Broad Therapeutic Product Class Labelling Strategies for Rx & CDx Products

FDA Guidance Evolution
 
The Guidance for Industry: “Developing and Labeling In vitro Companion Diagnostic Devices for a Specific Group of Oncology Therapeutic Products [1]” was recently finalized for use as of April 16, 2020; it describes considerations for the development and labeling of in vitro companion diagnostic (CDx) products to support the indicated uses of multiple drug or biological oncology products; the draft guidance was initially released in December 2018. This guidance elaborates on the original principle of a CDx being appropriate for use with a specific group of therapeutic products, which was expanded from FDA’s Guidance for Industry and FDA Staff:  “In Vitro Companion Diagnostic Devices”, August 2014. [2]
 
Risks of the Current CDx Framework
 Within this final guidance, FDA highlights the risks of the current CDx development strategy:

1. Delay in treatment because clinicians and/or physicians require multiple CDx test results to decide on the appropriate therapeutic regimen for their patient.
2. If another CDx test is needed, an additional invasive biopsy may be required to obtain the needed tissue for testing.  

 
Labelling Strategy for a Multiple CDx Broad Therapeutic Product 
"Some companion diagnostics in oncology could be developed in a way that results in labeling for a specific group of oncology therapeutic products.  Similarly, for sponsors seeking to broaden the labeling of already approved or cleared companion diagnostics, sponsors may submit a marketing application supplement in support of broader labeling." [3]
 
Boudicca Dx. has identified multiple pathways for consideration to achieve this broader labelling claim for the IVD.  Therapies have a broad labelling claim: "use an FDA-approved test" (and in the future potentially: "use an FDA-cleared test," should FDA consider a Class II IVD to be clinically appropriate for an oncology therapeutic product).  
 
What are potential pathways to obtaining broad therapeutic product labelling for CDx IVDs? 
 
  Figure 1: Therapeutic Class Labelling Scenarios

Considerations for the above Regulatory Strategy
 
These are the important considerations in pursuing the aforementioned scenarios:

1. There must be sufficient and consistent positive clinical experience with at least two therapeutic products approved for the same biomarker-defined indication (e.g., cancer type, line of therapy, cancer stage, etc.) 
2. There must be strong biomarker rationale for the therapeutic products in the same class 
   1. Biomarkers must be clearly defined in Rx. and CDx labelling  
3. There must be one FDA-approved CDx that accurately, precisely, and robustly detects the biomarker and adequately identifies therapeutic product patient population 
   1. Adequate analytical validation data for detection of the biomarker, e.g., accuracy, precision, analytical sensitivity (e.g., Limit of Blank [LOB], Limit of Detection [LOD], minimum tumor content, minimum sample input, etc.), analytical specificity (e.g., interfering substances, etc.), and additional fit-for-purpose studies based on the specific platform.
   2. Adequate clinical validation data for one CDx in one registrational/pivotal therapeutic product clinical trial 
4. Must have early regulatory engagement:
   1. To identify the appropriate regulatory submission pathway for Rx. & Dx. Sponsors; interactive Q-submissions, IND meetings, Information Meetings, etc. 
   2. Alignment with FDA on: "What is the level of evidence required to support broad therapeutic product labelling of the CDx IVD?" Totality of the analytical and clinical validation will be important.

 
 The first therapeutic class labelling product is likely to be an EGFR-targeting therapy.

Case Study: CDx for EGFR-targeting therapies in Non-Small Cell Lung Cancer (NSCLC)

Clear Biomarker Definitions
 
It is important to have clear biomarker definitions and detailed CDx reporting results to enable the oncologist to prescribe the optimal therapy. Broad therapeutic product class labelling could confound the prescription of the optimal therapy for treatment-naïve patients with tumors harboring EGFR mutations. For example, EGFR exon 20 T790M mutation is not an appropriate biomarker for the prescription of these EGFR-targeting therapies described above for treatment-naïve patients as it is a gatekeeper mutation that emerges as a consequence of tumor evolution from patients being on tyrosine kinase therapies. The presence of this biomarker would signal that progression and resistance have emerged, and a therapy that is clinically appropriate in an EGFR T790M genomic context should be prescribed. 

Biomarkers matter! 
 
Boudicca Dx. can support your regulatory strategies and regulatory engagements using fit-for-purpose focused solutions and our preferred partner AveniCom QR can support your regulatory submissions through their template solutions and publishing services.

1. Guidance for Industry: “Developing and Labeling In vitro Companion Diagnostic Devices for a Specific Group of Oncology Therapeutic Products. Issued April 16, 2020.”  https://www.fda.gov/media/120340/download.
2. FDA’s Guidance for Industry and FDA Staff: In Vitro Companion Diagnostic Devices, August 2014, page 11, available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/vitro-companiondiagnostic-devices.
3. Guidance for Industry: “Developing and Labeling In vitro Companion Diagnostic Devices for a Specific Group of Oncology Therapeutic Products. Issued April 16, 2020.”  https://www.fda.gov/media/120340/download.
​4.https://www.fda.gov/medical-devices/vitro-diagnostics/list-cleared-or-approved-companion-diagnostic-devices-vitro-and-imaging-tools
5. An affiliate of Astellas Pharma US, Inc.
6. https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P120022
7 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=P120019S007
8 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=p160045
9 https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpma/pma.cfm?id=p170019