Where is European Regulation 536/2014 Taking Us?

The centralised clinical trial authorisation process, introduced by European Regulation 536/2014, came into force on 31 January 2022. The Regulation is inflexible, both legally and in the technical detail of the authorisation process itself. The principal justification for moving away from the older European Directive 2001/20 seems to be limited to multinational trials: multiple applications to national competent authorities (NCAs), would theoretically be replaced by a single, internationally harmonised authorisation. In fact, the Regulation itself reserves many powers to the NCAs, and the latter, in any case, can lawfully impose further requirements even after that harmonised approval; the year's experience reflects these disadvantages. It would have been better if Regulation 536/2014 had been written to allow the European Medicines Agency greater flexibility, and offered an alternative, optional approach to clinical trial authorisation in the European Union.

Why Does the Precautionary Principle Suffice for Blood Regulation?

Traditional approaches to blood regulation emphasise the precautionary principle and pursue zero-risk for viral transmission; these traditional approaches have usually followed tragedy, such as the HIV and hepatitis C infections that followed the use of factor VIII concentrates. However, a much more haphazard haemovigilance system operates for general adverse events. Such imprecise assessment of hazards prevents sound benefit-risk assessment, and for blood products this is further confounded by the fact that their efficacy has attracted little systematic study. The ongoing COVID-19 pandemic has now prompted the proposal of a convalescent plasma (CP) blood product. Clearly, mere freedom from infectious agents will not suffice in assessing CP, and an objective measure of efficacy, so as to permit formal benefit-risk analysis, is essential. This is both a scientific and an ethical demand, as has been the case for other experimental COVID-19 treatments. With special reference to COVID-19 CP, the well-recognized adverse events of transfusion-associated lung injury (TRALI) and transfusion-associated circulatory overload (TACO) will be important. Furthermore, not only efficacy but also product quality attributes (e.g., antibody titre) will have to be defined. Both of these are outside the traditional regulatory philosophy for blood products and are needed to truly assess the benefit-risk of this putative therapeutic product.

How well do Regulation 28 reports serve future public health and safety?

Her Majesty's (H.M.) coroners issue Regulation 28 (Reg. 28) reports following inquests. These reports concern hazards which, if mitigated, might prevent future deaths, and have addressees who are best placed to take remedial actions. Since 2013, the reports and addressees' responses are copied to, and electronically published by, the Chief Coroner in non-exclusive demographic, aetiological or venue categories. Three of those categories were chosen so as to minimise the replication of unique cases - child deaths; alcohol, drugs and medications (ADM); and railways - with the most recent 50 reports in each category. A further ad hoc sample of neonates was taken after a finding in the first of these. The principal findings are: (a) H.M. coroners generate Reg. 28 reports at different rates (including 27 coroner areas with none at all; random variation probability p ≈ 10-6); (b) there is a large deficit of addressees' responses compared with Reg. 28 reports that are issued; (c) addressees from large organisations are more likely to respond than small ones; (d) substantive remedial actions appear in only a further subset of addressees' responses; and (e) there is a sex imbalance in Reg. 28 reports which is least explicable for neonates. It is concluded that the Reg. 28 report system is haphazard in many ways. As the only official publication from H.M. coroners' courts, Reg. 28 reports have a large scope for improvement, which might promote support from bereaved families and the wider public for the process of inquest. Suggestions for process improvement are made.

Differential research impact in cancer practice guidelines' evidence base: lessons from ESMO, NICE and SIGN.

BACKGROUND: This is an appraisal of the impact of cited research evidence underpinning the development of cancer clinical practice guidelines (CPGs) by the professional bodies of the European Society for Medical Oncology (ESMO), the National Institute for Health and Care Excellence (NICE) and the Scottish Intercollegiate Guidelines Network (SIGN). METHODS: A total of 101 CPGs were identified from ESMO, NICE and SIGN websites across 13 cancer sites. Their 9486 cited references were downloaded from the Web of Science Clarivate Group database, analysed on Excel (2016) using Visual Basic Application macros and imported onto SPSS (V.24.0) for statistical tests. RESULTS: ESMO CPGs mostly cited research from Western Europe, while the NICE and SIGN ones from the UK, Canada, Australia and Scandinavian countries. The ESMO CPGs cited more recent and basic research (eg, drugs treatment), in comparison with NICE and SIGN CPGs where older and more clinical research (eg, surgery) papers were referenced. This chronological difference in the evidence base is also in line with that ESMO has a shorter gap between the publication of the research and its citation on the CPGs. It was demonstrated that ESMO CPGs report more chemotherapy research, while the NICE and SIGN CPGs report more surgery, with the results being statistically significant. CONCLUSIONS: We showed that ESMO, NICE and SIGN differ in their evidence base of CPGs. Healthcare professionals should be aware of this heterogeneity in effective decision-making of tailored treatments to patients, irrespective of geographic location across Europe.

Fundamental Concepts Regarding Testosterone Deficiency and Treatment: International Expert Consensus Resolutions.

To address widespread concerns regarding the medical condition of testosterone (T) deficiency (TD) (male hypogonadism) and its treatment with T therapy, an international expert consensus conference was convened in Prague, Czech Republic, on October 1, 2015. Experts included a broad range of medical specialties including urology, endocrinology, diabetology, internal medicine, and basic science research. A representative from the European Medicines Agency participated in a nonvoting capacity. Nine resolutions were debated, with unanimous approval: (1) TD is a well-established, clinically significant medical condition that negatively affects male sexuality, reproduction, general health, and quality of life; (2) symptoms and signs of TD occur as a result of low levels of T and may benefit from treatment regardless of whether there is an identified underlying etiology; (3) TD is a global public health concern; (4) T therapy for men with TD is effective, rational, and evidence based; (5) there is no T concentration threshold that reliably distinguishes those who will respond to treatment from those who will not; (6) there is no scientific basis for any age-specific recommendations against the use of T therapy in men; (7) the evidence does not support increased risks of cardiovascular events with T therapy; (8) the evidence does not support increased risk of prostate cancer with T therapy; and (9) the evidence supports a major research initiative to explore possible benefits of T therapy for cardiometabolic disease, including diabetes. These resolutions may be considered points of agreement by a broad range of experts based on the best available scientific evidence.

Safety Pharmacology in Drug Discovery and Development.

Safety pharmacology is essential throughout the spectrum of drug discovery and development. Prior to first-in-human studies, safety pharmacology assays, tests, and models predict the clinical risk profile of a potential new drug. During clinical development, safety pharmacology can be used to explore--and potentially explain--both predicted and unpredicted side effects (e.g., adverse events, changes in vital signs, abnormal laboratory values) in order to refine the original clinical risk profile. This chapter will introduce the reader to safety pharmacology's role in translational medicine: the science of translating potential drugs' on- and off-target nonclinical properties to clinical consequences in order to select the best drug candidates to move into early clinical testing. Case studies will be used to illustrate the importance of safety pharmacology testing throughout all phases of drug development.

Davunetide: a review of safety and efficacy data with a focus on neurodegenerative diseases.

Davunetide is the first neuroprotective peptide in its class, and has preclinical evidence for neuroprotective, neurotrophic and cognitive protective properties. Davunetide has also been shown to prevent apoptosis or programmed-cell death in a range of in vitro and in vivo models by promoting microtubule stabilization. Potential clinical uses of davunetide include neurodegenerative disorders such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), frontotemporal dementia (FTD) or cognitive impairment in other diseases such as schizophrenia where microtubule structure and function is known to be impaired. The nonclinical and clinical safety of davunetide is reviewed here in detail. Pre-clinical toxicology studies in rats and dogs using the maximum feasible dose of davunetide provide strong evidence that davunetide is well-tolerated. Similarly, data from 10 separate clinical trials of davunetide, investigating safety and efficacy provide evidence that davunetide is generally safe and well-tolerated, and has shown some signs of clinical efficacy.

Efficacy, end points and eventualities: sumatriptan/naproxen versus butalbital/paracetamol/caffeine in the treatment of migraine.

Migraine is a widespread, relapsing, remittent syndrome. No animal model predicts whether test medications will be clinically useful. Using a modern, well-controlled, sophisticated study design, Derosier et al. demonstrates not only that a butalbital formulation has modest efficacy as an acute treatment for migraine but also that a sumatriptan-naproxen combination is superior. These conclusions are reached using a variety of internally consistent secondary efficacy end points. The primary end point chosen (highly conservative and fashionable in some academic circles) was a technical failure (and not a negative experimental finding). Migraine is intrinsically pleiomorphic: diverse treatment options help match patient with therapy. This study does not justify blanket bans on (admittedly hazardous) barbiturate therapies, and regulators should not impose end point conservatism to an extent that will stifle further progress.

Conducted energy devices: pilot analysis of (non-)attributability of death using a modified Naranjo algorithm.

Alleged fatalities associated with conductive-energy devices (CEDs) are similar to alleged serious adverse events (SAEs) after the use of pharmaceutical products: both types of case arise rarely, in complex (if not unique) combinations of circumstances, frequently when there are multiple concomitant putative aetiologies for the injury, and after the suspected product has been previously well-designed and tested. Attribution (or otherwise) of SAEs to pharmaceutical products is often assessed by use of the Naranjo algorithm. The purpose of this study was to investigate whether an adapted Naranjo algorithm could be used to assess alleged CED-associated fatalities. Unique cases had four independent identifiers. Prospectively, 7 (of the 10) Naranjo algorithm questions were chosen as being potentially applicable to CED use. These had maximum score 9, and the associated ordinal probability scale (doubtful, possible, probable, and definite) was retained by linear proportion to the integral scores. An arbitrary requirement was for database sufficiency≥50%=([n unique cases×7 questions answerable]×0.5); a pilot sample (n=29 unique cases) suggested feasibility (see below). One hundred and seventy-five unique cases were found, with a data sufficiency of 56.8%. Modified Naranjo algorithm scores had an unequally bimodal distribution. CED-attributability was suggested in 21 (12% of 175) cases. Substantial numbers of concomitant conditions existed among cases with low algorithm scores, all being potentially lethal under field conditions without CED exposure. The number of CED-administered shocks sustained was unrelated to CED-attributability of fatality. Two of the Naranjo questions (regarding dechallenge and the effects of challenge with a non-identical but similar agent) proved to be non-contributory. An algorithmic approach to assessment of CED-associated fatality seems feasible. By these pharmacovigilance standards, some published case fatality rates attributable to CED exposure seem exaggerated. CED-attributable deaths have close similarity to Type-B SAEs. The latter are rare, unpredictable, and usually due to a patient idiosyncrasy. In the person being restrained, such idiosyncratic factors may be unavoidable by law enforcement officers (LEO) in the field. These are unlike predictable (Type-A) SAEs, which have their corollary amongst secondary CED-associated deaths, e.g., head injury among cyclists or ignition of an inflammable atmosphere by the CED, and are identifiable risk factors for which LEO can train. Regardless, absolute CED tolerability is obviously greater than that for firearms. A prospective registry of CED deployments would measure this more precisely.

Drug development of intranasally delivered peptides.

Intranasal drug delivery has attracted increasing attention as a noninvasive route of administration for therapeutic proteins and peptides. The delivery of therapeutic peptides through the nasal route provides an alternative to intravenous or subcutaneous injections. This review highlights the drug-development considerations unique to nasal therapeutics and discusses some of the factors and strategies that affect and can improve nasal absorption of peptides. The selectivity and good safety profile typical of peptide therapeutics, along with the dose limitation for intranasal administration, can provide challenges in drug development. Therefore, nasal peptide therapeutics often require special considerations in the nonclinical safety evaluations, such as determining drug exposure in the context of the maximum feasible dose in order to adequately prepare nasal products for clinical studies.

Elder abuse.

Five types of elder abuse (physical, psychological, sexual, neglect and financial) are recognized. They are not new, occur worldwide and are associated with persistent morbidity and mortality. The forensic clinician has responsibilities to: (i) the patient, with competent history taking and examination, (ii) interpret findings and recognize patterns of harm and (iii) promulgate this issue in wider professional and public forums. Research into elder abuse is relatively recent; standardized terminology remains unsettled, and small-scale, local studies are hard to generalize. Cross-sectional, population-based studies of elder abuse should be possible, and standardized endpoints will require forensic science contributions.

Oral sumatriptan and almotriptan--delimiting the MAOI effect.

OBJECTIVES/BACKGROUND: (1) To investigate whether a parsimonious model for sumatriptan pharmacokinetics can apply to oral administration; (2) for a successful model, whether a monoamine oxidase A inhibitor (MAOI-A) perturbs it; and (3) whether such a model is generalizable to oral almotriptan. These goals respond to statements in US product labeling. METHODS: Extension of a previous model for subcutaneous sumatriptan. Numerical solutions to 3 concurrent differential equations were found, with prospective criteria for model acceptance based upon comparison with clinically observed data. RESULTS: The model was successfully extended by inserting a time factor into the absorption phase. This extension was robust: it imitated clinical data for 3 oral sumatriptan dose sizes (both without and with a concomitant MAOI-A) and also for oral almotriptan. CONCLUSION: A model for oral sumatriptan pharmacokinetics can be found using the differential calculus, and it is generalizable to oral almotriptan. The model suggests that an MAOI-A probably has greater effect on elimination kinetics than first-pass metabolism, and that this interaction appears to be overstated in product labeling.

Needle-free subcutaneous sumatriptan for triptan users requiring a change in migraine therapy: efficacy and impact on patient-rated functionality, satisfaction, and confidence.

OBJECTIVE: To evaluate efficacy of, satisfaction with, and confidence in SDP (SUMAVEL DosePro *) among triptan users requiring a change in therapy. SDP is a needle-free, subcutaneous sumatriptan product that confers relief as early as 10 minutes postdose. RESEARCH DESIGN AND METHODS: In an open-label study, SDP was administered for ≤4 migraine attacks over ≤60 days by migraineurs currently treated with triptans (any form/dosage). In the 90 patients with baseline Migraine-ACT scores ≤2 (indicating the need for a change in therapy), efficacy data were collected from patient diaries, and satisfaction was measured with the revised Patient Perception of Migraine Questionnaire (PPMQ-R). CLINICAL TRIAL REGISTRATION NUMBER: NCT01016834 on clinicaltrials.gov. RESULTS: Across all attacks, the rates of pain relief were 30.7%, 66.4%, 80.1%, 81.6%, and 77.6% at 0.25, 0.5, 1, 2, and 24 hours postdose, respectively. Corresponding results for pain-free response were 0.7%, 14.8%, 35.0%, 48.0, and 65.7%. Sustained 24-hour pain relief was observed in 61.0% of attacks. PPMQ-R scores (transformed to 0-100 scales, mean ± SD) improved from baseline to end of treatment for Efficacy (52.5 ± 17.8 versus 74.8 ± 23.4, p < 0.0001) and Functionality (46.2 ± 22.3 versus 71.3 ± 25.2, p < 0.0001) with no deterioration in Tolerability (80.6 ± 14.7 versus 83.5 ± 17.7, p = 0.12). PPMQ-R Overall Satisfaction score increased from baseline to end of treatment (55.1 ± 23.2 versus 74.6 ± 27.7, p < 0.0001). The percentage of patients (90% confidence interval) confident or very confident in treating migraine attacks increased from 22.2% (15.2, 30.6) at baseline to 57.8% (48.6, 66.6) at end of treatment. Results should be interpreted in the context of the open-label design of the original study. CONCLUSION: With SDP, triptan users requiring a change in therapy experienced increased efficacy, satisfaction with therapy, and confidence in treatment without deterioration in tolerability.

Satisfaction with and confidence in needle-free subcutaneous sumatriptan in patients currently treated with triptans.

OBJECTIVE: To evaluate patient satisfaction with and confidence in Sumavel® DosePro® (needle-free subcutaneous sumatriptan) among current triptan users administering Sumavel DosePro for up to 4 migraine attacks. BACKGROUND: Sumavel DosePro is a needle-free, single-use device that facilitates subcutaneous injection of sumatriptan 6 mg and confers relief as early as 10 minutes after dosing. DESIGN/METHODS: In this open-label, multicenter study, Sumavel DosePro was self-administered for ≤4 migraine attacks (over a ≤60-day period) involving moderate or severe baseline pain by adult migraineurs who currently were using triptans (any form, any dosage) and reported being less than very satisfied with their current therapy (i.e., baseline satisfaction ranging from satisfied to very dissatisfied). Treatment satisfaction was measured via the Patient Perception of Migraine Questionnaire, revised (PPMQ-R). RESULTS: Among the 212 patients using Sumavel DosePro to treat ≥1 migraine attack, PPMQ-R Overall Satisfaction (primary endpoint) increased significantly from baseline to the end of treatment (mean ± SD 65.7 ± 19.8 vs. 73.7 ± 29.1, P = .0007), an improvement that met the criterion for clinical significance. From baseline to the end of treatment, PPMQ-R scores also improved significantly for Efficacy (62.2 ± 17.6 vs. 76.2 ± 23.7, P < .0001), Functionality (59.0 ± 22.3 vs. 73.8 ± 25.3, P < .0001), and Tolerability (83.9 ± 13.1 vs. 86.4 ± 15.0, P = .02), but declined for Ease of Use (82.6 ± 15.3 vs 67.8 ± 27.6, P < .0001). For all global satisfaction domains, the percentage of patients satisfied or very satisfied increased from baseline to the end of treatment (Overall Satisfaction 36.3% vs. 64.0%, Satisfaction with Medication Effectiveness 40.1% vs. 68.2%, Satisfaction with Side Effects 48.6% vs. 67.3%). The percentage of patients who were confident or very confident in treating repeated migraine attacks also increased (baseline: 41.0%, 90% confidence interval [CI] 35.4, 46.9 vs. end of treatment: 66.5%, 90% CI 58.9, 70.1). The efficacy results (pain relief, pain-free response, sustained 24-hour pain relief and pain-free response) were consistent with those previously observed with needle-based sumatriptan. CONCLUSIONS: Patients currently treated with triptans and less than very satisfied with their acute migraine therapy experienced a statistically significant and clinically relevant increase in satisfaction with therapy and enhanced confidence in treatment after use of Sumavel DosePro for up to 4 migraine attacks.

Subcutaneous sumatriptan pharmacokinetics: delimiting the monoamine oxidase inhibitor effect.

BACKGROUND: The absolute bioavailability of subcutaneous (s.c.) sumatriptan is 96-100%. The decay curve for plasma concentration after 6 mg s.c. sumatriptan (ie, after T(max) = about 0.2 hours) includes a large distribution component. Metabolism by monoamine oxidase-A (MAO-A) leads to about 40% of the s.c. dose appearing in the urine as the inactive indole acetic acid. Product labeling states that co-administration of an inhibitor of MAO-A (a MAOI-A) causes a 2-fold increase in sumatriptan plasma concentrations, and a 40% increase in elimination half-life. OBJECTIVE: The objective of this study is to determine whether MAOI-A therapy should deter the use of 6 mg s.c. sumatriptan on pharmacokinetic grounds. METHODS: Summary pharmacokinetic data were taken from the literature and from GlaxoSmithKline (GSK) study C92-050. Half-times were converted into rate constants, which were then used in a parsimonious compartmental model (needing only 3 simultaneous differential equations). Acceptance criteria for the model included observed plasma sumatriptan concentrations at T(max), 1, 2, and 10 hours post-dose. A set of 1000 concentration measurements at a resolution of 36 seconds was generated. The model was then perturbed with elimination constants observed during concomitant moclobemide administration, creating a second set of concentration measurements. The 2 sets were then plotted, examined for their differences, and integrated for a second time to obtain and compare areas under the curve (AUCs). RESULTS: The greatest absolute difference between the 2 sets of measurements was 2.85 ng/mL at t = 2.95 hours. A 2-fold difference between the 2 sets occurred only after t = 5.96 hours, when the concentration in the presence of the MAOI-A was 3.72 ng/mL (or <4% of C(max)). At t = 10 hours, the concentrations in both sets were <1 ng/mL (ie, below the lower limit of assay quantitation), and AUC(0-10h) was 97.4 and 117 ng.hour/mL in the absence and presence of the MAOI-A. CONCLUSIONS: There are no pharmacokinetic grounds to deter co-administration of an MAOI-A and subcutaneous sumatriptan. The dominance of the distribution phase and completeness of absorption of a 6 mg dose of s.c. sumatriptan explains the trivial effect size of the MAOI-A on plasma sumatriptan concentrations. Importantly, these findings should not be extrapolated to other routes of administration for sumatriptan.

Needle-free subcutaneous sumatriptan (Sumavel DosePro): bioequivalence and ease of use.

BACKGROUND: Subcutaneous (s.c.) injection of sumatriptan is currently associated with needle aversion in some patients, and sharps disposal issues. OBJECTIVES: To investigate whether a needle-free system can deliver s.c. sumatriptan. If so, to examine whether needle-free administration is bioequivalent to a 26-gauge needle-based auto-injector. Lastly, to assess the needle-free system for clinical acceptability and ease of use during migraine attacks. METHODS: Two clinical trials. Study A: Pharmacokinetics and bioequivalence was studied in normal adult volunteers (n = 57 total), directly comparing needle-free (Sumavel DosePro) with needle-based (Imitrex STATdose System) administration of 6 mg s.c. sumatriptan. An incomplete, randomized, partial factorial, crossover design was used. Each subject received 2 administrations of each product, at 2 of the 3 anatomical sites (abdomen, thigh or arm). There were appropriate "washout" periods between each. Pharmacokinetic sampling was at standard time points, and tests for bioequivalence then followed. Study B: The term "ease of use" was used for clinical acceptability and utility of the needle-free system when it was assessed among 52 outpatients treating migraine attacks. Instructional materials were used as would be provided after ordinary prescription. The primary endpoint was successful use of the needle-free system to administer sumatriptan at the first attempt, including appropriate injection site selection. Second and subsequent uses of the needle-free system were also documented. RESULTS: For administration sites in the thigh and the abdomen, but not the arm, the needle-free and needle-based systems were bioequivalent (for all pharmacokinetic endpoints the mean ratios between the 2 devices were always between 90.1% and 115%). Among outpatients treating a migraine attack with the needle-free system, 51 of 52 on first attempt used the needle-free system successfully when treating a migraine attack. CONCLUSIONS: Sumavel DosePro needle-free delivery system is a new presentation of s.c. sumatriptan that delivers drug effectively, is bioequivalent to the existing needle auto-injector when used at the thigh or abdomen, and is easy to use.