The EU regulatory landscape of non-biological complex drugs (NBCDs) follow-on products: Observations and recommendations.

"Non-biological complex drugs" (NBCDs), such as liposomal formulations, iron-carbohydrate complexes and glatiramoids, gained increased interest from a regulatory perspective in recent years. Similar to biologics, the quality of NBCD products is highly dependent on a robust and well-controlled manufacturing process. This provides challenges for generic drug developers to replicate NBCD products once market exclusivity of the originator product is expired. However, unlike biologics for which a consistent regulatory framework was established with the biosimilars pathway, NBCDs are not recognised as a distinct category of medicines and hence no formal regulatory pathway for their approval is defined. Currently, a "case-by-case" approach is applied for regulating NBCD follow-on products in the EU. Furthermore, NBCDs can follow a non-centralised authorisation procedure, leaving regulatory approvals to national competent authorities. This can lead to heterogeneity in the regulatory approach and outcomes when assessing NBCD follow-on products throughout the EU, which for some product classes has already resulted in some safety and efficacy implications. Here, we explore the regulatory landscape of NBCDs and their follow on products. This study shows that almost all of the 85 NBCD follow-on products available in the EU in 2018 have been approved via various non-centralised procedures. Although most NBCD follow-on products followed an Article 10(1) procedure, we clearly see a recent increase of the use of the hybrid pathway via Article 10(3). This study shows the heterogeneity in the regulatory approach taken for many NBCD follow on products. To what extent this may have consequences for their safety and efficacy evaluations is unknown and needs to be further investigated. The present study should stimulate the rethinking to design prudent regulatory pathways for NBCD follow-on products.

How do the EMA and FDA decide which anticancer drugs make it to the market? A comparative qualitative study on decision makers' views.

BACKGROUND: The process leading to a regulatory outcome is guided by factors both related and unrelated to the data package, defined in this analysis as 'formal and informal factors', respectively. The aim of this qualitative study was to analyse which formal and informal factors drive the decision-making process of the European Medicines Agency (EMA) and Food and Drug Administration (FDA) regulators with regard to anticancer drugs, using in-depth semi-structured interviews with regulators of the two agencies. METHODS: In line with the theory and practice of qualitative research, no set sample size was defined a priori. Respondent enrolment continued until saturation and redundancy were reached. Data were collected through means of in-depth semi-structured interviews conducted either in a face-to-face setting or via Skype(®) with each regulator. The interviews were audio-recorded and verbatim transcribed. The analysis was manually carried out on the transcribed text. Data were independently coded and categorized by two researchers. Interpretation of the findings emerged through a process of triangulation between the two. RESULTS: Seven EMA and six FDA regulators, who had extensive experience with making decisions about anticancer medicines, were interviewed between April and June 2012. There is an open dialogue between the FDA and EMA, with the two moving closer and exchanging information, not opinions. Differences in decision-making between the agencies may be due to a different evaluation of end points. Different interaction modalities with industry and patients represent an additional source of divergence with a potential impact on decision-making. The key message of our respondents was that the agencies manage uncertainty in a different way: unlike the EMA, the FDA has a prevailing attitude to take risks in order to guarantee quicker access to new treatments. CONCLUSIONS: Although formal factors are the main drivers for regulatory decisions, the influence of informal factors plays an important role in the drug evaluation process.

The association between exposure to COX-2 inhibitors and schizophrenia deterioration. A nested case-control study.

BACKGROUND: COX-2 inhibitors (COX-2i) have been reported to have beneficial effects on schizophrenia. This observational study assesses the association between exposure to COX-2i or/and NSAIDs and schizophrenia deterioration. METHODS: We conducted a case-control study within a cohort (n=3,485) of antipsychotic users with a schizophrenia diagnosis (ICD-9=295.x) in IMS-Lifelink, a US claims database. Case events indicating exacerbation of schizophrenia were: switching antipsychotic medication, starting combination therapy, using parenteral antipsychotics or an increasing dose. For each case one control was selected. Exposure to COX-2i/NSAIDs (current/recent/none) and cumulative exposure in Defined Daily Doses 90 days before the index/event date were assessed. Age, sex and co-medication were evaluated as confounders. Logistic regression analysis was used to assess the association. RESULTS: 1,443 case events occurred. For current use, no benefit on schizophrenia case events from exposure to COX-2i was found (adjusted OR 1.16; 95% CI 0.83-1.62). Instead, recent COX2i use with a duration of 0 to 93 days was associated with an increased risk for schizophrenia deterioration (adjusted OR 2.56; 95% CI 1.35-4.87). This association was strongest in rofecoxib. No relation was found for NSAIDs. CONCLUSION: The use of COX-2i was not associated with a decreased risk for schizophrenia deterioration in this population.

Between-country variation in the utilization of antihypertensive agents: Guidelines and clinical practice.

Variation in antihypertensive drug utilization and guideline preferences between six European countries (Denmark, Finland, Germany, Norway, Sweden, the Netherlands) was investigated. Our objectives were to compare between-country variability in utilization per class of antihypertensive agents and to assess guideline preferences in relation to actual use. Antihypertensive consumption data (2003) was retrieved. We classified antihypertensive agents using ATC-codes: C02CA - alpha-blockers (AB), C03A - thiazide diuretics (TD), C07AB - beta-blockers (BB), C08CA - dihydropyridine calcium antagonists (CA), C09A/C09BA/C09BB - ACE-inhibitors+combinations (AI) and C09C/C09D - angiotensin II receptor blockers+combinations (AT2). For each class, DDDs/1000 persons/day and share (%) of total antihypertensive utilization was calculated. Per class, relative standard deviations (RSD) across countries were computed. Current hypertension guidelines were requested from national medical associations. Total antihypertensive utilization varied considerably, ranging from 152.4 (Netherlands) to 246.9 (Germany) DDDs/1000 persons/day. RSD was highest for TD (106.2%) and AB (93.6%). Where guidelines advocated TDs (Norway and Netherlands), TD utilization was below (Norway) or just above (Netherlands) median TD use. Guidelines recommended TD (Norway and Netherlands), TD/BB/AI (Finland, German Physicians Association) or TD/BB/CA/AI/AT2 (Denmark, German Hypertension Society), Sweden had no recent national guideline. In conclusion, antihypertensive utilization patterns varied largely across these six countries, in absolute and relative terms. Furthermore, guidelines seem disconnected from clinical practice in some countries, and none of the guidelines discuss current utilization. Whether this reflects a need for change in prescribing or re-evaluation of guidelines warrants further research.

Changes in the defined daily dose; CYP2D6/CYP3A metabolism as an indicator for dose-setting problems.

OBJECTIVE: Interindividual variability is common at all stages of drug absorption, distribution, pharmacodynamics, metabolism and elimination. In this study, we focused on two enzymes involved in phase-I drug metabolism as markers of pharmacological variability: the CYP3A and CYP2D6 subsystems of cytochrome P450. The main aim of our study was to determine whether substrate drugs for CYP2D6 and/or CYP3A enzymes, showing high interindividual matabolic variability, are more prone to postmarketing adjustments of defined daily dose (DDD). METHODS: A case-control design was used. We identified all DDD changes between 1982 and May 2004 through the website of the WHO Collaborating Centre for Drug Statistics Methodology. Cases were drugs with a DDD change and controls were other drugs with unchanged DDDs. Information about metabolism pathway, introduction year, literature exposure and administration route was retrieved. RESULTS: We included 88 cases and 176 controls. Of the 88 cases, 51 were dosage decreases (58.0%). Overall, DDD changes were not associated with CYP2D6/CYP3A metabolism (OR 1.92; 95%CI 0.78-4.72). However, DDD decreases were associated with CYP2D6/CYP3A metabolism (OR 3.21; 95%CI 1.25-8.26). Adjusting for introduction year weakened this effect (OR 2.78; 95%CI 0.98-7.90). CONCLUSION: Our study indicates that CYP2D6 and CYP3A substrates are more likely to require a DDD decrease after granting of market authorisation. However, this effect was diminished by adjusting for period of introduction. The implication of this finding is that variability indicators, as is demonstrated in this study for CYP2D6/CYP3A metabolism, can exert their influence on a wide variety of drug measures, such as the DDD.

Fate of abstracts presented at five International Conferences on Pharmacoepidemiology (ICPE): 1995-1999.

BACKGROUND: Meetings are an important way of exchanging scientific information, but full diffusion of new information can only be achieved when results are published in scientific journals. PURPOSE: (1) To determine the publication frequency of accepted abstracts for the yearly international conferences on pharmacoepidemiology (ICPE) and to examine predicting variables; (2) if published, to determine impact differences between 'oral' and 'poster' abstracts and to determine type and nature of publishing journals. METHODS: Abstracts accepted for ICPE 1995-1999, published in the official conference supplement of Pharmacoepidemiology and Drug Safety, were included. Publication status for the information contained in each abstract was evaluated through MEDLINE and IPA searches. Impact factors of publishing journals were retrieved and journals were included in one of five groups. RESULTS: Overall, one out of three abstracts resulted in a publication in the peer-reviewed journals studied. Abstracts from North America were more often presented orally than abstracts from Europe, but had lower publication chances. 'Oral' abstracts were more likely to be published than 'poster' abstracts; abstracts with a strong methodological content had a lower publication frequency. Most of the published abstracts were found in pharmacology and pharmacy journals (33%) and journals on specific clinical topics (30%). CONCLUSIONS: Only one out of three papers presented at ICPE ends up in established peer-reviewed journals. Although the publication characteristics for ICPE are not very different from other conferences, there are certain questions that warrant further investigation.

Differences in wound contraction between horses and ponies: the in vitro contraction capacity of fibroblasts.

The contribution of wound contraction to wound closure determines the speed of second intention wound healing and it has been shown that significant differences exist with regard to both contraction and inflammatory response between horses and ponies and between various areas of the body. In this study, the contraction capacity of fibroblasts from limbs and buttocks of 4 Dutch Warmblood horses and 4 Shetland ponies was studied in vitro, in order to determine whether differences in wound contraction are due to differences in the inherent contraction capacity of the fibroblasts or to differences in tissue environmental factors, such as the inflammatory response. Fibroblasts were harvested from subcutaneous tissue, cultured and then suspended in both floating and anchored collagen gels. Contraction capacity was assessed by measuring the decrease in area of the floating gels and by measuring the microforces generated in the anchored gels using a custom-built measuring device. In the floating gels, no difference existed in the contraction capacity of fibroblasts from horses and ponies, or from limbs and buttocks. In the anchored gels, no differences existed between horse and pony fibroblasts, but the fibroblasts from the limbs started to contract significantly sooner and produced significantly higher forces than those from the buttocks. It is concluded that the in vivo differences in wound contraction between horses and ponies and between different sites of the body are not caused by differences in the inherent contraction capacity of fibroblasts. The in vitro differences between fibroblasts from limbs and buttocks are thought to be due to the lower proliferation rate and the longer culture time of the fibroblasts originating from the limbs, because mature fibroblasts can develop higher contraction forces than immature fibroblasts. This means that tissue environmental factors, such as cytokine profiles during the inflammatory response, determine the extent of contraction during wound healing. Further research should be directed towards the role of the inflammatory response in wound healing.

The effectiveness of the haemodialysate Solcoseryl for second-intention wound healing in horses and ponies.

Second-intention healing of limb wounds in horses is often problematic. Solcoseryl is a protein-free, standardized dialysate/ultrafiltrate (HD) derived from calf blood, which has been shown to improve healing in both animals and humans. The efficacy of HD in the healing of deep wounds in horses and ponies was investigated. Deep wounds of 20 by 35 mm were created on both metatarsi (skin, subcutis, periosteum) and on both femoral biceps muscles (skin, subcutis, muscle) of five horses and five ponies. The wounds on one side were treated with HD, four times a week during the period that the wounds were bandaged and once daily thereafter. The wounds on the other side were left untreated. In the first 4 weeks of the healing period HD stimulated healing but inhibited healing thereafter. This pattern was significant for all wound groups (P < 0.001). Because of this change in effect, the overall effect on wound healing over the entire period was not significant (P = 0.77). HD stimulated healing initially by provoking a greater initial inflammatory response, faster contraction and faster formation of granulation tissue. Subsequently, HD inhibited healing because it significantly delayed epithelialization and caused protracted inflammation. The effects of HD were most pronounced in the horses. Because this study distinguished between contraction and epithelialization, it could be shown that HD stimulated contraction but inhibited epithelialization. Therefore, HD is useful in horses for the treatment of deep wounds during the initial phase of healing by second intention, i.e. during the first weeks when wound contraction can be expected. Treatment should be ceased when epithelialization becomes predominant.

Differences in second-intention wound healing between horses and ponies: macroscopic aspects.

Second-intention healing of deep wounds was studied in 5 horses and 5 ponies. Standardised wounds were created on the distal limbs and hind quarters. Wounds on the metatarsi extended onto the metatarsal bone; the depth of the wounds in the femoral biceps muscle was 18 mm. The wound margins were marked by tattoos. Photographs were taken at weekly intervals to determine the wound area. The relative contribution of contraction and epithelialisation to wound closure was quantified by means of the tattoos. Swelling of the limbs was measured; and regularity and aspect of the granulation tissue were semi-quantitatively scored. Second-intention wound healing occurred significantly faster in ponies than in horses, and muscle wounds healed significantly faster than metatarsal wounds. These marked differences reflected the greater contribution of contraction to wound healing. Moreover, demarcation was seen earlier and a healthy granulation bed developed more rapidly in ponies, whereas in horses the granulation tissue remained irregular and purulent for longer. Healing of the metatarsal wounds of horses differed markedly from that of all other wounds: these wounds increased to almost twice their original size in the first 2 weeks, exuberant granulation tissue was persistent, epithelialisation started later, and contraction played a minor role in wound closure. Limb swelling was greater in horses than in ponies. Periosteal new bone formation was more extensive, and was active over a longer period in the metatarsal bones of horses than of ponies. From this study it is concluded that second-intention healing of deep wounds occurs faster in ponies than in horses. This difference can be largely attributed to a more pronounced and faster wound contraction in ponies than in horses. Therefore, attempts to improve second-intention wound healing in clinical practice should be directed at stimulation of wound contraction.

Differences in second-intention wound healing between horses and ponies: histological aspects.

The histological aspects of second-intention healing were studied in 5 horses and 5 ponies. Biopsies were taken weekly from standardised wounds on the metatarsus and femoral biceps muscle of one horse and one pony. Sections were stained to enable cell counting and the detection of DNA synthesis, fibrin, smooth muscle actin (SMA), collagen, and bacteria. In the ponies, the number of polymorphonuclear leucocytes (PMNs) was high during the first 3 weeks and subsequently decreased rapidly. In the horses, the initial number of PMNs was lower, but remained persistently elevated during the evaluation period. PMNs were found mainly in the superficial zones. Significantly more fibrin was present in the wounds of the horses. No significant differences were observed in the number of fibroblasts, the amounts of SMA and collagen. However, myofibroblasts were significantly less regularly organised in the wounds of the horses, particularly in the metatarsal wounds. The mitotic activity of the epithelium was temporally reduced in week 3. The mitotic activity of the granulation tissue was initially high but declined rapidly from week 1 onwards, with the exception of the metatarsal wounds of the horses, in which mitotic activity remained significantly higher. Histology confirmed and explained the macroscopical differences in wound healing between horses and ponies by the strict organisation of the myofibroblasts and the more effective acute inflammation in the ponies. Stimulation of the organisation of myofibroblasts and improvement of the efficacy of the inflammatory response in horses may therefore result in better second-intention wound healing in horses in clinical practice.

Total replacement of the metatarsophalangeal joint in the horse. A single pilot study.

In this paper the successful replacement of an equine metatarsophalangeal joint by a human total condylar knee prosthesis is reported. In the period of observation following implantation of the endoprosthesis the experimental animal showed almost no lameness when exercised at walk, bearing weight on the operated limb. Flexion and extension of the joint were markedly reduced. The clinical and histological observations clearly support further investigation into the equine metatarsophalangeal joint replacement by an endoprosthesis.

[Neurodegenerative disorders of the central nervous system in horses]. / Neurodegeneratieve aandoeningen van het centrale zenuwstelsel bij het paard.

The most important neurodegenerative diseases of the horse are reviewed. In addition to the literature, neurodegenerative diseases occurring in patients (horses, Mongolian Przewalski-horses, and two zebras) referred to the Utrecht Veterinary Faculty are mentioned. Neurodegenerative diseases described are: I. ataxia associated with: A/ static stenosis, B/ dynamic stenosis, C/ lesions at various locations in the central nervous system, D/ equine herpesvirus infections, E/ equine degenerative myelo-encephalopathy, or F/ cerebellar abiotrophy; II. equine motor neuron disease; III. grass sickness or equine dysautonomia; IV. postanaesthetic myelomalacia; and V. equine leuko-encephalomalacia. The patient descriptions show, that mixed forms of some of the differentiated diseases can be diagnosed. Little is known with certainty about the aetiology of the neurodegenerative lesions found. In some patients vitamin E may play a role, possibly in combination with other factors. A mycotoxin known to interfere with myelin metabolism is involved in leuko-encephalomalacia.

The relationship between intra-articular and juxta-articular intraosseous pressures in the metatarsophalangeal region of the pony.

Eight metatarsophalangeal (fetlock) joints were studied in anaesthetized young ponies. Pressure measurements were made in the joint and at various sites in the marrow cavity of the third metatarsal bone with simultaneous measurement of systemic arterial and venous blood pressures. Fetlock joint flexion was always associated with a statistically significant initial decrease in intra-articular pressure (p < 0.05) followed by a marked increase in pressure (p < 0.05). Subsequent extension was accompanied by a similar pressure pattern, although there appeared to be a hysteretic relationship. Fetlock joint distension induced by incremental injection of saline caused a stepwise increase in the intra-articular pressure. Both joint flexion and effusion were associated with an increased intraosseous pressure within the third metatarsal bone. This effect was most pronounced at the distal end of the bone, probably through partial obstruction of the vessels draining the epiphysis and metaphysis.

Ultrasonographic assessment of the proximal digital annular ligament in the equine forelimb.

Ultrasonography was used with 6 normal cadaver forelimbs of Dutch Warmblood horses to delineate the ultrasonographic anatomy of the palmar pastern region, with emphasis on the proximal digital annular ligament. Using a 5.5 MHz sector scanner, the thin proximal digital annular ligament was not visible on offset sonograms. Only if the digital sheath in the normal limb was distended was the distal border of this ligament outlined. In all normal limbs the palmarodistal thickness of the combined skin-proximal digital annular ligament layer in the mid-pastern region was 2 mm. The flexor tendons and distal sesamoidean ligaments were easily identified as hyperechoic structures. Distension of the digital sheath in the normal limbs clearly outlined the anechoic digital sheath pouches. In 4 lame horses ultrasonography aided the diagnosis of functional proximal digital annular ligament constriction. In all 4 diseased forelimbs ultrasonography demonstrated thickening of the skin-proximal digital annular ligament layer and distension of the digital sheath. In one of these limbs the distended digital sheath was also thickened. The flexor tendons and distal sesamoidean ligaments were normal. There was no radiographic evidence of additional bone or joint lesions.

Intra-osseous pressure and pressure pulse gradients along the equine third metatarsal bone.

Intra-osseous pressure measurements in the third metatarsal bone of anesthetised young and mature ponies demonstrated that a pressure gradient exists along the bone, the pressure being highest at the level of the nutrient foramen and decreasing distally and proximally from this point. The height of the intra-osseous pressure pulse also decreased toward the bone ends. It is concluded that the sites of measurement of the intra-osseous pressure in clinical and experimental studies should be standardized.

Different types of inguinal herniation in two stallions and a gelding.

Three horses with different and unusual types of inguinal herniation outside the vaginal cavity are described in detail. Attention is paid to the differences between these conditions and the more commonly occurring inguinal herniation inside the vaginal cavity.