The Pain Clinic with Kate O'Brien
Former senior research nurse Kate O’Brien examines the most common problems facing clinical trials today and what the potential solutions to them are.
The Pain Clinic
with Kate O'Brien
Solving the most common problems in clinical trials
Kate O’Brien worked for almost 20 years as a research nurse delivering phase 2-4 clinical trials in Primary Care and now spends her time promoting research awareness and improving the patient experience.
At Partnerships in Clinical Trials (Nov 2018) she led a problem solving forum called The Pain Clinic. The hope was to identify the most common issues that face different areas of the industry when developing, setting up and conducting trials, and coming up with solutions to solve them.
Based on these discussions with senior figures from across clinical trials, as well as her decades of experience, O’Brien wrote a series of pieces focussing on the most common problems and ways that they can fixed. Here we have gathered them all together in one place.
Rules for choosing
the right site
37% of sites under enrol. 11% of sites fail to enrol a single patient. There's a 30%dropout rate in enrolled patients (Tufts CSSD). So why are the same sites repeatedly selected to conduct clinical trials? How can we improve the site selection process? High quality, experienced sites are out there – how do Sponsors find them?
Currently the site selection process is very much a paper exercise. It is inflexible and relies heavily on information provided by sites without corroboration. Much of the requested information could be collected prior to an onsite visit which then allows the Sponsor to focus on assessing the investigator and site staff’s attitude and professionalism.
This should contain most of the tick box information:
- GCP and IATA training certificates.
- Staff members CVs, roles and experience.
- Training certificates for EDC systems.
- Equipment calibration certificates.
- IMP temperature monitoring SOP.
- Source data verification SOP.
- Details of the electronic system used for patient records.
- Number of patients the site has access to.
- Details of past performance – percentage recruitment to target, retention rate, FPFV dates met, first global recruits.
- How long has the site been involved in trials, and what phase trials are they experienced in conducting.
- Audit findings.
- Directions to the site, parking information.
Assessing the facility
This then allows the Sponsor to focus on assessing the facility and the staff at the site selection visit. Points to be considered are:
- How many staff attend the meeting?
- Are the investigators engaged, have they read the Protocol, do they have insightful questions?
- The general appearance of the facility, what space is available, are appropriate access restrictions enforced?
- Are anonymised search results available?
- Are evening and weekend sessions available?
- Does the site demonstrate any extra initiatives, do they have a research patient group, how do they support patients on a trial, how do they promote research awareness and patient engagement?
- Are comments available from patients who have participated in previous trials? A display of positive comments not only helps to promote research awareness but helps to reassure those who are trial naïve.
- Claims around previous performance, numbers recruited/retained should all be verifiable. Sites should now be keeping comprehensive data metrics.
- If the Sponsor has worked with the site previously they should check whether key staff have left. The loss of an experienced research nurse or study coordinator can seriously affect performance.
- In the UK, sites that have participated in an NIHR portfolio study are entitled to free membership of the Society of Clinical Research Sites.
- This organisation offers excellent webinars and training for which it provides certificated evidence of participation. Sites that have completed these show that they are committed to delivering research at the highest standard.
The Rule of P's
The Sponsor needs to be able to get an impression of the sites attitude. Are they genuinely interested in furthering medical knowledge and helping to develop new treatments, or are they “in it for the money”? Below is a tool that I developed to highlight the standards sites should aim for.
No site should be expected to run clinical trials at a financial loss, but the focus should be on conducting trials to a high standard, providing excellent quality care to patients and delivering data as per Protocol. If these criteria are met then the financial aspect is taken care of.
These are the sites that will recruit well, selecting the appropriate patients. They may employ pre-screening visits, or a pre-consent discussion to ensure the patients enter the trial confident and fully informed.
In order to effect change and ensure that patients are receiving the best quality care, Sponsors need to become more rigorous in the site selection process. It is important to verify a sites claims regarding previous achievements as well as predicted recruitment figures. Sponsors need to be open to selecting sites that they have not worked with previously as opposed to staying with those that they are familiar with, who perform at a lower level. Excellent sites are available but they need to be given the opportunity to demonstrate what they can do.
Improving the site feasibility process
The feasibility process is necessary to determine which sites have the capacity, experience and suitable patients available in order to recruit effectively. However, the statistics demonstrate that this process is not reliable; less than half the sites selected deliver the numbers promised and one in ten fail to recruit a single patient. This results in costly delays to the trial completion. So – why is this area such a problem?
The site’s perspective
From the site’s perspective, there are a number of issues:
- The criteria provided by the Sponsor are often difficult to search, on which leads to inaccurate results.
- There is no payment for completing feasibilities, so the coordinator must achieve a fine balance of time management, trying to provide enough information for the Sponsor, without impacting on the cost effectiveness of the unit.
- Sites are aware that the Sponsor is looking for a limited number of sites and so can over estimate their potential performance in order to secure work.
- Once a site has submitted a feasibility there is often a lengthy delay before they are notified they have been awarded the trial, and in the meantime may have applied for other studies.
- Sites that aren't selected are often not notified, and so more time is spent contacting Sponsors. No useful feedback is provided on why they weren't successful, so the site is unable to act on this to improve. Often the only information they are offered is that the Sponsor has selected sites that can provide more patients, which then leads to a vicious circle of sites promising higher numbers in order to secure work and then not being able to deliver causing problems for the Sponsor. It is vital that the reasons for non-selection are reported to the site so that the Sponsor can then assess whether the site has taken steps to remedy the problem if approached in the future.
Searchable national database
From the Sponsor’s perspective the Protocol is unlikely to be finalised at the time of site selection, so they are unable to provide the final criteria. They are unaware of the computer systems used at site’s so cannot specify searchable information.
There are a limited number of computer systems used to collect patient data at sites. In Primary Care the GP systems of choice is a contractual framework to supply IT systems and services to GP practices and associated organisations in England. The two systems they provide are SystmOne and EMIS web. Both these systems have the facility for a single search to be built and exported to all users.
The Sponsor could assume the responsibility for constructing the search and exporting it to
potential sites. The sites are then able to run the search and report the anonymised data collected. This would give the Sponsor control over the criteria used to identify possible numbers and provides a level playing field for sites as it standardises the information generated.
Some sites may protest that they do not read code all their patient information, unless the circumstance occurs when this affects the majority of sites, perhaps the Sponsor needs to question the suitability of using these centres. This solution would counteract the issues of sites not being provided with enough information at this stage, and not being able to search on some of the criteria provided.
Many of the more forward-thinking sites now have websites containing information about their team and studies that are recruiting. These can be used to check transparency over capacity and workload.
A national database of previous performance could provide valuable information, including:
This information could then be used to extend the database to highlight sites that repeatedly meet or miss recruitment targets. Information on FPFV dates met and recruitment timelines would give a positive indication on a team’s efficiency to Sponsors just as the capacity to record Sponsor/MHRA inspection findings or concerns over a site’s performance may help to guide support to where it is needed. This record would help sites to provide supporting evidence for their feasibility assessment.
Transparency is necessary to maintain high standards within the industry and deliver the best experience for both Sponsors and patients.
- Recruitment target
- Numbers enrolled
- Numbers randomised
- Number of screen failures
- Number of subjects discontinued
and changing public
perception of clinical trials
It is known that a lack of research awareness is a major barrier to clinical trial enrolment. A small survey at my previous site of research-naïve patients attending for a flu vaccination demonstrated that 40% were not aware that the Practice participated in clinical trials. The positive finding however was that 80% of these were interested in being involved. This site had been highly active in research trials for over 15 years which illustrates there is a failing within the medical profession in discussing clinical trial participation with their patients.
There are measures that can be taken at a site to increase research awareness. Committing time and resources at this stage can lead to an increased database of potential participants, shortening the time needed to recruit to target.
Screens in waiting areas could show short videos and clips of patients talking about their experiences in trials. The National Institute of Health website contains a number of personal stories, so it is important to select experiences that are relevant to the type of patients attending your site. Similarly, NIHR’s I Am Research site contains a link to video stories from patients involved in clinical trials
To support this, information should be provided for patients to take home and sites can provide links to their own website as well as other useful organisations. The NIHR provide I Am Research leaflets, but probably most importantly patients need a contact with a member of the research team.
Sites could run Open Days with sessions for anyone to drop in to meet the team and find out what taking part in a study involves. This needs to be widely advertised, not just at the site but also in local pharmacies, on local radio and in supermarkets to ensure a good attendance.
National Health Awareness days offer opportunities for research teams to engage with the general public. For example, promotion for Diabetes Week could include drop-in sessions for patients to have their height, weight, BP and blood glucose checked. Distribution of packs containing lifestyle advice by the staff offer the opening to discuss participating in studies.
Patient feedback and public perception
A useful tool is to have a “Positive Comments” display. I conducted an anonymous survey of trial participants to identify areas where improvement could be implemented. The number of positive comments received was gratifying and these were collated into a display to inform and reassure those new to research.
This led to a further initiative. Recognising the commitment patients had to research and their feelings when a trial came to an end, I started a Research Interest Group. In the first six months they ran a focus group for a company providing a payment system, trialled an eConsent programme and looked at the research ambassador role. These are the people who can help to increase research awareness. Local groups, the Women’s Institute, the U3A are always looking for speakers; you could offer to give a talk and if a patient is happy to help it gives an added dimension. Encourage your patients to talk to friends and family about their experiences, there is a need to demystify research and normalise trial participation.
Going a step further would involve bodies at a national level. Join Dementia Research is a national service for anyone to register an interest in participating in dementia research and matching them to suitable studies. Often people are interested in being involved in research but do not know how to find out how to do this or what trials are available. The UK Clinical Trials Gateway is currently being redeveloped but does offer this service. It needs to be widely promoted, perhaps as part of health screenings and chronic disease reviews it should be mandatory for a discussion around the benefits of registering for this service to be discussed with QoF points attached.
As a research nurse one barrier to recruitment was the public’s negative perception of clinical trials. Patients often referred to “being a guinea pig” or the 2006 incident involving a Phase 1 trial of TGN1412. It is difficult to reassure not only the patient, but also their family about how rare it is that problems occur especially when there are so few constructive articles in the media. I would love to see one of the main soap operas run a storyline about a character with a chronic disease such as type 2 diabetes, psoriasis, or asthma for example taking part in a trial and the positive outcome this can have on their life.
Positive patient comments
To end this first article I would like to share a few of the positive comments I received from patients:
"“When asked if I would like to participate in a recent research study, at first I was unsure. After the first meeting with the team involved I was put at ease. All questions I had been answered, I felt, with confidence and honesty.
Appointments were made to fit around me. I came to enjoy the feeling that the research I was participating in could one day help other people and me too. For anyone considering taking part in a research study I would say, go along for a talk with the Doctor or nurse, it costs only a little of your time but could one day have a huge impact on medicine.”"
"“Since starting the trial I have been much happier in myself, more confident and generally have felt healthier. Should I be asked how I feel about doing the trial, I would recommend it to anyone knowing how I feel regarding being involved and hope this helps sufferers in the future, and the fact I have a great team behind me should I need help.”"
"“Due to the fact I struggled with any degree of self-control, my health suffered. I was also unaware of the serious nature of Type 2 Diabetes and the contribution my lifestyle choices had made. Thank you for the opportunity to take part in the Pioneer 3 clinical trial, the help, guidance and time you have given has been of immense value. Your encouragement and support are most appreciated.”"
"“Taking part in the research was one of the best decisions I’ve ever made. I was dubious at first, as I didn’t think anything would work for me, but after the first injection I noticed a change.""
Low literacy issues and the Patient Information Leaflet
THE AVERAGE READING AGE 0F ADULTS IN THE UK IS THAT OF AN ELEVEN YEAR OLD
This alarming statistic has a dramatic impact on patient engagement in clinical trials. Clinical trials have become increasingly complex, involving more procedures and collecting data using different technologies. A recent survey by KNect365 found trial complexity was felt to be the biggest challenge facing clinical trial professionals, so how much more does this impact on patients and their willingness to participate in a trial? Low health literacy is now widely recognised, but this issue cannot be tackled until low literacy has been addressed.
Part of the patient recruitment process is ensuring that a patient fully understands all aspects of the trial to enable them to comply with the requirements. To support this, they are provided with the Patient Information Leaflet (PIL), however, these documents are lengthy, use technical terms and can be intimidating. Patients are reluctant to admit that they do not understand the information and the easier option is to not be involved.
How can we change this?
The first step is to simplify the process. Ensure that sites are provided with a letter to send to potential recruits informing them that they may be eligible to take part in a study and some basic information about what is involved, in language easy to understand. This needs to include a reply slip for patients to enter their contact information. A telephone call prior to sending this out enables the site to initiate a relationship with patient and personalise communication. If this call can come from someone that they are already familiar with at the Practice this helps to reassure the person. This also enables them to expect the letter and increases the likelihood of a response.
A face to face discussion about the trial enables the research team to use a language format that the patient can easily understand. One method I used was to invite potential participants in for a group talk with myself and an investigator. The doctor would give some information about the condition and current treatment options, I would explain what being in a trial involved and the investigator then would discuss some of the specifics of the study. I would try to have a patient involved who had previously taken part in a trial to give that perspective. At the end of the talk we would book a one to one appointment for those that were interested, and give out the Patient Information Leaflet. The whole session was relaxed and informal with plenty of tea and coffee. I wanted those attending to feel comfortable and be able to ask questions. Family members were welcome as we were aware that often it was their fears that deterred patients from enrolling in a trial.
Olivia Neely at Dr Ainsworth’s site in Leamington has a similar approach. She will often invite patients in to talk about the trial three or four times prior to signing Informed Consent to ensure that they feel fully informed and comfortable with all aspects of the trial. This results in a high retention rate and compliance with the Protocol. She likens this to decorating – the more time spent in preparation, the better the outcome!
However, these talks and visits are often not included in the costings for the study. Experienced site staff recognise the value of dedicating this time to ensure the best outcome for both patients and Sponsors. Perhaps it is time that this knowledge is recognised, and funding is allocated to recompense the time spent in preparation. After all, sites with a high retention rate ultimately lower the cost to the Sponsor.
What can Sponsors do?
Sponsors could also help sites by providing the Patient Information Leaflet in a more acceptable format to patients. Provide the information in smaller chunks, perhaps enable sites to tailor this to the patients’ requirements. As an example, often there is a whole page focussing on pregnancy, this could be removed for post-menopausal women or men. More care needs to be taken with how the information around side effects is communicated. Regularly patients told me that they didn’t want to take part because of getting ALL these problems. At an appointment I was able to reassure them that they were highly unlikely to have all these problems and may not experience any side effects. I used a Patient Information Leaflet for Paracetamol to demonstrate the requirement of informing those taking a product of possible side effects. Listing pancreatitis and hepatitis did not mean that all patients would be afflicted if they took Paracetamol. However, I was unable to do this for those patients receiving the PIL by post, or for their family members.
As an industry it is easy for familiarity with what we do to cause us to become blasé about the understanding of those outside the profession. Employing a specialist company to design information leaflets with low literacy in mind is one solution, another is to involve patients in providing feedback. A trap companies fall into is using “professional” patients which then distorts the relevance of their contribution.
It is recognised that literacy and numeracy issues affect a patient’s ability to comply with routine appointments, planning journeys to arrive at the correct time and generally understanding what is required of them. Assistance with this is vital, not only providing reimbursement for taxi costs, but booking the transport and confirming this with the patient. Most patients find text appointment reminders useful. These could also include prompts to fast prior to their appointment, return IMP, return diaries etc. However, all this takes up more of the sites’ time so the Sponsor could consider using a company that provides a concierge service to relieve this burden.
The ethics of patient consent in clinical trials - Dr Kieran Doran, Senior Healthcare Ethics lecturer at University College Cork, argues that one of the current big failings of patient-centricity in clinical trials is patient consent.
Six ways to improve patient understanding
- Ensure all language used is low literacy compatible
- Provide information in smaller, easy to digest sections
- Recognise and reward sites that are committing extra time, visits, phone calls to ensure full patient understanding
- Utilise specialist companies to design the PIL
- Enable sites to tailor the PIL to individual needs
- Employ a concierge service to aid appointment attendance as per Protocol
How sites and sponsors can support patients in trials
Sites and Sponsors need to start supporting patients as soon as they have expressed an interest in joining a trial. The relationship that develops between the patient and site staff directly impacts on the experience the patient has of clinical research, the probability that they will complete the trial and their likelihood of participating in future studies.
This support begins with the Informed Consent. The problems with the Patient Information Leaflet were discussed in the previous article so I will now focus on other areas. This may be the first time the patient meets the research team and they are not sure what to expect. The site needs to ensure that they have a calm, informal approach encouraging the patient to relax and feel comfortable.
Taking time to fully explain all aspects of the trial, checking that the patient understands what is involved and what will be required of them, encouraging them to ask questions and voice concerns means that at the end of the process the patient will be 100% happy with their decision.
I found that the best outcomes were when this was a team effort with the nurse explaining the general aspects of taking part in a trial, the visits, the lab tests and investigations and other methods of collecting data. The investigator would focus on the rationale for the trial, the IMP and possible side effects, as well as other treatments available.
I also liked to introduce them to the administrator who was their point of contact for technological support. The emphasis was placed on the patient being part of the research team, this is not the usual doctor – patient roles. This meant that they were not afraid to ask questions or contact us if they had any issues, however minor, preventing potential problems escalating into Protocol violations. As clinical trials are our focus it is easy to forget what an alien experience this is for most people.
"Taking time to fully explain all aspects of the trial, checking that the patient understands what is involved and what will be required of them, means that at the end of the process the patient will be 100% happy with their decision."
I think it is important that Sponsors recognise sites that engage with patients outside the remit of trial participation to push forward the development of Best Practice for research.
- Provide scope for pre-consent activities in the site budget.
- Consider scheduling a pre-consent visit
- Allocate resources to support retention
- Obtain patient feedback when selecting retention items on what is most useful.
- Provide a personalised schedule of projected visit dates at the start of the trial so that patients know when their appointments will be and enable them to plan for this.
- Provide IMP dosing instructions either clearly on the packaging or on a small laminated card.
- Have a dedicated patient helpline provided by the vendor for technology issues and ask for feedback to ensure it is user-friendly.
- Enable sites to perform visits in the evening or at weekends, often couriers have restrictions around collecting packages to go to central labs that prevent this.
- Reimburse patients for their time as well as travel. Patients are expected to be altruistic when it comes to clinical trials. Looking at the chain of those involved – they are the ones who can least afford this.
- Develop an app for patients to install. This could provide updated information, record details and track progress as well as remind patients about appointments and visit requirements.
9 ways to support patients during trials
- Having a direct line, with an answerphone, so that callers do not have to go through the rather frustrating systems normally in place when calling a medical Practice so that patients are not deterred from calling.
- Using a text messaging service to remind patients of their appointment date and time, if they need to fast, or the need to return unused IMP and diaries ensures better compliance. Texts can also be used as a prompt to complete any procedures required between visits.
- Providing personalised feedback on their progress. This can take the form of graphs and tables to highlight achievements such as weight loss, improved HbA1C, better control of BP or cholesterol.
- For trials involving devices that patients may be unfamiliar with, identify a member of the team to act as their IT support. Make sure that this person will use technophobe friendly language.
- Use a holistic approach. Adverse events need to be identified, evaluated and recorded as do changes to concomitant medications so treating other conditions at a study visit means that all data is collected efficiently. I had the misfortune to work with a GP who refused to do anything other than what was required for that visit insisting the patient returned for a routine appointment for other problems. Not only did this mean chasing records later to identify changes, it was also extremely inconvenient for the patient.
- Identify patients that may be likely to withdraw during the trial. Warning signs may include missed appointments, difficulty booking appointments or contacting the patient, non-compliance with IMP dosing, frequent illnesses, difficult external circumstances, problems at home or with travel and no visible improvement. Early discussion and offers of help may resolve issues and enable the patient to continue in the trial. It is important that the patient identifies a solution that will work for them rather than having a decision made for them that they may be reluctant to accept.
- A patient may have a specific problem that causes them concern. For example, many people have a needle phobia, and most trials require numerous blood tests. Explain why this is necessary and recognise their worries. Lie the patient down for the procedure, make sure you have an experienced phlebotomist and have someone talk to them whilst it is done to distract them.
- At each visit reinforce how important their contribution is and show that they are appreciated.
- Remember to say thank you.
Making the patient's life as easy as possible
This series of articles has focussed on multiple methods of engaging with patients and promoting enrolment in clinical trials. Here we look at a summary of the advice and suggestions that should make life easier for patients.
At all stages of their clinical trial journey, the patient and their family need to receive support from the site, and indirectly from the Sponsor. This is often a new and unfamiliar experience for them, and it is essential for the future of the industry that this is an enjoyable time and one that they wish to repeat. We know that most patients feel very positive about their participation when they complete a trial but this does not include those who have withdrawn during the course of the study having encountered problems.
- All information to be provided in a low literacy compliant format.
- Use a specialist provider for patient material.
- Have an invitation letter with a reply slip, and a basic
synopsis of what the trial involves.
- Scope for pre-consent visits to be included in costings.
- Include family members if the patient wishes.
Placing clinical trials in Primary Care with Kate O'Brien
During the trial
- Provide a personalised schedule of projected visit dates at the start of the trial so that they know when their appointments will be and enable them to plan for this.
- Provide IMP dosing instructions either clearly on the packaging or on a small laminated card.
- Have a dedicated patient helpline provided by the vendor for technology issues and ask for feedback to ensure it is user-friendly.
- Reimburse for time as well as travel.
- Make travel arrangements for patients when required. Book a taxi to enable them to attend a visit in poor weather conditions, or if parking is an issue at the site. Use a concierge service for overnight stays or long-distance travel.
- Use a payment system acceptable for patients as well as convenient for staff.
- Enable sites to conduct evening and weekend appointments for convenience.
- Text message reminders of appointments, and any special requirements.
- Sites to have a direct line to the research department for easy contact. Regular checking of the answerphone and a prompt response to messages left.
- Personalised updates on progress during the trial. Highlight positive outcomes, for example weight loss, improved glycaemic control, lower BP. Provide this in a printout.
- Enable patients to provide feedback on their experience to help shape trials in the future.
At the end of the trial
- Enter the patient into follow up in routine care if appropriate.
- Provide full explanations of the treatment options available.
- Offer options to remain engaged in research, for example patient groups.
- Provide the code break information when received.Provide a summary of the trial results.
The potential of remote data collection
Many people are keen to engage but are prevented due to work and family commitments. By embracing remote data collection we can enable a much wider population to become involved - I recommend reading Michelle Petersen’s excellent article on how full virtual clinic trials can become a reality in the next 10 years. This is already demonstrated by the recruitment rates to ADAPTABLE – The Aspirin Study- the figures shared in a Society for Clinical Research Sites webinar on the Site of the Future (14 May 2019) made impressive viewing, and certainly offers food for thought.
The excitement around virtual trials is clear from the recent KNect365 Clinical Trials State of the Industry Report 2019, which shows that 55% of survey respondents were 'Likely' or 'Certain' to increase their use of virtual trials in the next two years.
Clinical trial site finances: Tips for budgets, payments and invoicing
Personally, I found dealing with finances, from budget negotiation to reimbursing patients, one of the most frustrating areas of my job and discussions with other experienced research nurses suggest that this is a common issue. This article will look at some of the areas that cause headaches.
Despite having a standardised costing template this still requires verifying for complete correctness. This means cross checking against the contract that all procedures have been included and have been allocated to the correct role in the study team. Then each procedure needs assessing for the amount of time that it will take, and it is often this area that causes issues. Whilst the procedure itself may not take long, companies do not allow for the fact that sites are dealing with real people who ask questions when completing questionnaires, make mistakes that need to be identified and corrected, and also need to get undressed for physical examinations and ECGs.
There is also concern that experienced sites who can accurately assess timings and costings can be undercut by less knowledgeable sites who are keen to take on more trials.
Personal experience has led me to believe that surprisingly this seemingly easy area is one that can cause the most difficulty. There are several ways that payments can be made:
Cheque – now old-fashioned and means a trip to the bank for patients.
Bank Transfer – some people are cautious about who they release their bank details to.
Cash – this either involves the study team holding their own float or obtaining the required amount from their finance department. The first instance means that a secure storage is required, and time is spent balancing the receipts. The second is the method I was familiar with, but this entailed notifying the accounts clerk of upcoming visits and the amount required to ensure that they had enough funds available, collecting and signing for the cash, and returning it if they patient failed to attend. Enough hassle on its own but if you are unlucky enough to have an uncooperative accounts clerk…
Patient Payment systems – I admit to being sceptical when first hearing about these methods! However, my Research Interest Group agreed to hold a focus group providing patient feedback on the ClinCard system for Greenphire. They highlighted some very important issues. They wanted secure ways of carrying their payments and felt that a card system is safer than cash. It allows them to track their receipts so that there can be no concerns over missed payments. Some patients liked the idea of an easy method of saving up an unexpected income for a special occasion or treat. Finally, it was transparent if they need to declare this to the inland revenue. From a site’s point of view, it is quick, easy to use, transparent, and allows for those awkward amounts if a patient uses taxis. They were all very enthusiastic about this as a method of payment.
I repeatedly relayed these findings to companies when setting up trials, who all displayed an interest. However, this was never taken forward and we remained with the same old problems, convenience for the companies, and a headache for the sites!
As a rule, the amount is calculated by the CRA/company and the site is requested to raise an invoice. However, this still requires checking for accuracy and completeness. This involves cross checking against the amounts agreed in the contract, the visits completed, and the tasks included. Payments to patients and external providers need to be factored in.
If the site is required to complete the whole procedure this can take a great deal of time. Spreadsheets are very useful to track visits, payments made and specific items that need to be included. However, this relies on all staff completing these accurately, if not it adds to the workload of the person generating the invoice and payments can be missed.
Once the invoice amount is agreed it then takes time for the account to be settled dependent on the policy of the company involved. I found this varied enormously and had to be conscious of checking that payments had been received.
It is strange that in an industry dealing regularly in multi-million-pound sums, so little consideration is given to the end user. It seems to be generally accepted that sites are happy with invoicing at a minimum of three-monthly intervals and can wait even longer for payment. This is not the case; most sites have a limited cash reserve.
This often impacts directly on a site’s ability to continue to conduct clinical trials if delayed payments affect their operational cash flow. Finance related issues can take up a considerable quantity of time that would be better directed at patient focused tasks.
I found it difficult to understand why Sponsors did not utilise the automated invoicing systems that are available. These provide prompt payment, are transparent and enable sites to manage their cash flow. Time spent administering accounts is time away from recruiting and caring for patients.
There are two excellent whitepapers by the Society of Clinical Research Sites in collaboration with Greenphire highlighting the importance of this topic. Financial Barriers to Site Sustainability, Patient Experience and Overall Trial Success (Feb 2019) identifies limited operating cash, the manual invoicing process, untimely payment frequency and lack of financial transparency as the four main areas of concern. This flags that this is a global issue for sites and impacts directly on their ability to function effectively.
Site Payments and Patient Reimbursement - A Global Perspective (Apr 2017) again demonstrates this. A future article for this series talks to two top investigators, involved for over 25 years in conducting trials at the highest level who have both now ended their involvement citing financial stresses as one of their reasons.
I would urge Sponsors to investigate the use of automated site payment systems and patient reimbursement methods such as ClinCard. Remember that we are primarily doctors and nurses and our skills are in patient focused areas.
By maximising efficiency at sites we can shorten timelines and therefore overall costs. This also helps to maintain job satisfaction, keeping the high quality investigators engaged for the future.
How clinical trial Principal Investigators
can maintain oversight
It is now a requirement under ICH GCP E6 (R2) addendum for the Principal Investigator (PI) to demonstrate their oversight of a clinical trial. Sites need to be able to provide evidence that the PI is actively involved in the conduct of the trial and is assuming the required responsibilities. As they are considered personally responsible for conducting and supervising the conduct of all trial activities the PI should have a plan for the supervision of all staff working on the trial. The delegation log is not a paper exercise, the PI needs to be able to support their actions if questioned.
There has been considerable thought around the format that will be required in the case of an inspection.
Centres should hold regular meetings of the research team. These should be minuted, documenting all those present. Most sites run multiple trials and so confidentiality must be a consideration. Study names could be used but sites must be wary of making restricted information available to outside parties. However, the minutes could contain study status, SAEs and AEs discussed, safety issues and Protocol violations and deviations – these are linked to particular members of the team indicating inappropriate delegation or that re-training is required. If necessary, agreed identifiers could be attributed to each trial so that the Sponsor can evaluate the amount of discussion for their study.
The Sponsor can be involved with monitoring PI oversight. The CRA has a close working relationship with the site staff and can flag concerns. During SDV they can identify how often the PI is present at patient visits, and how regularly the visit is completed by a sub-investigator. How often the PI is present at informed consent can be verified by the signature on the form. The CRA is also able to record the availability of the PI at a monitoring visits in their follow up letter and all issues discussed. This should also be used as an opportunity for the Sponsor to assess the PIs knowledge of the Protocol, the patients enrolled and how the trial is progressing at site. Concerns can then be addressed at an early stage.
Together with the site staff the CRA could identify the amount of data queries linked to each staff member. The PI would then need to document the steps taken to correct issues. Notes to file can be raised if there is no other document appropriate to record actions taken.
"Sites need to be able to provide evidence that the PI is actively involved in the conduct of the trial and is assuming the required responsibilities."
10 tips for Principal Investigator oversight
- Minuted team meetings
- PI plan for team supervision
- PI to sign off AEs and SAEs
- PI to review lab results to identify trends in abnormal values
- CRA to monitor staff present at patient visits
- CRA to monitor PI availability at monitoring visits
- Concerns over deficiencies in knowledge to be followed up by Sponsor
- Number of DQs per staff member to be checked
- All retraining to be documented
- Actions to be taken in a timely manner during the course of a trial, not at the end or when an inspection is announced
Site and Sponsor staff responsibilities
It is important to retain a balance between compliance with the ICH GCP regulations and not over burdening the PI with additional paperwork. However, patient safety and the protection of their rights is the priority for all those involved in clinical trials and so research teams should recognise the importance of this requirement. By identifying the criteria necessary to demonstrate PI oversight early in contract negotiations it allows sites to budget for this in the costings agreement.
As the addendum is recent and uncertainty is prevalent over the evidence required, site staff should be prepared to voice their opinions and rationalise the practicalities of requests to the Sponsor. In turn, the Sponsor has to be prepared to listen to the views of the site and work with them to identify the optimal solution to ensure compliance. It is in both parties’ interests that demonstrating PI oversight becomes routine.
The PI is responsible for delegating responsibilities to the appropriate staff in his team and this should not be taken lightly. The staff should be able to demonstrate that they are qualified and have the necessary experience. The tasks should be adhered to and the team should be able to demonstrate this to an auditor.
At my previous site I discovered that a new research nurse (with only a few months experience) was taking informed consent and asking the investigator to sign the form. This directly contravened the delegation log, yet both the nurse and the PI were happy to disregard ICHGCP. I suggest that it should be part of an inspection that the investigators are required to demonstrate an informed consent to the auditor as a role-playing exercise.
The Sponsor should also be more rigorous in reporting infringements, the same nurse had taken two consents to a Protocol amendment, signing the paperwork herself. The CRA picked up this breach and yet as one consent was not required due patient completion this was not reported to the MHRA. It is only by strict monitoring and enforcing regulations that are in place to ensure patient safety that “loose cannons” can be brought into line. Investigators should view staff that are prepared to violate codes of practice as liabilities, not a way to cut corners and maximise profit. Site sustainability is an ongoing issue, this should be directly related to the quality and transparency of their delivery of clinical trials.
Once again, this comes back to selecting sites that focus on delivering clinical trials transparently and are prepared to account for their actions. As the direct link to the site the CRA’s are vital to communicate their opinions to Sponsors, and their concerns should be taken seriously. There are many great sites with committed, hard-working investigators and they should be recognised and rewarded when it comes to awarding future trials.
A clinical trial investigator's insider view
Recent conversations with ex-colleagues brought to my attention that highly experienced investigators are deciding to discontinue their involvement in clinical trials. As these are precisely the sites that are vital to recruitment and the delivery of quality data this is an alarming fact. This article focuses on why this is happening.
Two investigators, Dr Bhavesh Bodalia and Dr Phil Marazzi, who have over 25 years of experience each, have been kind enough to discuss with me their reasons for withdrawing from commercial research. Other input has been provided by sites that will end their involvement when a key member of staff retires.
Dr Bhavesh Bodalia, based in Coventry, could easily be described as the perfect PI. Extremely hands on, he would see patients early in the morning, in the evening or at weekends to fit in with their daily lives. Much of what is now being discussed as Patient Engagement, Dr Bodalia was practicing years ago. His recruitment figures were phenomenal, for the ARRIVE trial he recruited 110, my site managed 36 from a much larger patient pool. Much of this can be credited to the fact that he spoke to the patients personally, taking time to fully explain everything as their doctor. His patients all had his mobile number in case of problems, it was rarely needed but this meant reassurance for them, plus any issues could be quickly resolved. Speaking to Dr Bodalia his passion for research and that this was an opportunity to provide the best possible care for his patients shone through.
Dr Phil Marazzi, based in Guildford, was early to identify the benefits to his patients of their involvement in clinical trials and he was a founding member of Profiad. His site had been participating in research since the 1970s. Again, Dr Marazzi had a highly professional attitude to conducting trials, recognising the need to work with an experienced research nurse and ensuring that the quality of data collected was top quality. His expertise in managing trials was widely recognised.
I have also included comments from another research nurse with over 25 years of experience. Here they will remain anonymous (referred to only as Research Nurse X) as the site will also cease their involvement in clinical trials when that person retires, but are currently still engaged.
What are the changes you saw over your research career?
Dr Bodalia: “We have seen a progressive move towards increased monitoring of research, a heightening of standards with increased protection for trial subjects, increased documentation at every level, more policing of research activities and a constant requirement to prove credibility. Significantly, most of the evolution has made the clinical research industry more robust and credible in the eyes of the public and reassuring for those who volunteer to participate and so is a positive evolution. We have always welcomed this as this gave our research subjects the reassurance that they are safe. Additionally, there has been a transition from paper-based records to electronic records which has also been a positive evolution. The downside for us in this arena is that we found ourselves doing much of the work that previously was done by data clerks which again is something we support.
However, we have found that funding did not follow proportionally to the work involved and indeed, research funding has fallen to a point that it is difficult to have a research team "ready" to deliver studies without the guarantee of work to come or a reassurance of funding. If a site encounters a year when work levels are low, then we have clinical research staff sat doing nothing and this becomes an unmanageable cost pressure which forced many research sites to abandon research work. We have been fortunate and despite concerns, always managed to secure projects in time to avoid "downtime", but with the unreliable nature of the arena, we also decided to finally retire from clinical research.”
- "Increasing standardisation and globalisation: These are good, but mean that inclusion/ exclusion criteria can be much more difficult as may not ‘apply’ in our patients due to different clinical practice for example. This was a massive problem as even with our population of 10,000 patients, there were often only very small numbers meeting the criteria, and only a proportion of them would agree to a trial. When I started doing trials, investigators could influence the criteria to help make them ‘real’. Investigator meetings were earlier in the process and allowed a protocol to be carefully looked at in practical terms and then amended. Later, we were just presented with the final product and no possibility to amend it, especially in bigger multinational studies.
- Huge increase in admin and ‘paperwork’: We were approaching a stage where my research nurse was spending up to 75% of her time doing admin and only a small proportion seeing patients.
- Reduction in fees paid by pharma: The timings used by pharma/CRO to calculate fees became based largely on face to face patient contact time and not all the admin. This meant that actual payments remained virtually constant over 20+yrs even though inflation and amount of work we were doing was MUCH greater. We used to negotiate the investigator fee, but I think that ‘standardising’ it was actually a way of reducing it! It became non-viable as a business in primary care as we did not have enough patients for enough trials to cover costs at some points. ‘Feast or famine’. No trials for a while then several in the same therapy area competing for the same patients. More time was needed to find patients and the increasing demands of NHS general practice made this difficult. In order to take more time out for trials, you need more income to cover the NHS work. If the trial income is not regular, you run the risk of the whole process actually costing money, not making it.
- Hospitals and phase 1 units starting to do ‘primary care’ type trials causing loss of opportunities: When I started, we used to do a lot of phase 2 work, with PK studies etc. That stopped completely.”
Research Nurse X: “The expectations placed on investigators - to be far more involved on a daily basis than they might have been previously and as a very busy GP, that is not always possible. And as for paperwork - once upon a time you would have one site file for a study, now there are five or six in some cases!”
Do you feel that the relationship with the industry is now different?
Dr Bodalia: "The relationship with the industry is more intense and timeline pressures are a constant. There is often a failure in the industry to recognise the need to guarantee projects at site level so research sites can offer assurances over job security for staff. The industry needs to establish more financial certainty for small independent centres so that it can maintain diversity amongst its research centres and recruit appropriate selections of subjects."
"CRAs expect more to be done in less time. It was always better working with big pharma direct, the minute CROs became more and more involved, the knowledge and quality of staff started to drop. Staff from pharma had better knowledge of the drugs, trials and so on, so were generally of a higher standard."
Dr Phil Marazzi, ex-clincal trial investigator
Did you notice a change in the complexity of the Protocols (that may not have corresponded with a change in income)?
Dr Bodalia: "Yes. Protocols became more complex, increased use of IT (often unreliable and time consuming) and not adequately supported by the funding. We have had occasion to give up on a study because of this."
Kate O'Brien: "The inclusion and exclusion criteria have become more restrictive which limits the pool of patients available to enrol. Then as the Protocols are more complex, this involves lengthier visits that deters patients. Often when I completed a feasibility, I did not have the final Protocol, by the time this was produced the original figures predicted were obsolete."
How easy is it to find experienced research nurses and study co-ordinators?
Dr Marazzi: "Staffing was not easy though I did manage to keep some very good nurses. They required quite high pay however and so this was a problem.
Kate O'Brien: "I found it impossible to attract experienced research staff on the salary I was permitted to offer. This resulted in employing staff with no experience, having to train them from scratch with no idea if they would demonstrate any aptitude for research or commitment to the job."
What are your thoughts on costings and payments?
Kate O'Brien: "Negotiating costings in order to make a trial viable to run at a site was time consuming and consideration is not given to a site’s experience."
"It needs better consideration at site level. It costs the same to set up a trial that recruits two patients as recruiting 20, but obviously the former is not practical to run."
Dr Bhavesh Bodalia, ex-clincal trial investigator
How do you view the increasing use of technology?
Dr Bodalia: "A necessary facet of research in the future. Sites need to embrace this but ensure the time it takes is factored into their costs."
Dr Marazzi: "Different IT systems is not a major problem but an irritation. A good nurse could always cope with different systems/couriers/labs etc."
Research Nurse X: “Definitely a growth area with increasing use of electronic diaries etc for patients. Also a big growth in the number of vendors involved in studies - for example, we have just started a study that involves the eCRF (RAVE), IWRS (clinphone), a study portal (intralinks), an adjudication website, and a website for viewing patient diary data. That's five vendors requiring setting up (and remembering passwords!!)"
What are your thoughts on the Clinical Research Networks?
Dr Bodalia: "These networks are good as they provide good support for sites. We, as a site, did not take any significant projects from these networks as we had robust relationships with the Pharma companies and CROs."
Dr Marazzi: "NIHR (our SE network anyway) didn’t do much to help. Initially all the work was more academic and generally very poorly paid. Little more than a distraction. Not sure if that has improved."
Research Nurse X: “Mixed thoughts really - they've raised the profile of research, which is good, but I can't help thinking that they're an additional layer of red tape. We've had a couple of run ins with our local CRN."
Kate O'Brien: "I echo all of the above, the networks are useful for inexperienced sites but those with a strong background gain little. Pressure to take on low paying non-commercial work that is often set up inefficiently is unhelpful. This occurred as these studies often required large numbers of recruits which boosted the overall recruitment figures to meet national targets."
Why did you decide to end your involvement in clinical trials?
"We stopped because the flow of work was irregular, the income inadequate, NHS pressures increased, difficult trial design in populations that were ‘well treated’, and increasing admin. I was very sorry to stop as I felt that I had really contributed to some good work but could not guarantee to make it viable any more."
Dr Phil Marazzi, ex-clincal trial investigator
Dr Bodalia: "We decided that the level of regulation, the complexity of the protocols and our motivation to constantly deliver timelines on the backdrop of a busy general practice and a failure of research companies to recognise this, finally dealt the blow to give up research. The difficulty is that the companies fail to recognise that research takes resource and to meet deadlines often means that it costs sites to back fill their normal daily work. I found that the recognition by research companies of the commitment required began to fail. For example, being constantly audit ready for inspection takes resource."
Kate O'Brien: "Following the retirement of the PI who set up the unit, priorities changed to focus more on profit making and less on producing quality data. It became harder to maintain standards, the investigators didn’t seem to take research seriously, one regularly slept through investigator meetings and would only attend site meetings if lunch was provided! I was working with staff that I was unable to trust, and research is too important for that."
Would anything make you reconsider?
Dr Bodalia: "No. The increased regulation, difficult timelines, increasing complexity of protocols and expectations which are not matched by an equivalent increase in investment in sites by Sponsors has made research increasingly difficult to deliver by smaller research sites and has made research not viable for investigators such as myself.
I would not return to research until this balance has been redressed. Should this balance be redressed, then there is a great potential for experienced mentors and new investigators to become involved in clinical research at general practice level in the future.
Perhaps this is a thought for the Sponsors to take back to the table when considering how to reach out to future research sites in the UK."
"I wonder if the only real possibility now would be to run studies across a very local network, for example a group of practices with 50-100,000 patients. I am still not sure how financially viable it would be, but would be nice to try!"
Dr Phil Marazzi, ex-clincal trial investigator
Kate O'Brien: "I recognise that there are some excellent sites with committed investigators and am happy to bring these to the attention to Sponsors. Using my experience to look at problem solving is enjoyable, I wouldn’t return to the problems of trying to manage a difficult site."