An individualized digital twin of a patient for transdermal fentanyl therapy for chronic pain management.

Fentanyl transdermal therapy is a suitable treatment for moderate-to-severe cancer-related pain. The inter-individual variability of the patients leads to different therapy responses. This study aims to determine the effect of physiological features on the achieved pain relief. Therefore, a set of virtual patients was developed by using Markov chain Monte Carlo (MCMC) based on actual patient data. The members of this virtual population differ by age, weight, gender, and height. Tailored digital twins were developed using these correlated, individualized parameters to propose a personalized therapy for each patient. It was shown that patients of different ages, weights, and gender have significantly different fentanyl blood uptake, plasma fentanyl concentration, pain relief, and ventilation rate. In the digital twins, we included the virtual patients' response to the treatment, namely, pain relief. Therefore, the digital twin was able to adjust the therapy in silico to have more efficient pain relief. By implementing digital-twin-assisted therapy, the average pain intensity decreased by 16% compared to conventional therapy. The median time without pain increased by 23 h over 72 h. Therefore, the digital twin can be successfully used in individual control of transdermal therapy to reach higher pain relief and maintain steady pain relief. (Created with BioRender.com)

Sponsorship in non-commercial clinical trials: definitions, challenges and the role of Good Clinical Practices guidelines.

BACKGROUND: Non-commercial clinical research plays an increasingly essential role for global health. Multiple partners join in international consortia that operate under the limited timeframe of a specific funding period. One organisation (the sponsor) designs and carries out the trial in collaboration with research partners, and is ultimately responsible for the trial's scientific, ethical, regulatory and legal aspects, while another organization, generally in the North (the funder), provides the external funding and sets funding conditions. Even if external funding mechanisms are key for most non-commercial research, the dependence on an external funder's policies may heavily influence the choices of a sponsor. In addition, the competition for accessing the available external funds is great, and non-commercial sponsors may not be in a position to discuss or refuse standard conditions set by a funder. To see whether the current definitions adequately address the intricacies of sponsorship in externally-funded trials, we looked at how a "sponsor" of clinical trials is defined in selected international guidelines, with particular focus on international Good Clinical Practices codes, and in selected European and African regulations/legislations. DISCUSSION: Our limited analysis suggests that the sponsors definition from the 1995 WHO Good Clinical Practices code has been integrated as such into many legislations, guidelines and regulations, and that it is not adequate to cover today's reality of funding arrangements in global health, where the legal responsibility and the funding source are de facto split. In agreement with other groups, we suggest that the international Good Clinical Practices codes should be updated to reflect the reality of non-commercial clinical research. In particular, they should explicitly include the distinction between commercial and non-commercial sponsors, and provide guidance to non-commercial sponsors for negotiating with external funding agencies and other research counterparts. Non-commercial sponsors of clinical trials should surely invest in the development of adequate legal, administrative and management skills. By acknowledging their role and specificities, and by providing them with adapted guidance, the international Good Clinical Practices codes would provide valuable guidance and support to non-commercial clinical research, whose relevance for global health is increasingly evident

Payers perspective

Payers are facing challenging times. Not only the economic crisis but also the aging population, suffering from various chronic diseases, and the high prices of new drugs increase the pressure on drug reimbursement systems. Moreover and especially in the oncology area, launch volumes are expected to increase when considering the current pipeline1. With the sustainability of health care systems at stake, most parties involved realize that a change of mentality, not only in drug development plans, but also in the pricing and reimbursement policies imposes. From a payers perspective, some suggestions can be made. At the registration level, adding values such as clinical relevance to the classical registration parameters could be considered, as relatively little attention seems to have been paid to the availability of (good) alternative treatment options until recently2. In order to better define the best Standard of Care, academic head-to-head trials comparing available treatments, objective registers or trials challenging the optimal dose or duration of treatment offer an important added value to the registration trials, and should therefore be promoted. In the set-up of such trials, participation of the reimbursement systems, defining the current gaps and the research questions, is absolutely necessary. Reimbursement systems need guidelines, which should be – at least partly – based on the results of these academic studies. The scope of those guidelines can be international especially in the field of the mentioned scientific assessments, but since reimbursement decisions are taken on the national level, national guidelines adapted to the local situation can be helpful. Organizations editing these guidelines should be as independent as possible and free of Conflict of Interest. Payers need more than statistical significant endpoints. In order to maintain equity, an important basis of our current health care system, they will need extra information such as the clinical and societal relevance of these endpoints, the actual real medical need, the price society is willing or able to pay for parameters such as a life year gained or, in the expanding area of oncology, a month of progression free. 1. Berggen R. et al. Outlook for the next 5 years in drug innovation. Drug Discov. 11, 435-436 (2012) 2. Putzeist M., et al. Factors influencing non-approval of new drugs in Europe. Nature Rev. Drug Discov. 11, 903-904 (2012)status: publishe

Implementing physics-based digital patient twins to tailor the switch of oral morphine to transdermal fentanyl patches based on patient physiology.

Fentanyl transdermal patches are widely implemented for cancer-induced pain treatment due to the high potency of fentanyl and gradual drug release. However, transdermal fentanyl up-titration for opioid-naïve patients is difficult, which is why opioid treatment is often started with oral/iv morphine. Based on the daily dose of morphine, the initial dose of the fentanyl patch is decided upon. After reaching a stable level of pain, the switch is made from oral/iv morphine to transdermal fentanyl. There are standard calculation tools for transferring from oral/iv morphine to transdermal fentanyl, which is the same for all patients. By considering the variations in the physiology of the patients, a unique switching strategy cannot meet the needs of different patients. This study explores the outcome in terms of pain relief and minute ventilation during opioid therapy. For this, we used physics-based simulations on a virtually-generated population of patients, and we applied the same therapy to all patients. We could show that patients' physiology, such as gender, age, and weight, greatly impact the outcome of the therapy; as such, the correlation coefficient between pain intensity and age is 0.89, and the correlation coefficient between patient's weight and maximum plasma concentration of morphine and fentanyl is -0.98 and -0.97. Additionally, a different combination of the duration of overlap between morphine and fentanyl therapy with different doses of fentanyl was considered for the virtual patients to find the best opioid-switching strategy for each patient. We explored the impact of combining physiological features to determine the best-suited strategy for virtual patients. Our findings suggest that tailoring morphine and fentanyl therapy only based on a limited number of features is insufficient, and increasing the number of impactful physiological features positively influences the outcome of the therapy

Challenges and threats of investigator-initiated multicenter randomized controlled trials: the BACE trial experience

status: publishe

Sponsorship in non-commercial clinical trials: definitions, challenges and the role of Good Clinical Practices guidelines

Non-commercial clinical research plays an increasingly essential role for global health. Multiple partners join in international consortia that operate under the limited timeframe of a specific funding period. One organisation (the sponsor) designs and carries out the trial in collaboration with research partners, and is ultimately responsible for the trial's scientific, ethical, regulatory and legal aspects, while another organization, generally in the North (the funder), provides the external funding and sets funding conditions. Even if external funding mechanisms are key for most non-commercial research, the dependence on an external funder's policies may heavily influence the choices of a sponsor. In addition, the competition for accessing the available external funds is great, and non-commercial sponsors may not be in a position to discuss or refuse standard conditions set by a funder. To see whether the current definitions adequately address the intricacies of sponsorship in externally-funded trials, we looked at how a "sponsor" of clinical trials is defined in selected international guidelines, with particular focus on international Good Clinical Practices codes, and in selected European and African regulations/legislations.status: publishe