The 21st Century Cures Act, enacted in December 2016, focuses on the use of real world data (real world data, RWD) and real world evidence (real world evidence, RWE) to support regulatory decisions, including new indications for approval of approved drugs.
regulations define RWE as data on drug use or potential benefits and risks from a traditional clinical trial.
the FDA extended the congressional definition to define RWE as clinical evidence of the use and potential benefits or risks of pharmaceutical products obtained from RWD analysis.
RWE may be generated by different research designs or analyses, including but not limited to randomized trials, including large-scale simple trials, practical tests, and observational studies (forward or retrospective studies).
RWD is data on patient health and healthcare providers that are regularly collected from a variety of sources.
RWD can come from a number of sources (Image Source: References) Traditionally, drug approvals have been based on clinical trial evidence, while RWE has been used for post-market monitoring studies.
randomized clinical trials (RCT) can accurately measure efficacy and short-term toxicity in a highly controlled environment, and RWD provides information on treatment accessibility, drug use, and long-term safety and efficacy from everyday clinical practice.
complements clinical trial information, RWD provides an in-depth understanding of cancer medical care.
in an effort to speed up the use of new therapeutic drugs, the FDA has repeatedly made clear its willingness to change the traditional regulatory paradigm, allowing RWE to replace clinical trial evidence to support drug approvals.
so far, there are three FDA-approved drugs and indications under RWE.
recently, Dr. Michael J. Raphael of Queens University in Canada, Dr. Bishal Gyawali of Harvard Medical School's Brigham and Women's Hospital, and others published an op-ed on Nature Reviews Clinical Oncology to discuss rWE approval of new drugs for cancer treatment and new indications.
first approved under RWE: Bona spitting monotodrinis in 2014, the FDA accelerated approval of Bonatuumab for the treatment of adult Philadelphia chromosomal negative recurrent/refractive precursor B-cell acute lymphoblastle leukemia.
FDA based its approval on data from a single arm 2 study conducted between 2012 and 2013 for 189 patients.
data show that the total remission rate (complete remission, CR) or partial hematologic recovery (CRh) was 43%.
used a historical control group of RWE to support the approval of the application.
the control group included 694 patients treated between 1990 and 2013, with a relatively complete remission rate of 24%.
notable, the RWD of 1,706 patients treated between 1990 and 2013 was reported by researchers enrolled in the Bona toss, and the overall total overall remission rate (CR rate) was higher after 2005, at 45%.
Results of a phase 3 randomized controlled trial (RCT) after the accelerated approval of Bonatona monotomatox showed that the use of Bonathazumab was superior to the overall survival of standard therapeutic chemotherapy (median OS: 7.7 months vs. 4.0 months; HR (risk ratio) 0.71,95% CI 0.55-0.93; P-0.01).
, the relevant pharmaceutical companies have formally conducted validation trials of Bonata-spitting and have indeed demonstrated the efficacy of the relevant drugs.
, however, it is easy to think that many other drugs show edifying compared with low-quality historical controls, but in subsequent randomized controlled trials using standard care arms, their efficacy may not be proven.
there may be delays, completion, or failure to conduct post-marketing clinical trials due to FDA-requested post-approval studies.
at the same time, many post-market clinical trials often share many design flaws with pre-approval trials.
this understanding has aroused a lot of concern.
because it has the potential to cause many patients to be unnecessarily exposed to the toxicity of ineffective or less effective drugs.
therefore, there are real risks to this drug approval model.
the author believes that the drug regulatory agency in the review and approval, in the use of RWE to support conditional approval of drugs at the same time, the RCT test is not biased, to confirm the therapeutic effect is necessary, should be as a condition of conditional approval to start the RCT trial.
the second example of RWE, which supports RWE approval for new drugs or new indications, from Electronic Medical Records (EHR), is the FDA's accelerated approval of the anti-PD-L1 monoantibutalumab in 2017 for patients with sexually metastatic Merkel cell cancer (MCC) at age 12.
fda for the first time based on RWE evidence from Electronic Medical Records (EHR).
approval was based primarily on the results observed in the single arm 2 study of 88 patients from 35 cancer research centers: 33% objective response rate (objective response rate) and 86% long-lasting response rate (june).
image source: References, avelumab's basis for accelerated approval, including comparative historical data from the iKnowMed database.
iKnowMed database is the Cancer Network of the United States( Cancer Network) specifically for physicians's electronic medical records system.
in 14 patients with metastatic MCC, or patients who received first-line chemotherapy after the ongoing disease progression, the historical response rate to second-line chemotherapy was 29%, and there was no sustained response in patients in June.
note, there were 14 patients in a case group that were thought to be fully used for historical queue comparisons.
in addition, in seeking to define historical queues through the iKnowMed database, the researchers initially determined that 39 potential metastatic MCC patients should receive second-line chemotherapy.
, however, a retrospective chart test later showed that 11 of these patients had no metastatic disease, four were involved in clinical trials, and the four patients did not receive standard chemotherapy alone, and three patients did not actually receive second-line chemotherapy.
these results show that in the use of RWE, there are concerns about specific issues such as data quality, effectiveness, reliability and access to medicines, adverse effects and sensitivity to outcomes of interest.
another one-arm historical control study in MCC patients, in line with a post-market research commitment that avelumab received accelerated approval.
the study needed to be conducted in patients who had not previously received chemotherapy.
the authors argue that this example illustrates the broader concern that the mere existence of related immunotherapy is therefore used as a basis for proving the clinical balance of power ineffective? The limitations of using historical controls, coupled with the frequent lying high response rates in Phase 2 clinical trials, are not uncommon in Phase 3 clinical trials where failure to translate into survival benefits is not common.
therefore, the authors argue that there is reason to question whether new chemotherapy drugs that are less toxic for metastatic MCC will also be approved using evidence similar to the evidence on which avelumab monotonabics are approved. Of course, post-marketing research required after approval will be more than just a large-scale study with an unproven alternative endpoint and the same suboptimal design in different treatment regimens.
the level of evidence required to support the approval of immunotherapy should not differ from the level of evidence required to support cytotoxic chemotherapy.
Pabosini Extendive Indications, the third approved by RWE, is the Palbocilib indications extension.
the drug's initial approved indications are used in conjunction with aromatase inhibitors or fluorovis groups and are used in women with advanced estrogen receptor-positive, HER2-negative breast cancer.
April 2019, the FDA approved the extension of Pabosini indications to the treatment of patients in the men affected, based on RWE, a three-business database of Flatiron and Pfizer.
data showed that of the 37 male patients who received first-line treatment with palbosini and lysic, the median "prescription duration" was 8.5 months, compared with 214 men who received only the treatment of lysic, with a corresponding value of 4.3 months.
so far, the overall survival (OS) or progression survival of these populations has not been stated.
RWE used to determine safety, from a review of adverse events recorded in Pfizer's global security database, and the retrieval of FDA adverse event reporting systems.
due to the limited nature and characteristics of adverse events, the FDA "primarily relies on the established palbociclib safety characteristics to characterize the safety risks to male patients."
"S rWE approved Pabosini's main reason for the very rare case of male breast cancer, making it difficult to conduct large randomized clinical trials.
but the author of the article believes that such a reason is far-fetched.
, the FIRM-ACT clinical trial for advanced adenocarcinoma and the ALLIANCE A091105 clinical trial for advanced gliomas had a incidence of 2 to 4 to 0.7 million years in men, respectively, lower than the incidence of breast cancer in men by 1.06/100,000 years.
the authors therefore believe that randomized clinical trials could also be conducted for rare cancers.
three lives? RWD and RWE play an important role in establishing evidence of the safety and effectiveness of cancer treatment.
RWE has many important uses, especially after the drug is approved for market, to study patients' access to new treatments and whether the efficacy demonstrated in RCT translates into the effectiveness of conventional treatments.
the authors argue that the real problem preventing timely access to these real is not the delay in regulatory review, but the design of stymied randomized clinical trials that are old, too strict, not pragmatic enough and have limited distribution of test sites.
RWE helps accelerate the expansion of indications in the approval of new drugs for cancer treatment or existing cancer treatments, but rWE approaches face a variety of risks.
authors are concerned that the use of RWE in regulatory approvals will increase uncertainty about the true benefits of providing therapeutic drugs to patients.
patients should have timely access to new cancer treatments, and strong evidence that drugs can significantly improve their lives in a qualitative and quantitative manner.