Since 1997, the Food and Drug Administration Modernization Act (FDAMA) Section 114 has allowed biopharmaceutical companies to “provide health care economic information [HCEI] not in labeling to formulary committees and similar entities.” The purpose of FDAMA 114 is to provide safe harbor to manufacturers when communicating HCEI to health plans seeking to make reimbursement decisions. Health care economic information has been defined as any analysis of the economic differences or consequences of the use of one drug in comparison to another or to no treatment. This information has to be considered to meet the competent and reliable scientific evidence (CARSE) standard and be “directly relate[d]” to an approved drug indication for the purposes of proactive communication to health plans. While intended to spur communication, the FDA provided no guidance in the ensuing 20 years, thereby leaving manufacturers reticent to disseminate HCEI more broadly because of the risk of sanctions if found to be promoting off-label uses of their products. As stated by Dr Peter Neumann of Tufts University, “All health economic information contains clinical assumptions, and you’re potentially letting drug companies make clinical claims about their products through economic analysis.” In comparison, to promote clinical claims to providers and patients, manufacturers must meet the level of “substantial evidence” which includes at least 2 adequate and well-controlled trials. This is the standard requirement for new drug applications, biological license applications, or applications for supplemental indications.
In June 2018, the FDA released its long-awaited final guidance related to FDAMA 114 to clarify outstanding vagaries. This guidance was based on their interpretation of Section 3037 of the 21st Century Cures Act which amended Section 114 of FDAMA. This final guidance removed the word “directly” from the clause stating claims must “directly relate to an approved indication,” stated that differences in the analysis population with the approved indication must be disclosed, and that recipients of communication can include “payers”, specifically. In addition the guidance states that manufacturers may disseminate information about unapproved uses of products provided that the information is “unbiased, factual, accurate, and non-misleading.”
Historical Methods of HCEI Communication According to FDAMA 114
- Evidence dossier
- Reprint of a publication from a peer-reviewed journal
- Software package comprising a model with a user manual
- Budget impact model
- Slide presentation
- Payer brochure
In addition to clarifying how HCEI can be used in communications with payers, the 21st Century Cures Act also included Section 3022 directing the FDA to evaluate how real-world data (RWD) and real-world evidence (RWE) can be used to support approval of new indications or post approval study requirements. Since that time the FDA released their strategic framework to advance the use of RWD/RWE in regulatory decision making. Most importantly, this framework clarifies that the safe harbor for manufacturers to provide HCEI extends to investigational products and new uses of legally marketed products for both drugs and medical devices. What this guidance means is that the data, studies, or analyses of RWD which adhere to CARSE standards can be included in promotional communication. The 21st Century Cures Act makes it clear that HCEI does contain clinical information which permits some flexibility in which endpoints can be presented in various materials. Whether or not RWD/RWE meets the requirement of “substantial evidence” of effectiveness is an area of ongoing research and debate. Researchers acknowledge the limitations of RWD/RWE and are developing methods to overcome confounding, data quality, and bias which are removed through the process of randomization in clinical trials.
One recent example of using RWD and RWE in promotional materials is found in the work by Boehringer Ingelheim and its GioTag research study. GioTag was a real-world retrospective, observational, and unblinded study which examined the impact of treatment with afatinib followed by osimertinib in EGFR-mutated non-small cell lung cancer (NSCLC) patients with T790 mutations. The indication for afatinibis first-line treatment for patients with NSCLC whose tumors have non-resistant EGFR mutations as detected by an FDA-approved test. Using electronic health record data, researchers demonstrated that that overall survival among patients who received this sequence of therapy was almost 4 years, a finding not available or reported in the clinical trial program. Results of the GioTag study have been widely publicized at national and international meetings in addition to being disseminated in multiple abstracts and peer-reviewed manuscripts. Cardinal Health team members in attendance at the European Society for Medical Oncology 2019 conference in Barcelona, Spain, observed the results of the study depicted on the display boards at the company’s booth for all attendees to review. This marks one of the first occurrences of the promotional use of RWD at a medical congress a trend which is likely to increase based on the frequency of RWD studies being conducted.
The frequency of RWE publication has dramatically increased over the last decade. In a PubMed search conducted in March of 2020 the number of MEDLINE indexed publications describing “real-world evidence oncology” peaked at 200 in 2019 representing an increase of nearly 500% from 2015.