitted to the FDA. |
Site of disease | “Breast”; “Digestive”; “Gastrointestinal”; “Endocrine and Neuroendocrine”; “Genitourinary”; “Gynecologic”; “Leukemia”; “Lymphoma”; “Musculoskeletal”; “Neurologic”; “Other - Multicentric Castleman’s Disease”; “Other - Other”; “T-cell malignancies”; “Respiratory/Thoracic”; “Skin” | Cancers by body location/system (following the classification by the National Cancer Institute (www.cancer.gov/types/by-body-location). |
Regulatory characteristics | ||
Priority review | “Standard”; “Priority” | Priority review is an expedited FDA review program for drugs that provide a significant improvement over existing therapies. |
Accelerated approval | “Yes”; “No” | Expedited FDA approval pathway for drugs that (a) treat serious conditions, (b) provide a meaningful advantage over available therapies, and (c) demonstrate effects on a surrogate endpoint that is reasonably likely to predict clinical endpoints. Accelerated approved drugs do not meet regulatory standards for traditional or full approval and are therefore required to provide evidence of clinical benefit in subsequent pivotal trials. |
Breakthrough therapy designation | “Yes”; “No” | An expedited program at FDA introduced in 2012 for drugs that are (a) intended to treat serious conditions and (b) provide preliminary clinical evidence of substantial improvement over existing therapies. |
Orphan designation | “Yes”; “No” | A status assigned by the FDA to rare disease indications if less than 200,000 people in the US are affected. |
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the first-ever available FDA drug label from the Drugs@FDA database [3] for information about the FDA-approved indication(s).
Approval packages
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Medical review (sometimes referred to as clinical review)
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Statistical review
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Drug label
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Cross-discipline team leader review
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Summary review
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Multi-discipline review.
Step 2: Trial selection and characterization
Identification of trials, eligibility assessment, and data extraction
Variable | (Data type), data value or code | Description and further elaboration |
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Trial characteristics (for any trial identified in step 2) | ||
Trial name reference | (Character string) | Reference trial name. |
Trial name 1 | (Character string) | Alternative trial name 1. |
Trial name 2 | (Character string) | Alternative trial name 2. |
Pivotal | “Yes”; “No” | Trial eligibility criteria: the trial is described as “pivotal” (or similar). |
Randomized | “Yes”; “No”; “Single-arm” | Trial eligibility criteria: patients are randomly assigned to treatment arms. |
On-label | “Yes”; “No”; “Partially”; “Not reported” | Trial eligibility criteria: the drug of interest is tested in the approved indication. |
Comparator | “Yes”; “No”; “Partially”; “Not reported” | Trial eligibility criteria: the control intervention does not contain the active component of the drug under review. |
Relevance | “Yes”; “No” | Trial eligibility criteria: two reviewers consider that this trial was definitely used for approval, but none of the abovementioned eligibility criteria are met. |
Eligible rationale | “explicitly pivotal”; “likely pivotal”; “other pivotal”; “not eligible” | The rationale for trial eligibility based on eligibility algorithm. |
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the trial was described as pivotal (criterion 1 alone is met; categorized as “explicitly pivotal”)
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the trial was not described as pivotal but was randomized (criterion 2), enrolled a population that matched the approved target population (criterion 3), and had a control arm that did not contain the intervention under review (criterion 4) (categorized as “likely pivotal RCT”)
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the trial was not “explicitly pivotal” or a “likely pivotal RCT” but considered otherwise essential (criterion 5) for the approval decision (categorized as “other pivotal”). Such trials were typically single-arm studies in accelerated approval settings.
Variable | (Data type), data value or code | Description and further elaboration |
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Trial characteristics (for any trial deemed eligible in step 2) | ||
Randomization | “Yes”; “No” | Random allocation of patients to trial arms |
N arms | (Integer) | The number of trial arms. |
Other trial characteristics | “Parallel”; “Cross-over”; “Uncontrolled/historic control” | Patients are randomized to a concurrent control (“Parallel”) or to a sequence of treatments (“Cross-over”). |
Comparison characteristics | ||
Arm 1 | ||
Type | “Experimental”; “Active”; “Placebo”; “No treatment”; “Dose-comparison” | In add-on trials, comparators were categorized as “active” whenever an intervention given on top of an active treatment (for example, standard of care with or without placebo). Comparators were categorized as “No treatment” if “supportive therapy” or “usual care” was given which included a wide variety of treatments rather than a specific intervention. |
Characteristics | (Character string) | All interventions in arm 1, including drug names, doses, and route of administration. Interventions used to avoid treatment-related complications were not recorded, such as pre-treatment with acetaminophen/diphenhydramine to reduce infusion reactions with intravenous infusion of therapeutic biologics, or anti-emetics to reduce nausea and vomiting associated with certain chemotherapies. |
Arm 2 | ||
Type | “Active”; “Placebo”; “No treatment”; “Dose-comparison”; “Uncontrolled/historic control” | See “Arm 1” above. |
Characteristics | (Character string) | See “Arm 1” above. |
Step 3: Treatment effect estimates on overall survival, progression-free survival, and response rate
Data extraction
Variable | (Data type), data value or code | Description and further elaboration |
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Overall survival OR progression-free survival | ||
Is the endpoint reported | “Yes”; “No” | . |
Response criteria | (Character string) | Progression-free survival only: response criteria used to measure response to treatment |
Number of patients in arm 1 | (Integer) | Number of patients in arm 1 included in the endpoint analysis |
Number of patients in arm 2 | (Integer) | Number of patients in arm 2 included in the endpoint analysis |
Number of events in arm 1 | (Integer) | Number of patients with events in arm 1 included in the endpoint analysis |
Number of events in arm 2 | (Integer) | Number of patients with events in arm 2 included in the endpoint analysis |
Hazard ratio: coverage probability | (Float) | Confidence level (1-alpha) in the endpoint analysis |
Hazard ratio: point estimate | (Float) | Hazard ratio point estimate (selection rule: primary analysis according to the US Food and Drug Administration, but longest follow-up) |
Hazard ratio: lower confidence bound | (Float) | The lower bound of the confidence interval of the hazard ratio estimate |
Hazard ratio: upper confidence bound | (Float) | The upper bound of the confidence interval of the hazard ratio estimate |
Randomization ratio | “1:1”; “Not 1:1” | |
Regression P value | (Float) | |
Test type | “1-sided”; “2-sided”; “Not reported” | |
Hazard rate in arm 1 | (Float) | |
Hazard rate in arm 2 | (Float) | |
Logrank observed minus expected events in arm 1 | (Integer) | |
Logrank observed minus expected events in arm 2 | (Integer) | |
Logrank variance | (Float) | |
Median survival time in arm 1: point estimate | (Float) | Median survival time (point estimate) in arm 1 |
Median survival time in arm 1: lower confidence bound | (Float) | The lower bound of the confidence interval of the median survival time in arm 1 |
Median survival time in arm 1: upper confidence bound | (Float) | The upper bound of the confidence interval of the median survival time in arm 1 |
Median survival time in arm 2 | (Float) | Median survival time (point estimate) in arm 2 |
Median survival time in arm 2: lower confidence bound | (Float) | Lower bound of the confidence interval of the median survival time in arm 2 |
Median survival time in arm 2: upper confidence bound | (Float) | Upper bound of the confidence interval of the median survival time in arm 2 |
Time unit | “Days”; “Weeks”; “Months”; “Years”; “Not reported” | Time unit used to measure median survival improvement |
Tumor response | ||
Is the endpoint reported | “Yes”; “No” | . |
Primary endpoint | “Yes”; “No” | Is the tumor response endpoint described as the primary endpoint of the trial |
Type of hypothesis tested | “Superiority”; “Not 1° endpoint”; “Non-inferiority” | Is the trial designed to demonstrate the superiority of the test drug over control in tumor response |
Response criteria | (Character) | Set of response criteria used to measure tumor response |
Number of patients in arm 1 | (Integer) | Number of patients in arm 1 included in the tumor response endpoint analysis |
Number of patients in arm 2 | (Integer) | Number of patients in arm 2 included in the tumor response endpoint analysis |
Number of events in arm 1 | (Integer) | Number of patients with events in arm 1 included in the tumor response endpoint analysis |
Number of events in arm 2 | (Integer) | Number of patients with events in arm 2 included in the tumor response endpoint analysis |