Case Studies: Research & development
Clinical Trial Recruitment and Retention
Nancy Meyerson-Hess is an internationally renown expert for clinical operations and an Associated Partner of admedicum® Business for Patients. She has cooperated directly with patients related to clinical trial design, recruitment and retention on numerous occasions.
A company starts a clinical trial in patients for treating Pain due to Diabetic Neuropathy over a period of 6 months. Several Key Opinion Leaders (KOLs) give input to the clinical development program. Clinical trial recruitment is very slow and several patients enrolled discontinue participation. This has an impact on replacement of trial materials, extension of contracts with vendors, additional recruitment activities, revision of development timeline, etc. The clinical trial team tries to find solutions.
Understanding the reasons for slow recruitment and low retention from a patient view; adapting the trial set up accordingly.
Understanding what makes a patient accept or reject the burden of a clinical trial; adapting an ongoing clinical trial to patient’s needs.
- After review with clinical trial providers and investigators, two major aspects seem to drive the resistance to enroll and/or drop out of the trial: a high number of visits to treatment centers far away from home and overwhelming obligations for documentation several times a day. The travel time and inconvenience to the patients and care givers has a negative influence upon motivation to participate in the clinical trial and/or to remain in the trial over an extended time of six months.
- The company decides to work with a questionnaire to patients who were interested in participating but decided against it, and to patients who dropped out of the trial. The objective of the questionnaire is to confirm the previous findings and to understand which changes are needed to make those patients enroll and stay in the trial respectively.
- The company requests the involved clinical research organizations and investigators to ask these patients to fill out the questionnaires or to provide information. Most of the patients respond positively to the request and are open to provide their input.
- With the outcome of the questionnaires, the company sits down with some of the physicians for review and sets priorities for adapting the clinical trial protocol.
- The revised version is presented to a small group of coordinating investigators and vendors and a patient from each involved site.
- The final revised clinical trial protocol reflects the input from patients, investigators and vendors, in as far as possible. The company also introduces new information targeting patients through newsletters, publications and indirectly via investigator information days. All of these changes need to be submitted and approved by the respective ethics committees or review boards as appropriate.
- Following implementation, recruitment picks up and retention improves, however the clinical trial still takes longer and costs more than expected.
What went well
Once the issue was identified, the company took reasonable measures to understand the patient perspective. The questionnaire was the result of homework with vendors and investigators. Additionally, the company did a good job reaching out to patients they had to convince, rather than those on the trial that are most simple to reach.
What can be improved?
Patient involvement early in the design of the first clinical protocol would have significantly reduced the challenges met. Early engagement is an opportunity for direct exchange, to identify and bridge gaps in understanding and to come up with practical, innovative approaches to drug development.
The company did not have a formal process in place for patient involvement. Establishing such processes is time-saving and forward thinking.
Considerations and recommendations
Involve patients in your design process!
There is evidence, including insights from FDA and EMA, on the positive impact of patient engagement on recruitment and retention in trials. Both aspects are often negatively influenced by the logistics of the trial and frequent visits to the investigator site, which disrupt a normal routine or work. Patient involvement in the design of clinical trial is therefore highly recommended. Here is some evidence that can help your internal review of the benefits:
- The DIA Patient Engagement Study reported reduced screen failure rates, faster patient recruitment rates, improved subject retention rates, reduced numbers of protocol amendments, and a greater number of patient relevant endpoints as positive aspects of patient involvement.
- The FDA Executive Summary Patient Engagement Advisory Committee leads you to further publications and materials that give guidance regarding patient involvement related to clinical trials.
- The Tufts Center for Drug Development Impact Report reported that 57% of all protocols, across all phases, have at least one substantial global amendment. The most frequent changes stem from amendments associated with modifications and revisions to study volunteer demographics and eligibility criteria. Based on the additional time and costs, it seems more cost efficient to reduce amendments by involving patients early on in the trial design and protocol discussions.
- EUPATI's article on collaboration in an oncology trial shows another good case study for insightful involvement of patients in an oncology trial by Sanofi in France.
The US based Clinical Trials Transformation Initiative (CTTI) developed some useful tools:
- CTTI Recruitment Tool Decisiontree provides a checklist that helps you to define “when” to involve other stakeholders.
- CTTI Recruitment Tool Stakeholder helps you to prepare a strategy regarding which stakeholders to approach and for what reasons.
Please keep in mind that stakeholder involvement means really giving patients a chance to understand and express themselves, rather than guessing what a minimally burdensome trial design is. The patient knows best!
Get early management buy-in for the co-creation with patients
Involving patients in clinical trial planning yields a number of opportunities that go beyond successful recruitment and retention alone. Examples are the critical review of primary and secondary clinical trial endpoints, patient reported outcomes and the patient view on benefit-risk assessment. However, all of this requires resources, time and budgets. Therefore getting senior management buy-in early on is a key to success.
Feedback across the board!
Remember that although there is an obligation to publish your clinical trial, this does not provide individual trial participants with information regarding “their” participation in the clinical trial. Please don’t forget the patient experts you worked with, once the collaboration comes to an end. Prepare final information regarding what suggestions will be implemented, which ones will not, and provide reasons why.. It is good to have agreement on feedback to involved patient experts before trial commencement. And again, patient experts and investigators can probably tell you best what they would like to know from this excersize.
If you want to go deep we recommend the following multi-stakeholder best practice sources:
- The EUPATI guidance and toolbox for involvement of Patients in R&D can be downloaded at www.eupati.eu. Although designed primarily for patients, the EUPATI materials also provide a basis for collaboration for industry.
- Page 4 of the EUPATI Guidance for patient involvement in ethical review of clinical trials may also be of interest as guidance for involvement of patients in the definition of the ethical conditions for clinical trials
- Last but not least the DIA Patient Engagement Considerations Guide is a source for many important aspects when considering patient collaboration in R&D (see pages 28 to 32 in particular).
Help us improve this guide
Considerations for Implementing Expert Patient/Patient Group Input
Recommended Contributors :
- Program leaders
- Patient liaisons
- Sponsor representatives
- Clinical investigators
- Research team
- Trial site staff
- Expert patient(s)/Patient Group representatives
Communicating with Patients throughout the Program
- How does the phase of drug/biologic/device development process covered by this program impact communication with patients?
- What translation and/or cultural adaptions?
- Wat language will be used to communicate with and about the patients?
- Are research questions and procedures culturally sensitive and appropriate?
- How will patients be referred to (e.g. “subject” vs. “patient” vs. “participant”)?
- What is the communication plan for patients throughout the program?
- Message content
- Delivery mechanisms
- Feedback mechanisms
- What feedback mechanisms and processes are in place for the patients to comment on sites, investigators, and the study participant experience?
- What role will social media play in the communications?
- How is social media defined?
- What restrictions should there be, if any?
- How can social media be used to advantage (e.g. for trial recruitment, to educate patients)?
- What limits should be placed on use of social media, if any? Why?
- How will those limits be communicated and enforced?
- What methods will be used to interact with patients and other stakeholders?
- Focus groups
- Inclusion on advisory councils
- Inclusion in meetings with researchers
- What data/information can and will be shared with the patients and when?
- Aggregate (de-identified)
- What are the restrictions (propieratry and regulatory) constraining the release of data?
- How do we ensure that this information is shared in patient-friendly language? How will that be determined/monitored?
Communication Handbook for Clinical Trials.
Guidance for Biomedical HIV Prevention Trials, p 37-38: “Stakeholder education plan.”
Preparing a collaboration
Defining the interaction
Patients, patient representatives and industry should take responsibility to ensure interactions are meaningful by clearly defined processes and actions, progressed to timelines. In addition, all participants should be prepared for the interaction.
Prior to each interaction, agree mutually on (where applicable):
- The objective of project involving patients and/or areas of common interest to establish agreed structured interaction, providing all parties with necessary protection with regards to independence, privacy, confidentiality and expectations (see section 11. written agreement)
- The type of input and mandate of the involved person
- The tools and methods of interaction, e.g. types and frequency of meetings, ground rules, conflict resolution, evaluation
- Desired patient / patient partner organisation to foster long-term working partnerships, with independence ensured (in scope)
- The profile of the type of patient/s or patient representatives/s to be involved and their number
- How activity outputs will be used and ownership of outputs
- How and when the patient/s involved will be informed of outcomes
- Contractual terms and conditions including consent and compensation (see section 11, written agreement).
- Other elements according to the specific project
Preparing a collaboration
The four key principles for collaboration:
1. Clarity of Purpose
Each party should be clear about the reason for and the planned outcome of the collaboration – and the ultimate benefit for patients
Each party should act and be seen to act honestly and with integrity at all times
Each party should maintain their independence
Each party should be open and honest about the purpose of the collaboration and be able to account publicly for the associated activities and any exchanges of funding
Using this guide: a checklist
- Has there been a frank discussion about the purpose and expected benefits of the collaboration, and any risks, addressing all the issues in this guide?
- Are the objectives and planned outcomes of the collaboration specified?
- Are the roles of each partner and reporting mechanisms specified?
- Has a written agreement or contract been put in place, which sets out how each party will adhere to the four key principles?
- Is there a named senior individual accountable for managing and maintaining the relationship and monitoring adherence to the four key principles?
- Is information about the collaboration published on the company and charity websites?
- Can each party confidently explain the collaboration in public?
There are many ways to identify patients to be involved in an interaction. The main routs are through:
- existing patient organisations
- EUPATI or similar project
- advertising opportunities for patient participation
- existing relationships with healthcare providers, hospitals and researchers and other agencies
- unsolicited requests previously made by interested parties
- existing advisory boards / groups (e.g. EFPIA Think Tank, Patients and Consumers Working Party at the EMA)
- this party agencies
Defining role patients
Although you may not have selected the expert patients or patient groups (EP/PGs) yet, outlining their roles and responsibilities at this stage helps to define your needs. Keep in mind that EP/PG roles may vary at different of the program or may evolve in response to new requirements. Once selected, discuss the roles with your EP/PGs to clarify what they can contribute based on their unique expertise and experience and avoid misunderstandings at the outset, e.g., if they’re expecting to have a partnership role but you’ve designed reactor role (see Types of Patient Roles chart below).
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