1. School of Healthcare
"Reading it makes my brain just want to shut down“ Improving the readability of clinical trial participant information sheets.   Peter Knapp (With thanks to Theo Raynor, Jon Silcock & Brian Parkinson)

2. Consent to trial participation - context
Push to include more NHS patients in trials
How can trials recruit more participants?
(Jenkins et al, 2010: 83% cancer patients would participate)
Is valid consent compromised?
The issues for trials apply to research generally
…and to notions of shared decision making about treatments

3. Consent to trial participation - health literacy
Information sheets being good or bad is a matter of provision
….ie imparting knowledge (functional HL)
However, NRES reasoning suggests something more…
Information should enable potential participants to ask…to question…to make an informed decision (interactive or critical HL)
Do potential participants and recruiters have a shared view?

4. Concern over consent 40% did not know they could withdraw
(Lynoe et al 1991)
20% did not know the name of the trial drug
(Griffin et al 2006)
33% did not know the trial was primarily for research
(Lavori et al 2007)
Important information not given; some aspects interpreted incorrectly by patients
(Jenkins et al 2011) 4

5. Are Patient Information Sheets too difficult?
Understanding particularly poor in older people and fewer years of education (Sugarman et al 1998)
Written at the “college graduate level“ (Paasche-Orlow et al 2003)
Most require a level of literacy that is too high (Burman et al 2003)
Risks and benefits not understood well (Cox 2006) 5

6. After the TGN1412 (“elephant man”) trial in 2006…
UK Department of Health Expert Scientific Group, 2006
Clarity of information communication between investigators & trial participants - extremely important and high priority
Report on First in Man Studies - Royal Statistical Society 2007
Good communication of risk essential to conduct of trials
Risk should be expressed numerically
ABPI Guidelines for Phase 1 Clinical Trials, 2007
Give subjects oral and written information that is free of jargon and easy to understand
UK National Research Ethics Service, 2007
Use simple non-technical terms a lay person will understand easily

7. How might we involve patients in improving information?
User Testing in brief:
Select key points
Relevant to safety and effectiveness
Design & pilot a questionnaire which tests:
Finding each piece of information
Understanding (express in own words)
Recruit 10 or 20 people from target
patient group
People who are potential users or participants
Interviewed individually
For medicine leaflets: 80% to find and understand each point

8. Try, Try and Try Again User Testing is iterative and developmental
Draft material
Test material
Identify problems
Remedy problems, applying:
research evidence
good practice in writing & design
Test again

9. User Testing trial PIS: TGN1412
TGN1412 Patient Information Sheet
Phase 1 trial of human monoclonal antibody
Sheet obtained from the web
11 pages
>5,500 words
Difficult language
‘‘pharmacokinetics‘‘, ‘‘immunogenicity‘‘
Poorly presented
Lack of useful headings 9

11. Applying User Testing to the PIS
Research design:
Test original version
Re-write and re-design
Test revised version
Amend as required
Test further revised version
Finding & understanding for each point of information
Proportion of participants having a ‘clear round’

12. User Testing the TGN1412 sheet
Participants recruited:
Men aged 18-40
Range of occupations & education
21 key points selected
nature and purpose of the trial (3)
aspects of consent (6)
trial procedures (7)
safety and efficacy of the medicine (5)
Questionnaire designed
Individual interviews
Q. What phone number should you ring in an emergency?
Q. How is it decided which treatment a participant receives in the trial?
Followed by opinions on the tested sheet

13. TGN1412: Results Difficulty with 6 of the questions:
Presence of a placebo group
Action needed if medically insured
Pre-drug fasting
Informing GP of participation
Number of follow-up clinic visits
Emergency telephone number
Would have failed if a leaflet for a licensed medicine

14. TGN1412 Sheet Revision Design Wording
Presented as an A4 eight page folded booklet
Wording
Added a summary of most important points and brief table of contents to first page
10 section headings
Shortened sentences (where necessary)
Lay language
Removed text repetition
Related information brought together under relevant heading
Use of ‘bullets’ to indicate lists. 14

15. Clinical Trial Patient Information Sheets

17. Revised wording
Each treatment regimen will involve slightly different timelines Each type of treatment lasts a different amount of time First time into human study This is the first time it will be tested in humans

18. TGN1412 PIS testing paper
Improved scores on finding and understanding information;
No impact on reading time.
P Knapp, DK Raynor, J Silcock, B Parkinson.
Journal of Medical Ethics 2009; 35: 18

19. Poor Responders?
The ‘Poor Responders’ Phase 3 trial of In-vitro Fertilisation
For women for whom initial IVF treatment had not been successful
7 pages
Information sheet obtained from the published paper
Study design: test original, then revise, test revised

22. ‘Poor Responders’ Trial: participant comments (1)
Original version
Medical terms:
"The technical terms are a bit hard to understand" (P6);
"It's a bit confusing to work out which drug's having what effect on the body" (P17).
Introducing the study:
"There should be more information about what's involved in taking part in the study at the beginning...it launches into quite scientific explanations" (P13);
"It's quite confusing to begin with all the FSH, GnRH and so on" (P16).

23. ‘Poor Responders’ Trial: participant comments (2)
Original version
Layout:
"The way it is laid out is very intimidating" (P26);
“Reading it makes my brain just want to shut down straight away" (P25).

24. ‘Poor Responders’ Trial: participant comments (3)
Revised version
Appearance:
"It doesn't look like it's a scary thing to read" (P40);
"It looks...like a leaflet you'd want to pick up and read" (P37).
Organisation & wording:
"If you look on the front and you need to find out where stuff is you go through each section and I think the headings just sum up what's in it" (P33);
"(There are) no huge big medical words there, they were explained in laymen's terms" (P28);
"(It) seemed to flow...” (P38).

25. ‘Poor Responders’ Trial: participant comments (4)
Revised version
Appearance:
"It makes you feel like it's not just come from a printer, it's been produced with a lot of thought and care" (P24);
"Possibly it seems like there is less information in (revised version) but I think actually it gives you more. Because of the way it's laid out you pick up more" (P22);
"If I was paying for my own treatment I may prefer (the original version) because I may think that all my money is going to produce glossy pamphlets like (revised version), but in terms of being easier to work your way through (revised version) is better" (P31).

26. Phase 3 trials testing papers
‘Poor Responders’ Trial:
P Knapp, DK Raynor, J Silcock, B Parkinson.
Trials 2009; 10: 79.
SHARP (cholesterol reduction intervention) trial:
British Pharmaceutical Conference, (Abstracted into Int J Pharmacy Practice) 26

27. 3 trial sheet studies… Promising results, but:
Small numbers of participants
Relatively weak study design (can we sure the ‘original’ and ‘revised’ participants are similar?)

28. RCT of original vs revised versions of a PIS: AML16
Research design:
Test original version
Re-write and re-design
Test revised version
Then run parallel groups RCT of original vs. revised versions
Powered to find a doubling of the proportion of participants having a ‘clear round’ (finding and understanding all points of information)
n=116
Stratified by age; education; previous experience of testing; regular use of documents
Participants sent sheets at least a day before testing

29. RCT of original vs revised versions of a PIS: AML16
AML16 trial: series of Acute Myeloid Leukaemia trials
MRC-funded
AML16 focussed on older people
Participants:
123 randomised; 116 tested (55 original; 61 revised)
Male 43; female 73
Aged (mean 64.9)
29 (23.6%) educated to graduate level
36 (29.3%) used written documents in their work
83 (71.5%) had attended readability testing before

30. RCT of original vs revised versions of a PIS: AML16
‘Clear round’ (finding & understanding all points):
Original 8 / 55
Revised 40 / 61
Chi2= 31.5; p<.001; Odds ratio = 11.2
Reading time (minutes):
Original (sd 11.4)
Revised (sd 12.9)
F = 0.30; p=.86
Participant preference:
Original 15 / 116
Revised 101 / 116
Sign test p<.001

31. Testing clinical trial information sheets – where next?
Consent can be improved with brevity and clarity (Jefford & Moore 2008)
But systematic review: amending information does not increase recruitment (Caldwell et al 2010)
Does one offset the other?

32. Testing clinical trial information sheets – where next?
What are the effects within an actual trial?
(working with U of York CASPER trial)
What impact is seen on participant recruitment and retention?
How should we assess the impact on consent, understanding, recall, etc? (ie what patient outcomes matter most?)
Can HL help to inform this work?