What's New in FDA's Draft Guidance "Use of Data Monitoring Committees in Clinical Trials"?

In early 2024, the FDA unveiled its latest drug guidance for the industry titled "Use of Data Monitoring Committees in Clinical Trials." This forthcoming guidance will supplant the existing DMC guidance, "Establishment and Operation of Clinical Trial Data Monitoring Committees," which dates back to March 2006. Notably, the title of the guidance has been modified.

What distinguishes this newly issued guidance? And why the necessity for a fresh approach to DMC guidance?

The subsequent articles endeavor to tackle these queries.

• RAPS.org FDA issues new draft guidance on data monitoring committees
• FDA Law Blog: How to Run DMC? It’s Tricky – FDA’s New Draft Guidance Provides Updated Recommendations on How to Best Use Data Monitoring Committees in Clinical Trials
• RAPs.org (April, 2024) Industry advises practical fixes for new FDA guidance on data monitoring committees

The new guidance actually mentioned the following "Significant changes in DMC structure and practice since the 2006 guidance was issued include: 

• The increased use of DMCs in trials (Califf et al. 2012) of modest size as reflected in the clinical trials data bank housed at ClinicalTrials.gov 
• A trend for DMC charters to become longer and more detailed
• An increased use of DMCs to implement certain adaptive clinical trial designs
• An increased use of some DMCs to oversee an entire clinical development program rather than a single clinical trial
• The potential for expansion of functions of a DMC; for example, for review of aggregate data for safety reporting for trials under an investigational new drug  application (IND) 
• An increased globalization of medical product development and use of multiregional trials with DMCs

In the early 2000s, the concept of Data Monitoring Committees (DMCs) began gaining traction, inspired by their use in NIH studies since the 1980s, albeit without formal FDA acknowledgment until later. These committees, born from the need for independent oversight, particularly in trials with serious outcomes or severely ill patients, initially operated with considerable flexibility, leading to varied implementations. Recognizing the evolving landscape, stakeholders engaged in discussions, culminating in the Clinical Trial Transformation Initiative's partnership with the FDA in 2015. Through a series of meetings, including one in Washington, recommendations were made to address the observed diversity in DMC practices. This dialogue ultimately contributed to the drafting of a new guidance document in 2024, aimed at refining DMC usage. The proposed revisions underscore not only the importance of study rigor and integrity but also prioritize participant safety, potentially influencing the early termination or modification of trials. Moreover, the guidance acknowledges the increasing prevalence of adaptive trial designs, suggesting a responsiveness to emerging trends. The new guidance suggested adaptation committee for clinical trials utilizing the adaptive design. The adaptive committee may or may not be the same as the DMC. Overall, the iterative process of refining DMC guidance reflects a collaborative effort to adapt to evolving clinical trial practices and prioritize patient well-being.

In recent years, there has been considerable discourse surrounding the creation of a distinct committee, often referred to as a safety assessment committee, tasked with the ongoing review of aggregate safety data. The requirement was spurred by the FDA guidance "Safety Assessment for Investigational New Drug Application Safety Reporting;" in 2015 that was subsequently withdrew. I have contended that the oversight of aggregate safety data can effectively be carried out by the independent Data Monitoring Committee (DMC), obviating the need for an additional safety assessment committee. The newly issued DMC guidance reflects this perspective, affirming that either the DMC or an independent safety team may undertake the review of aggregate safety data. The guidance specifies the following:

We are witnessing a growing prevalence of DMC utilization across various types of clinical trials, spanning from those focusing on rare diseases to trials characterized by high morbidity and mortality rates, as well as trials featuring innovative designs like adaptive designs. Furthermore, DMCs may find application in open-label studies, dose escalation studies, gene therapy trials, and beyond. Occasionally, sponsors may opt to incorporate DMCs as a means to enhance the study's credibility.

New champion for the most expensive drug in the US

It's widely acknowledged that medications for rare diseases and gene therapies come with a hefty price tag. In the United States, the FDA oversees drug approval, but there's no governmental oversight on pricing. After FDA approval, drug sponsors and manufacturers have the autonomy to propose and set the drug's price. Typically, pricing considerations revolve around factors like patient population, investment in drug development and approval, and anticipated financial gains, rather than the drug's effectiveness or its benefit-risk profile.

Before this month (March, 2024), the top 10 most expensive drugs in the US are:

Brand Name	Cost	Manufacturer	Indication	FDA approval date	Reason for high cost
Hemgenix	$3.5 million per one-time dose	CSL Behring	Hemophilia B	November 22, 2022	Gene therapy
Elevidys	$3.2 million per one-time dose	Sarepta Therapeutics	Duchenne Muscular Dystrophy (DMD)	June 22, 2023	Gene therapy
Skysona	$3 million per one-time dose	Bluebird Bio, Inc.	Cerebral Adrenoleukodystrophy (CALD)	September 16, 2022	Gene therapy
Zynteglo	$2.8 million per one-time dose	Bluebird Bio, Inc	Beta-thalassemia	September 16, 2022	Gene therapy
Zolgensma	$2.1 million per one-time dose	Novartis	Spinal Muscular Atrophy	May 24, 2019	Gene therapy
Myalept	$1.3 Million annually	Amryt Pharmaceuticals	Lipodystrophy/Leptin deficiency	February 24, 2014	Ultra rare disease
Danyelza	$1.2 million annually	Y-mAbs Therapeutics	Neuroblastoma	November 25, 2020	Ultra rare disease
Zokinvy	$1.2 million annually	Eiger Biopharmaceuticals	Progeria and Progeroid Laminopathies	November 20, 2020	Ultra rare disease
Kimmtrak	$1.1 million annually	Immunocore	Uveal Melanoma	January 25, 2022	Ultra rare disease
Luxturna	$850,000 per one-time dose	Spark Therapeutics	Biallelic RPE65-Mediated Inherited Retinal Disease	December 19, 2017	Gene therapy

In the past month, a new titleholder emerged for the most expensive drug in the US. Orchard Therapeutics, a subsidiary of Japan's Kyowa Kirin, now claims the top spot for producing the priciest medication.

Brand Name	Cost	Manufacturer	Indication	FDA approval date	Reason for high cost
Lenmeldy	$4.25 million per one-time treatment	Orchard Therapeutics, a unit of Kyowa Kirin	Metachromatic Leukodystrophy (MLD)	March 18, 2024	Gene therapy

There's an organization known as the Institute for Clinical and Economic Review (ICER), tasked with suggesting drug prices based on health economic assessments or Health Technology Assessments (HTAs). However, manufacturers often diverge from ICER's recommendations, frequently setting prices significantly higher. Take, for instance, a recent case where Merck, the drug's manufacturer, proposed a price nearly ten times higher than ICER's recommendation.

These exorbitant prices must ultimately be endorsed by health insurance companies or the Centers for Medicare & Medicaid Services (CMS). Consequently, it's the insurance companies or the Medicare & Medicaid program that bear the burden of these steep costs, as patients are unable to afford medications with such astronomical price tags.