Twittering from the ICR conference next week

Next week will see the Institute of Clinical Research 30th Anniversary Conference & Exhibition, taking place on March 17th & 18th at the ICC in Birmingham. Of course, I will be there to:

• Cover the meeting for CRfocus (along with a team of roving reporters!)
• Help with the organisation and operation of the meeting (ICR is the parent organisation of CRfocus)
• Chairing a session on the tension between pricing and patient value, and how you can accurately assess either

I also plan to Twitter live from the conference (I’ll be too busy to live-blog like I normally do from such meetings). You can see my most recent “tweets” on the main CRfocus webpage, or follow me on Twitter itself. I’m also hoping to have time to do some other neat things, such as one or two audio interviews with delegates or speakers, and post some photos live from the meeting…

This is going to be a great conference, and I’m looking forward to it immensely. If you haven’t registered yet, take a look at the conference programme, and come along (we have passes available from a half day up to the entire meeting).

I’d love to see you there…

ICR/EMWA conference on writing clinical trial protocols: Audio wrap-up

Following on from the ICR/EMWA joint symposium that took place earlier this week (and was partially reported on this blog), I have interviews with Wendy Kingdom and Adam Jacobs, who chaired the morning and afternoon sessions respectively.

These will be posted on the CRfocus website (www.crfocus.org) but as I’m currently having technical difficulties there, I’ll post them here as well…

Update: These files are now available from the main CRfocus website, and have been removed from the temporary host:

Interview: Wendy Kingdom on ICR/EMWA joint symposium on Writing Clinical Trial Protocols

Interview: Adam Jacobs on ICR/EMWA joint symposium on Writing Clinical Trial Protocols

Panel discussion on development of clinical trial protocols

Following on from the last presentation of the morning session, the speakers came back to discuss the morning’s topics.

Initial discussion concerned lists and flowcharts to summarise what needs to be done and what data needs to be collected at which visit. Sue Mackay agreed that this would be useful, but some sponsors prefer to avoid duplication wherever possible. This is precisely the kind of thing that the CDISC standard discussed earlier would resolve.

A delegate followed up by asking what sort of aid site staff use to schedule visits and activities. This varies according to the type of study (eg, patient types, working hours etc.) but Sue Mackay said she tries to create a schedule as far as possible. Adam Jacobs said that including this in the protocol would be beneficial. Another delegate said that this could cause confusion over which document is the source document for GCP purposes. In many cases, patient notes are used; eCRFs are being increasingly used, although these can be restrictive if patients report additional information.

Another delegate raised the issue of global trials, where practical issues differ between regions. Sandra Waechter mentioned that some units make local protocol amendments to accomodate local differences in care.

Adam Jacobs discussed the pros and cons of detailed protocols vs broad protocols with more detailed appendices. One delegate questioned whether we could ever reach a ‘perfect’ protocol when it needed to meet the requirements of such a diverse set of stakeholders. Adam stressed the importance of having time to do the job properly: the situations in which his team have had problems have been when time pressure (eg, to meet an ethics deadline etc.) has been extreme. Although as little as 3 days is required to do the actual writing of the protocol, he agreed with the earlier speaker that 3 months would be an appropriate period to allow for the discussion, reviewing and negotiation processes.

Adaptive designs

Peter Thomas of Novartis spoke in the theme on adaptive study designs about the involvement of sponsor senior management with Data Monitoring Committees (DMC). He started by saying that this involvement is widely discouraged, eg in the EMEA discussion paper. However, sponsors often feel uncomfortable with the notion of not having access to interim confirmatory data during the study, and also if the data evolves in a way not predicted as a possibility in the pre-trial modelling. He cited an ongoing Novartis study in which phase IIb and phase III are combined, with certain dose and comparator arms being continued into the later phase while others are dropped. To do this, the DMC require a number of rules to be defined to guide them in determining which doses to drop. This is done by defining a threshold for efficacy, with the lowest dose producing this effect is retained. Of course, safety issues would be weighted against this. Peter set out a number of scenarios that were considered, from the ideal to the less than ideal (eg, none of the doses meet the threshold) and the unexpected, which cannot be parsed according to the preset rules. One might expect that the DMC would want to consult with the sponsor in the latter case. Peter then set out the standard composition and process of a DMC. He proposed that sponsor involvement could be permited if a clear rationale existed, based on the complex unexpected situation, and given that the individuals involved would be suitably distanced from the study (eg, senior clinician and statistician) and only be involved at the point where their decision was required. In some cases, Peter stated, sponsor involvement might be required. The sponsor must make a strong case that appropriate procedures are in place and follows, and these will need to demonstrate that the integrity of the study is intact, and paramount. The final presentation in this session was given by Jerry Schindler of Merck. He gave a simple and easy strategy for implementing adaptive trial design. He summarised this concept as designing a study using information that wasn’t available when you started designing it! His role is maximising benefit (eg, earlier decision-making or reduced sample size) while minimising risk (eg, not being able to do the trial). Having written off an entirely hybrid phase I-III approach, he looked at the different information points discovered in the different phases, to explore the potential to group them. He thought that the division should come just before the pivotal phase II study, to combine phase I with phase IIa, and late phase IIb with phase III. As a product moves from early development to pre-registration development, the number and variety of adaptive options are constrainted. These constraints reflect the fact that you’ve learned something from the earlier studies. Once you’ve constrained these options, the process becomes simpler. In pre-pivotal studies, he argued that statisticians could be able to see unmasked data as it comes in, enabling a flexible decision process to consider many options that could allow options to be eliminated or even new ones to be added. Conversely, in the pivotal phase, masking and use of an independent DMC are often necessary. Decisions should be driven by algorithms (contrary to the view of the previous speaker) with limited and decreasing options and futility analysis of individual dose arms during the study. Jerry closed his presentation by summarising his 8 key points.

Patient recruitment

Ingrid Klingmann introduced the Tuesday afternoon session on more efficient approaches to patient recruitment infomation. She traced the history of investigator’s estimates and feasibility studies. She stated that, even with the best intentions, investigators frequently over-estimate patients’ interest in participating in a study. Ingrid challenged us to put ourselves into an investigator’s shoes, with drivers from meeting patients’ needs to running a smooth clinic or medical department. Involvement in a commercial clinical trial is often a low priority. Sites often feel overloaded with feasibility enquiries: when Ingrid worked as an investigator, she received a new study enquiry every couple of week, and the time to complete them detracts from existing work and patient time. She also gave examples of some impossible questions that are often asked, from patient numbers across multiple clinicians to attitudes of patients to clinical research. Many hospitals still have paper-based systems, with little retrospective information. The impact of exclusion criteria requires a medically-trained person to analyse patient data, limiting the time an invesigator can contribute. As this is already a low priority, Ingrid suggested that more companies pay for completing the feasibility study. Her overall recommendation was for a paradigm shift in feasibility studies. She suggested that companies should collect as much information as possible themselves, from disease prevalence to hospital infrastructure and availability of staff. Do not ask investigators to “guess” at enrollment figures, but collaborate with them to collect the information and establish the most suitable protocol (eg, to weed out inclusion/exclusion criteria that would hinder recruitment but actually have little impact on the scientific validity). Finally, enable the investigators to enrol by investing in their infrastructure and capacities by paying for all study-related activities, from feasibility onwards and offering other technologies and resources as appropriate.. Another key point was, once you have found an investigator who is keen and meets practical criteria, ask them to recommend other sites who they think can perform this study to a similar standard: within the same therapeutic area, they should have a good idea of who to target (or avoid).

Lunchtime wrap-up

The DIA EuroMeeting is big… really big… I mean, you might think it’s a long way down the street to go to the chemist, but that’s peanuts to the DIA EuroMeeting. (With apologies to Douglas Adams!)

The conference is huge, with over 3000 delegates and over 110 sessions in 11 parallel streams. This is both a blessing and a curse: you can be relatively confident that your “pet topic” will be covered at some point in the meeting, but you can also be relatively confident that there will be times when you want to be in two or even three places at once! We’re only at lunchtime on the first full day (yesterday was a write-off for me due to my travel schedule, so I missed the keynote plenary session and was too travel-weary for the opening evening reception) and that’s happened to me already. Twice.

So, if you’re speaking here and I haven’t come up and complimented you, or if you’re exhibiting and I haven’t discussed the latest updates from your company, please don’t take it personally: I could have a team of journalists here and still not get everything done that I want to achieve here! (This is why, of course, I DO have a team of reporters covering the sessions at the ICR conference next month.) There will doubtless be many post-conference emails to people I know are here, but I wasn’t able to catch up with…

So, I’m off for a brief lunch before heading to the fray once more…

Health economics

Jens Grueger of Novartis spoke on handling uncertainty in cost-effectiveness analysis and the possibility of risk-sharing in reimbursement decisions. He is concerned with “material uncertainty” that could could switch the decision on whether or not to reimburse. Three of the main causes of this is the extrapolation of RCT results to a broader patient population and to longer timescales, and consideration of efficacy vs effectiveness. These sources of uncertainty are highlighted when approval is accelerated due to, eg, societal pressure for conditional approval. He stated that decisions have to be made and waiting for final outcomes is not an option, but that uncertainty will exist over false positives (ie, wasted money) and false negatives (ie, patients have forgone benefits that would eventually have been proven). Uncertainty is increased under conditional approval or exceptional circumstances (eg, via the Orphan medicines route). He suggested that one solution might be possible using conditional reimbursement in cases of conditional approval, with periodic reassessment of price based on continuing collection of evidence. Using this model, pricing could increase or decrease based on the evidence, and the “evidence corridor” for acceptance of the price point could itself be updated. Ultimately, when evidence has been collected to justify a final approval, financial information would also exist to set the final pricing. This approach could also be applied retrospectively to longer-term outcomes with other medicines. However, will this continuing collection of evidence actually reduce the uncertainty, or does the issue then become what happens if the therapy is withdrawn? The problems of disinvestment go far beyond this. Similarly, will granting conditional reimbursement prevent the use of an optimal study design? Jens proposed another solution for use in exceptional circumstances (eg, orphan medicines) where sufficient pricing data cannot be generated and a formal HTA assessment is not possible. In these cases, a price notification procedure could be used, considering price information about (reimbursed) analogues. As the condition is rare, this will have a low budget impact. Risk-sharing agreements are also becoming prevalent, mostly in the form of moeny-back guarantees where payment is only made for responders. One example of this is Velcade in the UK. This is particularly useful where there is uncertainty over whether a given patient will respond. However, the “next frontier” is performance based reimbursement, where the pricing is non-linear and value-based. For example therapies given as third-line might be reimbursed at a higher price than the same therapy used as first-line. Thus, the reimbursement depends on the specific patient population (eg, for different indications) or based on other risk factors (eg, age, treatment history etc.) This obviously creates significant data requirements, but may be possible in the context of registries. This would return the prescribing decision to being based solely on expected clinical impact.

Advanced therapies

Unfortunately, my first draft report on the advanced therapies session was foiled by technology! In the session that I atended, representatives of large and small companies developing cell and gene therapy products gave their perspectives on the EU Advanced Therapies Regulation published at the end of 2007. Each raised issues that they hoped the accompanying guidelines would address, and called for greater harmonisation between EU member states, and between the EMEA and the FDA, under its ongoing process of dialogue. One speaker was concerned that the scientific advice process was too slow, too expensive and insufficiently accessible for small companies working in early development. Another delegate asked how the experts on the Committee on Advanced Therapies (CAT) would be selected. Nicholas Rossignol of the European Commission said that he shared this hope for increased dialogue, and mentioned that, although the guidelines would be issued for public consultation later in the year, there were limits to which aspects could be centralised, as trial approval processes etc were governed by the Clinical Trials Directive, which, as a directive, is subject to interpretation and implementation in each member state. Changes to the Directive are not planned for the 2008 work programme, and with European elections and a new Commission in 2009, he did not expect much to change next year either.

Guidelines in Review

Birka Lehmann of BfArM chaired a session on guidelines in review. She opened the session with discussion of the Paediatrics regulation. The paediatric committee (PDCO) has set up 7 subcommittees to produce consider guidelines for specific disease areas. They have already decided not to produce entirely new guidelines where they already exist in adults, but will adapt these guidelines where possible, looking for situations where findings from adult research can be used to inform paediatric research. This is particularly concerned with the selection of an appropriate endpoint. She then introduced Dr Kevin Blake of the Irish Medicines Board and a member of the CHMP-Efficacy Working Party, to give an update on the guideline on obesity and weight control. These guidelines were adopted late in 2007 and will come into effect in May 2008. He looked at some of the contentious issues during their development, and gave some suggestions on how they should be interpreted. The CHMP-EWP advises the CHMP under EMEA/P/24143/2004 and produces guidelines which, although not binding, are highly recommended. The new obesity guideline is CPMP/EWP/281/96 revision 1. He talked us through the timeline of its development, from April 2006 through to its adoption in November 2007. The group defined obesity in adults as a chronic clinical condition that needs long-term therapy, based on the WHO definitions. Dr Blake mentioned that comments were made on racial differences in definition of obesity, which were indeed included. The guideline acknowledged non-pharmacological options under certain conditions, but primarily discussed the pharmacological options, to be used alongside a calorie-controlled diet. Comments related to pulmonary artery hypertension risk with centrally acting anorectic agents. As weight loss can be controlled by behaviour modification alone, the dropout rate in pharmacological studies is high. As a result, they recommend a placebo group to be compared on dropout rate as well as efficacy. However, he suggested that dropouts should be followed up, to base the analysis on the full ITT population, asking participants to at least notify triallists of their weight after 1 year. Participants who withdraw their consent can make this difficult, so great care must be taken when obtaining initial consent. In terms of primary endpoint, they defined it as at least 10% of baseline weight from the start of the run-in period, and at least 5% greater than associated with placebo (with appropriate loss of body fat demonstrated). Comments to this questioned whether 5% weight loss might be appropriate in specific conditions (eg, comorbid diabetes); this was accepted, provided this subgroup of patients is pre-identified. Another query asked whether a change in concomitant medication might be acceptable as a secondary endpoint, but this was rejected. Moving to patient selection, the guidelines require a BMI >30 in otherwise healthy adults. Kevin had already mentioned a degree of controversy over run-in periods. Comments had questioned whether this was necessary, but he stated that it was crucial to establish a behavioural pattern and confirm motivation. This alone would skew the baseline, but this is overcome by taking the baseline from the start of the period. In the development of the addendum under development on paediatric obesity. This does not use the adult definition, nor the classical US definition, which are based on arbitrary cut-offs. Instead, it uses a statistical model based on pooled international data to link accepted adult cut-offs back to younger ages. Treatment goals are composite, encompassing age, stage of growth degree of overweight and presence of associated comorbidities. Halting or decreasing the rate of weight gain could be primary endpoints, while weight loss could be a primary endpoint for subjected with related complications. On selecting a trial population, children over 6 should be selected (split into pre- and post-puberty), with a run-in period of 3-6 months and only children not achieving adequate weight loss in this period being entered into the active study.

Going to DIA

4.15am is a particularly uncivilized time to get up for any reason, but by 5am I was on my way to the airport to report from the DIA EuroMeeting in Barcelona. Check back over the next 3 days for highlights from the conference.