FMQ (FDA Medical Query) and SMQ (Standardized MedDRA Query)

For clinical trials, the safety analyses are mainly based on the analyses of the adverse events including serious adverse events. The adverse events are recorded in CRFs/eCRFs with investigators' verbatim terms (text field). Before the adverse event data can be summarized and analyzed, the verbatim terms need to be coded and standardized. The common practice is to code the adverse events based on the MedDRA dictionary and the coded terms are then summarized and analyzed by system organ class and preferred term. For a while, this approach seems to work very well. However, there are issues with this approach, mainly because different preferred terms may point to the same disease/condition. 

Last Wednesday, The FDA in collaboration with the Duke-Margolis Center for Health Policy hosted a one-day virtual meeting focused on advancing premarket safety analytics. In the morning session, FDA officers discussed the FMQ (FDA Medical Query). In the afternoon session, FDA discussed the standardized presentation of the safety data including the tables and figures for adverse event data and laboratory data. 

The FDA Medical Queries (FMQs) is a standardized approach to group preferred terms. Recognizing the limitation of the current analysis of adverse event data by preferred term, using FMQs can consolidate a medical condition with scattered preferred terms and be more likely to identify any signal of safety issues. The rationales for FDA's efforts in developing various FMQs are described in the slide below: 

FMQs were defined as the following: 

FMQs can be used to identify the safety signals that may be missed by using the conventional preferred term approach. When FMQs are adopted by the regulatory agency and the industry, FMQs (grouped term information) can be included in the ADVERSE REACTIONS Section of the Prescribing Information (or product label). The slide below illustrates a fictitious example of using FMQ term in the ADVERSE REACTIONS section of the product label. The AE table in the product label will include the mixture of the FMQ term (grouped term) and the MedDRA preferred terms. 

A real example of FMQs in the product label can be the drug called Injectafer. The tables for adverse reactions included the mixture of the preferred terms and the grouped terms (based on FDA's FMQs). 

FMQ is exactly the same concept as the SMQ (standardized MedDRA query). The SMQ was defined as the following: 

With each version of the MedDRA dictionary, a set of available SMQs will be included. Included is also the document "Introductory Guide for Standardised MedDRAQueries (SMQs)". 

Both FMQ and SMQs included narrow terms and broad terms. However, the narrow terms are more commonly used in practice. 

One natural question is: what is the difference between FMQ and SMQ? why can't we just use the SMQ? Here are a couple of slides indicating the differences between FMQ and SMQ. There are almost equal numbers of FMQs (104 FMQs for now) to SMQs (110 SMQs).

It is true that SMQs have primarily been used in pharmacovigilance, not in premarket safety assessment. I have previously written a couple of articles about the SMQs: 

• Adverse Event of Special Interest (AESI), Standardized MedDRA Query (SMQs), Customer Queries (CQs), and SAS Programming
• Standardized MedDRA Queries (SMQs) and Standardized Drug Groupings (SDGs)

One drawback of FMQ is that it is developed by the US FDA and its use and application may be limited for market authorization applications in countries outside the US. 

One thing for sure is that we will hear the term FMQ more often in the future and may see the request from FDA to present the grouped terms according to FMQs in the summary and analysis tables for AEs. 

Further reading:

Biomedical Informatics and Safety Analytics in the Office of New Drugs, CDER/FDA – A 2021 Update

Communicating with FDA: Type A, B, C, D meetings, and INTERACT meeting,

For any drug development program, the early and sometimes frequent communications are critical. However, the formal communications between the sponsor and the FDA are a cumbersome process. The sponsor representatives can not directly reach out to FDA reviewers (such as medical reviewer, statistical reviewer, clinical pharmacology reviewer, CMC reviewer,...). On the sponsor side, the communications with FDA is always through the regulatory affairs group. On the FDA side, the communication with the sponsor is through the regulatory project manager (RPM) - each review division at FDA has its own RPM. Direct communications between the sponsor representatives and the FDA reviewers/officers are not good practice and can cause the trouble down the road. We all knew how badly the situation was with Biogen's Aduhelm approval where Biogen executives met with FDA officials outside the normal communication channel. See "FDA chief asks for independent investigation into approval of Biogen's Alzheimer's drug Aduhelm".

Best Communications Practices with FDA is as the following:  

The FDA RPM: The review division regulatory project manager (RPM) is the primary point of contact for communications between IND sponsors and FDA during the life cycle of drug development, and has comprehensive knowledge of the drug and its regulatory history. The RPM is also the primary contact for facilitating the timely resolution of technical, scientific, and regulatory questions, conflicts, or communication challenges between the sponsor and the review team. If sponsors encounter challenges in obtaining timely feedback to inquiries to the review division RPM, they should contact the RPM’s next level supervisor for timely resolution of the issue. 

Communications with FDA are usually through the formal meetings. There are different type of meetings for different purpose. The processes for requesting the formal meetings are described in FDA's guidance below:

• Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products Guidance for Industry
• Best Practices for Communication Between IND Sponsors and FDA During Drug Development Guidance for Industry and Review Staff Good Review Practice

In Regulatory Education for Industry (REdI) Annual Conference 2022 - Day 1, Dr Kevin Bugin gave a PSUFA overview where additional type of meetings with FDA were discussed and FDA officer, Jeannie Roule presented "Guidance for Industry: Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products".

Different type of Meetings with FDA and the Comparisons:

The Prescription Drug User Fee Act (PDUFA) was created by Congress in 1992 and authorizes FDA to collect fees from companies that produce certain human drug and biological products. Since the passage of PDUFA, user fees have played an important role in expediting the drug approval process. PDUFA needs to be reauthorized by Congress every five years. PDUFA VII for fiscal years 2023 through 2027 is being discussed by Congress and is expected to be reauthorized before the end of the current fiscal year. 

To-be-reauthorized PDUFA VII will create some additional meetings with FDA, specifically, Type D meeting. Once the PDUFA is reauthorized by Congress, the sponsor can request for Type D meeting. 

According to PDUFA REAUTHORIZATION PERFORMANCE GOALS AND PROCEDURES FISCAL YEARS 2023 THROUGH 2027, the Type D meeting is described as the following: 

FDA also had a meeting called INTERACT. INTERACT stands for INitial Targeted Engagement for Regulatory Advice on CBER/CDER ProducTs. It is like the pre-pre-IND meeting and is especially useful in CAR-T, Gene therapy, xenotransplantation development programs.