FDA Lax in Evaluating Drugs Approved Through Expedited Pathways, Studies Show

Health Letter, January 2018

By Azza AbuDagga, M.H.A., Ph.D.

drugs
Image: Orawan Pattarawimonchai/Shutterstock.com

The Food and Drug Administration (FDA) describes its mission as, in part, “protecting the public health by ensuring the safety, efficacy, and security of human and veterinary drugs.”[1] As part of its mandate, the agency determines whether prescription drugs are safe and effective based on the evidence it receives from the makers of these drugs.

Despite criticism from misinformed observers that it is “slow and burdensome,”[2] the FDA exceeds its counterparts in other developed countries in its speed of reviewing applications for novel drugs and biologics and in the number of such products that it approves.[3]

Notably, the FDA has been granting a growing number of drug approvals through expedited development and review pathway programs.[4] Congress created these programs to expand access to new therapies for patients with rare, life-threatening diseases or those with few or no approved treatment options.[5] Drugs approved through these mechanisms, however, can sometimes cause significant public health risks because the approvals for these drugs often are based on much weaker evidence than that required to approve drugs through the traditional (standard) pathway.

Two recent studies highlight important shortcomings of these programs. The first[6] illustrates weaknesses in the preapproval and postapproval studies that support drugs that have been approved through the accelerated-approval pathway. The second[7] shows more postapproval safety-related label changes, the vast majority of which indicate elevated risks, for drugs and biologics approved through three expedited pathways, compared with those for drugs approved through the standard pathway.

Below, we discuss the various FDA review pathways, present the findings from the two new studies and discuss the implications of these findings.

Standard versus expedited pathways

In the standard drug-review pathway, the FDA makes its approval determinations based on adequate studies that start with phase 1 studies involving preliminary assessments of safety most often conducted in healthy volunteers and progress through phase 2 studies that use small groups of ill subjects and larger phase 3 randomized, controlled trials intended to establish a drug’s efficacy and safety for a particular indication (for example, treatment of asthma).[8] Ideally, these trials use clinically meaningful outcomes, such as survival or improved disease symptoms. As of 2015, the FDA has met its goal of taking no more than 10 months to review and reach a decision about whether to approve or reject at least 90 percent of the drugs that it considers under this standard pathway.[9]

In contrast, several expedited pathways permit the FDA to approve products more quickly, often based on limited evidence. For example, drugs may be approved based on a single phase 2 trial under the fast-track pathway.[10] Drugs can be approved under the accelerated-approval pathway based on “surrogate” measures of disease progression that are only “reasonably likely” to predict actual clinical benefit, rather than clinically meaningful outcomes.[11] The priority-review pathway guarantees no more than six months of drug application review time for drugs that seem to offer a therapeutic advantage over currently available therapies for a serious condition.

Study focusing on the accelerated-approval pathway [12]

A study published in the Journal of the American Medical Association on Aug. 15, 2017 examined two study types — preapproval studies (which form the basis for FDA approval) and postapproval studies (which the FDA can require to further evaluate the safety and efficacy of drugs after approval) — for drugs that reached the market through the accelerated-approval pathway between 2009 and 2013.

The study revealed that the FDA approved 24 indications, involving 22 drugs or biologics, through the accelerated-approval pathway during the study period. Nearly 80 percent of these indications were cancer-related.

As permitted by the accelerated-approval pathway, most preapproval studies did not use strong designs that yield the most reliable evaluations of benefit and risk. Specifically, 63 percent of the 30 preapproval studies used to support these indications were single-group studies (with no control groups). The median number of subjects enrolled in the 30 studies was only 132. Most of these studies used surrogate measures.

Postapproval studies were mostly completed long after approval of the drug: Only 18 of the total 38 studies that the FDA required for the 24 relevant indications were completed and had published reports as of early April 2017. Of the remaining studies, eight were either more than one year behind schedule or had been terminated, and the remaining studies were still ongoing as scheduled several years after their respective drugs had been on the market.

Moreover, the design of postapproval studies was not much better than that of the preapproval studies. For example, eight (44 percent) of the 18 completed and published studies were single-group studies. The median number of subjects across the completed postapproval studies was just 345. Additionally, most of these studies (94 percent) were based on surrogate measures; only one study used survival as an endpoint.

Study of expedited drugs’ safety [13]

The second study was published in The BMJ on Sept. 7, 2017. It examined postapproval changes in one or more of five safety sections (black-box warning [also called boxed warning], contraindication, warning, precaution or adverse reaction) in the labels of 382 new products (drugs and biologics) approved by the FDA between 1997 and 2014.

Changes to these safety sections are important because they typically reflect new safety risks that were not known to the FDA when it approved these drugs. Thus, drugs with such safety changes are generally less safe than originally thought at the time of their approvals.

The researchers found that 135 (35 percent) of the new products were approved through one of three expedited programs: accelerated approval, priority review or fast track pathways. These expedited products had an almost 40 percent higher rate of safety-related label changes after they were approved than drugs that were approved through the standard pathway. Specifically, expedited drugs had nearly 50 percent more changes to the boxed warnings and contraindications (the two most clinically important categories of safety warnings) sections than did standard drugs. More than 95 percent of the changes in high-profile boxed warning sections reflected increased risks, rather than lower risks, discovered after the products were approved.

Take-away message

The findings from the aforementioned studies raise concerns as to how well the FDA is striking a balance between maximizing access to new treatments and guarding against the potential risks associated with those treatments. Especially concerning is the possibility that the agency has become “too permissive” by not requiring traditional randomized, controlled trials for postapproval evaluations of drugs approved through the accelerated-approval pathway — a concern expressed by the FDA’s own former commissioner, Robert Califf.[14]

For 46 years, Public Citizen’s Health Research Group has continuously emphasized that the FDA should protect patients by adhering to strong standards for efficacy and safety when it approves drugs, biologics or devices for marketing in the U.S. To this effect, we have filed numerous FDA citizen petitions asking the agency to ban dangerous products or strengthen drug safety warnings, among other things. We also testified before numerous FDA advisory committees that review drugs and devices.

Recently, we opposed the 21st Century Cures Act, which is currently being implemented,[15],[16] because it opens the possibility for more new drugs to qualify for the FDA’s expedited development and review pathways. This legislation pressures the FDA to rush approval for new medical products, including antibiotics, stem cell therapies and devices, based on weak evidence of safety and efficacy.[17] It also will expand the pharmaceutical industry’s ability to pressure insurance companies to cover uses of drugs that have not been approved by the FDA.

Finally, we recommend that consumers follow the 7-Year Rule:[18]  Wait at least seven years after the FDA approves a new drug before using it, unless the drug represents a true breakthrough by offering a documented therapeutic advantage over older approved drugs. We make this recommendation because previous research has shown that a large proportion of new drugs withdrawn from the market or stamped with a new black-box warning in their product labeling due to newly discovered risks have had these actions taken within the first seven years after approval.[19]


References

[1] Food and Drug Administration. FDA mission. Last updated April 4, 2017. https://www.fda.gov/AboutFDA/WhatWeDo/. Accessed December 6, 2017.

[2] McGinley L. Trump calls the FDA ‘slow and burdensome,’ but it’s faster than ever. Washington Post. March 2, 2017. https://www.washingtonpost.com/news/to-your-health/wp/2017/03/02/trump-calls-the-fda-slow-and-burdensome-but-its-faster-than-ever/?utm_te. Accessed December 6, 2017.

[3] Downing N, Aminawung J, Shah N, et al. Regulatory review of novel therapeutics — comparison of three regulatory agencies. N Engl J Med. 2012;366(24):2284-2293.

[4] Kesselheim AS, Wang B, Franklin JM, Darrow JJ. Trends in utilization of FDA expedited drug development and approval programs, 1987-2014: cohort study. BMJ. 2015;351:h4633.

[5] Food and Drug Administration. White paper: FDA and accelerating the development of new pharmaceutical therapies. March 23, 2015. https://www.fda.gov/AboutFDA/ReportsManualsForms/Reports/ucm439082.htm. Accessed December 6, 2017.

[6] Naci H, Smalley KR, Kesselheim AS. Characteristics of preapproval and postapproval studies for drugs granted accelerated approval by the US Food and Drug Administration. JAMA. 2017;318(7):626-636.

[7] Mostaghim SR, Gagne JJ, Kesselheim AS. Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study. BMJ. 2017;358(Sep 7):j3837.

[8] Food and Drug Administration. Drug development process. https://www.fda.gov/downloads/drugs/resourcesforyou/consumers/ucm284393.pdf. Accessed December 6, 2017.

[9] Food and Drug Administration. FY 2016 performance report to Congress for the Prescription Drug User Fee Act. March 22, 2017. https://www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Reports/UserFeeReports/PerformanceReports/UCM548128.pdf. Accessed December 6, 2017.

[10] Calsyn M, Huelskoetter H. FDA is not the problem. https://www.americanprogress.org/issues/healthcare/reports/2016/03/09/132850/fda-is-not-the-problem/. Accessed December 6, 2017.

[11] Food and Drug Administration. Guidance for industry expedited programs for serious conditions — Drugs and biologics. https://www.fda.gov/downloads/Drugs/Guidances/UCM358301.pdf. May 2014. Accessed December 6, 2017.

[12] Naci H, Smalley KR, Kesselheim AS. Characteristics of preapproval and postapproval studies for drugs granted accelerated approval by the US Food and Drug Administration. JAMA. 2017;318(7):626-636.

[13] Mostaghim SR, Gagne JJ, Kesselheim AS. Safety related label changes for new drugs after approval in the US through expedited regulatory pathways: retrospective cohort study. BMJ. 2017;358(Sep 7):j3837.

[14] Califf RM. Balancing the need for access with the imperative for empirical evidence of benefit and risk. JAMA. 2017;318(7):614-616.

[15] Public Citizen’s Congress Watch. A risky shortcut. Proposal to permit the FDA to rely on journal articles to approve high-risk medical devices is misguided. February 9, 2016. https://www.citizen.org/sites/default/files/risky-shortcut-fda-medical-device-report-2016.pdf. Accessed December 6, 2017.

[16] Outrage of the month: 21st Century Cures – Gift to Big Pharma and medical device companies, bad deal for patients. Health Letter. January 2017. https://www.citizen.org/outrage-month-21st-century-cures-—-gift-big-pharma-and-medical-device-companies-bad-deal-patients. Accessed December 6, 2017.

[17] Outrage of the month: 21st Century Cures – Gift to Big Pharma and medical device companies, bad deal for patients. Health Letter. January 2017. https://www.citizen.org/outrage-month-21st-century-cures-—-gift-big-pharma-and-medical-device-companies-bad-deal-patients. Accessed December 6, 2017.

[18] Editorial: The Seven-Year Rule for safer prescribing. Worst Pills, Best Pills, News. October 2012. https://www.worstpills.org/member/newsletter.cfm?n_id=816Wo. Accessed December 6, 2017.

[19] Protecting yourself and your family from preventable drug-induced Injury. Worst Pills, Best Pills News. http://www.worstpills.org/public/page.cfm?op_id=45. Accessed December 6, 2017.