spacer
home > ict > autumn 2011 > methods for motivation
PUBLICATIONS
International Clinical Trials

Methods for Motivation

Clinical trials performed in central and eastern Europe are on the increase. Christian Reh at PRA analyses the centralised hospital structure adopted by the region and discusses the advantages of this method

Clinical research in central and eastern European (CEE) countries has become increasingly attractive over the last two decades, especially following the expansion of the European Union and the associated obligation to follow the European Clinical Trial Directive (1). The centralised health care system in these countries, as well as the less developed private sector, allows rapid recruitment once the study has been approved. Differences in standard of care (SoC) or significant differences in the diagnostic and therapeutic procedures might help in patient recruitment as well. On the other hand, long approval periods can prove a major disadvantage. Most of the European member states located in CEE have adopted a 60-day review period by the competent authorities – the maximum period allowed for NCEs. In most of the countries this timeline is met. However, in countries such as Romania these timelines are still seen as ambitious. The vast majority of these studies are larger Phase 2 and 3 trials for which these countries are well positioned. Excellent access to patients counterbalances long approval periods.

For most of the first-into-man trials, CEE countries are not well positioned. Firstly, healthy volunteers in general are available in western Europe to the same extent. The longer approval periods of 60 days do not compare well with countries that are more traditionally used for Phase 1 trials such as Netherlands (where it is as low as 14 days) or Germany (30 days, or even 14 days in case subsequent trials with the same drug and formulation).

Due to this regulatory limitation, the competent authorities and ethics committees are less experienced in assessing the limited information available, and there is an increased risk that they will come back with questions and comments, which are not typically requested in western European countries. Rigid meeting schedules, especially at ethics committees, do not allow for a flexible study performance with need of frequent protocol amendments and design adaptations.

PATIENT POPULATIONS

There is, however, an increasing interest in performing studies up to proof-of-concept in this region, refl ecting a trend in drug development to go into patients early. Often first-into-man trials are performed in patient rather then healthy volunteers. Although this approach is used to cut corners on the development path and get to proofof- concept earlier, there might be good reasons to do so. Classical examples include studies with cytostatic or cytotoxic properties, which cannot be administered in healthy volunteers or biologicals without a certain risk of developing neutralising antibodies, which as a consequent would prohibit potential treatment later on in this particular patient.

Other attractive patient populations are those where a small sample size is needed to proof the concept with limited information available from healthy volunteers. Multi-purpose protocols in western European countries have been submitted successfully for performance of the single ascending dose trials and multiple ascending dose trials in healthy volunteers, and under the same protocol these have been submitted in CEE countries for the respective patient groups. This made it possible to establish approval of the study by the competent authorities and the ethics committees on the study procedures and on the pharmaceutical compound, whereas minor protocol adaptations based on the findings in healthy volunteers were addressed in an amendment with a reduced approval period. This approach requires significant interaction between CRO or sponsor, and the competent authorities and ethics committees, as both of these external parties should support this approach. Open and honest communication upfront, as well as of clinical findings throughout the development process, is essential.

PATIENT RECRUITMENT

Motivated investigators and study teams that are convinced about the usefulness of a particular trial are key. Their motivation not only supports a high level of quality in the trial, but encourages patients to participate in the trial. Investigators and their teams in CEE are enthused by having access to new technology, medication and information on the latest developments, as well as any fi nancial benefi t. In Phase 2 and 3 trials, patient motivation is often driven by their potential access to drugs, which either have a better efficacy or safety or tolerability profile compared to drugs already on the market.

In Phase 1/2a trials it is difficult to offer therapeutic benefits, so the motivation for trial participation will have to come from other incentives. Often, patients are motivated by developing drugs for a better future, because of access to better diagnostic procedures or treatments or just to get higher attention by their treating physicians. Without therapeutic benefit, these motivating factors are usually influencing the decision to participate in a trial, but often they are too weak to influence subsequent retention. Based on our experience with patients in Phase 1/2a trial, subject retention can only be achieved if the patient’s motivation is renewed continuously.

CHOOSING THE RIGHT METHOD

Phase 1/2a trials in healthy volunteers with pharmacokinetic or pharmacodynamic endpoints are often performed in Phase I units with highly standardised conditions, special infrastructure and experience established over years. Preferably early studies in patients should be performed in similar sites. However, traditional recruitment methods have consistently failed to get a sufficient number of patients into exploratory trials. Unlike healthy volunteers, most patients have no interest to spend time in a clinic that is unable to treat them and receive drugs that are unlikely to work.

On the other hand there are large, centralised hospital-based polyclinics focusing on specific diseases with dedicated and well trained clinical investigators and access to a significant number of suitable patients. However, these hospitals cannot provide a fully controlled Phase 1 environment. The pharmaceutical and biotech industries, as well as CROs, have invested a significant amount of time and effort to train clinicians in GCP and in monitoring and auditing these sites, but there is still a significant gap between performing such trials in a dedicated Phase 1 unit compared to a hospital setting. Support can be provided in many different ways.

BEST OF BOTH WORLDS

One business model used in the CRO industry combines these two options, in which a small Phase 2-like environment is set up within participating hospitals containing patient bedrooms, all equipment and study procedures, and a room for monitoring, storage and data entry (‘unit on demand’). During the study, investigators are supported by trained research nurses and research physicians who are experienced in performing Phase 1/2a trials. Responsibilities are split neatly insofar as both the investigator and CRO can focus on their core competences: the investigator concentrates on patient recruitment, screening, diagnosis and treatment of patients; the CRO provides the logistical knowhow to organise and perform a Phase 1 trial. On behalf of the investigator, the CRO performs the regulatory and ethics submissions, all clinical activities under his medical supervision, and documents the entire study as required by GCP. In doing so, the patients can remain in an environment that they are used to, and the treating physician or investigator can focus on the patient without the burden of timed assessments and administration.

Patient recruitment is further supported due to the CRO being ever present at the site, acting as a continuous reminder for the investigator about the need for patients. Being present also enables the CRO to help the investigator with their recruitment and screening activities, and as part of the study team they can efficiently pre-screen patients at the site.

A recent case study compared the power of this innovative business model with a conventional Phase 3 setting. Fifteen US-based clinical sites were recruited for a multicentre first-into-man trial with a new monoclonal antibody in patients with rheumatoid arthritis. In addition to these 15 sites, three Hungarian sites were identified using the ‘unit on demand’ model. Thirty-five patients were to be recruited for the multiple ascending dose part of the trial. At the end of the trial, six of the US-based sites had not recruited a single patient. The remaining nine sites recruited with a recruitment rate of 0.3 patients per site per month, as initially expected, whereas the three Hungarian sites recruited with a rate of 1.7 patients per site per month (see Figure 1). At the same time, the recruitment of the patients was performed in a much more efficient way, as 64 per cent of patients were screening failures in the US, whereas only 20 per cent of patients were screening failures in the ‘unit on demand’ model (see Figure 2).

CONCLUSION

CEE countries are proving to be an interesting market even in early Phase trials, especially when it comes to patients being the study population. With increasing experience of competent authorities and ethics committees, this geographic area will play a significant role in successful drug development strategies.

Reference

  1. Clinical Trials in Poland – Key Challenges, PriceWaterhouseCoopers, November 2010

Read full article from PDF >>

Rate this article You must be a member of the site to make a vote.  
Average rating:
0
     

There are no comments in regards to this article.

spacer
Christian Reh leads PRA’s Early Development Services operations in central and eastern Europe, focusing on Phase 1/2a trials in a variety of different patient populations. He is responsible for all operational and scientific development activities, and for ensuring GCP compliance in the CEE operations. Christian has more than 20 years of experience in the pharmaceutical and CRO industry. During this time, he has held several positions at major clinical pharmacology units in Europe. He performed approximately 500 early phase trials and brought about 45 drugs fi rst into human and about 20 drugs fi rst into patient. Email: rehchristian@praintl.com
spacer
Christian Reh
spacer
spacer
Print this page
Send to a friend
Privacy statement
News and Press Releases

Softbox successfully supports Pfizer in the global cold chain distribution of Covid-19 vaccines

Long Crendon, Buckinghamshire, UK, 10 March 2021 – Softbox, a leading global innovator and provider of passive temperature control packaging solutions for the pharmaceutical, life science and cold chain logistics industries, is proud to support Pfizer in the distribution of Covid-19 vaccines through the supply of a high-performance temperature-controlled parcel shipper developed specifically for ultra-low temperature applications.
More info >>

White Papers

Successfully managing the unique demands of cell therapy supply chains

PCI Pharma Services

Cell therapy professionals joined a specialist webinar by industry experts from PCI Clinical Services and TrakCel, addressing the unique complexity of an autologous therapy supply chain. Hosted by European Pharmaceutical Manufacturer magazine, the webinar was delivered by Rachel Griffiths, Associate Director, Technical Services, PCI Clinincal Services, and Dr. Matthew Lakelin, Vice President, Scientific Affairs and Business Development, TrakCel . Here, we present the white paper from that webinar event.
More info >>

 

 

 

©2000-2011 Samedan Ltd.
Add to favourites

Print this page

Send to a friend
Privacy statement