Regulatory Issues of Platform Trials: Learnings from EU-PEARL.

Although platform trials have many benefits, the complexity of these designs may result not only in increased methodological but also regulatory and ethical challenges. These aspects were addressed as part of the IMI project EU Patient-Centric Clinical Trial Platforms (EU-PEARL). We reviewed the available guidelines on platform trials in the European Union and the United States. This is supported and complemented by feedback received from regulatory interactions with the European Medicines Agency and the US Food and Drug Administration. Throughout the project we collected the needs of all relevant stakeholders including ethics committees, regulators, and health technology assessment bodies through active dialog and dedicated stakeholder workshops. Furthermore, we focused on methodological aspects and where applicable identified the corresponding guidance. Learnings from the guideline review, regulatory interactions, and workshops are provided. Based on these, a master protocol template was developed. Issues that still need harmonization or clarification in guidelines or where further methodological research is needed are also presented. These include questions around clinical trial submissions in Europe, the need for multiplicity control across the whole master protocol, the use of non-concurrent controls, and the impact of different randomization schemes. Master protocols are an efficient and patient-centered clinical trial design that can expedite drug development. However, they can also introduce additional operational and regulatory complexities. It is important to understand the different requirements of stakeholders upfront and address them in the trial. While relevant guidance is increasing, early dialog with relevant stakeholders can help to further support such designs.

Anatomical Variations of the Pectoralis Muscle and Its Importance for Breast Implant Surgery.

In breast augmentation, during submuscular or dual plane dissection, anatomical variations of the inferior and costal origin of the pectoralis major muscle (PMM) play a key role to ensure optimal implant coverage. Especially, a short and narrow muscle or surgical release along the sternum increases the risk of irregularities and animation deformities of the implant. Methods: In 84 consecutive aesthetic breast augmentations intraoperatively, measurement of PMM dimensions was performed bilaterally. These PMM measurements were then correlated with the preoperative breast width, the inframammary fold, and the placement of the implant's lower pole. Results: One hundred sixty-eight PMMs of 84 patients were dissected with a dual plane II or III technique for primary aesthetic breast augmentation. In 88% of breasts, the calculated implants' lower pole was below the inferiomedial origin of the pectoralis muscle. In 10% of patients, a separation (more than 1 cm wide and 2 cm wide) in the inferior-medial origin of the PMM was noted. An asymmetry more than 0.5 cm in length between the left and right pectoralis major was noted in 36% of patients. Conclusions: In this series, the anatomy of the PMM demonstrates a substantial variability in width and length and a considerable asymmetry in its dimensions. These findings emphasize the importance of good access and visualization of the origin of the PMM fibers before its division.

A systematic review of the early dialogue frameworks used within health technology assessment and their actual adoption from HTA agencies.

Introduction: Early advice in the process of developing health technologies allows manufacturers to plan their production and transfer to health care systems more accurately. This review aims to describe frameworks used within HTA and their current use by HTA Agencies. Material and methods: We carried out a systematic literature review in Pubmed, Embase, Scopus, and WoS, including all references published in Spanish and English. This was last updated in March 2022. We extracted all available information regarding the organizations involved, services offered, types of technology, collaborators involved, fees, output and impact. Websites of several HTA organizations and Google were also searched in order to update and complete the information obtained from this generic search. Results: Five-hundred and forty one articles were identified and screened, of which 26 met the eligibility criteria and were selected. Seven of them were non-systematic reviews that described two or more HTA organizations. Ten studies were focused on the advice offered by individual organizations, and eight described the EMA and EUnetHTA parallel or joint advice. We found variations in the technology assessed, services offered, stage of development and costs for advisory services. Conclusions: Early and scientific advice would help manufacturers focus their product development on what is needed for the management of specific diseases. Most of the examples or services found refer to drugs as well as to some medical devices and diagnostics. A common definition of the type of advice that could be offered for different health technologies by HTA bodies to ascertain health care systems and manufacturers' needs, in addition to the timeline in which that advice needs to be given, would help HTA bodies provide the right support at the right time. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020219401, PROSPERO CRD42020219401.

Conservative mastectomies and Immediate-DElayed AutoLogous (IDEAL) breast reconstruction: the DIEP flap.

BACKGROUND: With the development of conservative mastectomies, there are an increasing number of women seeking immediate implant based and autologous breast reconstruction. Despite the oncologic safety of the procedures, the focus will be on the timing of reconstruction. METHODS: Our plastic surgery unit is focused primarily on autologous breast reconstruction and is part of an interdisciplinary breast center. We offer immediate breast reconstruction (IBR) with autologous tissue for patients with positive BRCA 1 and 2, ductal carcinoma in situ (DCIS), invasive cancer without margin problems to the skin, as well as to correct poor oncologic and aesthetic breast conserving therapy (BCT) outcomes. In the majority of cases we prefer an Immediate-DElayed AutoLogous (IDEAL) breast reconstruction concept with a two-stage procedure. RESULTS: Over the last 10 years we performed more than 1,600 breast reconstructions with free flaps, performing the deep inferior epigastric perforator (DIEP) flap as our first choice for autologous tissue. We recommend IDEAL breast reconstruction, however approximately 15% of our cases are immediate one stage conservative mastectomies and breast reconstruction with the DIEP flap. CONCLUSIONS: For immediate reconstruction, the aesthetic outcome should not take precedence over oncologic considerations. Immediate one-stage, breast reconstruction with autologous tissue can be offered to the suitable patients which is most likely a healthy women with a small-to-medium sized non ptotic breast receiving a conservative mastectomy. In all other cases, we recommend an IDEAL breast reconstruction approach in order to achieve a final result that is both satisfyingly pleasing and oncologically safe.

The influence of social media and easily accessible online information on the aesthetic plastic surgery practice: literature review and our own experience.

INTRODUCTION: Patients interested in aesthetic plastic surgery procedures increasingly seek advice on social media and rely on easily accessible online information. The investigatory goal was to determine the impact of this phenomenon on the everyday aesthetic plastic surgery practice. METHODS AND PATIENTS: Five hundred consecutive patients completed a questionnaire prior to their consultation with a plastic surgeon at our clinic. A questionnaire was also completed by 128 plastic surgeons practising in 19 different countries. A literature review was performed. RESULTS: Almost all patients (95%) used the internet to collect information prior to consultation, for 68% of them it being their first search method. Social media were used by 46% of patients and 40% of these were strongly influenced when choosing a specific doctor. The majority of plastic surgeons (85%) thought the information found on social media could lead to unrealistic expectations. However, 45% of plastic surgeons believed that their consultations became easier after the advent of social media, 29% found them more difficult. A literature review showed a high percentage of poor quality internet websites regarding plastic surgery and an increase in use of social media among plastic surgeons. CONCLUSION: The internet and social media play an important and growing role in plastic surgery. This results in more informed patients but may create unrealistic expectations. Even if the internet provides ample information, it cannot replace the face-to-face consultation, which always should remain a detailed process, covering both risks and limitations of alternative procedures. Available literature on how social media influences the medical practice is still scarce and further research is needed. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Suprathel-antiseptic matrix: in vitro model for local antiseptic treatment?

Acetic acid is a traditional antiseptic agent that has been used for more than 6000 years. The main goal of this study was to demonstrate the suitability of Suprathel (PolyMedics Innovations GmbH, Denkendorf, Germany) in combination with various antiseptic agents to create an "antiseptic-matrix" especially designed for problematic microorganisms such as Proteus vulgaris, Acinetobacter baumannii, or Pseudomonas aeruginosa, which are frequently associated with burns. The study was designed to test the in vitro antimicrobial effect of a "Suprathel-antiseptic matrix" (Suprathel combined with acetic acid 3%, povidone-iodine 11% [Betaisodona], polyhexanide 0.04% [Lavasept], phenoxyethanol 2%/octenidine dihydrochloride 0.1% [Octenisept], mafenide acetate 5%, and chlorhexidine gluconate 1.5%/cetrimid 15% [Hibicet]). As a means to assess the typical bacterial spectrum of a burn unit, the following Gram-negative and Gram-positive bacteria strains were tested: Escherichia coli, P vulgaris, P aeruginosa, A baumannii, Enterococcus faecalis, Staphylococcus epidermidis, Staphylococcus aureus, methicillin-resistant S aureus, and ß-hemolytic streptococcus groups A and B. The tests showed a positive bactericidal effect of the Suprathel-antiseptic matrix, particularly with problematic Gram-negative bacteria such as P vulgaris, P aeruginosa, and A baumannii, except for the combination of Suprathel and mafenide acetate. It can be concluded that Suprathel-antiseptic matrix appears to be suitable as a local antiseptic agent, but clinical studies need to be performed to confirm these in vitro observations. The authors' previous studies have shown that acetic acid demonstrates a wide antiseptic spectrum for microorganisms typically found in burn patients. The combination of Suprathel and acetic acid worked well in this study and appears to be promising for future clinical application.