Sponsors of clinical trials need participants, but people do not need to participate. They may want to, but they do not have to. Want implies freedom of action and an expectation of persuasion. The difference between want and need tells us who ultimately should be in charge of the arrangement.
A Clinical Trial Team is an agent for a sponsor because they represent the sponsor to the trial participants in all respects. It may be novel to describe them in this way; sponsors, agents and trial participants together constitute a marketplace. A marketplace operates according to laws of supply and demand, regulation and people’s behaviour.
Collaborate properly, and the marketplace will operate more effectively to everyone’s benefit. It needs to.
The first “Road To” article addressed the challenge of encouraging People with Parkinson’s (PwP) to participate in Parkinson’s Disease research. There are plenty of PwP but not enough of us are properly engaged. Rather than in generalised campaigns to involve people, participation efforts must be focused on where it is relevant to do so. Where is it relevant? Where the things that the different communities know can be combined usefully and in situations where that can be seen to be happening. Sounds easy? Unfortunately, from here on the road to collaboration gets bumpy.
Clinical trials are where “the rubber meets the road”, where the participant meets the sponsor’s drug or a placebo. For several reasons the participant meets only the agent. One of the ironies of standard practice is that sponsor only meets PwP when something has gone badly wrong.
Structural change in the industry is distancing communities and disrupting relationships. Small Pharma companies, often focused on one potential treatment, rely on Contract Research Organisations (CROs) to bring a drug to trial. At any time the drug and/or the company may become attractive for commercial and/or strategic reasons to another organisation. CROs are also increasingly used by the larger Pharma companies as they shed staff to reduce overheads and concentrate on specific drug discovery agendas.
As the industry changes it is re-connected by negotiated agreements. The Clinical Trials Charter, the result of collaboration amongst a who’s who of the industry, is an otherwise admirable wrapper around a fait accompli. Not surprisingly there are commitments by the participant, but no commitments to the participant.
There is no negotiation with the community on which trials depend – the participants.
We see the industry changing, and yet is does not. We see the PD research effort ramping up, but no comparable visible change in a modus operandi that is demonstrably only able to fix a long-term disease with the active involvement of the victims. Diabetes and HIV/AIDS are cases in point. The regulatory burden is usually cited as the reason why this that or the other trial protocol or restriction cannot be changed.
Symptoms of prevailing attitudes can be seen in the academic world that is paradoxically the source of so much positive input to the PD treatment sphere. For many PwPs some way down the disease track, Levodopa-Induced Dyskinesia (LID) becomes a problem. Invited to comment on a recent proposal for a LID drug trial, a senior UK academic in the PD research field asserted that LID was a non-problem as it could be managed by reducing the levodopa intake. Such breath-taking ignorance of the quality of life consequences illustrates a disconnect between academic research and the lived experience that is still with us in some institutions. Does such ignorance go unchallenged because of the influence wielded by opinion holders? Why collaborate with such an institution or contribute to its funding?
A report published in June 2018 by the US National Academies of Sciences, Engineering, and Medicine concluded that scientists and their institutions should routinely and carefully consider whether to return study results to participants. A co-author commented “It’s really calling for a sea change in how we handle the issue of research results in studies with human specimens”. If the sea change is just from a default “do not disclose” to “whether to”, and “human specimen” reflects the language in use, why would PwP collaborate with this community?
Prevailing attitudes and the primacy of standard practice are the rocks on which collaborative intent founders.
The world of IT Systems offers another diagnostic aid. IT project failures, some spectacular, include the definition of end-user (participant) requirements without adequate information and system design driven by management prejudice (aka “vision”). Above all as a contributing factor is the consequence of these problems. System implementation teams are expected to compensate for constraints set, shortcomings built-in and mistakes made earlier in the process. Inevitably the participant suffers. Clinical trial teams are truly between a rock and a hard place.
These and many other arguments are deployed to assert that the industry model is bent out of shape, if not broken. Many PwP have lost faith in the ability of the research community and Pharma collectively to address the lived experience issues of PD. This is leading on the one hand to systematic efforts to make progress outside the current research paradigm, and on the other hand to uninformed discussion and the pursuit of inappropriate if not downright dangerous remedies.
A significant specific issue is the identification of types of PD. Failure to account properly for this in trial protocols has led to inappropriate clinical diagnostic eligibility tests and entry criteria. The “lived experience” outcome for some participants has come into conflict with formal clinical trial conclusions. The most significant problem reports inevitably come from embargoed sources, but a simple example will illustrate the situation.
A current Phase 2 LID drug trial requires two sessions of a 3-day duration tick-box chart recording the LID status every waking half-hour. The status is to be assessed only by the participant. However, since the movements are involuntary, almost by definition the participant is not properly aware. A Carer/Partner has a much more objective view. The complication, however, is that another person has to be bound in to the trial sign-up. This would seem simple enough to fix but, like a Russian Doll, the next problem is that the chart and process is the intellectual property of another party. If the CRO is unwilling to validate the revised conditions, nothing changes.
A typical trial protocol is a single-variate study, in which every effort is made to reduce the number of variables to one – the drug itself. For example, this could mean taking the trial LID drug, but having to come off amantadine meanwhile. A PD drug trial protocol usually ignores dietary and exercise regimes, and life events. The sponsor is expecting the quantity of participants to wipe out any bias. However, diet and exercise affect drug uptake and utilisation, and different types of PD attract different drug combinations. If this information is not collected there is no basis for assessing outliers, and at worst an invisible bias in recruitment that will skew the outcome.
The PwP condition is a multi-variate challenge which standard trial practice seems unwilling or unable to address.
It would complicate the already burdensome trial protocol documentation, which for a typical Phase 2 trial occupies 18” shelf space and grows by 1” per participant. Crucially the cost implications could rule it out, those least able to raise finance being the small innovative Pharma companies on whose shoulders the destruction of PD would seem to rest.
There are also consequences downstream. Responsibility for determining suitable and safe combinations of drugs, very common in PwP prescriptions, falls entirely on the world of clinical practice. The regulatory world, otherwise so diligent, does not inspire confidence in this situation. For example, the US FDA has not acted on a petition to black list dopamine agonists, despite the evidence of danger in the higher doses and the failure to recognise this in drug leaflets.
As an active supporter of PwP involvement in research, I found a clinical trial relevant to my symptoms and of sufficient scope to give an insight into the reality. I have completed a Phase 2 Trial of Foliglurax (NCT03162874). This is an ongoing randomized, placebo-controlled, parallel-arm study. The drug’s aim is to reduce motor complications for those experiencing end-of-dose wearing-off and notably LID. This is an example of the small Pharma situation, with a CRO doing the heavy lifting of trial logistics. I had no contact with the sponsor or the CRO. “My” clinical trial team is at the Lind Institute on the premises of Derriford Hospital, Plymouth.
A clinical trial team has divided loyalties. I used the word agent earlier to convey their position as a contractual partner to the CRO for conducting the Trial Protocol and to emphasize their sole ownership of the relationship with the trial participant. Their competence in handling this aspect is second in importance only to professional conduct of the trial protocol. The better teams will accumulate knowledge and expertise on the complexity of the PD condition. The better teams will also manage recruitment and retention more effectively.
Unfortunately, the prevailing attitude to clinical trial teams seems to be “they are what they are”.
I suspect that these teams are rarely self-sufficient . “My” team is constructed entirely from arrangements with the adjacent NHS Hospital. It follows that staff selection is crucial to this organisational sleight of hand, because the team must give PwPs a sense of permanence and stability (anxiety is never far below the surface). The inclusion of staff managing their own long-term conditions conveys a message of understanding about the psychological consequences of PD. The other side of this coin is the patchwork of funding needed to keep a team together during droughts of sponsor funding, or to bid for a new Trial contract. So, as the IT system analogy demonstrates, clinical trial teams are the weakest link in the chain, most likely to encounter real-world issues and least able to do anything about it.
From a systematic perspective the PD Trial System today is not fit for purpose. It is at its most discordant state in Phase 2.
The prevailing attitude to a clinical trial portrays it as an advanced healthcare event and so subject to the primacy of the healthcare professional to patient relationship. This is a necessary but not sufficient condition. The trial takes place only if the participants say “yes”. A very different dynamic should operate here, between a customer (participant) and the clinical trial team, a proxy supplier for the sponsor.
The industry calls it a Clinical Trial, I call it a Customer Experience. A person with Parkinson’s Disease is offering their body and some of their soul in furtherance of medical science. The trial will usually require a considerable amount of time and travel, disrupting personal, family and business life. Trials may require onerous drug changes in a trial period determined without any reference to the lived experience consequences.
The sponsor is ultimately in the business of return on investment, and although it means different things in the personal sphere, the principle of a return must also apply to the participant. I expect the Trial protocol to have been moderated at the outset by informed PwP. For my own investment I expect entitlement to personal medical data (e.g. ECGs , UDPRS scores). I expect disclosure of placebo or drug assignment, preferably at the end of any washout period, but certainly on closure of recruitment to the Trial. I do not want monetary compensation beyond expenses. I expect a fundamental issue at Phase 2 to be addressed with an offer to PwP, not a litany of reasons why the industry cannot.
What is the payback for the investment of PwP altruism at Phase 2? Is there not a moral imperative arising from success? Nobody is committed to do anything at any time to restore the benefit the participant gained.
There is a simple consequence. I am not minded to volunteer for another Phase 2 Trial until there is a better deal, a new Trial Compact, on the table. I could be waiting a very long time. The industry could sit on its hands. Influence by the PwP community can only be effectively applied when the trial protocol is being developed, but the PwP community is far too diffuse. It has no standing body or forum of its own with the necessary credibility and logistical capacity. We need to find other ways forward.
The clinical trials marketplace could operate more effectively to everyone’s benefit if these messages about PwP involvement and commitments to PwP were taken on board. The four roads ahead from here are:
- Charities funding projects in Research Institutions and Pharma
- Advocates working with influential PwP who have scientific credentials
- Integration of independent PwP researches with clinical trial centres
- Pharma taking a lot more interest in their agents.