ngoing challenges in US prescription drug pricing have led many pharmaceutical companies to create financial support or assistance programs to help patients offset the price of their prescription drugs. One recent article reports that there are currently 2,000 active patient assistance programs (PAPs) offered by approximately 500 companies. But this author has observed that such programs, designed to expand patient access to safe and efficacious drugs, can unintentionally complicate downstream programs designed to protect patient safety.

Starting Scenario

Most PAPs are created or managed by the drug company’s medical affairs or marketing departments, professionals who are not necessarily knowledgeable or experienced with regulatory requirements for post-marketing safety reporting of serious adverse events/adverse events (SAEs/AEs), which is the responsibility of the pharmacovigilance department.

AEs commonly arise (often in great number) from these programs and must be processed in compliance with pertinent regulations and GVP requirements. But PAPs are rarely, if ever, designed with this safety reporting end in mind.

Regulatory Challenges in Safety Reporting

As a result, pharmacovigilance departments are often blind-sided by this new source of AE reports to process and can receive potentially hundreds or even thousands of AE reports, many of which are serious and unlabeled and get submitted on an expedited basis because, if they follow post-marketing rules, each is considered “related” by default.

Why such a large volume of reports? Because of the active company outreach associated with the patient support program. These programs might not have been intentionally constructed to acquire safety data, BUT they invariably present safety information to the company simply because the company is speaking to the patient about their experience taking their product.

Experience suggests that some professionals in the post-marketing space may consider these adverse events to be spontaneous in nature. But others question how truly “spontaneous” such reports are, since they are unlikely to have been reported by the patient without direct contact by the company.

Although the EMA’s GVP Module VI acknowledges that AE reports arising from patient programs often can be considered solicited, there is no clear regulatory guidance on this specific topic in any jurisdiction. What needs to be in place to ensure that an inspector would agree that the PAP qualifies these AEs as solicited remains unclear, although blogs from the MHRA in the UK and other publications provide some direction.

Two Undesirable Options

By not developing a patient support program in a manner in which AE reports can be considered to be solicited, companies find themselves with two possible circumstances, both undesirable. First, if the company considers all AEs from support programs to be spontaneous, they will be submitting a volume of expedited reports that they otherwise would not have to. Not only do these “extra” expedited reports consume valuable resources, but they don’t even add to the safety knowledge of the product if they are clearly not related to the product but rather occur due to the underlying disease process or arise as some type of an intercurrent event (e.g., the patient is in a motor vehicle accident or contracts a viral illness).

Second, if a company considers all AEs from support programs to be solicited, a regulatory inspector may find that the program is not designed in a manner that clearly shows the solicited nature of AE report collection. This may lead to a negative inspection finding. (Regulatory authorities do not publish their findings and citations at this level of detail, so this possibility is broadly anecdotal.)

Without appropriate documentation in place, the risk is that a patient support program may not be deemed to collect AEs and, importantly, SAEs, in a solicited environment, thus allowing a causality assessment to be performed rather than accepting the default “related” position for standard post-marketing reports.

If the sponsor was not submitting expedited reports because they were treating the SAEs as solicited and assessed as unrelated, but the program was deemed lacking in proper documentation to allow such reports to be considered solicited, the relevant government inspector could cite the sponsor for failing to submit expedited reports on time.

Searching for Clues and Concepts

The challenge is constructing the PAP in a manner that identifies the solicited nature of AE data collection so clearly that this process passes regulatory scrutiny.

As previously explained, there is little clear regulatory guidance on this topic, particularly from the US FDA. The EMA GVP Module VI recognizes that safety reports from qualified PAPs can be considered solicited BUT provides few details concerning the specific requirements that would qualify these programs, and the MHRA has provided some helpful details but no formal guidance in the UK. One industry survey found quite a bit of variability across the industry in terms of vendor oversight, applicable SOPs, training, and contractual language.

Although there is no clear answer that would necessarily satisfy all regulators, industry has discovered and cobbled together several clues about generally applicable concepts. The first task is to raise awareness of this issue (through articles like this). The next task is to develop concepts that companies can apply to begin to “future proof” their PAPs, such as:

1. Ensure there is contractual language regarding collection and forwarding of safety information with third parties running these patient support programs
2. Provide training of company staff and third parties on pharmacovigilance concepts and safety data collection tools
3. Conduct quality assurance activities including audits, reconciling data between parties, and source data verification, and take all required remedial action
4. Clearly define the nature of interactions between the sponsor and program patients, ideally in a formal document such as a contractual appendix or annex, including how safety information may be received from patients and how follow-up may be conducted.

Conclusion

A properly designed patient support program can collect useful information that supports the ongoing safe use of the product AND reduce the burden of expedited reporting in a manner that withstands regulatory scrutiny.

But the more important lesson is that regular and frequent communication between pharmacovigilance and other departments can mitigate such situations with unintended consequences. Sponsor companies will avoid a multitude of downstream problems by ensuring that pharmacovigilance departments are involved when other departments start programs with safety reporting implications.