Review of Safety in FDA Medical Reviews

Analysis of the latest review of safety sections for new drug applications (NDAs and BLAs)

I found interesting to analyze the latest Reviews of Safety for the FDA submission classification Type 1 – New Molecular Entity. To obtain the medical reviews I accessed the FDA Approved Drug Products web page, and selected “Drug Approval Reports by Month”, and then “Original New Drug Approvals (NDAs and BLAs) by Month. I chose twenty clinical reviews, from October 2018 to March 2019.

Some of the clinical reviews were found as individual documents on the approval package, under the name of “Medical Reviews“, while other clinical reviews were embedded into a big file named “Multi-discipline Review“, containing the summary review, office director, cross discipline team leader review, clinical review, non-clinical review, statistical review, and clinical pharmacology review.

Another interesting aspect of this analysis is that older reviews have a specific headline for “Reviewer comments”, being each section followed by the comments of the reviewer at the end of it. However, more current clinical reviews do not differentiate the reviewer comments; actually, it looks like all text comes from the reviewer, instead of separating what the applicant submitted from what the reviewer commented. I think the newer approach is better, as the reviewers elaborate their thinking in a more extensive fashion.

If you are in a hurry, just go to the Conclusions at the end of this post.

CDER Clinical Review Template

According to the CDER Clinical Review Template 2015 for New NDA or BLA, the Review of Safety outline is as follows:

1. Review of safety
1.1 Safety review approach
1.2 Review of the safety database
1.3 Adequacy of applicant’s clinical safety assessments
1.4 Safety results
1.5 Analysis of submission-specific safety issues
1.6 Specific safety studies / clinical trials
1.8 Additional safety explorations
1.9 Safety in the postmarket setting
1.10 Additional safety issues from other disciplines
1.11 Integrated assessment of safety

However, although the basic outline for the review of safety section is the same, there are some variations, depending on the drug evaluated, wheter or not a subsection is pertinent and, possibly, the reviewer preferences or style.

Let’s go through each section and analyze what the reviewers have to say.

Safety review approach

Reviewers explain what the evaluation of safety for the product in questions is based on, which is, most of the time clinical trials. Among the clinical trials, which ones contribute the most, whether or not they perform pooling of data from different trials, and which treatment arms are to be considered.

Also, reviewers determine whether or not the methods to assess safety in the individual clinical trials and in the integrated summary of safety are considered appropriate.

FDA performs their own analysis using a variety of applications for drug safety analytics, like MedDRA Adverse Event Diagnosis Service (MAED), JMP amd JMP Clinical, while using analysis data model (ADAM) and study data tabulation model (SDTM) data sets, looking for differences in findings by the FDA reviewer compared to the applicant, among other aspects of the analysis.

If there are adverse events of special interest (AESI), they are stated here.

Review of the safety database

The review of the safety database includes the overall exposure, relevant characteristics of the safety population, and the adequacy of the safety database.

Overall exposure is summarized in a table. Depending on the product, the table may content number of individuals by arm, and if for example race is an important variable to understand pharmacokinetics (PK) data, that information should be included too, at least in the text.
Duration of exposure is an important aspect of exposure described here. They make a lot of emphasis in comparing median exposure times among groups. Reviewers will be concerned if those times are significantly different.

In this section, relevant characteristics of the safety population are also described. Demographics and baseline characteristics are included. Populations that are underrepresented are also highlighted. Whether or not important subgroup populations are well represented is something reviewers take into account. It is important to highlight whether or not the final safety database is well balanced in terms of baseline demographics and disease characteristics.

With respect to the adequacy of the safety database, the reviewers determine if the data are sufficient as to characterize the safety profile of the product. They evaluate if the total number of individuals in the safety database is enough or lower than recommended in FDA guidance, depending on the product under study. On occasions, the reviewer may recommend adding additional information to confirm safety of long-term use of the investigational product, in general or in specific subpopulations (like older people).
Another aspect of relevance is if there are evidence of safety signals in the clinical and pre-clinical development program.

Adequacy of applicant’s clinical safety assessments

Reviewers evaluate:
– Issues regarding data integrity and submission quality, that have an effect on the safety review.
– Categorization of adverse events. Adverse event and serious adverse event definitions are evaluated, as well as the safety reporting period for SAEs. Identification of issues with respect to recording. coding, and categorizing AEs, and if the applicant has used SOC and PTs applying MedDRA coding. Categorization of AE severity according to the CTCAE criteria is used in the majority of occasions. Interestingly, they tend to perform analysis of AEs/SAEs Grade 3 and up. Basis for the causality assessment. MedDRA version is also stated, as well as the selection of PTs by the use of Standardized MedDRA Queries (SMQ).
– Routine clinical tests, pregnancy tests, and acceptability of the schedule of events.

Safety results

Here reviewers pay attention, specifically to:
– Deaths. Reviewers evaluate whether or not they agree with applicant assessment of relatedness with the use of the investigational product.
– Serious Adverse Events (SAEs). Same as for deaths, reviewers make an opinion of agreement / disagreement with Company causality for each one of the SAE cases, as well as for the death cases.
– Dropouts and/ or discontinuations due to adverse effects. Here there is an evaluation of AEs leading to discontinuation. These significant adverse events are evaluated in terms of severity (defined by the applicant), and of the presence of patterns or concerns for these events. Distinction is made here to not include patients who discontinued due to events related to the disease rather than to the product.
– Treatment emergent adverse events (TEAEs) and adverse reactions. In general, this is the section where AEs are presented in tables, depending on the percentage of occurrence by study arm. Sometimes reviewers recommend including laboratory-related adverse reactions in a separate table in the package insert.

INTERESTING: Adverse Reactions. In one study, the applicant defined Adverse drug reaction as: “one that was reported in at least 2% of subjects who received the investigational product, occurred at a higher incidence than in placebo in the pooled pivotal trials, and was attributed to the study drug by the investigator. And the reviewer stated:

Using that definition, no ADRs would be listed in Section 6 Adverse Reactions section of the package insert. In the opinion of this reviewer, stating that there were no ADRs associated with the investigational drug might mislead health care providers and patients about the risks and benefits associated with taking the investigational drug. Therefore, the adverse events reported in at least 1% of subjects in the pivotal trials will be included in the package insert.

Comments regarding laboratory values, vital signs, ECG, QT, and immunogenicity were related to the presence of trends or abnormal values taking into account the expected changes explainable by the underlying disease. They analyze dose-dependency in relation to change in all those values.

A variety of statistical and epidemiological analyses may be applied here. It is not infrequent to find survival analysis curves applied to time-to-adverse event analysis.

Analysis of submission-specific safety issues

Here reviewers analyze a set of safety concerns that are related to the specific submission. For example, if hepatic toxicity is a concern, they evaluate liver effects. In some cases, those events are considered adverse events of special interest.
Description of clinical cases is something that occurs when a specific safety concern is analyzed.

Safety analysis by demographic subgroups

The purpose of this sub-section is to provide analyses of safety information for demographic interactions. Several methods and analytics may be applied here to explore the effects of possible interactions on safety signals / events. For many applications, individual clinical trials may not be powered enough to reach conclusions regarding safety among the demographic subgroups (age, gender, and race). Pooled analysis, when appropriate, will have greater power, interpretations about subgroup data should be made with caution. Nonetheless, these analyses should be performed when feasible, and tables and graphics should be created. Analysis of adverse events (real world data) by geographic region is also appropriate.

This type of analysis could be placed on Safety analysis section. Sometimes it appears here.
In this section, specific safety analysis and tables by age, gender, and race are presented and discussed. What is important here is if there are safety differences by age groups, sex, or race that could indicate a different safety profile or behavior.

Clinical outcome assessment (COA) analyses informing safety/tolerability

Sometimes, when pertinent, this section is included. For example in case of the application of patient reported outcomes (PRO) instruments. According to one reviewer, “PRO results are not likely to offer unbiased and conclusive evidence of patient’s quality of life.” This statement was probably made because the applicant wanted to include some benefit language in the product label.

Specific safety studies / clinical trials

Reviewers evaluate here if there was a study for the assessment of a specific safety issue, to identify or quantify a particular safety concern.

Additional safety explorations

Typically here human carcinogenicity or tumor development, human reproduction and pregnancy, and pediatrics and assessment of effects on growth are explored here. Moreover, overdose, drug abuse potential, withdrawal and rebound issues are discussed here too.

Safety in the postmarket setting

Sometimes the drug under investigation has some postmarket experience, in some specific countries, for example. That postmarket experience needs to be analyzed y evaluated from the safety point of view. The safety review of postmarket experience centers basically on serious adverse events. The expectations from safety in the post-marketing setting are also stated. In general, routine pharmacovigilance activities are in order.

Additional safety issues from other disciplines

In general, safety issues from other disciplines are discussed in their respective sections of the approval review.

Integrated assessment of safety

I have found a variety of approaches reviewers take to write this section. It goes from a minimalist (and I believe a little off) “The above safety assessment incorporates data from X trials and is therefore integrated”, to a short summary of all the previous sections, to an extended safety assessment of 2-3 pages. It normally determines if there are or not concerning safety findings. It is also stated whether or not the safety issues are correctly communicated in the product label, or determine if the applicant should include any AEs in “Warnings and precautions” section of the product label.

Postmarket commitments like PMR studies or REMS, boxed warnings, and enhanced pharmacovigilance are recommendations made by the reviewers in the integrated assessment of safety.

Conclusions

• Analysis of the clinical reviews found in the approval packages from recently approved drugs is of great help understanding how review of safety is performed.
• Read the FDA Clinical Review Template. That will give you an incredible insight on what reviewers are looking for.
• After reviewing the first 10 reviews of safety, little to no information was added to my analysis by reading the next 10 ones.
• Reviewers follow the main clinical review outline, but there is a wide variety of approaches to the evaluation of the different aspects and data of the Review of Safety.
• Many of the subtle differences among the reviews of safety evaluated are product-related. So it would be advisable to review, for example, the 10 latest clinical reviews from approved oncology products if you are submitting an oncology product.
• There is no mention of statistical analysis in the Review of Safety. Reviewers do a great job with extensive descriptive analysis. This is also helpful to avoid arguments related to applying statistical testing to pooled data.
• Honest description of our safety data, making use of our current knowledge is generally more than enough to elaborate an appropriate safety profile of our product in our population(s). No rocket science needed.
• This exercise helped me to obtain responses on what reviewers are looking for and, consequently, better prepare for NDA/BLA submission and success from the safety review perspective.
• Although this post refers to the review of safety section of the clinical review, this approach can be applied to the rest of documents constituting the submission package for NDA / BLA approval.