Retrospective Chart Review Study in Patients with Osteoporosis

With a rapidly ageing population, the prevalence of osteoporosis in Japan is predicted to increase significantly over the next several years. Whilst some studies have reported the treatment patterns in Japanese patients with osteoporosis, little information is available among patients with osteoporosis at high risk of fracture.

This study was conducted to describe clinical characteristics and current treatment practices for patients with osteoporosis at high risk of fracture in Japan, and provide a comprehensive understanding of current treatment practices to help improve disease management.

In Japan, osteoporosis (OP) patients are typically diagnosed and treated by specialists. Specialists also perform follow-up management of OP patients after treatment initiation.

The study Sponsor had originally envisaged collecting data for all female OP patients that first met the criteria of being at high risk of fracture at the index date, according to the 2011 Japanese guidelines ( Orimo H, Nakamura T, Hosoi T, Iki M, Uenishi K, Endo N, et al. Japanese 2011 guidelines for prevention and treatment of osteoporosis-executive summary. 2012;7(1-2):3-20) and collecting follow up data for 18-24months. However, based on this incident patient population, the Sponsor was unsure whether sufficient patient data would be available within the patient medical notes to reach the required recruitment target and data collection requirements. An alternative solution was to target the prevalent population of allfemale OP patients at high risk of fracture regardless of the time since the patient first became high risk.

An important consideration when conducting non-interventional research is to select a representative sample of real-world sites with geographical and practice setting diversity. Often, as many as 7 times the required number of sites need to be approached and assessed to ensure suitability.

Unlike western countries where it is acceptable practice to approach potential investigators by e-mail or phone, in Asian countries, and in particular Japan, there is a cultural expectation and necessity for much of the initial contact to be conducted face-to-face.

In Japan, site identification and feasibility activities are both time and resource heavy endeavors, that require formal meetings to be held with the prospective Principle Investigator. An introduction through the Sponsor affiliate company, if present in Japan, is often times the best terms under which to schedule and conduct that first study introductory meeting. This helps in establishing a cohesive and trusting relationship between the Investigator, the Sponsor, and the CRA. Depending on the site, the initial meeting might be with the site clinical research department or head of the department prior to approaching the Investigator.

During this visit, and through the CRA, the Sponsor affiliate representative will introduce the study and its objectives to the investigative team. This allows the prospective Investigator to meet and discuss the nature of the proposed research. A translated study synopsis or a copy of a draft study protocol and draft CRF is most commonly shared at this visit.

For this program, ICON’s project team reached out to the local Sponsor Japan affiliate member - their Japan Medical Affairs Director - to consult on the initial site identification, feasibility, and selection activities. A total of 22 sites were shortlisted and approached sequentially until 11 sites were considered suitable and accepted to partake in the research program. No sites were rejected. A total of 22 visits (an average of 2 visits per site) were performed prior to SIV in order to activate 11 sites throughout Japan.

When conducting retrospective chart review studies, careful consideration should be given to the type of data that is to be collected, the phrasing and question construction for that data, alongside allowances for differences between sites standards of practice. In this OP study the expectation of the advisory board members was that FRAX % would be available for close to 100% of patients. Unfortunately, FRAX % was noted to be absent from patients at as many as 10 of the 11 participating sites.

Had the CRF been designed to allow for the capture of the FRAX % or the data entry of the risk factors used to calculate FRAX, the majority of patients would have had this information available from their patient medical files.

There is a need to balance the collection of data specific enough to allow interpretation of the study objectives yet broad enough not to limit its collection.

Following the completion of the study, the Sponsor elected to conduct a simple data collection study to collect FRAX variables for patients and calculate FRAX based on tools author/licensee guidelines.

Osteoporosis - Japanese Population Insights obtained from study:

• More than 700 patients were enrolled, with an average age of over 75 years.
• Almost 90% of patients were prescribed OP medication during the follow-up, with most receiving their medication soon after diagnosis of high risk.
• Almost 15% of patients who were not taking OP medication stated that they were ‘unwilling to take medication’.
• The most common OP medications prescribed were minodronic acid, alendronate, teriparatide and raloxifene.
• A large majority of patients were still on their initial medication 18-24 months after it being prescribed.
• Of patients initially prescribed oral bisphosphonates who switched therapy, the most common medication classes switched to were SERMs, HRT or another oral bisphosphonate.
• Of those switching from teriparatide, the most common classes switched to were RANKL or IV bisphosphonates.
• The most common prescribed supplement/concomitant medication was vitamin D.

Conducting non-interventional research in Japan – Regulatory Landscape

In order to maintain transparency of the processes used in performing clinical trials, Japanese (J)-GCP places great responsibility on the institute and on the institutional head where a trial is performed:

• The contract is always between the Sponsor (or delegated CRO) and the institute and not between the Investigator and the Sponsor
• The head of the institute must consult the Institutional Review Board (IRB) about the planned clinical trial / post-marketing study

The right knowledge and expertise

Conducting non-interventional research throughout Asia Pacific can be daunting and complex - even more so when conducting research in Japan. ICON’s experienced regional clinical operations team which includes regionally-based Clinical Operations Director, Project Directors, Project Managers, Clinical Team Leaders, and Clinical Research Associates help alleviate the burdens of doing this alone. With years of experience conducing Real World Evidence studies in Japan and across Asia Pacific, ICON’s team of dedicated Late Phase researchers is well suited help you conduct your studies in confidence.

Cultural Sensitivities

ICON recommends a hybrid approach to monitoring in Asia Pacific, in light of the varied cultural expectations and site management needs of investigative sites partaking in clinical research. In Japan, regular on-site activities coupled with well-timed centralised/remote communications, which are clearly established within the Clinical Monitoring Plan, are essential components to a successful study.