Patient Advocacy Groups in Drug Development and Clinical Trials For Patients With Rare Diseases

I just saw an article on clinicalleader.com "Best Practices For Designing And Running Clinical Trials For Patients With Rare Diseases" by my previous colleague, Mary L Smith. 

Best Practices For Designing And Running Clinical Trials For Patients With Rare Diseases

She had some excellent points about the important role of the patient advocacy group in the drug development process in rare disease areas.

Now that the drug development has been moved to the patient-centric, the patient's voice (usually through the patient advocacy group) is critical. Over the years, I have seen or directly interacted with some of the patient advocacy groups in various activities.

We saw that the patient advocacy group (i.e Parentprojectmd.org) played a critical role in pushing FDA to approve the first drug for Duchenne Muscular Dystrophy even though there wasn't substantial evidence to support the efficacy. 

• Parent Project Muscular Dystrophy 
• To sway drug approval, patient advocates turn up the heat on the FDA
• The FDA’s Controversial Duchenne Drug Approval And The Moral Impulse To Rescue

Cystic Fibrosis Foundation is probably the most successful patient advocate group and it is very well run and organized. In the US, it is extremely to do any clinical trials in CF patients without going through the Cystic Fibrosis Foundation. Cystic Fibrosis Foundation may also be the richest patient advocacy group and received a lot of money from the royalties from CF drug developers. 

• Cystic Fibrosis Foundation: Our Advocacy Work
• Cystic Fibrosis Foundation Receives $3.3 Billion Royalty Pay Out
• Deal by Cystic Fibrosis Foundation Raises Cash and Some Concern

In conducting the clinical trials in patients with Alpha-1 antitrypsin deficiency (a genetic form of severe COPD), we were very closely working with Alpha 1 Foundation - a patient advocacy group created by three Alpha-1 Antitrypsin Deficiency patients.  Alpha-1 Foundation's help pushed FDA/NIH to organize the workshops to discuss the efficacy endpoints that are realistic in clinical trials in Alpha-1 Antitrypsin patients. One of the endpoints was to measure the lung density through CT scan - so-called lung densitometry that was eventually accepted by the FDA to be the primary efficacy measure in Alpha-1 Antriypsin Deficiency trials.   

Other examples of patient advocacy groups are:

• Jeffrey Modell Foundation and primary immune deficiency foundation that we used to work with them for the patient survey.
• Progeria Research Foundation: I was intrigued by this disease and was moved by the story of late Sam Bern and his famous TED talk "My Philosophy for a Happy Life"
• Evan Foundation: established by Evan's father. Evan died of a rare tumor in Children - Neuroblastoma. I listened to Evan's father describing the cruelty of this deadly disease and was encouraged to continue working on clinical trials arming to find the cures for Neuroblastoma. 
• GBS-CIDP Foundation: I used to work on clinical trials in GBS and CIDP and had IGIV approved in CIDP in multiple countries and IGIV approved in GBS in Canada. 
• Cholangiocarcinoma Foundation: One of my friends recently died of Cholangiocarcinoma. 
• Hemophilia: 
• ......

Are we moving away from data listings now that the standard data sets (such as CDISC-compliant SDTM and ADaM data sets) are mandated by FDA?

After a clinical trial is concluded, the statistical group (statisticians and statistical programmers) will generate the tables, listings, and figures (TLFs in short) for the clinical study report (CSR). If the clinical trial results are good, the CSR including the TLFs and the data sets where the TLFs are generated from will be submitted to the regulatory authorities (such as FDA) for marketing authorization application (such as new drug application (NDA) and biological license application (BLA). 

From the statistical standpoint, the clinical trial is a process to collect the data (demographic, efficacy, and safety). The data sets we collected will be converted and mapped to the standardized format according to the CDISC standards - SDTM for tabulation data sets and ADaM for analysis data sets. The standardized data sets are then used for generating the tables, listings, and figures (may also be called the post-text TLFs). The post-text TLFs will be the building block for constructing the CSRs. 

The data listings are required as part of the CSRs and post-text listings are included in the CSRs as appendices. As specified in ICH E3 "STRUCTURE AND CONTENT OF CLINICAL STUDY REPORTS", data listings will be organized according to the sections/numbers below: 

A data listing will be looking like the below with a listing of adverse events as an example (the mock-up shell). Notice that the listing for adverse events is numbered as Listing 16.2.7 corresponding to the section number indicated in ICH E3 (above).

With the FDA's mandate for submission of the standardized data sets, the CDISC standard tabulation data set is SDTM (study data tabulation model), the natural question is if the data listings are still needed. The data listings are just the simple display of the SDTM data set (or ADaM data set) with format/layout beautified. Some sponsors have moved to the direction of not generating the formal data listings and they think that the CDISC-compliant data sets will be sufficient to replace the data listings. 

According to an FDA Final Guidance Webinar Q&A at Pinnacle21 website, the response indicated that the data listings would be replaced by the standard data sets. 

28: With the advent of a new “misc folder” instead of listings do you think that FDA is getting away from generating listings for each study? It seems that the datasets (SEND, SDTM, and ADaM) would stand alone to support any listings.

Once the standards requirements are in effect, the idea would be that listings would be replaced by the SDTM tabulations data, so yes.

The Final FDA Guidance on Standardized Study Data was initially published December 17, 2014 and has subsequently been revised several times. The FDA Binding Guidance requires Sponsors whose studies start after December 17, 2016 must submit data in FDA-supported formats listed in the FDA Data Standards Catalog. The FDA Data Standards Catalog specifies the use of CDISC standards such as SDTM, ADaM, and Define-XML as well as Controlled Terminology.

FDA has organized or participated in multiple webinars to emphasize the criticality of submitting the data sets in standardized formation, however, there is no subsequent mention about the standardized data sets replacing the data listings. 

I did an informal survey and asked the statisticians and statistical programmers working in other pharmaceutical companies and CROs, almost all responses were that they continue to generate data listings and have no plan to stop generating data listings even though they have been fully compliant with the CDISC data standards for their clinical trials.

Even though the CDISC compliant data sets make the data listings redundant and unnecessary, stopping generating the data listings entirely is a risky approach at this point. The data listings should still be generated until we see FDA's guidance indicating otherwise or until the ICH E3 is revised to indicate that the data listings can be replaced by the standardized data sets. 

Some links to this topic: 

• FDA website: Study Data Standards Resources
• FDA website: Study Data for Submission to CDER and CBER
• FDA Webinar: The FDA Study Data Technical Conformance Guide v4.4 - Nov 22, 2019
• Study Data Technical Conformance Guide - FDACDER Small Business and Industry Assistance (CDER SBIA) Webinar - Study Data Standards in eCTD: What You Need to Know about the New Technical Rejection Criteria - October 12, 2016
• Duke Margolis Center for Health Policy in collaboration with FDA organized a public workshop: Advancing the Development and Implementation of Analysis Data Standard: Key Challenges and Opportunities: