Drugs Cleared Through The FDA’s Expedited Review Offer Greater Gains Than Drugs Approved By Conventional Process

The Food and Drug Administration (FDA) requires various phases of testing to establish a drug’s safety and efficacy before it can be marketed in the United States. ¹ However, when the FDA deems a drug to meet a particular unmet clinical need, it has the flexibility to expedite its review. Four different programs offer this flexibility for drugs meeting different qualifying criteria: priority review, accelerated approval, fast track, and breakthrough therapy. ²

By focusing its resources on drugs believed to offer the largest clinical advances or address the most significant unmet needs, the FDA can enhance public health, increase regulatory efficiency, and promote drug development. We assessed the FDA’s record with these programs by examining whether drugs approved through them have offered larger health gains than therapies approved through conventional processes.

The 21st Century Cures Act, enacted in December 2016, contained various provisions intended to speed FDA approvals. These provisions include additional expedited review programs to further speed new medical technology to the market. Opponents have raised concerns about expanding the existing programs, fearing that loosening the FDA’s evidentiary standards would increase the likelihood that vulnerable patient populations would be exposed to harmful or ineffective drugs. ^3–5

In light of the added expedited review programs, an understanding of how well the existing programs are performing is valuable. Because of the FDA’s experience with the previous expedited review programs—three of the four were established more than two decades ago—our hypothesis was that drugs in the programs have, on average, provided larger health gains than drugs not in the programs. To compare the clinical advances offered by drugs included and those not included in expedited review, we examined incremental health improvements measured by the additional quality-adjusted life-years (QALYs) provided by a new drug, compared to prevailing treatment options.

Study Data And Methods

We developed a data set of incremental QALY gains associated with drugs the FDA included in the expedited review programs and those the FDA did not include. We used drug-indication pairs as the unit of analysis. In other words, when incremental QALY data were available for a drug for multiple indications, each indication was included separately in the data set. We previously used this data set and a similar methodological approach to compare the incremental health gains associated with specialty and traditional drugs. ^6,7

The QALY is a standard metric of health that accounts for both quality and length of life. One QALY is equal to one year experienced in perfect health. A year experienced in some degree of impairment or disability is valued at a number between zero and one, depending on the degree of impairment. For example, four years lived in perfect health equal four QALYs. Eight years experienced with a quality of life of 0.5 per year is also equal to four QALYs. We used QALYs as the metric of health gain, as they facilitate comparisons of treatments indicated for different diseases. ^8–10

Search Strategy And Data

We identified all new molecular entities—that is, drugs that had not previously been approved by the FDA or marketed in the United States—approved by the FDA in the period 1999–2012 from the FDA’s database of approved drug products. ¹¹ We used information provided on the FDA’s website to classify each drug with respect to its inclusion in the priority review, accelerated approval, and fast track programs. ^12–15 We excluded drugs in the breakthrough therapy program because it was implemented in 2012. Because of the lag between drug approval and publication of cost-utility analyses, we did not include drugs approved after 2012. ¹⁶

For each drug, we searched the PubMed database for cost-effectiveness analyses reporting a cost per QALY gained (cost-utility analyses) and for comparative effectiveness studies that compared the benefits and risks of competing treatments in terms of QALYs. We searched this database using the drug’s brand and chemical names and the search term quality-adjusted life year OR quality-adjusted life-year OR QALY . We restricted our search to studies involving human participants and published in English-language journals.

We included studies that evaluated drugs for their labeled indication or indications and that compared the drugs with prevailing treatment options available at the time of FDA approval. We excluded studies that evaluated the drug of interest for an off-label indication; included comparator treatments that were unavailable on the date of its FDA approval; or, in our judgment, did not compare the drug to an appropriate active treatment—that is, the included comparator treatment was a placebo or no treatment, despite the availability of an active comparator. For each study, we considered the investigators’ reasoning for their choice of comparator treatments—for example, whether it represented prevailing clinical practice or was consistent with current treatment guidelines.

Because evidence suggests that pharmaceutical industry sponsorship may influence cost-utility study findings, ^17,18 we categorized each study according to its source of funding: whether it was funded by a non-industry source; was sponsored by the pharmaceutical industry; or was unfunded. To be conservative, we included only unfunded studies and studies funded by non-industry sources.

Also to be conservative, when a study compared the drug of interest to multiple alternatives, we selected as the comparator the most effective intervention available at the time of FDA approval—that is, the comparator treatment with the largest reported QALY gain. For example, one study compared the drug of interest (adefovir, a drug the FDA approved in 2002 for the treatment of chronic hepatitis B) to four alternatives: best supportive care, lamivudine (approved in 1995), subcutaneous or conventional interferon-α (1998), and pegylated interferon α-2a (2005). ¹⁹ Of the drugs available before the FDA approved adefovir, lamivudine was estimated to be most effective (it offered 18.08 QALYs compared to adefovir’s 19.15 QALYs). We therefore used a QALY gain of 1.07 for adefovir in our data set.

QALY Gains

We used the included cost-effectiveness and comparative-effectiveness studies to develop the data set of incremental QALY gains associated with each drug. When the FDA had approved a drug for multiple indications, we considered each indication separately (as noted above). For example, we identified incremental QALY gain estimates for dabigatran for two indications: reducing the risk of stroke in patients with nonvalvular atrial fibrillation, and treating deep venous thrombosis and pulmonary embolism. The FDA first approved dabigatran in 2010 for patients with atrial fibrillation and included the drug in the priority review program. It subsequently approved dabigatran in 2014 for treatment of deep venous thrombosis, which was not in an expedited review program.

We included estimates of incremental QALY gains reported in each study’s base-case analysis in the data set. When the study reported multiple incremental QALY gain estimates in the base case—such as estimates pertaining to different time horizons or patient populations—we calculated a mean estimate from the different scenarios. For example, Mari Elshout and coauthors compared aflibercept to alternatives for the treatment of age-related macular degeneration using two time horizons (five and two years) in base-case analyses. ²⁰ In these situations, we calculated the mean of the reported values to assign a single estimate of incremental QALY gain for each study.

When we identified multiple studies that met our inclusion criteria, we applied an equal weight to each study to calculate an aggregate estimate of incremental QALY gain. For example, if a drug was associated with three studies, we assigned a weight of one-third to each study estimate.

Analysis

We compared incremental QALY gains for drug-indication pairs reviewed through the conventional process—that is, they were not in any expedited review program—with the gains for pairs in at least one program. We then compared incremental QALY gains for drug-indication pairs in a single program with the gains for pairs in two or more expedited review programs. We compared incremental QALY gains using Mann-Whitney U tests (to compare median values of the different distributions) and Kolmogorov-Smirnov tests (to compare the shape of the different distributions). We used these nonparametric statistical tests because the number of drugs with high QALY gains skewed the data set.

In a second set of analyses, we examined each expedited review program separately, using the same statistical tests to compare incremental QALY gains for drug-indication pairs in the expedited review program versus pairs not in the program.

In sensitivity analyses, we repeated each of the above analyses using first the highest and then the lowest reported estimates of incremental QALY gains for each drug-indication pair. Furthermore, because a preponderance of orphan drugs in our sample was included in at least one expedited review program, we repeated the analyses with orphan drugs excluded in a second sensitivity analysis.

In supplementary analyses, we examined whether the QALY differential between drugs included in the expedited review programs and those not included had changed from 1999 to 2012. We used univariate regression to conduct these analyses.

Limitations

Our study had a number of limitations. An important one is that because estimates of incremental QALY gains were not available for all of the drugs the FDA approved over the study period, our sample might not be fully representative. As noted above, because of the lag between drug approval and publication of cost-utility analyses, we did not include drugs approved after 2012. ¹⁶

A second limitation is that the included cost-utility analyses are likely subject to some degree of publication bias—that is, they tend to report favorable cost-effectiveness ratios and thus favorable incremental QALY gain estimates. ¹⁸ Because drugs approved through the accelerated approval program are approved based on surrogate endpoints, a drug’s true efficacy is unknown before the results of the required confirmatory studies are available. Furthermore, surrogate endpoints in some areas, such as oncologic trials, have been shown to have poor correlation with outcomes such as survival. ²¹ Accordingly, cost-utility studies that use surrogate endpoints to estimate QALY gains should be considered with caution.

Third, the included published studies varied with respect to methodology, country, perspective, and other attributes. ^22–24 Because we relied on the reported mean QALY gains from each study, we did not account for heterogeneity of treatment effects—that is, the fact that some patients will benefit from the drug more than others will.

Fourth, while QALYs facilitate comparison of the health gains offered by drugs across indications, they might not adequately capture all of the benefits and harms associated with products. ^8,9 Fifth, our study did not account for safety concerns associated with the included drugs that became apparent after the cost-utility analyses that contributed estimates of incremental QALY gain to our data set were published.

Sixth, because the aim of this study was to quantify the additional health benefits of new drugs compared to prevailing treatment options, the choice of comparator treatments was integral to our research. For drugs with multiple contributing studies, the comparator varied across studies on occasion. However, we mitigated this limitation by selecting from studies with multiple comparators the most effective comparator available at the time the drug of interest was introduced.

Seventh, unlike previous research that has examined the association of various drug attributes with FDA approval time—for example, the number of previous drugs approved by the FDA in the same class—we did not examine the attributes of the drugs included in the expedited review programs. ²⁵

Despite these limitations, given the strengths of the data noted above, and the conservative assumptions, this research should provide insight into whether drugs that the FDA prioritizes with expedited review offer larger health gains.

Study Results

Four different FDA programs offer flexibility in approving drugs that meet different criteria ( Exhibit 1 ). Priority review (for drugs that target serious conditions and offer significant improvements over existing care) has a six-month review window, compared with the ten-month standard. Accelerated approval (for drugs that provide meaningful clinical advancement for serious conditions and for which effects on intermediate endpoints are reasonably likely to predict clinical benefit) offers approval based on intermediate endpoints but comes with postapproval requirements to extend results from surrogate to clinical outcome. Fast track designation (for drugs for serious conditions that demonstrate the potential to address unmet needs) provides the possibility of a “rolling review” application and more frequent interaction with the FDA to expedite the review process. Breakthrough therapy (for drugs that target serious conditions and for which preliminary evidence indicates substantial improvement over existing therapies) offers rolling review and intensive guidance on efficient drug development.

We identified at least one appropriate QALY gain estimate for 118 drugs across a range of disease categories (see online Appendix Exhibits 1–3), ²⁶ roughly 30 percent of the new molecular entities approved by the FDA in the period 1999–2012. ¹¹ Our data set contained 66 of the 166 drugs the FDA included in the priority review program, 16 of the 41 drugs in the accelerated approval program, and 30 of the 79 drugs in the fast track program in the study period.

In total, we analyzed 135 drug-indication pairs. Sixty-eight were in the priority review program, thirty-one in the fast track program, and seventeen in the accelerated approval program. Thirty were in multiple programs, and 59 were in none.

Thirty-nine drug-indication pairs in our data set (29 percent) were estimated to be no more effective or less effective than existing care—that is, they had zero or negative incremental QALYs. This was the case for twenty-four pairs (40.7 percent) reviewed through conventional processes and fifteen pairs (19.7 percent) in at least one expedited review program.

Exhibit 2 presents the distribution of aggregate incremental QALY gains across drug-indication pairs reviewed through conventional processes and pairs included in at least one expedited review program. Drug-indication pairs reviewed through conventional processes had median gains of 0.003 QALY, versus 0.182 QALY for those in at least one expedited review program ( Exhibit 3 ). Pairs in multiple expedited review programs had median gains of 0.307 QALY versus 0.126 QALY for those in a single expedited review program.

SOURCE Authors’ analysis. NOTE Fifty-nine drug-indication pairs were not included in any expedited review program, and seventy-six were included in at least one of the programs.

Drug-indication pairs in each expedited review program were associated with larger QALY gains than pairs not included in that program. For example, pairs in the priority review program had median gains of 0.175 QALY versus 0.007 QALY for drugs not in the program ( Exhibit 4 and Appendix Exhibit 4) ²⁶ (for additional information on pairs in the fast track program and the accelerated approval program, see Appendix Exhibits 5 and 6, respectively). ²⁶

The results of sensitivity analyses in which we included the highest and lowest reported estimates of incremental QALY gains were qualitatively the same as our primary findings in terms of the significance, sign, and order of magnitude (Appendix Exhibit 7). ²⁶ Similarly, the results of the sensitivity analyses that excluded orphan drugs from the data set did not differ meaningfully from the main study findings (Appendix Exhibit 8). ²⁶

In the supplementary analyses, we found no significant change in the QALY differential between drug-indication pairs included in the expedited review programs and those not included in the programs over time (Appendix Exhibit 9). ²⁶

Discussion

We found that drugs in at least one expedited review program were associated with larger QALY gains than drugs reviewed through conventional processes. We also found that drugs in multiple expedited review programs were associated with larger QALY gains, compared to drugs in a single program. Additionally, we found that drugs in the priority review, fast track, and accelerated approval programs tended to be associated with larger QALY gains than drugs not included in them. These findings suggest that the FDA has prioritized the review of drugs offering the largest clinical advancements over existing care by including them in the various expedited review programs. However, because QALY gain estimates were not available for all FDA-approved drugs, our findings should be interpreted with caution.

Each expedited review program has different criteria, but it is unclear whether these differences would result in drugs in one program being associated with larger QALY gains than drugs in a different program. In future research, we plan to investigate this point and examine the possible reasons for any identified differences.

Encouraging innovation to address unmet health needs is a long-standing priority for health policy makers. The FDA’s various expedited review programs are important regulatory levers and respond to the growing call for more rapid access to new drugs. Easing the path toward innovation is a worthy goal, but the key question is how the initiatives will improve health outcomes. The FDA’s record with policies to expedite the approval of drugs that address a particular unmet clinical need or that provide a significant improvement in safety or effectiveness over available therapies is instructive in this regard.

Our analysis provides policy makers with new information about the performance of existing expedited programs and an empirical context for considering the appropriateness of introducing additional programs. To be sure, our analysis does not capture all of the factors the FDA must consider. Drugs subject to shorter reviews are more likely to be withdrawn for safety reasons, for example, and to carry subsequent black-box warnings. ²⁷

In one high-profile example, the FDA approved bevacizumab for metastatic breast cancer in the accelerated approval program in 2008, only to withdraw the expanded approval later when new data showed that the drug did not improve survival rates for this indication. ²⁸ In another example, the FDA approved ponatinib—a drug in the priority review, accelerated approval, and fast track programs—for chronic myelogenous leukemia, only later to temporarily withdraw the drug from the market because of reports that patients were experiencing greater-than-expected adverse events. ²⁹

Furthermore, for drugs in the accelerated approval program, the FDA has had limited success in ensuring that mandated postapproval trials to validate the findings from surrogate endpoints are performed in a timely manner. ³⁰ For example, in 1996 the FDA approved midodrine under the accelerated approval program for the treatment of symptomatic orthostatic hypotension, but trials verifying actual clinical benefit to patients were not completed. ³¹ Nevertheless, because drugs in the expedited review programs have the potential to treat severe diseases and address unmet medical needs, physicians and patients may be willing to accept a greater degree of risk. ^32,33

While it is challenging to predict how the 21st Century Cures Act will affect product safety, our findings offer another input into the complex debate surrounding the act as the country embarks on a new era of expedited review and approval. The act added a range of initiatives intended to streamline the regulatory process (among them, proposals to allow for greater flexibility in clinical trial design) and to better incorporate patients’ preferences in the FDA’s decision-making process. The legislation also adds a new pathway for “regenerative advanced therapy”—including cell therapy, therapeutic tissue engineering products, and human cell and tissue products—antibacterial and antifungal drugs for use in a limited population of patients and a new priority review program for medical devices. Other provisions expand the use of accelerated approval (which is based on surrogate endpoints) beyond drugs intended to treat patients with life-threatening illnesses and unmet needs.

The law has alarmed some observers, who are concerned that expanding the expedited review programs will lower the regulatory standard and undermine the FDA’s role of ensuring that approved drugs are safe and effective. ³⁴ These observers have argued that the FDA already reviews and approves the majority of drugs faster than is the case with regulators in other countries, and that the benefits of sending drugs to the market even faster may not outweigh the risks of doing so. ^35,36 Furthermore, in 2016, sixteen of the twenty-two (73 percent) approved novel drugs were in at least one expedited review program: fifteen (68 percent of the twenty-two drugs) in the priority review, eight (36 percent) in the fast track, six (27 percent) in the accelerated approval, and 7 (32 percent) in the breakthrough therapy program. ³⁷ Further expanding the expedited review programs could have the effect of making expedited review the standard rather than the exception for FDA review and lead to questions of whether the FDA is efficiently channeling limited resources to the most promising treatments. Greater scrutiny of the expedited review programs is warranted going forward.

Expedited review programs offer the FDA greater discretion for hastening the delivery of highly promising and much-needed treatments to patients and for providing incentives for pharmaceutical innovation. However, the key will be to maintain an appropriate balance of benefits and risks to improve population health.

Conclusion

Our comparison of the QALY gains of drugs in the FDA’s expedited review programs and the gains of those not in the programs suggests that, at least for the products in our sample, the FDA has prioritized drugs that offer the largest health gains.

NOTES

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