The Food and Drug Administration (FDA) requires a new drug’s manufacturer to present affirmative evidence of its efficacy and safety before it can be marketed. Because testing new drugs requires a delay between identification of an important, novel prescription drug and FDA approval, some patients with serious or life-threatening illnesses and no satisfactory options will not live to see a potentially life-saving medication approved for public use.

To address this concern, the FDA and Congress have established several programs—with the support of pharmaceutical manufacturers and some patient advocacy groups—that allow new drug approval based on less evidence, so that patients and their physicians have faster access and potentially a greater choice of therapies. These regulatory pathways shorten either the pre-approval testing period or the FDA's review time: the fast-track designation, accelerated approval pathway, priority review designation, and, most recently, the “breakthrough therapy” designation (Table 1).

However, expedited development and regulatory approval pathways for prescription drugs at FDA present ethical and policy dilemmas regarding the balance between more timely access to promising new drugs for patients in need and assuring that new drugs are effective and safe. An expedited therapeutic enters clinical practice without the same amount or quality of supporting data as a therapy subject to the standard FDA evidentiary requirements. But the quantity or quality of information needed to describe the benefits and risks of a drug remains is the same no matter what pathway led to its approval. In this post, we analyze these challenges and recommend how to address them.

Ethical tensions in FDA expedited pathways

Paternalism vs. Autonomy

Patients value autonomy, or the ability to do what they decide is in their best personal medical interest based on their discussions with their physicians. Expedited development and review programs are often justified on the basis of giving patients—particularly those in life-threatening situations—greater autonomy with regard to therapeutic choices. Patients with life-threatening and serious conditions whose pressing medical needs are not met by approved drugs may accept greater uncertainty about the safety and efficacy of new drugs than other patients.

Drugs approved via expedited development pathways have less evidence of efficacy than drugs approved via standard pathway. For example, they are more likely to demonstrate effects on surrogate endpoints, such as tumor markers or time to progression of cancer, rather than clinical endpoints, such as improved survival or reduced symptoms. Many drugs approved or used on the basis of preliminary surrogate outcomes have later been found to be ineffective or unsafe after more rigorous testing.

By contrast, through the regular approval process, approval is more likely to be based on a demonstration of real clinical benefit or a beneficial effect on a surrogate that has been validated to predict clinical outcomes. Drugs approved via expedited development pathways also have less evidence of safety, because they have been tested on fewer patients. Uncommon adverse effects may not be detected in clinical trials with relatively few participants.

Thus, patients seeking to exercise their autonomy in these situations may be exposed to drugs that do not work or have an unclear safety record. Autonomous choices relating to drugs approved through expedited review programs require that patients recognize the increased risks related to less evidence when drugs are approved. However, patients may not recognize this additional risk and also may overestimate the effectiveness and strength of supporting evidence of drugs described as “breakthrough” drugs in FDA press releases.

There are also important deficiencies in decision making by patients facing such choices; for example, severely ill patients have less retention of information discussed in the informed-consent process and less understanding of the risks of therapy as compared to healthier patients.

Physicians seeking to help patients exercise their autonomy face similar hurdles. In one survey, physicians were shown to overestimate the rigor of the data leading to the “Breakthrough Therapy” designation. Finally, data on approved drugs may not be available to physicians seeking to counsel their patients if the data submitted to FDA have not been published or are considered commercially confidential information.

Individual- vs. Population-level Decisions

The FDA requires that new drugs demonstrate “substantial evidence of efficacy” on the basis of “adequate and well-controlled trials.” According to current FDA rules, isolated case reports, random experience, and reports, lacking the details that permit scientific evaluation will not be considered as pivotal data satisfying the requirement for population-level rigorous studies.

By contrast, expedited development and review programs acknowledge that individual patients may seek to experience benefits from investigational drugs or other trial interventions before the totality of the evidence about a drug is known. These patients may want to proceed with treatment based on highly preliminary data, such as initial case reports or small-scale Phase 1 or Phase 2 studies intended only to test safe drug dosage levels in which individuals appeared to benefit.

But in such uncontrolled settings, positive outcomes may be due to random chance, variations in the natural history of a disease, placebo effects, or unidentified genetic differences among patients. Numerous reviews have shown the rate of failures in controlled Phase 3 trials among products showing promise in Phases 1 and 2 is usually about 50 percent. When drugs are not subject to Phase 3 studies before approval, lack of efficacy may be harder to identify clearly in routine clinical practice, leading these products to persist on the market.

At public FDA hearings, dramatic stories from patients about the benefits they received from a drug are often presented alongside data from clinical trials. Such narratives often have great dramatic and emotional impact. However, the stories of patients who were harmed or did not benefit are much less common, or even absent. Consequently, patient stories overweigh effective outcomes.

To better address these ethical tensions, we offer four recommendations:

1. Increase Post-Market Surveillance and Confirmatory Trials

When the evidence burdens for new drugs shifts from the pre- to post-market setting, adequate post-market surveillance and evidence generation becomes more important. Sentinel is a post-market active surveillance tool that allows FDA to query claims and real-world clinical data to rapidly identify associations between specific exposures and adverse events. Nearly a decade after its creation, the methodology for use of these data sets is still in development, and unresolved issues remain related to access for outside researchers.

There are three steps that policymakers and researchers can take to support greater use of post-market surveillance. First, FDA, Congress, and other stakeholders provide more resources to fulfill Sentinel’s potential to identify safety signals and to develop its ability to support studies of a drug’s effectiveness. Furthermore, FDA needs to develop Sentinel’s capacity in precision medicine, to help identify how a patient’s genetic and molecular profiles can predict the effectiveness and safety of therapies. Such new knowledge might help resolve the ethical tension between individual- and population-level decision making.

Second, the FDA should use more effectively its ability to recommend (or mandate) prospective controlled trials as a condition of approval. In the context of expedited review based on a drug’s activity in biomarkers, clinical trials showing how the drug works on real clinical endpoints are supposed to be organized after approval.

However, drug manufacturers have a poor track record of following through with these commitments and doing so in a timely fashion. In such circumstances, the FDA can impose civil monetary penalties, or remove a drug from the market. But the fines are relatively small, and have never been invoked due to administrative complexity. At the other extreme, it is difficult to remove a drug once it is on the market, particularly given pressures from the sponsor, professional organizations, patients, and other stakeholders.

For example, bevacizumab (Avastin) received accelerated approval for metastatic breast cancer, on the basis of the surrogate endpoint of progression-free survival. The FDA used its authority to require two additional confirmatory trials, which did not show a sufficient reduction in tumor growth or an increase in overall survival to justify the risks of the drug. Despite these negative trials, the manufacturer along with some patient advocates strongly pushed to maintain the breast cancer indication for the sake of individuals who might benefit. After nearly a year of deliberation, the FDA withdrew this indication, particularly because it would be difficult if not impossible to determine in advance which patients would benefit.

Third, stronger incentives for post-marketing studies should be enacted. One option is for FDA to require Risk Evaluation and Mitigation Strategies (REMS) until required post-marketing trials are carried out. REMS are regulatory limitations that require manufacturers to restrict access to providers who have received training and certification or enroll all patients in registries to more closely monitor drug use.

Experience with one REMS program has shown that they can substantially reduce prevalence of off-label prescribing. However, the FDA currently only has the power to impose REMS on drugs that have a strong safety signal during pre-approval testing, and drugs tested via expedited development programs may have not yet been given to enough patients to uncover such issues (if they exist).

Congress should give the FDA authority to impose REMS on all drugs approved after expedited review to give sponsors strong incentives to carry out additional studies to lift the restrictions. Another option is for FDA to heighten pre-marketed evidence requirements in subsequent submissions for expedited approval for sponsors who fail to carry out required post-marketing research or even register required trials. Yet another policy tool is for CMS and private insurers to reimburse at a lower rate sponsors who fail to meet deadlines for additional trials for drugs approved on expedited pathways.

2. Build Consensus around Definitions of Unmet Medical Need

Expedited review is driven by the desire to help patients in desperate clinical situations. Expedited development and review programs have expanded beyond the original intent. Such programs are being applied to significantly increasing proportions of new drugs, in particular a greater number of non-first-in-class drugs. Additional drugs in the same class, however, are more likely to be refinements rather than dramatic therapeutic advances. Similarly, the recently-enacted Breakthrough Therapy pathway was intended to apply to drugs that “show exceptional results for patients”—maybe a few each year—but with nearly a hundred investigational drugs labeled as “breakthroughs” in the past three years, even the Senator who initiated the program, Michael Bennet (D-CO) indicated that the “rollout has been faster than I expected.”

To better support patient autonomy, policymakers should clarify what conditions are eligible for expedited review programs and scale the evidence needed for expedited approval to the severity of unmet medical need. To do so, Congress and FDA should ask the National Academy of Medicine to convene an interdisciplinary, balanced expert panel to review the expedited review programs, to recommend what kinds of unmet medical need in different conditions should qualify for various types of FDA expedited approval, and to consider placing the amount and type of evidence needed for a regulatory decision on a sliding scale depending on the number of patients with an unmet need and the expected morbidity and mortality of the condition. Such a sliding scale would tailor the evidence required for expedited approval to need and risk, helping patients whose conditions give them the least time to wait for more rigorous evidence.

3. Give Patients and Physicians Better Tools to Make Informed Decisions about Drugs Approved by Expedited Pathways

Patients with serious and life-threatening conditions and unmet medical needs are best served if their decisions to use drugs approved by expedited pathways are informed. To that end, the FDA should revise the labels and FDA press releases for drugs approved via expedited pathways to increase patients’ understanding of the benefits and risks of these drugs and the limitations of the evidence on which the FDA based its approval. These revisions should be evidence-based, drawing on well-designed, rigorous studies of how patient understanding is affected by changes in how these drugs are labeled and described.

Physicians play an important role in helping patients make informed decisions about their care. However, since physicians also have misunderstandings about FDA breakthrough designations, the revised labels and press releases should also be designed to decrease physician misconceptions.

4. Increase the Use of Expanded Access

Making investigational drugs in expedited development and review pathways available to patients in life-threatening situations before approval, even if those patients do not qualify for the available clinical trials, would better balance the needs of such patients and the collection of rigorous data on safety and efficacy. Expanded access programs allow patients without any alternatives for serious illness and no access to clinical trials to receive promising therapeutics substantially sooner and still contribute individual data to FDA review. A meaningful system of expanded access is critical to reducing the ethical tensions that have arisen in the drug regulatory approval process.

However, expanded access programs are underutilized. To reduce administrative hurdles to expanded access, FDA recently unveiled a new process that takes only 45 minutes for physicians to complete. Manufacturers are reluctant to develop such programs, because they divert resources away from the formal trials needed for FDA approval. What is more, negative outcomes among expanded access patients might undermine an eventual New Drug Application or lead to unwanted safety warnings. But the latter concern is exaggerated because the FDA takes into account the context of administration when it reviews adverse event reports. We recommend that the FDA issue guidance about how they use data arising from expanded access patients in the course of a drug’s review to encourage manufacturers to implement expanded access programs.

We also recommend that payors incentivize sponsors to provide resources for expanded access, for example by agreeing to cover patients prescribed an investigational drug in the context of expanded access program oversight. Currently, most payors refuse to cover treatments formally classified as experimental. Any incentives would be best targeted to drugs that have completed positive clinical trials and are waiting the few months for FDA review.

Summing Up

Expedited approval programs allow the FDA to respond to the needs of patients with serious or life-threatening conditions and no good therapeutic options. However, these pathways can be ethically problematic, since patients may not be able to make informed decisions about the true risks and benefits of the product and because apparent individual-level improvements may not persist when the drugs are tested in larger, controlled trials. Our recommendations can help to ensure that expedited approval pathways strike an optimal and sustainable balance between promoting patient autonomy and providing patients and their physicians the evidence about the benefits and risks of new therapies.

Table 1. Expedited Development and Review Programs at the FDA

Program Year Created Regulatory or Legislative Origin Effect Limited to Serious or Life-Threatening Condition Orphan Drug Act 1983 Congress Provides sponsor with tax breaks, access to special grant funding, waiver of regulatory fees, and seven years of market exclusivity post-approval. Most orphan-designated drugs are approved based on trial designs (such as single-arm studies) not as widely accepted for non-orphan-designated drugs. No, but limited to rare disease indication Fast-track review, under Subpart E 1988 FDA, later codified by Congress Affords the sponsor frequent interactions with the FDA review team and the promise of more efficient review, including design of a single Phase 2 trial that would produce safety and efficacy data sufficient for approval. Yes Priority review 1992 FDA, later codified by Congress Guarantees initial FDA review within six months instead of the standard 10 month deadline, but does not formally change the review criteria. No Accelerated approval, under Subpart H 1992 FDA, later codified by Congress Allows approval to be based on a surrogate endpoint or intermediate clinical endpoint “reasonably likely” to predict a drug’s clinical benefit on how patients feel, function, or survive. Yes Breakthrough therapy 2012 Congress Allows certain practices “intended to expedite development and review” of investigational drugs including working closely with sponsors and assignment of a “cross-disciplinary project lead.” Yes

Author's Note

Dr. Kesselheim is a Greenwall Faculty Scholar in Bioethics and is also funded by the Harvard Program in Therapeutic Science and the Laura and John Arnold Foundation. Dr. Kesselheim has received grants from the FDA Office of Generic Drugs and Division of Health Communication.