Trial Participants: The Unsung Heroes of Clinical Research

Applied Clinical Trials

Ingrid Klingmann, chair of EFGCP, speaks to Applied Clinical Trials about the efforts industry can make to change the way all stakeholders can improve clinical research.

"It's obvious, but it's not center-stage," says Ingrid Klingmann, chair of EFGCP. "Clinical trials do not always benefit all the patients participating in the research – despite all the injunctions of the Declaration of Helsinki and GCP." She points to the risks run by participants exposed to non-optimal treatment in a clinical trial, or enrolled in trials that are badly designed, poorly managed, conducted against an unsuitable comparator, or never completed.

 

Society has more than 50 years experience of systemized clinical research, and it is time to ask whether it is working well enough for trial participants, she told Applied Clinical Trials in an interview in Brussels in mid-January. Trials are of course mandatory for demonstrating the efficacy and efficiency of a treatment, and there is a political obligation to enable faster patient access to more and better treatments, she recognizes. "But are we doing trials in the right way from the point of view of participants? We should never forget that patients entering into the unknown are taking a risk – and there is something heroic about that. We have an ethical obligation to keep these heroes at the center of all these efforts."

 

Klingmann reels off a long list of possibilities she sees as just crying out to be exploited across the wide range of clinical research stakeholders – all of them holding out chances of giving trial participants a better deal. One area of promise she identifies is a more adventurous exploration of how to meet regulators' needs for demonstrations of efficacy and safety. Evidence-based decision-making demands data, and clinical trials deliver a lot of data – but is the best use being made of all that data, she muses. Recently increased openness among some regulators to consider conditional authorizations or adaptive pathways is welcome, but clarity is seriously lacking about the wider use and acceptance of new approaches.

 

Many of the outstanding questions about the use of real-world evidence, for instance, demand urgent answers to make sure that patient experience – good and bad – is fed into the choice and use of medicines. More determined efforts should be made to leverage patients' often hard-won, real-life exposure into valuable insights, through greater data standardization and interoperability, linking registries, or agreeing guidelines on use of placebo or comparator. And there is a world of virtual possibilities still to be exploited effectively, she says, citing moves to develop a global regulatory acceptability framework and prototypes for simulation and extrapolation through artificial intelligence, as already applied in imaging to improve diagnosis.

 

Klingmann sees many instances where industry could also refocus its approach to give greater priority to the interests of trial participants. Over and above its evident moral obligation to reduce harm to patients, industry could do itself a favor by going the extra mile to make a reality out of rhetorical claims to "patient-centered" development – at the same time improving their frequently uneven public image.

 

The realms of academia also hold real potential for improvement, she argues. Current academic clinical research projects are not reliably optimal, she considers, citing recent claims that about half the studies initiated are never reported – sometimes because they are not completed, sometimes because sponsors are reluctant to publish, sometimes because journals are unwilling to accept results and sometimes because the studies are so poorly designed that the results are not interpretable. Clinical trial methodology merits development as a medical discipline to ensure that only experts recognized in that discipline are entitled to take responsibility for a clinical trial. "It is unacceptable for participating patients to be sub-optimally protected or involved wastefully," she insists.

 

Also high among her priorities are the physicians who are actually treating patients. These represent in her view a massively underused resource. Most practicing physicians are currently unwilling to engage in trials, partly because of limited trust in a collaboration with the pharmaceutical or medical device industries. This is compounded by a politically supported reluctance to expose patients to the risk of treatment options still not evidence-based. In addition, clinical research does not enjoy a favorable reputation among much of the medical community, and the low level of engagement is due in part to a lack of understanding, with clinical research still conspicuously absent from the curricula of medical schools' and post-graduate education.

 

Changing that perception could bring benefits to patients as well as to research. At its best, participation in trials is good for patients: if there is no treatment alternative, patients get a chance of access to a first treatment option; and in indications where treatments are available, they get more tests, they are more frequently seen and more closely monitored, and – as increasingly reported in life-threatening disease areas - they enjoy better survival. In addition, widening the net of investigators would ease the chronic challenge of adequate recruitment, and at the same time would widen perspectives by avoiding the current re-use of the same pool of investigators.

 

Patients too are themselves an under-exploited resource. There is a patient community that is increasingly informed, and that wishes to contribute expertise in everything from defining research priorities to study design and study conditions, but there is still no adequate infrastructure for their systematic engagement. And it is still the case that very few patients are aware of their options to impact the development of better treatments for their disease. Clinical research remains too susceptible to emotional discussion, and greater objectivity would allow a more mature relationship between public and research.

 

"In the public debate on innovation we are also faced with a paradox," says Klingmann. "While there is growing concern that 95% of new medicines come from industry, the funding of clinical research still depends predominantly on the private sector because society has decided not to risk public investment into new treatments." Without a change in funding arrangements, that situation cannot change, she remarks. The limitations of public funding inhibit the engagement of many university-based physicians in clinical research. Meanwhile, the research support efforts made by the EU have so far not been successful in finding ways of efficiently developing new treatments at the same time as making patients safer in clinical trials, she says.

 

Klingmann wants to see a change that will put patients' welfare center-stage – and so do many of her colleagues and peers in the different subgroups of the clinical research community in Europe. So the organization she chairs is bringing a bunch of them together in Brussels in late February in a bid to make change happen. "By getting people in the same room for two days we can hopefully get a clearer view of how to re-center and coordinate the work each of us does with a sharper focus on the patient – so that we better fulfil our ethical and societal obligations to these heroes."