FDA’s Benefit–Risk Framework for Human Drugs and Biologics: Role in Benefit–Risk Assessment and Analysis of Use for Drug Approvals

Abstract

Background

Structured, descriptive approaches are utilized by drug regulatory agencies to support and communicate approval decisions about human drugs and biologics. The US Food and Drug Administration (FDA) uses the Benefit–Risk Framework (BRF), which has been integrated into its drug review process. This paper reviews how FDA review teams have used the BRF to communicate approval decisions.

Methods

This paper (1) uses content analysis to systematically review the decision factors communicated by FDA review teams in all BRFs associated with novel drugs approved by FDA in 2017–2018 and (2) presents a case study about how the BRF was used for three drugs approved for HIV-1 in 2018–2019.

Results

The content analysis found most BRFs for novel drug approvals communicate what we call an “urgent” context and complicating decision factors around benefit and/or risk; the HIV-1 case study highlights the flexibility of the structured BRF tool.

Conclusions

FDA’s BRF provides a flexible mechanism for communicating important decision factors, allowing it to support the diversity of drug approval decisions made by FDA.

Introduction

Marketing authorization of human drugs and biologics—drugs for short—by the US Food and Drug Administration (FDA) involves first an assessment of whether the drug is effective, and then an assessment of whether the benefits of the drug outweigh its risks [1]. To support this assessment, interdisciplinary review teams assess large amounts of scientific and clinical data and use the assessment to come to a regulatory decision [2]. The body of evidence available at the time of a regulatory decision is inevitably imperfect, thus creating the need for scientific and regulatory judgment to determine whether the product’s benefits outweigh the risks despite this uncertainty, and whether additional measures are needed to address this uncertainty. The quantity and diversity of information considered, and the potential impact of the decision, makes drug approval a complex decision problem.

Structured approaches to regulatory decision-making can help with synthesizing the scientific and clinical trial evidence, evaluating the benefit–risk profile, and communicating the rationale for the decision [3, 4]. FDA and other drug regulatory bodies generally utilize systematic, structured, and qualitative approaches [5]. While there are similarities, a common approach is not used by all regulators. FDA’s approach, development of which started in 2009, is described in greater detail below. Other examples include the European Medicines Agency (EMA), which follows the PrOACT-URL framework and includes an effects table and a structured, narrative benefit–risk assessment. Japan’s Pharmaceuticals and Medical Devices Agency uses “points to be considered by the review staff,” including a check sheet for the major review considerations that would lead to a favorable or unfavorable decision [6]. Guidance to industry from the International Council on Harmonization advises inclusion of a narrative assessment of the therapeutic context, benefits and risks of the proposed product, and an overall assessment [7]. Similar approaches have been developed by the pharmaceutical industry, including the Pharmaceutical Research and Manufacturers of America Benefit–Risk Assessment Team (PhRMA BRAT) [8–10]. Reports from the Innovative Medicines Initiative Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (IMI-PROTECT) provide a thorough review of structured qualitative benefit–risk assessment frameworks [11]. All of these approaches focus on integration of the important components of the decision: the therapeutic or decision context, expectations for benefits and risks in the real world, and assessment of the balance of those benefits and risks given the context.

FDA’s approach to structured drug benefit–risk assessment is found in the Benefit–Risk framework (BRF) [12]. Developed jointly by the Center for Drug Evaluation and Research and the Center for Biologics Evaluation and Research, the BRF was phased into new drug review for the two centers between 2013 and 2017 [13, 14]. While visually structured in a tabular format, the BRF is fundamentally a narrative discussion of the therapeutic context (the clinical characteristics of the condition or disease, the population affected, the currently available treatments, and the degree of unmet medical need), what is known about the benefits and risks of the drug under review, an integrated assessment of the benefit–risk balance, need for risk management, and the regulatory decision. A 2019 public meeting, organized by FDA in partnership with the Duke Margolis Center for Health Policy, highlighted the key considerations FDA review teams may take into account for each dimension of the decision problem (Table 1 provides a simplification of the key considerations table from the discussion document for the 2019 meeting) [15]. The BRF includes questions to consider to facilitate completion of the BRF, which are intended to guide the review team through the decision-making process and to provide a mechanism for documenting uncertainties and identifying and resolving disagreements. The final result provides a structured mechanism to support a decision, and also serves as an efficient communication mechanism of FDA’s rationale for the final regulatory decision.

Table 1.

Sample of Key Considerations for FDA’s Premarket Benefit–Risk Assessment of Human Drugs Taken from the Discussion Document for the 2019 Public Meeting on the Topic [15].

	Evidence and Uncertainties	Conclusions and Reasons
Analysis of condition	Context of use for proposed indication: intended medical use, target patient population Relevant clinical aspects of the condition Patient-focused disease burden
Current treatment options	Goals of current standard of care Efficacy and safety of available therapies Burden of treatment (e.g., administration) Aspects of disease burden not addressed by current therapies
Benefit	Strengths/limitations of clinical trial: potential implications for assessing drug efficacy Clinical relevance of the study endpoints: ability to measure or predict clinical outcomes of importance to patients Demonstrated results and their clinical significance Generalizability of the clinical trial evidence to the to-be-marketed patient population in the postmarket setting
Risk and risk management	Strengths/limitations of safety evaluation: potential implications on assessing drug risks Serious adverse events or safety signals—clinical significance and remaining uncertainties Adverse effects (e.g., nausea) that could affect tolerability or adherence Potential impact of product quality or device issues on effectiveness or safety Additional safety issues considering how prescribers and real-world use in the postmarket setting may differ from the clinical trial setting Effectiveness of strategies to manage risks
Conclusions regarding benefit-risk
How therapeutic context affects threshold for benefits and tolerance for risk and uncertainty
Importance of unresolved uncertainties Need for labeling (e.g., boxed warning) or REMS to support favorable benefit-risk assessment Need for postmarketing evidence to address uncertainty

This paper looks at how the BRF has been used by FDA review teams to communicate approval decisions. We first conducted a systematic content analysis [16, 17] for all BRFs published for novel drug approvals in 2017 and 2018 to assess how often review teams communicated different aspects of their assessment. Second, we considered BRFs for three drugs approved for HIV-1 between 2018 and 2019 to highlight the flexibility of the BRF as a structured approach for communicating drug regulatory decision-making. While these three products have the same high-level therapeutic context, differences in the specific indication and expected benefits and risks were communicated by their review team through the respective BRFs.

Content Analysis: Novel Drug Approvals 2017–2018

Materials and Methods

We considered the 105 new molecular entities or original biologics (referred to here as novel drugs) approved by FDA between January 1, 2017 and December 31, 2018 [18, 19]. We obtained all available BRFs (n = 237; several products had multiple BRFs, for instance if multiple members of the review team completed BRFs as part of separate review documents) in review documents. Of the 105 novel drug approvals, 104 had at least one BRF; the drug with no BRFs, safinamide, was approved in 2017 on the second cycle and was dropped from the analysis. The unit of analysis was the drug; Table 2 provides the review division for all 104 products.

Table 2.

Clinical Review Divisions for the Novel Drug Approvals Included in the Content Analysis.

Division	2017	2018	Total
Hematology	7	13	20
Oncology I and II (combined)	7	9	16
Neurology	4	8	12
Anti-infective	5	6	11
Gastroenterology and inborn errors	5	5	10
Antiviral	3	5	8
Pulmonary, allergy, and rheumatology	2	4	6
Dermatology and dental	3	2	5
Bone, reproductive, and urologic	1	3	4
Metabolism and endocrinology	4	0	4
Transplant and ophthalmology	2	2	4
Cardiovascular and renal	1	1	2
Psychiatry	1	0	1
Anesthesia, analgesia, and addiction	0	1	1
Total	45	59	104

Content analysis is a systematic method for decomposing and classifying written documents to identify common themes [16, 17]. Analysts carefully and systematically review each document and assign codes to portions of the text. The coded portions can then be qualitatively reviewed across documents to identify common themes. In this paper, the codes were also quantitatively assessed by determining the number of drugs that had a code assigned to one or more of its BRFs.

The set of codes is defined in a codebook, which in this case was based on the guiding prompts given to FDA review teams for completing the BRF and was similar to the key considerations in Table 1. The codebook had only minor additions and modifications after coding began and the final definitions are provided in supplemental materials. Codes for the therapeutic context elements of the BRF (analysis of condition and current treatment options) were designed to be comprehensive and to indicate different degrees of condition severity and unmet medical need: for example, life-threatening or life-shortening, severe for a subset of patients, or mild and/or self-limiting for the large majority of patients. Codes pertaining to the benefit, risk, and integrated assessment elements of the BRF were designed to be used when the text of the BRF communicated that the factor was an actual or potential decision issue that was either resolved, or remained unresolved, at the time of approval. This allowed the content analysis to focus on BRFs that communicated situations where nuanced FDA judgement was required for one or more decision component. These differentiated from cases where the BRF communicated a straightforward assessment of the decision component. While few decisions are “close-calls,” many, especially for novel drug therapies, have at least one component in their development requiring careful consideration and judgement by FDA.

Coding was not limited to the corresponding rows of the table as review teams sometimes discussed concepts outside of a particular row. A few BRFs, particularly in 2017, used a different tabular format but were coded anyway as the text clearly aligned with the dimensions of the BRF. In particular, some BRF tables did not include an integrated assessment section. In these cases, we considered review text either immediately preceding or following the BRF, depending on the document, to comprise the integrated assessment.

The majority of drugs had more than one BRF because individual members of the review team authored separate BRFs for the same application and indication (32 drugs in 2017 and 23 in 2018). In a subset of these (2 each year), drugs were also reviewed for two separate indications, either in a single BRF (1 each year) or in two separate BRFs (1 each year). All BRFs in review documents were analyzed and in most cases the coded results were similar between BRFs. Of the 55 drugs with more than one BRF, only 10 had multiple codes related to the therapeutic context (5 each in the 2017 and 2018 cohorts). For example, one indication may have had some approved treatments available, but the second indication sought had no approved treatments available. Multiple codes could also occur if BRFs authored by different members of the review team communicated different therapeutic contexts.

All coding was completed in NVivo Pro (versions 10, 11, and 12 were used over the course of the project). To begin, we randomly selected four drugs from each year to be fully coded by each of the two coders. Discussion of the eight drugs served to align the two coders on the codebook and its application. Then, each of the 96 remaining drugs were assigned a primary coder who reviewed all BRFs for that drug and coded in NVivo according to the agreed-upon codebook. Final codes were determined by consensus among the two coders. Because our review was limited to the text of the BRF, we can make no judgement about the degree to which the text accurately reflects the internal deliberation process or the full set of decision factors the review team considered.

When coding was complete, we used NVivo’s cross-tabulation function to tally the number of times each code was used among BRFs for each drug. We utilized the cross-tabulation, together with review of coded excerpts, to identify the themes presented below. Results discussed below are not the full accounting of all coding. Selected quotes are used solely to illustrate how the code or theme was communicated by review teams in the BRF and no significance should be ascribed to the selection of any drug.

Results

The majority of novel drug approvals in our analysis cohort, 76% in 2017 (n = 45) and 86% in 2018 (n = 59), had BRFs that described both a condition that is severe or life-threatening for all or a subset of patients (93% in 2017 and 97% in 2018) and to have an unmet medical need for all or a subset of patients (78% in 2017 and 86% in 2018) (Fig. 1); we describe the overlap (severe or life-threatening and unmet medical need) as an “urgent context.” For example, a BRF for cerliponase alfa, approved in 2017 for ceroid lipofuscinosis type 2, describes the condition as: “a rare, devastating neurological degenerative disease of early childhood…death typically occurs between 10 and 16 years of age…there are no pharmacological treatments.” Unmet medical need was not limited to conditions where no treatments were available. For example, a BRF for burosumab, approved in 2018 for an inherited form of rickets, stated: “conventional therapy has major drawbacks…better therapies are urgently needed.”

Figure 1.

Percent of novel drug approvals (2017–2018) with BRFs that communicated decision factors related to the therapeutic context (2017 n = 45; 2018 n = 59); urgent context is the combination of severe or life-threatening and unmet medical need for all or a subset of patients.

Issues, or potential issues, related to establishing the benefit of a novel drug were discussed in BRFs for 58% of approvals in 2017 and 68% of approvals in 2018 (Fig. 2). As these are all approvals, these issues or potential issues were discussed by the review team but ultimately did not preclude approval. These issues included clinical relevance of the endpoint, clinical meaningfulness of the effect, real-world benefit, limitations or weaknesses in the trial, and whether the evidentiary standard has been met. A single BRF, or the collection of BRFs for a given drug, could have more than one issue coded. For example, a BRF for tagraxofusp, approved in 2018 for blastic plasmacytoid dendritic cell neoplasm, described the steps taken to determine the clinical relevance of the endpoint: “this novel endpoint was assessed by qualification in the patients in the initial cohorts of the study and affirmed by FDA prior to analysis of the pivotal cohort.” An example the clinical meaningfulness of the effect comes from a BRF for edaravone, approved in 2017 for amyotrophic lateral sclerosis (ALS): “prevention of even 1 unit of worsening in a single domain seems meaningful and desirable for individuals with ALS.” An example of the uncertainty about real-world benefit comes from a BRF for ivosidenib, approved in 2018 for myeloid leukemia: “follow-up is too short to determine whether there is a long-term benefit or substantial effect on survival from use of this differentiating agent.” As an example of limitations or weaknesses in the trial that did not preclude approval, a BRF for benralizumab, approved in 2017 for severe asthma with an eosinophilic phenotype, states: “a sufficiently powered study to demonstrate a treatment benefit would be impractical to conduct given the rarity of this severe asthma phenotype.” Finally, an example of discussion of whether the evidentiary standard has been met can be found in a BRF for fish oil triglycerides, approved in 2018 as a source of calories and fatty acids in pediatric patients with parenteral nutrition-associated cholestasis, where: “additional evidence was reviewed to support the proposed indication due to the above limitations. We determined [fish oil triglycerides]’s effect by comparing [fish oil triglyceride] study data to gender and age-standardized growth charts.”

Figure 2.

Percent of novel drug approvals (2017–2018) with BRFs that communicated decision factors related to benefit (2017 n = 45; 2018 n = 59).

Serious safety concerns or limitations to assessing the safety profile were discussed in BRFs for 64% of approvals in 2017 and 56% of approvals in 2018 (Fig. 3). Serious safety concerns included novel, unexpected, or otherwise significant risks, as well as risks that were described as being serious but well known—expected or routine for the drug class or indication. As these are all approvals, the review teams ultimately concluded that these risk-related issues did not preclude approval. An example of a serious safety concern comes from a BRF for brodalumab, approved in 2017 for psoriasis, which discussed: “a unique safety concern that emerged…[was] the observed incidence of completed suicide…this number of suicides in a psoriasis development program is unprecedented.” In contrast, an example of a serious but well-known safety risk comes from a BRF for avelumab, approved in 2017 for metastatic Merkel cell carcinoma, which determined: “avelumab demonstrated [adverse reactions] previously identified for this class of molecules…the incidences… were not excessive for this class of molecule.” An example of limitations to assessing the safety profile is found in a BRF for larotrectinib, approved in 2018 for cancer with specific genetic features: “due to the small number of pediatric and adult patients, the single arm design of clinical studies, and confounding factors…it is not possible to determine whether differences in the incidence of adverse reactions…are related to patient age or other factors.”

Figure 3.

Percent of novel drug approvals (2017–2018) with BRFs that communicated decision factors related to risk (2017 n = 45; 2018 n = 59).

Overall, a little more than a third of all novel drug approvals (38% in 2017 and 37% in 2018) had BRFs that described an urgent therapeutic context, discussed one or more issue related to establishing benefit, and discussed a serious safety concern (or serious but well known) or limitations to assessing the safety profile. These complicated tradeoffs frequently were discussed in the BRFs through extended discussions of how decision factors were weighed against one another (18% in 2017 and 19% in 2018). For example, a BRF for lofexidine, approved in 2018 for opioid withdrawal, discussed the benefit–risk tradeoffs for the drug and concluded it to be favorable for patients: “who are not at undue risk for clinically significant cardiovascular adverse effects,” and for patients: “at increased risk for the cardiovascular adverse effects of lofexidine provided that they can be adequately monitored and that their withdrawal could interfere with reaching their treatment goals or is otherwise clinically significant enough to justify the risk.” Occasionally, disagreements among the review team were noted (7% of 45 novel drugs approved in 2017 and 3% of 59 novel drugs approved in 2018). For example, a BRF for ocrelizumab, approved in 2017 for multiple sclerosis, states: “The review team is in partial agreement… that the applicant has provided substantial evidence of effectiveness for the use of [ocrelizumab] for the treatment of patients with primary progressive multiple sclerosis.” Not every approval identified or discussed issues related to benefit or risk in their BRFs; 33% of approvals in 2017 and 19% of approvals in 2018 had BRFs that did not communicate decision issues related to benefit or risk. For example, a BRF for netarsudil, approved in 2017 for glaucoma, noted that the product represents a “new class” of therapy; “was equivalent to a known effective product” as assessed using the “currently accepted standard;” and “no long term consequences of netarsudil administration have been identified.”

Case Study: Selected Drugs Approved for HIV-1 in 2018–2019

After completing the systematic content analysis, we conducted a case study to explore how the BRF has been used to capture nuanced considerations of benefit, risk, and clinical context. This case study examined BRFs for three drugs approved for human immunodeficiency virus 1 (HIV-1) infection between 2018 and 2019:

1. Doravirine: novel drug approved in 2018 as part of a three-drug fixed-dose combination product (doravirine/lamivudine/tenofovir); taken orally once daily; indicated as a complete regimen for the treatment of HIV-1 infection in adult patients with no antiretroviral treatment history.

2. Dolutegravir/lamivudine: fixed-dose combination product approved in 2019; combination of two previously approved drugs; taken orally once daily; indicated to treat HIV-1 infection in patients with no antiretroviral treatment history.

3. Ibalizumab: novel monoclonal antibody approved in 2018; administered by intravenous injection every two weeks; indicated for the treatment of HIV-1 infection in heavily treatment-experienced adult patients with documented multi-drug resistant HIV (MDR HIV).

We drew from the publicly available BRFs to develop a table highlighting key benefit–risk considerations for each product. Table 3 summarizes the distinguishing considerations from each BRF using quotes from the published frameworks.

Table 3.

Selected Quotes from HIV-1 BRFs (2018–2019).

BRF Section	Doravirine	Dolute gravir/Lamivudine	Ibalizumab
Analysis of condition	Without effective treatment, HIV-1 leads to progressive destruction of the immune system and therefore is a serious, life-threatening condition. With effective management, however, HIV-1 is a controllable chronic condition	Without effective treatment, HIV-1 leads to progressive destruction of the immune system and therefore is a serious, life-threatening condition. With effective management, however, HIV-1 is a controllable chronic condition	The subset of HIV-infected patients who cannot achieve virologic suppression due to the presence of MDR HIV are at high risk of AIDSa events and death
Current treatment options	The HIV treatment armamentarium would benefit from another antiretroviral treatment option that is efficacious, well tolerated, without clinically relevant drug-drug interactions and food restrictions, and has a convenient dosing regimen	Similar to doravirine, and: A two-drug regimen may reduce the complexity of ARVb treatment by eliminating any restrictions or adverse reactions of the third drug in the regimen	Healthcare providers have few, if any, drugs with which they can create an effective combination regimen for patients with MDR HIV infection Heavily treatment—experienced HIV-infected patients need effective antiretroviral products that lack cross-resistance with commercially available products
Benefit	The efficacy of [doravirine]-containing treatment in the HIV-1 treatment-naïve population…was established in two randomized Phase 3 trials. These trials support noninferiority of [doravirinej-containing treatment [Doravirine]-containing regimens have a favorable lipid profile…and statistically significantly lower proportions of subjects that experienced neuropsychiatric AEsc compared with EFVd-containing regimens The two trials lack an INSTe-containing active control comparison…[which] limits comparability of the…results to current standard of care, as it is unknown whether [doravirine]-containing regimens would result in favorable lipid profiles or neuropsychiatric profiles versus INSTe-containing regimens	The submitted clinical trial data demonstrated a meaningful benefit of [dolutegravir/lamivudine] in treating HIV-1 in treatment-naïve patients, and that the efficacy of the [dolutegravir/lamivudine] two-drug regimen is noninferior to the [control] three-drug regimen The uncertainties about extrapolating efficacy to patients with known or suspected resistance to either [dolutegravir] or [lamivudine], however, justify limiting the indication to only the population of adult patients who have no prior ARVb treatment history	The pivotal trial…demonstrated a significantly higher percentage of subjects achieving a [clinically meaningful] ≥0.5 logl0 decrease in HIV viral load Reductions in HIV-RNA levels are highly predictive of meaningful clinical benefit The Division agreed to several [clinical trial] design features, including lack of a control arm, small sample size, and individualized OBRf, that limit our ability to assess ibalizumab’s durability Because ibalizumab has been developed for…adults with MDR HIV infection with limited treatment options and high risk of disease progression and death in the absence of effective ARTg, some degree of uncertainty regarding ibalizumab’s contribution to durability is acceptable
Risk and Risk Management	The safety profile of [doravirine]-containing treatment in the treatment-naïve HIV population is well characterized Co-administration of DOR or [the 3-drug combination] with a strong CYP3A inducerh is contraindicated because significant decreases in [doravirine] plasma concentrations may occur, which may decrease its effectiveness A [postmarketing commitment] is recommended to evaluate the magnitude of increased M9i concentrations when [doravirine] is coadministered with rifabutin [a CYP3A inducerh]	The safety of both [dolutegravir] and [lamivudine] is well established, and no new or unexpected safety findings associated with either [dolutegravir] or [lamivudine] were observed from the two submitted clinical trials Although the [clinical] trials were not designed to show a benefit on the basis of any specific safety outcomes, the descriptive analysis of safety showed that the [dolutegravir/lamivudine] two-drug regimen lacked the additional safety concerns associated with a third drug…thereby avoiding their respective associated toxicities and drug interactions Because [dolutegravir/lamivudine] is meant to be a complete regimen for HIV-1, but provides only monotherapy for HBVJ infection, an alternative regimen should be considered for patients coinfected with HIV-1 and HBVJ	Although the safety database was limited for the proposed dosing regimen, it was sufficient for the assessment of safety for the rare population for which this drug will be indicated. Based on the data submitted…ibalizumab has a favorable safety profile The nature and frequency of the significant safety events (deaths, serious adverse events [SAEs], and discontinuations due to adverse events [AEs]) reported in the [application] largely reflect the patient population targeted for enrollment, i.e., advanced HIV/AIDS patients infected with MDR HIV and failing current ARTg
Conclusions Regarding Benefit-Risk	Approval of [doravirine]-containing therapy for treatment of HIV-1 infection in adult patients with no prior ARVb treatment history is fully supported by the available evidence of efficacy and safety	[dolutegravir/lamivudine] is the first two-drug combination to be approved as a complete regimen With all factors considered, the benefits of a one pill, once-a-day potent regimen of [dolutegravir/lamivudine] clearly outweigh the risks for adult patients with HIV-1 infection and no prior history of ARVb treatment	The overall benefit-risk profile of ibalizumab is favorable for the treatment of HIV-1 infection in heavily treatment-experienced adults with MDR HIV-1 infection failing their current antiretroviral regimen

^aAcquired immunodeficiency syndrome (AIDS).

^bAntiretroviral (ARV).

^cAdverse event (AE).

^dEfavirenz (EFV) has documented, treatment-limiting neuropsychiatric side effects.

^eIntegrase strand transfer inhibitor (INSTI) containing regimens are currently recommended in US HIV treatment guidelines as the initial regimen for most people with HIV.

^fOptimized background regimen (OBR).

^gAntiretroviral therapy (ART).

^hCytochrome P4503A (CYP3A) inducers increase the speed of drug metabolism by the liver, decreasing the effective dose.

ⁱM9 is a specific metabolite of doravirine no human pharmacokinetic data available at the time of approval.

^jHepatitis B virus (HBV).

Discussion

The content analysis of BRFs for novel drugs approvals between 2017 and 2018 shows how the BRF was used by FDA review teams to communicate the therapeutic context, benefit–risk assessment, and regulatory decision. The large percentage of drugs with BRFs communicating an urgent decision context is notable but perhaps not unexpected in the context of novel drugs and given recent, industry-wide trends to focus novel drug development on serious, rare diseases. Many times, review teams communicated an urgent context alongside discussion of potential concerns or issued related to establishing benefit and discussion of potentially serious safety concerns.

The subjectivity of the coding process in the content analysis paralleled the judgements inherent in drug regulatory decision-making. The greatest discussion between the two coders centered around how to code BRF communication of the therapeutic context; as coding requires some amount of judgement and inference based on sometimes limited text, discussion between the coders was necessary to resolve divergent codes. For FDA review teams, the therapeutic context defines the unmet medical need and, by extension, regulatory judgement about tolerance for uncertainty and acceptability of benefit–risk tradeoffs.

The case study of BRFs for drugs approved for HIV-1 highlights the flexibility of a structured, descriptive approach for benefit–risk assessment for drug regulatory decision-making. From the BRF for dolutegravir/lamivudine: “optimal management of HIV-1 is complex and must consider patients’ individual needs.” While each of these products was developed for treatment of HIV-1 infection, the benefit–risk assessment for each product had distinct considerations. Differences in the therapeutic context, unique therapeutic benefits of each drug, safety considerations, and limitations due to available trial data led to different benefit–risk profiles and different effects on the treatment armamentarium for HIV-1. Doravirine was approved as part of a three-drug regimen and provides an additional antiretroviral treatment option. Dolutegravir/lamivudine is the first two-drug complete regimen approved for HIV-1 and may provide a safety advantage for some patients by removing the concerns associated with a third drug. Ibalizumab had trial design issues, which introduced some uncertainty about the durability of benefit, but is intended for use in a high-risk subset of HIV-1 patients with few, if any, treatment options.

None of the reviewed BRFs in the content analysis or case study incorporated explicit statements of preferences or utilized benefit–risk modeling or analysis approaches. Indeed, it would be challenging to incorporate all of the complex decision factors communicated in each BRF into an integrated model. Nevertheless, there is potential for certain approaches to provide useful information for decision-making. Where additional benefit–risk analyses, sometimes including quantitative benefit–risk analysis approaches, may be useful by FDA to inform the decision, results can be communicated within the context of the BRF. Identification of the necessary situations, and the appropriate methodologies, remains an area of exploration for FDA and others [14, 20, 21].

Our content analysis and case study show the diversity of drug regulatory decisions and decision factors that can be communicated through a structured, descriptive benefit–risk assessment. FDA continues to refine its BRF approach and to more systematically integrate it into the drug review process [14]. The results presented here focus exclusively on how FDA’s benefit–risk assessment was communicated through completed BRFs. A potential future inquiry could be to compare FDA’s BRF to the benefit–risk approaches of EMA [22] or other organizations—both in terms of methodology and by comparing published benefit–risk assessments for products reviewed by both organizations. Various attempts have been made throughout the years to develop “unified” [23] benefit–risk assessment frameworks and models but so far only structured, descriptive approaches have been widely implemented [5].

Conclusion

This paper demonstrates the utility of having a succinct, structured, descriptive benefit–risk assessment tool to highlight and communicate important decision factors. In 2017 and 2018, BRFs for novel drug approvals by FDA tend to communicate serious conditions with unmet medical need, complex considerations for establishing benefit, and the potential for significant risks. A case study of selected 2018–2019 approvals for HIV-1 illustrates the flexibility of the BRF for communicating the nuances of the therapeutic context and drug regulatory decision. FDA is continuing to develop the qualitative framework and to explore decision analysis techniques that could support assessment of these complicated issues.