WHO informal consultation on revision of guidelines on evaluation of similar biotherapeutic products, virtual meeting, 30 June - 2 July 2021.

The WHO informal consultation was held to promote the revision of WHO guidelines on evaluation of similar biotherapeutic products (SBPs) adopted by the Expert Committee on Biological Standardization (ECBS) in 2009. It was agreed in the past consultations that the evaluation principles in the guidelines are still valid, but a review was recommended to provide more clarity and case-by-case flexibility. The opportunity was therefore taken to review the experience and identify areas where the current guidance could be more permissive without compromising its basic principles, and where additional explanation could be provided regarding the possibility of reducing the amount of data needed for regulatory approval. The meeting participants applauded the leading role taken by the WHO in providing a much-needed streamlined approach for development and evaluation of SBPs which will provide efficient and cost-effective product development and increase patient access to treatments. It was recognized that the principles as currently described in the draft WHO guidelines are based on sound science and experience gained over the last fifteen years of biosimilar approvals. However, since these guidelines when finalised will constitute the global standard for biosimilar evaluation and assist national regulatory authorities in establishing revised guidance and regulatory practice in this complex area, it was felt that further revision and clarity on certain perspectives in specific areas was necessary to dispel uncertainties arising in the current revised version. This report describes the principles in the draft guidelines, including topics discussed and consensus reached.

[Opportunities and challenges of extrapolation for biosimilars]. / Möglichkeiten und Herausforderungen der Extrapolation bei Biosimilars.

Although biosimilars approved in the European Union have proved to be safe and efficacious, their licensing requirements continue to be disputed by medical professionals. In particular, extrapolation to indications of the originator without one's own clinical data of the biosimilar is controversial. Conceptually, the development of biosimilars is derived from that of generics. However, due to their complexity and inherent variability, considerably more data are necessary for biosimilars to demonstrate comparability with the originator (the reference product) than for the usually low-molecular generics. Biosimilars increase competition and help contain healthcare, and they improve access for patients to valuable treatments with biologicals. However, biosimilar development is a laborious and lengthy process and requires major biotechnological know-how. The basis is comprehensive, structural, and functional characterization of the biosimilar and reference product as well as their comparison with suitable and sensitive methods. The clinical development programme is reduced and tailored to address remaining uncertainties and to confirm comparable clinical performance. Extrapolation of data to other indications of the reference product is the greatest cost advantage of biosimilar development, but must always be scientifically justified and, if necessary, substantiated by further data. The scientific principles underlying the comparability exercise for a biosimilar are the same as those applied to a change in the manufacturing process of an already licensed biological. In both cases, different versions of a biological substance are compared and the clinical relevance of observed differences is assessed. Competent authorities do have decades of experience in evaluating changes in the manufacturing process, which they can now apply to biosimilars. For approval of a biosimilar and extrapolation of data, the totality of the evidence from the complete comparability exercise is considered, as has been the case for the first biosimilar infliximab.

[Clinical practice of systemic lysis in prehospital resuscitation. Success and complication rates]. / Klinische Praxis der systemischen Lyse unter prähospitaler Reanimation. Erfolgs- und Komplikationsraten.

BACKGROUND: Systemic thrombolysis was introduced as the sole prehospital treatment option in patients with cardiac arrest in the setting of acute myocardial ischemia or pulmonary embolism; however, it remains the subject of discussion. PATIENTS AND METHODS: A total of 194 patients with sudden prehospital cardiac arrest were included in this retrospective case control study. Of these patients, 96 in whom circulatory arrest due to cardiac disease (pulmonary artery embolism or myocardial ischemia) was suspected underwent thrombolytic treatment and were compared to the remaining 98 patients that did not undergo thrombolytic therapy. In addition to the circumstances of circulatory arrest, the course and success of resuscitation, as well as in-hospital course (including bleeding complications), overall survival and neurological outcomes were compared. RESULTS: There were no significant differences between patients with or without thrombolysis in terms of the circumstances of cardiac arrest. Patients that received thrombolytic treatment were significantly younger and were more frequently treated with anticoagulants, platelet aggregation inhibitors and amiodarone. They also received higher doses of epinephrine and arrived at hospital under ongoing resuscitation significantly more frequently. A trend toward more prehospital return of spontaneous circulation (ROSC) following thrombolytic treatment was seen in the entire cohort. However, patients pre-treated with acetylsalicylic acid and heparin did not show better prehospital ROSC rates as a result of additional thrombolytic therapy. Significant differences in terms of bleeding complications or the need for blood transfusion could not be seen due to the small number of patients. DISCUSSION: The indication for systemic thrombolysis in the context of prehospital resuscitation should remain restricted to patients with clear symptoms of acute pulmonary embolism or recurrent episodes of ventricular fibrillation in the setting of acute myocardial infarction. Due to a lack of evidence, systemic thrombolysis should not be used as a treatment of last resort in younger patients with persistent ventricular fibrillation.

LASER demarcation photocoagulation for rhegmatogenous retinal detachments.

PURPOSE: to evaluate demarcation laser photocoagulation (DLP) for macula-sparing rhegmatogenous retinal detachments (RRD) with and without symptoms of posterior vitreous separation or progressive visual field defect. METHODS: retrospective, interventional, single surgeon case series of consecutive patients with RRD treated with demarcation laser photocoagulation between March 1999 and February 2008 at an academic center. The null hypothesis was that there exists no difference in the rate of progression for retinal detachment irrespective of the presence ('symptomatic') or absence ('asymptomatic') of symptoms of posterior vitreous separation or visual field defect at presentation. RESULTS: a total of 27 eyes of 26 patients were included in the study. In all, 22 of the 27 eyes (81.4%) did not require additional treatment and remained attached during mean follow-up of 38.4 months. None of the 14 asymptomatic patients required surgery (0%) whereas 5 out of the 13 patients (38.5%) who were symptomatic at presentation required further intervention (p=0.016): one patient required additional laser only and four patients required scleral buckling or vitrectomy. Pre- and post- DLP logMAR visual acuity was 0.15 and 0.14, respectively. CONCLUSION: demarcation laser photocoagulation is an effective alternative to scleral buckling or vitrectomy for treating asymptomatic RRDs. It has a high failure rate among eyes with symptomatic RRD.

Microsphaeropsis olivacea keratitis and consecutive endophthalmitis.

PURPOSE: To report a case of fungal keratitis with consecutive endophthalmitis caused by Microsphaeropsis olivacea. METHODS: Case report. RESULTS: A 51-year-old man developed fungal keratitis and consecutive endophthalmitis after sustaining a penetrating injury to the right eye. Cultures of the aqueous humor yielded M. olivacea. Infection resolved after intraocular fungal debridement, intravitreous amphotericin B, and aggressive topical natamycin and oral fluconazole. Persistent, low-grade smoldering corneal and intraocular inflammation required topical corticosteroid therapy. CONCLUSION: M. olivacea is an exceedingly rare ocular pathogen. The intraocular portion of the infection responded quickly to intravitreal antifungal treatment; however, the course was prolonged by smoldering corneal inflammation. Prompt recognition of intraocular spread and aggressive treatment may be beneficial in fungal infections caused by unusual organisms with uncertain virulence.

Alcaligenes xylosoxidans and Propionibacterium acnes postoperative endophthalmitis in a pseudophakic eye.

PURPOSE: To report a case of persistent polymicrobial postoperative endophthalmitis caused by Alcaligenes xylosoxidans and Propionibacterium acnes in a pseudophakic eye. A. xylosoxidans is a gram-negative bacteria resistant to most antibiotics. METHODS: Case report. RESULTS: A 72-year-old man presented with clinical signs of endophthalmitis on the first postoperative day after a phacoemulsification procedure with posterior chamber intraocular lens, left eye. Initial treatment included topical, subconjunctival, and oral antibiotics. After initial clearing, there was recrudescence of infection on postoperative day 37 that prompted referral of the patient to the Cullen Eye Institute. Treatment at that time included anterior chamber and vitreous taps with intravitreal antibiotic injections. Complete pars plana vitrectomy and intraocular lens explantation were eventually required because of persistent infection with a resistant organism. Cultures from the first procedure grew A. xylosoxidans and P. acnes. Cultures from the vitrectomy grew only A. xylosoxidans. At the final follow-up visit 6 months after the initial procedure. The eye was without inflammation with best-corrected visual acuity of 20/40. CONCLUSION: Both A. xylosoxidans and P. acnes can cause chronic progressive endophthalmitis after cataract extraction often resistant to corrective antibiotic therapy. Successful intervention may require complete vitrectomy with intraocular lens and capsule removal.

The human antimouse immunoglobulin response and the anti-idiotypic network have no influence on clinical outcome in patients with minimal residual colorectal cancer treated with monoclonal antibody CO17-1A.

Murine monoclonal antibodies (mAbs), when administered to patients, induce a human antimouse immunoglobulin immune response, especially when multiple infusions are required to obtain therapeutic efficacy. In a randomized Phase II clinical study, 83 patients with colorectal carcinoma of stage Dukes C were treated with the murine IgG2a mAb 17-1A (ab1) after curative surgery. The regimen consisted of a single infusion of 500mg of 17-1A within 2 weeks after surgery, followed by 100mg of mAbs four times every 4 weeks. Sera were taken every 2-3 weeks and screened for human antimouse antibodies (HAMA). HAMA were measured by a capture ELISA and an indirect antihuman immunoglobulin ELISA for the analysis of IgG and IgM isotypes. Anti-idiotypic antibodies (ab2) were detected by an inhibition ELISA, and anti-anti-idiotypic antibodies (ab3), recognizing the original antigen, were determined by flow cytometric analysis. About 20% of patients failed to develop HAMA; in the other patients, antibody titers were initially low after the first two infusions and reached their maximum only after a fifth infusion at 18-20 weeks after surgery. An analysis that differentiated between patients who developed recurrences and those who remained tumor-free did not show any difference in antibody titers between the two groups, neither for total HAMA nor for IgG, IgM, or ab2. The formation of ab3 was analyzed in eight patients and proved to be negative in all of them. HAMA remained detectable up to 2 years after the last treatment. In patients who experienced adverse events associated with therapy, HAMA titers tended to rise earlier; this difference, however, was not statistically significant. Thus, neither a beneficial nor a detrimental effect of HAMA formation could be determined for the clinical response to antibody therapy.

T-cell lymphoproliferative disorder of vitreous associated with mycosis fungoides.

59-year-old man with a history of mycosis fungoides developed loss of visual acuity and visual field in the left eye. Epiretinal lesions were present in the right eye and multifocal choroidal lesions, optic disc edema, and vitritis were present in the left eye. A diagnostic vitrectomy was performed and cytologic examination of the vitreous confirmed the diagnosis of T-cell lymphoproliferative disorder. Systemic and intrathecal chemotherapy resulted in marked improvement in ocular signs and symptoms. At last follow-up, the patient was found to have improved visual acuity in the left eye; however, significant worsening of his systemic condition developed and he died shortly thereafter.

Familial exudative vitreoretinopathy mimicking persistent hyperplastic primary vitreous.

PURPOSE: To report an unusual case of familial exudative vitreoretinopathy in an infant. METHODS: Case report. A 6-day-old girl had unilateral microphthalmia in the right eye, with a retrolental plaque initially diagnosed as persistent hyperplastic primary vitreous. Three months later, peripheral retinal vascular changes and a fibrovascular ridge were noted in the left eye, suggesting familial exudative vitreoretinopathy as the cause in both eyes. RESULTS: The microphthalmic right eye was unsalvageable. The left eye developed an exudative retinal detachment despite photocoagulation of the peripheral avascular retina. Additional cryotherapy resulted in resolution of the detachment and regression of the vascular changes. CONCLUSIONS: With highly asymmetric involvement, neonatal familial exudative vitreoretinopathy can mimic persistent hyperplastic primary vitreous. Fellow eye involvement can progress rapidly.

Diagnosis and therapeutic relevance of micrometastases.

The disseminated isolated tumor cell has become a formidable object of solid tumor research for at least three good reasons: it can be identified in organ compartments such as bone marrow, blood, and lymph nodes and, once found, it can be morphologically characterized with respect to tumor-associated antigens, oncogenes, tumor suppressor genes, proliferation markers, and/or growth receptors. Thirdly, it is also an ideal target for immunotherapy directed at accessible, well-defined membrane-associated antigens of the tumor cell.

Monoclonal antibody therapy for resected Dukes' C colorectal cancer: seven-year outcome of a multicenter randomized trial.

PURPOSE: As previously shown, antibody treatment increased survival of patients with resected colorectal cancer of stage Dukes' C. Since the 5-year analysis was criticized because of the wide range (2.7 to 7.5 years) of follow-up time, we performed a 7-year analysis with only four of 189 patients monitored for less than 5 years. PATIENTS AND METHODS: A total of 189 patients with resected Dukes' C colorectal cancer were randomly allocated to infusions of a total of 900 mg 17-1A antibody, 500 mg postoperatively followed by 4 monthly doses of 100 mg (n=99), or to observation only (n=90). Primary end points were overall survival and disease-free interval. Patients were stratified by a dynamic randomization according to center, sex, location of tumor, number of affected lymph nodes, and preoperative carcinoembryonic antigen concentration. RESULTS: Randomization produced balanced distribution of risk factors. After 7 years of follow-up evaluation, treatment had reduced overall mortality by 32% (Cox's proportional hazard, P < .01; log-rank, P=.01) and decreased the recurrence rate by 23% (Cox's proportional hazard, P < .04; log-rank, P=.07). The intention-to-treat analysis gave a significant effect for overall survival (Cox's proportional hazard, P < .01; log-rank, P=.02) and disease-free survival (Cox's proportional hazard, P=.02; log-rank, P=.11 ). While distant metastases were significantly reduced (Cox's proportional hazard, P=.004; log-rank, P=.004), local relapses were not (Cox's proportional hazard, P=.65; log-rank, P=.52). This differential effect of 17-1A antibody on disseminated isolated tumor cells versus occult local satellites may explain the increased significance seen in the overall survival. CONCLUSION: The now-matured study shows that 17-1A antibody administered after surgery prevents the development of distant metastasis in approximately one third of patients. The therapeutic effect is maintained after 7 years of follow-up evaluation.

Antibody-based immunotherapeutic strategies in colorectal cancer.

Monoclonal antibodies may well be on their way to becoming an integral part of therapy after the most recent success in prolonging overall and recurrence-free survival in patients with stage III colorectal cancer after potentially curative surgery. After a median follow-up of 5 years, antibody treatment reduced the overall death rate by 30% and decreased the recurrence rate by 27%. These results are similar with regard to efficacy but there is less toxicity with those obtained in contemporary and more recent chemotherapy trials. The key to success with high-molecular-weight substances such as immunoglobulines lies in the careful selection of the appropriate target population, i.e., patients with minimal residual disease, where only isolated tumor cells which are readily accessible to therapy are present. An argument for combining immunotherapy with chemotherapy can be made on the basis of the phenotype of individual disseminated tumor cells, which by immunocytochemistry were found to only rarely express proliferation-associated antigens and therefore are independent of the cell cycle. Further efforts to improve immunotherapy have also led to the combined clinical use of antibodies with biologic response modifiers which are known to enhance effector cell-mediated antibody-dependent cytotoxicity. Additional rationally designed clinical trials are ongoing in which specific immunotherapy is directed towards known, readily accessible, and abundant cell target structures, either alone or combined with treatment modalities which employ different action mechanisms.