by Charles S. Wilcox, PhD, MPA, MBA; Leslie Franceschi, BA; and ADAM SIMMONS, MPH

Dr. Wilcox is Chief Executive Officer at Praxis Research Consulting in Newport Beach, California. Ms. Franceschi is Senior Project Director at Syneos Health in Morrisville, North Carolina. Mr. Simmons is Director of Clinical Program Management at Alkermes Inc. in Boston, Massachusetts.

FUNDING: Funding for this manuscript was provided internally by Praxis Research Consulting.

DISCLOSURES: Leslie Franceschi is  an employee of Syneos Health, Inc. Adam Simmons is an employee of Alkermes, Inc.

ABSTRACT: The much-anticipated 2014 European Union (EU) Clinical Trial Regulation requiring Layperson/Plain Language Summaries (PLS) is slated for implementation in 2020. At the 10th Annual CNS Summit Conference (Fall 2019), a panel discussion was convened with the objective of evaluating the likelihood of the PLS legislation being implemented successfully in the EU and voluntarily (e.g., pro-actively) in the rest of the world. Points of the discussion embraced the notion that this is an excellent opportunity for the entire pharmaceutical industry. Moreover, in the United States, public opinion of the pharmaceutical industry hit an all-time low in 2019, surpassing the oil industry with regard to public distrust. For decades, clinical trial participants have stated that wanting to learn, in layperson terms, the results of the study was second only to wanting to learn the treatment group into which they were assigned under double-blind conditions. Our conclusion is that while confidentiality, commercial interests, total costs, regulatory concerns, as well as some operational aspects (i.e., patient access portals) are among the hurdles, our commentary strongly advocates systematic implementation not only within the EU, but that this should be implemented globally, without further delay.

Keywords: Plain Language Summaries, public distrust, patient access portals, EU CTR No.536/2014

Innov Clin Neurosci. 2020;17(7–9):41–44

According to Gallup’s most recent “Work and Education” poll,1 conducted August 1 to 14, 2019, the pharmaceutical industry is considered “the poorest regarded industry” by United States (US) citizens. In the poll, Americans were provided a list of 25 industries and asked to rate their overall view of each one as “positive,” “somewhat positive,” “neutral,” “somewhat negative,” or “very negative”—the pharmaceutical industry took last place on the list of 25, ranking lower than the oil and gas industry, the federal government, and the US healthcare system.1

Widely publicized news reports on unethical conduct by a few pharma companies,2–5 along with politically driven anti-pharma rhetoric, particularly during election years,6,7 no doubt have contributed greatly to the public’s current poor regard of “Big Pharma.” Direct-to-consumer pharmaceutical advertising (DTCPA) has also been argued to play an important, and sustained, role in the industry’s poor public image since the 1980s.8,9 Yet, while it seems media news sources are willing to propogate negative reports involving individual pharma companies, many important pharmacological advancements remain under-reported by the media and go largely unnoticed by the general public, such as the United States Food and Drug Administration’s (FDA) approval of new cancer-fighting chemotherapy agents and protease inhibitors (combined with other drugs) to combat human immunodeficiency virus (HIV), as well as numerous advances in central nervous system (CNS) therapeutics that have been made recently in the treatment of psychiatric and neurological disorders.

The first century of the new millenia is well underway, and the opportunity—indeed the need—for the pharmaceutical industry to enhance and more fully embrace the breadth and depth of its relationship with the public cannot be overstated, particularly when it comes to participants in clinical trials. In the era of the empowered consumer, one approach to addressing this need is by providing patients and their caregivers with access to evidence-based healthcare information that is written in nontechnical, understandable language, such as layperson/plain language summaries (PLS).10 Integrating PLS into US clinical trial protocols can help improve communication of important study information to patients and enable them to make better informed decisions regarding their own health, while also fostering a mutually beneficial relationship between patient and drug company. Patients who are empowered to play more active roles in their own healthcare may be more likely to participate in clinical trials, which, ultimately, will help us achieve better patient outcomes.11

The spirit and intent of this commentary is to 1) describe the benefits of PLS in clinical drug trials; 2) describe challenges and concerns of PLS implementation, based on panel and participant feedback during a CNS Summit Work Group Panel presentation; and 3) offer suggestions to ameliorate some of those concerns and recommendations on how to move forward to full PLS implementation—on a global scale—without much more delay.

Implementation of PLS in clinical trials—Benefits

Pertinent historical background encompassing more than four decades consistently highlights the challenges of timely, reliable, and appropriately selective patient recruitment.12,13 Moreover, the increased emphasis on speed of enrollment has, at times, unwittingly overridden quality, the resulting statistical variance, vis-à-vis an over-abundance of sites per study, further escalating the ever-increasing placebo response phenomenon, which has contributed to numerous “failed studies,” whereby even the marketed reference compounds did not statistically separate from placebo.14 This had led many to question whether clinical trials in the US are enrolling the most appropriate patients.15,16 In tandem, just as protocol complexity and demands on patient time have soared, so has the need for better ethnic diversity in patient cohorts.17,18 To wit, just as more studies are failing to provide definitive outcomes, they have also become more complex with the increasing difficulties of enrolling appropriate participants in a reliable and timely manner.

The EU Clinical Trial Regulation (EU CTR) No. 536/2014 adds impetus and urgency to the routine development and distribution of PLS as a means to bolster trust, transparency, and partnering between study sponsors, study sites, and study participants.19 Specifically, PLS are designed to enhance the understanding of study participants in regard to trial processes and outcomes, with the aim of enriching their overall clinical trial experience. Research has shown, across multiple therapeutic indications, that people who have participated in clinical trials want to be provided with trial results as soon as feasibly possible.20 Providing them with this information in a timely manner would not only reinforce their perception of a positive clinical trial experience, it might encourage them to advocate clinical trial participation to their friends and families, expanding the recruitment pool for better diversity and selectivity. Moreover, the PLS process could potentially provide a substantive opportunity for sponsors, contract research organizations (CROs), and sites to routinely convey their appreciation to patients for participating in their studies, which could, in turn, increase their trust and confidence that the study sponsor will actively protect their privacy and maintain confidentiality of their personal data.21–28

While implementation of PLS in the EU was originally targeted for December 2015, it has now been deferred until December 2020 due to “technical difficulties with the development of the IT systems.”29 In parallel, there has been voluntary adoption of PLS by some sponsors, with increasing evidence to support the value to patients.30

Legislation is in place in the US pertaining to the dissemination of study results within 12 months—but not in PLS format.31 The value of PLS is of particular importance in neuroscience research, where clinical trial participants might have cognitive issues as a result of their illness and might not understand the clinical trial disclosures made available to the public (i.e., via clinicaltrials.gov, news media, peer-reviewed publications). Additionally, many diseases for which psychopharmacologic medicines are being developed require lifetime or episodic treatment, so there is a direct benefit to these patients in knowing if the therapies they received under a research protocol could potentially be available to them in the future.

Implementation of PLS in clinical trials—challenges

CNS Summit Work Group Panel. At the 10th Annual CNS Summit, a work-group-panel was convened, with active audience participation, addressing the challenges and opportunities associated with the PLS initiative.32 Panelists presented audio-taped patient interviews from the site perspective, as well as hands-on experience from the perspective of sponsors and CROs.

Site perspective. While US-based sites have publicly advocated voluntary implementation of the PLS initiative, the logistical and operational concerns they expressed during the work group are noteworthy. For example, costs, such as those required to re-engage study participants long after their trial participation has ended (e.g., 12 months or longer, in some cases), was indicated as a focus of concern.

For all of the sites in attendance, the consensus was that referring study participants to a specific portal was preferable to having the sites directly disseminate the PLS. Important to note: the technical difficulties that delayed the implementation of this process in the EU were reportedly due to portal-related logistical difficulties. However, the EU portal remains the designated single point of entry for submission of data and information relating to clinical trials, as required by the EU regulation.33

Overall, PLS distribution and access were considered a significant opportunity by the sites to better partner with clinical trial participants and community. Paradoxically, while the sites indicated that their direct professional relationships with study participants mandated they should be “front line” in terms of PLS distribution, they indicated, during the work group, that they did not want to be the primary point of contact for study participants with any resulting PLS-related questions or general inquiries, due to cost concerns. They suggested that process improvements (e.g., training/ratings) might result in greater enthusiasm in the community to participate in future clinical studies.

Sponsor perspective. For sponsors, there have historically been strategic and regulatory implications to providing PLS, including disclosure of confidential study results and avoiding potential promotional communications for drugs being investigated in clinical trials prior to FDA approval. Given that US law now requires public disclosure of clinical trial results, sponsor confidentiality regarding trial results is no longer an issue, and many medical writing services adhere to best practices when preparing PLS to ensure they are written nonpromotionally.34–36

CRO perspective. From an operational and oversight perspective, CROs shared a great deal during the work group, based on their observations and lessons learned with PLS distributions to date. Their experience dealing with inside information on the disparate corporate cultures from one pharmaceutical company to another is invaluable. While we will tread lightly here, suffice to say that there are distinctly different levels of transparency, trust, and genuine patient centricity between sponsors!37–40 Corporate culture does play a significant role, and we believe that more of an across-the-board voluntary acceptance of this PLS mandate will serve everyone well. Furthermore, some CROs are uniquely positioned to share their “lessons learned” thus far, which can better facilitate the manner in which all of the key players (i.e., sponsors, CROs, and sites) can best serve our study participants, especially as it pertains to the PLS mandate (in the EU) and opportunity throughout the world.

Panelist and attendee perspectives. Panelists and attendees voiced the concern that by the time sponsors internally agreed on the format and wording of a PLS, the final version (i.e., “commercially and regulatory-compliant/correct”) would be too lengthy and/or too vague to be of any use to the study participants. This was a particular concern in regard to elderly caregivers or patients with mild cognitive impairment, prodromal Alzheimer’s or Alzheimer’s disease.

Involvement of other entities. Published articles and webinars by nonprofit and for-profit entities exisit that outline their beliefs regarding dos and don’ts of preparing and distributing PLS documents. Similarly, some nonprofit and for-profit institutional review boards (IRBs) have conveyed a willingness (and in some cases, a borderline insistence) that they play a role in PLS development. The majority consensus of the work group panel was that, at least initially, the added expense and potential for delay when involving these entities in PLS development might outweigh any benefit(s) they provide, though this opinion might change as our experience increases.

Fostering trust, transparency, and partnering with patients are easily articulated goals and values that are readily embraced symbolically; however, in a competitive commercial environment, with heavy regulatory oversight, achieving these goals is neither simple nor easy. A litigious person or group of persons might possibly garner public support, for example, based on hearsay and incomplete information (e.g., via social media culture/influence) in regard to the negatively perceived risk–benefit ratio of a new chemical entity, which can pose additional challenges. For pharma and everyone involved, even the best of intentions must be pursued with caution and thoroughness.

As we know, nearly every piece of legislative and regulatory action has been the result of the industry falling short on monitoring itself, even when the actions were perpetrated by relatively few companies or individuals. Nonetheless, citing Voltaire, one should not allow “the perfect to be the enemy of the good…” In harmony with the mandated circa 2020 implementation of PLS within the EU, a proactive parallel voluntary implementation within the US and rest of the world should be enthusiastically embraced as well. Granted, it ultimately might be determined that the IRBs should have an important role that understandably will further add to the costs.

Potential cost. “Doing the right thing” almost always equates to some additional costs. As far as the logistics and key factors for crafting and communicating PLS, there are more than ample published articles and summaries to guide the PLS processes.41–43 What’s needed most immediately is voluntary proactive implementation, not only in the EU but throughout the industry. Patients certainly want it and, we sincerely believe, richly deserve it as soon as realistically possible.

Admittedly, while there are still some risks to providing PLS, this should be weighed in the context of the need to markedly improve the public image of the pharmaceutical industry in general. PLS appears to be, comparatively speaking, a relatively low-cost measure that can potentially enable pharma to sustain and strengthen the connections it makes with its much-needed clinical trial volunteers.

In the context of our pre-, post-, and during-panel discussion at CNS Summit 2019, we did not focus on the overall direct and indirect cost aspects with much detail. One pharmaceutical company quoted $5,000 to $12,000, not including translations, for their PLS. In contrast, one of the CROs subsequently reported that costs can quickly add up to over $50,000 for a single trial. In 2020, for the overwhelming majority of trials, while $50,000 is certainly not an inconsequential line item, as a numerator above the total costs for a large-scale Phase II or Phase III investigation, this could be considered a modest outlay. Furthermore, if this means that, to some extent, sites and CROs must also share with sponsors in incurring some of the incremental costs to better serve, respect, and thank study participants, it will reflect well on all the industry as a whole. Granted, while the return on the investment might not be immediately or even accurately quantifiable, the industry as a whole can be proud that its doing more to convey its respect and appreciation for all study participants, including their caregivers or study partners. To win back public trust, it is essential for pharma and its related entities to place ethics and integrity before shareholder value.


Advocating for PLS Implementation in the US and Globally

Despite reasons that PLS is “the right thing to do for our patients/participants,” for a number of legal, logistical, commercial, and regulatory-related reasons, a number of sponsors, CROs, and sites might be, at the very least, hesitant to proactively and voluntarily embrace this initiative. While the hesitancy is justified, the advocation for and facilitation of a more comprehensive and expedited implementation of PLS distribution and access globally is needed. Admittedly, the current mandate is limited to the EU; nonetheless, the upside opportunity that implmentation of PLS offers clearly transcends Europe.

While acknowledgment of terms such as patients and volunteers is often supplanted with subjects, clients, and participants, volunteers in most clinical trials, especially Phase III, for most indications with large numbers of participants truly are patients. Patients in clinical trials must read lengthy (i.e., 20- to 30-page, sometimes longer, informed consent forms (e.g., ICFs), which are often written by lawyers for lawyers, with multiple pages outlining risks and a sentence or two explaining the possible benefits. It is incumbent upon all study sponsors, CROs, and sites to treat these individuals with the utmost respect and appreciation, and voluntarily and enthusiastically advocate for the implementation of the PLS strategy in US clinical trial protocols.

Conclusion

Can we re-inspire confidence and trust in the public? The authors of this commentary believe the answer is “yes!” By adhering to the highest ethical standards ourselves, we can empower others to demonstrate integrity (without regard to hierarchical position); prevent, detect, and deter any lack of integrity; and emphasize thoughtful deliberation to avoid any ethical lapses.44

Reversing the pendulum of public opinion will require concerted and sustained patient-centric endeavors by all involved entities in the pharmaceutical industry that may have little or nothing to do with short-term shareholder value or the financial bottom line. As we enter this new decade and acknowledge having hit rock bottom in public regard in 2019, the PLS EU mandate and rest-of-world opportunity is within our grasp. We all should continually work together to adjust our prioritized actions to discover and implement better ways to help our patients achieve optimal treatment outcomes and an even better quality of life.

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