Change from Baseline versus Percent Change from Baseline

The US Food and Drug Administration (FDA) has published its fourth and final guidance in a series of patient-focused drug development (PFDD) guidances meant to help sponsors collect and incorporate patient experience information that can factor into regulatory decision-making. The latest guidance "Patient-Focused Drug Development: Incorporating Clinical Outcome Assessments Into Endpoints For Regulatory Decision-Making" focuses on how clinical outcomes assessments (COA) can be used as endpoints to support a product. It is interesting to see that there is an entire section to discuss the difference between using change from baseline versus percent (or percentage) change from baseline as the endpoint. While the discussion is specifically for COA (clinical outcomes assessments) endpoints, the same discussion points are applicable to other endpoints where the outcome measures are continuous variables. 

Clinical trials are usually designed as longitudinal studies where the baseline measures are performed before the randomization or the first dose of the study drug and then there will be periodic measures (or repeated measures) for the post-baseline visits. 

The statistical analyses may be performed on the original measures, but are more often performed using change from baseline values. For each post-baseline visit, the change from baseline values will be calculated and statistical analyses will include the change from baseline values as the dependent variable and the baseline values will be used as a covariate in the model. Both FDA and EMA have guidelines related to the adjustment for baseline values. 

• FDA guidance (2021) "Adjusting for Covariates in Randomized ClinicalTrials for Drugs and Biological Products"

"Clinical trials often record a baseline measurement of a defined characteristic and record a later measurement of the characteristic to be used as an outcome. When using this approach, adjusting for the baseline value rather than (or in addition to) defining the primary endpoint as a change from baseline is generally acceptable."

• EMA guidelines (2015) "Guideline on adjustment for baseline covariates in clinical trials"

"5.6. Change from baseline’ analyses

When the primary analysis is based on a continuous outcome there is commonly the choice of whether to use the raw outcome variable or the change from baseline as the primary endpoint. Whichever of these endpoints is chosen, the baseline value should be included as a covariate in the primary analysis. The use of change from baseline with adjustment for baseline is generally more precise than change of baseline without adjustment. Note that when the baseline is included as a covariate in a standard linear model, the estimated treatment effects are identical for both ‘change from baseline’ (on an additive scale) and the ‘raw outcome’ analysis. Consequently if the appropriate adjustment is done, then the choice of endpoint becomes solely an issue of interpretability."

Percent change from baseline may also be used as the endpoint even though it is less commonly used in the analysis of clinical trial data. FDA's COA guidance clearly indicated the potential issues for using percent change from baseline in the analysis. 

For statistical modeling, Percent change from baseline has some undesirable properties: 

• It is asymmetric, e.g. a change from 4 to 5 is 25%, but a change from 5 to 4 is -20%. While this is asymmetric, the percent change has been commonly used in measuring the fluctuation of stock prices, a change from $50 to $100 is a 100% increase, but a change from $100 to $50 is a 50% decrease. 
• The variance is not easily defined. If we rewrite the percent change from baseline, it will be 1−Post-baseline measures/Baseline measure, so the variance is only defined by the ratio of the Post baseline values/baseline value. In statistical modeling, people don't like to deal with the ratio unless there is no better way. When we handle log-normal data (such as pharmacokinetic data), the geometric mean ratio is commonly used. 
• It is undefined if the baseline is zero

In a paper by Vickers "The use of percentage change from baseline as an outcome in a controlled trial is statistically inefficient: a simulation study", the following conclusions were made:

"Percentage change from baseline has the lowest statistical power and was highly sensitive to changes in variance. Theoretical considerations suggest that percentage change from baseline will also fail to protect from bias in the case of baseline imbalance and will lead to an excess of trials with non-normally distributed outcome data."

Nevertheless, the percent change from the baseline may still be used as the primary efficacy endpoint in some clinical trials. Recently, therapeutic trials for weight loss in non-diabetic patients are hot topics. In clinical trials for weight loss, the primary efficacy endpoint is the Percent Change from Baseline to Week x in weight or BMI (body mass index). 

In a paper by Weghuber, et al "Once-Weekly Semaglutide in Adolescents with Obesity", the primary efficacy endpoint was percent change from baseline to week 68 in BMI. 

Efficacy end points were assessed from baseline (the time of randomization [week 0]) to week 68, unless otherwise stated. The primary end point was the percentage change in BMI, and the secondary confirmatory end point was a reduction in body weight of

at least 5%.

In a paper by Rubino et al "Effect of Weekly Subcutaneous Semaglutide vs Daily Liraglutide on BodyWeight in Adults With Overweight or Obesity Without Diabetes The STEP 8 Randomized Clinical Trial", the primary efficacy endpoint was percentage change from baseline in body weight at week 68. Percent change from baseline was analyzed using analysis of covariance, with randomized treatment as a factor and baseline value of the outcome measure of interest (eg, baseline body weight in kilograms for analysis of percentage change in body weight) as a covariate. Multiple imputation approach was used to handle the missing values. 

In SURMOUNT-1 study by Eli Lilly (Jastreboff, et al "Tirzepatide Once Weekly for the Treatment of Obesity"), co-primary efficacy endpoints were specified: 

Percent change in body weight from baseline to Week 72

AND

Percentage of participants with ≥5% body weight reduction at Week 72

Obtaining standard deviations from standard errors and confidence intervals for group means

Sometimes, we need to obtain a standard deviation (SD) in order to calculate the sample size for a new clinical trial where the primary efficacy endpoint is continuous measure. However, when we look at the literature, the SD may not be presented. Instead, the standard error (SE) or confidence intervals (CIs) are presented. The SD can be obtained from the SE or CIs. 

Below are texts from Cochrane Handbooks:

A standard deviation can be obtained from the standard error of a mean by multiplying by the square root of the sample size:

When making this transformation, standard errors must be of means calculated from within an intervention group and not standard errors of the difference in means computed between intervention groups.

 

Confidence intervals for means can also be used to calculate standard deviations. Again, the following applies to confidence intervals for mean values calculated within an intervention group and not for estimates of differences between interventions (for these, see Section 7.7.3.3). Most confidence intervals are 95% confidence intervals. If the sample size is large (say bigger than 100 in each group), the 95% confidence interval is 3.92 standard errors wide (3.92 = 2 × 1.96). The standard deviation for each group is obtained by dividing the length of the confidence interval by 3.92, and then multiplying by the square root of the sample size:

For 90% confidence intervals 3.92 should be replaced by 3.29, and for 99% confidence intervals it should be replaced by 5.15.

 

If the sample size is small (say less than 60 in each group) then confidence intervals should have been calculated using a value from a t distribution. The numbers 3.92, 3.29 and 5.15 need to be replaced with slightly larger numbers specific to the t distribution, which can be obtained from tables of the t distribution with degrees of freedom equal to the group sample size minus 1. Relevant details of the t distribution are available as appendices of many statistical textbooks, or using standard computer spreadsheet packages. For example the t value for a 95% confidence interval from a sample size of 25 can be obtained by typing =tinv(1-0.95,25-1) in a cell in a Microsoft Excel spreadsheet (the result is 2.0639). The divisor, 3.92, in the formula above would be replaced by 2 × 2.0639 = 4.128.

 

For moderate sample sizes (say between 60 and 100 in each group), either a t distribution or a standard normal distribution may have been used. Review authors should look for evidence of which one, and might use a t distribution if in doubt.

 

As an example, consider data presented as follows:

Group	Sample size	Mean	95% CI
Experimental intervention	25	32.1	(30.0, 34.2)
Control intervention	22	28.3	(26.5, 30.1)

The confidence intervals should have been based on t distributions with 24 and 21 degrees of freedom respectively. The divisor for the experimental intervention group is 4.128, from above. The standard deviation for this group is √25 × (34.2 – 30.0)/4.128 = 5.09. Calculations for the control group are performed in a similar way.

 

It is important to check that the confidence interval is symmetrical about the mean (the distance between the lower limit and the mean is the same as the distance between the mean and the upper limit). If this is not the case, the confidence interval may have been calculated on transformed values (see Section 7.7.3.4).

In the literature, the SEs and CIs are usually calculated from more sophisticated models (analysis of covariance, mixed model,...) - analyses adjusted for additional covariates. The methods described above can still be used to obtain the SDs - the calculated SDs should still be provide a good approximation of the SDs that are needed for planning future trials. 

in a paper by Jastreboff et al (2022) "Tirzepatide Once Weekly for the Treatment of Obesity", the sample size calculation was based on group mean difference and common standard deviation. 

"We calculated that a sample size of 2400 participants would provide an effective power of greater than 90% to demonstrate the superiority of tirzepatide (10 mg, 15 mg, or both) to placebo, relative to the coprimary end points, each at a two-sided significance level of 0.025. The sample-size calculation assumed at least an 11-percentage-point difference in the mean percentage weight reduction from baseline at 72 weeks for tirzepatide (10 mg, 15 mg, or both) as compared with placebo, a common standard deviation of 10%, and a dropout rate of 25%."

However, the study results were presented with LS mean difference in percentage change in body weight between two groups and their 95% confidence intervals. Standard deviations were not provided, but can be easily calculated using the method described above. 

Using Tirzepatide 15 mg group as an example, SD for 'percent change in body weight' can be calculated as SD1 =sqrt(630) * (-19.9 - (-21.8))/3.92 = 12.2; SD for 'Difference from placebo in percentage change in body weight' can be calculated as sqrt(630) x (-16.3 - (-19.3))/3.92 =19.2. The actual SDs from the study data are a little bit higher than the assumed SD of 10%.

 

"Ensuring Public Trust in an Empowered FDA" - Accelerated Approval

 In the latest issue of New England Journal of Medicine, Drs Ross, Berg, and Ramachandran wrote a paper:

"Ensuring Public Trust in an Empowered FDA". 

The paper discussed the recent trend that FDA is granting drug approval using the accelerated approval pathway - approval based on the biomarker or surrogate end points that are deemed “reasonably likely” to predict clinical benefit. 

The accelerated approval pathway was one of the expedited pathways for drug approval in FDA's guidance "Expedited Programs for Serious Conditions – Drugs and Biologics". The guidance defined the accelerated approval as the following: 

Accelerated approval has been historically used in HIV drug approval and oncology drug approval (mostly successful), however, in recent years, the FDA has increasingly expanded the use of the accelerated approval program beyond HIV and oncology therapies - mainly in the neurology area such as DMD, Alzheimer's disease, and ALS. 

The FDA argued that the FDA should exercise “the greatest flexibility possible” under its statutory authority in considering accelerated approval for drugs for the treatment of serious conditions with unmet medical needs. However, applying "the greatest flexibility possible" can empower the FDA, but it may come with consequences. 

Accelerated approval is based on a surrogate endpoint that is reasonably likely to predict clinical benefits, however, the "reasonably likely to predict clinical benefits" can be difficult to prove, and a lot of time is claimed based on conflicting evidence. According to the paper by Drs Fleming and Powers "Biomarkers and Surrogate Endpoints In Clinical Trials", it is extremely difficult to verify a biomarker can be a surrogate endpoint and can reasonably likely predict clinical benefits. 

The authors concluded:

 "An empowered FDA may prioritize using its regulatory authority to enable timely access to innovative products, but to ensure continued trust in the agency, this priority should be balanced against the challenges clinicians, patients, and caregivers face when there is substantial residual uncertainty about product safety and efficacy."

Also noted was that the FDA established a website "Accelerated Approval Program" where drugs approved through accelerated approval pathway were listed and the status of confirmatory trials to prove the clinical benefit was also listed. 'Ongoing' indicates that the confirmatory trial is ongoing; 'verified clinical benefit indicates the clinical benefit has been confirmed; and 'withdrawn' indicates that the clinical benefit has not been confirmed in the confirmatory trials and the drug approved through accelerated approval has been withdrawn. 

Accelerated Approval is a hot topic lately: 

• FDA Issues Draft Guidance Aimed at Improving Oncology Clinical Trials for Accelerated Approval
• Clinical Trial Considerations to Support Accelerated Approval of Oncology Therapeutics
• Top FDA official: Agency needs to start using accelerated approval for gene therapies
• US FDA to take steps to help gene therapies get accelerated approval

The condition for FDA to grant the accelerated approval is that the sponsor is required to do a confirmatory study (either already ongoing or will start right after the accelerated approval) to verify the drug's clinical benefits. A recent article in JAMA titled "Timing of Confirmatory Trials for Drugs Granted Accelerated Approval Based on Surrogate Measures From 2012 to 2021" concluded the following:

"Accelerated approval expedites the marketing of medications based on uncertain efficacy evidence, but the process depends on timely follow-up trials.We found that more than half of so-called confirmatory studies were not completed in the agreed-on time. In contrast with a recent Office of the Inspector General Report of incomplete confirmatory trials, our study includes late completed trials and manufacturer-reported delays. Limitations include shorter follow-up for more recent accelerated approvals and inability to identify reasons for trial delays.

Incomplete confirmatory clinical trials harm patients who are prescribed expensive drugs

despite uncertain clinical benefits. However, drug manufacturers face few consequences for delays. The Consolidated Appropriations Act for 20236 included accelerated approval reforms, such as granting the FDA greater authority to ensure confirmatory trials are under way before approval, mandating progress reports every 6 months by manufacturers, and clarifying procedures for withdrawal if follow-up trials do not find clinical benefit. It will be important to monitor whether these changes lead to fewer delays or whether additional authority is needed to assure that confirmatory trials are completed in a timely manner for the benefit of patients."

Critical Dates after NDA/BLA submission: Filing Date (Day 1), Day 14, Day 60, Day 74, and PDUFA date

After the NDA/BLA is submitted to FDA, the FDA review clock starts. There are several critical dates relevant to the applicant (the sponsor).

Filing date (Day 1): the date that the NDA/BLA application is received by FDA. Nowadays, the NDA/BLA submission will be in eCTD format and go through FDA's electronic submission gateway. FDA will receive the NDA/BLA submission on the same day (or the next day) as the sponsor submits. The review clock (or PDUFA time clock) begins when the application is received by the FDA. 

Day 14: FDA acknowledges to the sponsor in writing (filing letter) that the application is received. Between Day 1 - Day 14, the FDA could request the sponsor to correct the conformance issues. For example, the data sets in the SAS transport file were created using incorrect procedures and could not be opened by the FDA. FDA would ask the sponsor to resubmit the data sets in the SAS transport file using the correct procedures. 

Filing Letter – a letter issued to notify the applicant that their submission has been filed and will be reviewed. Note: The filing letter also includes information stipulated by PDUFA and may contain any identified filing deficiencies.

According to OFFICE OF MANAGEMENT: Effect of Failure to Pay BsUFA Fees

If the applicant (including its affiliates) is not in arrears and has satisfied any fee requirements for the application, then the RPM /RBPM aligned with the review division sends an Acknowledgement Letter within 14 calendar days of receipt of submission to the applicant.

Day 60: The sponsor will be notified within 60 days of submitting the NDA/BLA whether the application has been accepted for filing (or conversely, if the FDA refuses to file the application due to lack of information or studies).

According to CDER 21st Century Review Process Desk Reference Guide, by Day 60, FDA needs to: 

• Inform the applicant of a Priority Designation in Writing Communicate Filing Determination to Applicant (for BLAs and priority NDAs) 
• Notify Applicant of a Refuse-to-File determination. Communicate an RTF action to the applicant by day 60 in the form of official correspondence. Refusal to file (RTF) is the Food and Drug Administration (FDA)’s formal decision to deny review of a New Drug Application (NDA), Biologics License Application (BLA), supplemental NDA (sNDA) and supplemental BLA (sBLA) due to application deficiencies. 

If the sponsor requested for priority review and did not receive a notification by Day 60, it is most likely that the priority review was not granted by the FDA. The standard review (10-months) will follow. 

Day 74 (Deficiencies Identified) Letter – a letter notifying the applicant of issues identified during the filing review phase that were not communicated in the filing letter. It is likely that the issues related to the statistical analyses will be included in the Day-74 letter. 

According to PDUFA REAUTHORIZATION PERFORMANCE GOALS AND PROCEDURES FISCAL YEARS 2018THROUGH 2022:

Day 74 Letter: FDA will follow existing procedures regarding identification and communication of filing review issues in the “Day 74 letter.” For applications subject to the Program, the timeline for this communication will be within 74 calendar days from the date of FDA receipt of the original submission. The planned review timeline included in the Day 74 letter for applications in the Program will include the planned date for the internal mid-cycle review meeting. The letter will also include preliminary plans on whether to hold an Advisory Committee (AC) meeting to discuss the application. If applicable, the Day 74 letter will serve as notification to the applicant that the review division intends to conduct an expedited review.

Review performance goals: For NME NDA and original BLA submissions that are filed by FDA under the Program, the PDUFA review clock will begin at the conclusion of the 60 calendar day filing review period that begins on the date of FDA receipt of the original submission. 

Day 74 Letter: If the application is accepted for filing (60 days after submission), then the sponsor will receive an FDA 74-day letter, which contains a planned NDA review timeline that varies based on several factors such as whether other similar drugs already exist or whether your drug treats an unmet medical need.

The FDA 74-Day letter also confirms your action date (PDUFA date), confirms standard versus priority review, and identifies any preliminary deficiencies in your application. Sponsors must act quickly to resolve the deficiencies noted in the FDA 74-day letter during the NDA review process.

According to CDER 21st Century Review Process Desk Reference Guide, by Day 74 (i.e., Day 60 + 14 Days), FDA needs to:

•  Communicate Filing Review Issues
•  Communicate “Program” Review Timeline to Applicant (if applicable)

According to MAPP: OFFICE OF NEW DRUGS  Review Designation Policy: Priority (P) and Standard (S), the sponsor will be informed of the priority review designation by Day 60. If the sponsor is not notified of the priority review designation by Day 60, it means that the request for priority review is not granted, and the standard review designation will be applicable. 

The division will inform the applicant in writing of a priority review designation by Day 60 of the review. The division will inform the applicant of a standard review designation in the filing communication by Day 74 of the review.

PDUFA date (FDA action date): 

Prescription Drug User Fee Act (PDUFA) dates refer to deadlines for the FDA to review new drugs. The PDUFA date is 10 months after the drug application has been accepted by the FDA or 6 months, if the drug is given a priority review designation.

By the PDUFA date, FDA needs to notify the sponsor if its NDA/BLA application is approved, tentative approved (pending the patent issues or exclusivity issues), or given a complete response letter (CRL). FDA issues a CRL when declining the NDA/BLA. The CRL will include the reasons why the FDA can not approve the NDA/BLA in its current format. 

Notice that the PDUFA date (6 months for priority review and 10 months for standard review) may not be calculated from the filing date (day 1), but rather is calculated from Day 60 after the filing date - this essentially adds two months to the review timeline. Two months are necessary for FDA to conduct the initial review to decide if the application is reviewable. With these two months (60 days), the PDUFA date may actually be 8 months for some applications with priority review designation and 12 months for standard review after the sponsor submits the NDA/BLA. 

The initial scheduled PDUFA date will be extended if additional data or materials are submitted during the review period, which constitutes a major amendment to the NDA/BLA submission. 

This Youtube video explained very well about NDA and BLA Application Review Process as part of the REdI Annual Conference (2019)

I have collected some recent NDA/BLA (or supplemental NDA/BLA) submissions to see when FDA notification date is relevant to the submission date and how the PDUFA date is determined. 

	Submission date/filing date	FDA notification date	PDUFA date	Actual Decision Date
Akebia NDA for Vadadustat for the Treatment of Anemia Due to Chronic Kidney Disease	March 30, 2021	June 1, 2021   By Day 60	March 29, 2022 Standard review – 10 months from Day 60	March 30, 2022   CRL was issued
Amarin sNDA for VASCEPA® for cardiovascular risk reduction	March 28, 2019	May 29, 2019   By day 60	September 28, 2019 Priority Review – 6 months from the filing date	December 13, 2019 Approved, 3 months of delay due to conducting Adcomm
Amylyx NDA for AMX0035 for the Treatment of ALS	November 2, 2021	December 29, 2021   By Day 60	June 29, 2022   Priority review – 6 months from Day 60	September 29, 2022 Approved 3 months of delay due to conducting two rounds of Adcomm
Blueprint Medicines sNDA  for AYVAKIT® for the Treatment of Indolent Systemic Mastocytosis	November 22, 2022	January 23, 2023   By Day 60	May 22, 2023   Priority review – 6 months from the filing date
Acadia Pharmaceuticals NDA for Trofinetide for the Treatment of Rett Syndrome	July 18, 2022	September 12, 2022   Within Day 60	March 12, 2023   Priority review – 6 months from Day 60
Argenx BLA for efgartigimod for treatment of generalized Myasthenia Gravis	September 21, 2022	November 22, 2022   By Day 60	March 20, 2023   Priority review – 6 months from the filing date
Cidara Therapeutics NDA for Rezefungin for treatment of Candidemia and invasive candidiasis	July 27, 2022	September 20, 2022 Within Day 60	March 22, 2023   Priority review – 6 months from Day 60
Ionis with Biogen NDA for tofersen for ALS		July 26, 2022	Jan. 25, 2023 Priority review – 6 months from Day 60
Biomarin BLA Gene Therapy for Hemophilia A	September 29, 2022 Resubmission	October 12, 2022	March 31, 2023 6 months from resubmission date
Gamida cell BLA for Omidubicel for hematologic and solid cancer	June 2, 2022	August 1, 2022   By Day 60	January 30, 2023 Priority review – 6 months from Day 60	PDUFA date is further extended by 3 months to May 1, 2023
Ascendis Pharma	August 31, 2022	October 31, 2022   By Day 60	April 30, 2023 Priority review – 6 months from Day 60
Biomarin BLA Gene Therapy for Hemophilia A	December 23, 2019	February 20, 2020 By Day 60	August 21, 2020 Priority review - 6 months from Day 60	August 18, 2020   CRL was issued
Arcutis’ ZORYVE™ (Roflumilast) Cream 0.3% For the Treatment of Plaque Psoriasis	October 4, 2021	December 22, 2021 By Day 74	July 29, 2022 Standard review – almost 10 months from filing date	July 29, 2022   approved
Apellis NDA for Pegcetacoplan for Geographic Atrophy	June 1, 2022	July 19, 2022   Within Day 60	November 26, 2022 Priority review – Less than 6 months from the filing date	February 17, 2023 Approved, Almost three months of delay due to a major amendment to the NDA (additional submission of long-term data)
TG Therapeutics BLA for Umbralisib for treatment of Lymphoma	June 17, 2020	August 13, 2020   With Day 60	February 15, 2021 Priority review – 6 months from Day 60	February 5, 2021 Approved, Then FDA withdrew the approval
Reata Pharmaceutics NDA for omaveloxolone for the Treatment of Friedreich’s Ataxia	March 31, 2022	May 26, 2022   Within Day 60	November 30, 2022 Priority review – 6 months from the filing date	February 28, 2023 Approved,  5 months of delay due to a major amendment to include the OLE data
Prevention Bio BLA for Teplizumab for Type 1 Diabetes	November 2, 2020	January 4, 2021   By Day 60	July 2, 2021 Priority review – 6 months from Day 60	July 2, 2021 CRL was issued
Liquidia NDA LIQ861 for treatment of PAH	January 27, 2020	April 8, 2020   By Day 74	November 24, 2020 Standard review – 10 months from the filing date	November 25, 2020 CRL was issued
Horizon sBLA for KRYSTEXXA® for Uncontrolled Gout	January 10, 2022	March 7, 2022   Priority review -	July 7, 2022 Priority review – 6 months from the filing date	July 8, 2022   Approved

Risk of Stopping Trial Early for Treatment Benefit - Story of Veru's Sabizabulin for Treatment of Covid

Today, we learned that FDA declined to approve the emergency use authorization (EUA) for Veru's sabizabulin for the treatment of Covid. The decision is not surprising given that in Nov 9, 2022, the FDA advisory committee voted 8-5 against the sabizabulin treatment aimed at hospitalized patients with moderate to severe infection who are at high risk for acute respiratory distress syndrome.

• "Veru's EUA ambitions crash after FDA declines to authorize its COVID treatment"
• Veru Provides FDA Update on Request for Emergency Use Authorization for Sabizabulin for Hospitalized COVID-9 Patients at High Risk for ARDS
• FDA Adcomm Votes Against Veru's COVID-19 Therapeutics

However, this case is a perfect example demonstrating the risk of stopping a clinical trial early for treatment benefit (or for overwhelming efficacy). 

The pivotal study was an international, multicenter, randomized, double-blind, placebo-controlled, parallel group study of 60 days duration that evaluated the efficacy and safety of VERU-111 (sabizabulin) in hospitalized adult subjects with COVID-19 infection described as being at “high risk for ARDS”. Subjects were included if they met criteria for World Health Organization (WHO) ordinal scale category 5 (non-invasive ventilation or high-flow oxygen) or category 6 (mechanical ventilation); or category 4 (oxygen by mask or nasal prongs) with the following comorbidities: asthma, chronic lung disease, diabetes, hypertension, severe obesity (BMI ≥40), 65 years of age or older, primarily residing in a nursing home or long-term care facility, immunocompromised. The primary efficacy endpoint is all-cause mortality at Day 60. 

According to the study protocol, approximately, 300 subjects were planned to be randomized at a 2:1 ratio into two treatment arms (200 subjects in the VERU-111 treated group and 100 subjects in the Placebo treated group). The protocol also pre-specified a formal interim analysis conducted by an independent data monitoring committee:

An efficacy interim analysis of the primary endpoint, all-cause mortality at Day 60, will be conducted when approximately 67% of the subjects (~200 subjects) have completed day 60, died or withdrawn for other reasons. The interim and final analyses will follow an O'Brien-Fleming group sequential design, with a plan of stopping the trial at the interim analysis if the results are statistically significant in favor of VERU-111. The criterion for efficacy at the interim analysis will be a two-sided 0.0121 p-value (a one-sided p-value <=0.0061 in favor of VERU-111). If the criterion is not met, the trial will continue, and the final analysis will have a criterion for efficacy of a two-sided p-value <=0.0463 (one-sided 0.0232 in favor of VERU111).

The formal interim analysis was conducted after 204 patients were randomized into the study and followed up to 21 days (134 patients in Sabizabulin group and 70 patients in Placebo group). Sabizabulin treatment resulted in a 24.9 percentage point absolute reduction and a 55.2% relative reduction in deaths compared with placebo (odds ratio, 3.23; 95% CI confidence interval, 1.45 to 7.22; P=0.0042). The mortality rate was 20.2% (19 of 94) for sabizabulin versus 45.1% (23 of 51) for placebo.

Given that the p-value 0.0042 is less than the criterion for stopping the trial for efficacy (0.0121), the sponsor (Veru) stopped the study and declared the overwhelming efficacy in the hope of FDA's approval for emergency use authorization. 

• Veru’s Stops COVID-19 Treatment Trial in Face of ‘Overwhelmingly Positive’ Results

The interim analysis results were then published in the top medical journal - New England Journal of Medicine "Oral Sabizabulin for High-Risk Hospitalized Adults with Covid-19: Interim Analysis".

The original sample size of 300 patients was already pretty small in trials for the treatment of COVID-19. The sample size was further decreased due to the early stop for 'overwhelming' efficacy. During the FDA's review, the small sample size was one of the big issues. FDA expressed their concern about the evidence for supporting the benefit outweighing the risk in their briefing document provided for the advisory committee:  

The FDA Review team acknowledges that Study 902 met its prespecified primary endpoint of all-cause mortality at Day 60. We also note that the VERU-111 program is quite small in size compared to other therapeutic programs for patients hospitalized with COVID-19. As detailed in the briefing document, our review has identified a number of uncertainties with the data, which we raise in the context of this small trial in critically ill patients. These include:

• High placebo group mortality rate
• Potential for unblinding events with enteral tube administration
• Baseline imbalances in standard of care therapies
• Differences in hospitalization duration prior to trial enrollment
• Uncertain effects of goals of care decisions on all-cause mortality
• Negative studies with other microtubule disruptors in COVID-19 
• Uncertainty in identification of a clinically relevant patient population 

Based on our review, none of these uncertainties or imbalances alone invalidate the mortality benefit observed in Study 902, but all of these issues together in a small trial which is more vulnerable to imbalances raise questions about the results. We conducted sensitivity analyses to investigate the potential impact of the noted imbalances. However, these analyses cannot eliminate the concern that certain baseline imbalances across treatment groups may have impacted study outcomes, due to the small study size. In addition, these issues raise concern that, even when using an objective endpoint such as mortality, observed results can be subject to biases in a small trial of short duration in critically ill patients. We ask the AC panel to consider these uncertainties together and how they affect the interpretation of the mortality data. 

When considering whether to authorize the emergency use of a product under EUA, the Agency must determine, among other requirements (see section 2.1.3), whether “the known and potential benefits of the product when used to diagnose, prevent, or treat the identified serious or life-threatening disease or condition, outweigh the known and potential risks of the product”. Evaluation of the potential risks in the VERU-111 development program is limited by the atypically small safety database, comprising a total of 149 subjects who received VERU-111 for the proposed use in COVID-19. While the small safety database limits our ability to identify clinically significant safety signals, potential safety signals identified in our review are urinary tract infections (including serious infections), ......

There is no guarantee that Veru's EUA application would be approved had the study not been stopped early. But I think that the chance of EUA approval would be much higher if the study was allowed to be completed according to the protocol and 100 additional patients were randomized into the study. To decide whether a study should be stopped early for efficacy, the stopping criterion is not the only factor to consider. I wished that the sponsor had consulted with the regulatory authorities before the decision to stop the study early for efficacy. 

On a separate note, FDA's "Good Review Practice: Clinical Review of Investigational New Drug Applications" spelled out their concerns about early stopping for efficacy: