By Jeffrey Trotter
The conditions under which medical products are examined for potential regulatory approval are rarely the conditions under which the products will actually be used. Underscored by recent post-approval scrutiny over a variety of marketed drugs and devices, most stakeholders recognize that the gold standard for pre-approval research programs, the randomized clinical trial (RCT), has limitations when it comes to understanding what really works under “real world” conditions. The recent deliberations over GlaxoSmithKline’s Avandia (rosiglitazone maleate) also highlights the challenges associated with post-approval research; indeed, the real world can be real complicated!
Nonetheless, it has become clear that real-world outcomes are of paramount importance, insofar as products tend to be used differently and in populations that are often far different from those included in pre-approval clinical trials. Ultimately, data from rigidly structured RCTs complement findings from more accommodating (while, perhaps, less definitive) post-approval studies and registries which, in order to capture the reality of actual practice conditions and outcomes, must generally be observational and noninterventional in design.
The challenge for today’s pharmaceutical and medical device manufacturers is to focus on accelerating commercial acceptance for their products while maintaining fundamental responsibility for their safety. These goals need not be mutually exclusive. Indeed, the most successful companies are those that actively embrace their responsibilities and transform them into opportunities for sustained success. The common trait of successful companies is proactive and strategic organizational collaboration to navigate the unique post-approval landscape.
The Need For Transformational Shift
Few truly successful companies in today’s environment are caught by surprise that a product on the regulatory approval track will have a safety issue to address in the post-approval setting. Similarly, these same companies recognize that documentation of value — clinical, economic, and humanistic (e.g. quality of life) is at least a de facto requirement in most countries. Indeed, the most successful companies acknowledge that safety and value are the foundations for post-approval activity and strive to “operationalize” their post-approval plans as strategically and cost-efficiently as possible. This is only attainable through leadership and critical shared insight throughout the organization. Two key manifestations of this progressive, strategic approach to post-approval activity are as follows:
- studies in support of both safety and value endpoints are increasingly being undertaken together
- real-world observational studies are increasingly employing development and implementation processes far different from pre-approval trials.
Both of these processes require true strategic and operational planning and unprecedented levels of organizational collaboration.
Although not all studies undertaken for post-approval safety purposes can be designed to include endpoints that are more purely commercial in motivation, the return on investment of a safety study can be improved by anticipating the needs of regulatory authorities, working with regulatory agencies in advance, and building in other measures that can address the value imperative. A study imposed on a sponsor at the last minute will rarely be able to accommodate any measure other than the intended safety outcome. Similarly, a study planned to examine real-world clinical performance, cost-effectiveness, or quality of life must also consider the fundamental responsibility (opportunity) to compile post-approval safety insights. Indeed, this responsibility reflects good corporate citizenship as much as it can be considered an expectation of a company’s shareholders. Corporate stakeholders, not surprisingly, also demand operational cost-efficiency, and therein lies another transformational post-approval opportunity. Successful companies have insisted upon the attainment of a strategic consensus among all parties involved in post-approval research such that all recognize that the post-approval real-world study requires an amalgam of perspectives that may be outside the comfort zones of all involved. Indeed, the successful post-approval study can be characterized as a “different animal” that can only be optimized with processes that reflect its unique purpose and requirements in nearly all aspects. For example, a post-approval observational study will not require traditional study monitoring activities, inasmuch as protocol adherence will not be an issue (as there is, essentially, no imposition of experimental medical procedures). The post-approval study that seeks external CRO support using a pre-approval clinical trial template and traditional “bid grid” will be overengineered from the start, overly costly, and as a result, may not get accomplished. For the post-approval study to be cost-efficient, operational processes must be challenged, reconfigured, and built on a foundation of internal and external organizational collaboration.
Conclusions about the real world increasingly require real-world study participants who may have been excluded (for appropriate reasons) from pre-approval studies, and also real-world practitioners for whom clinical research is far from a primary predilection. This fact and the reality of observational research merits refined approaches to nearly everything, including site recruiting, contracting, remuneration, training, start-up, and ongoing interactions and support. Similarly, the recruiting of real-world patients for an observational study requires a fresh look at ethics approvals, privacy, informed consent, recruiting practices, and other elements. Data collection processes, so as not to interfere with the normal practice of medical care, must typically be benign and efficient. Importantly, quality control procedures must not be compromised in order to maximize the integrity of the information being obtained; however, heroic efforts to ensure data perfection may not be appropriate for an observational study in which, to a very large degree, one has to live with the data obtainable. Nonetheless, through effective use of technology, data quality can typically be enhanced with little imposition on busy physician practices. Finally, a formal and informed statistical analysis plan must be developed, striving to make the most sense possible of the data collected, often by capturing additional seemingly innocuous data that may help explain the primary data being collected.
While these are standard components of any clinical study, the post-approval observational study demands that they be refined to meet unique needs. Absent this level of often nuanced refinement, the post-approval study can be burdened by inappropriate processes that may even compromise the observational design in the first place, in addition to being overly costly and time-consuming. And again, interdepartmental cooperation — ideally, manifest in the offline process of developing specific SOPs for observational research — is the critical foundation upon which to build these refined approaches. And top-level leadership is the critical requirement to “free” the organization from silo mentality and hurdles that will constrain the post-approval transformation necessary to truly optimize the post-approval response.
There has been an unprecedented level of shift happening in the medical products industry. The most successful companies are those that have embraced the shift by transforming their organizations and processes. Unquestionably, post-approval safety research is a requirement, reflecting the demand for real-world safety information in nearly every country. And increasingly, the demand for post-approval data on performance and value is shifting from de facto to a formal requirement. Clearly, companies have an obligation and responsibility not only to respond to regulatory requirements, but to anticipate and plan accordingly, both in research design and operational deployment. In so doing, requirement and responsibility is transformed into opportunity. Indeed, the very nature of the methods required to ensure the observational nature of a real-world post-approval study lend themselves to greater organizational collaboration and singularity of purpose and to shifts in processes that work perfectly well for pre-approval RCTs but that tend to constrain and burden post-approval research initiatives. Shift happens: embrace the shift!
About The Author
Jeffrey Trotter is executive VP, Phase 4 development at PharmaNet. He has been an innovator, entrepreneur, researcher, consultant, and industry leader in the evolving outcomes research community, providing strategic and operational direction to pharmaceutical and device companies on the importance of real-world clinical research, observational studies, and patient registries.