Anthony W. Fox

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.

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.

International expert consensus conference on testosterone deficiency and its treatment held in Prague, Czech Republic

Abstract An international expert consensus conference regarding testosterone deficiency (TD) (also known as hypogonadism) and its treatment was held on 1 October 2015, in Prague, Czech Republic. The impetus for this meeting was to address several key scientific issues that have been misunderstood or distorted during the recent intense media attention to this topic. Eighteen experts from 11 countries participated, from the disciplines of urology, endocrinology, andrology, diabetology, and basic science research. The goal was to identify scientific concepts for which there was broad agreement. It was noted that recent public controversies regarding testosterone therapy have been anchored by two retrospective studies reporting increased cardiovascular (CV) risks. Both these studies contained major flaws, and are contradicted by a large body of evidence suggesting CV benefits with testosterone therapy. Other topics discussed included the negative impact of TD on male health; the questionable validity of restrictions on treatment based on age-specific cut-offs, presence of identified underlying conditions, or application of rigid biochemical thresholds; and the lack of evidence regarding prostate cancer risks. Final consensus statements (resolutions) are under development. It is hoped these will serve as a scientific foundation for further discussion, and will thereby reduce misinformation regarding TD and its treatment.

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.

The Pharmaceutical Medicine Year that Was, 2012

The story so fary.. My annual review for 2010 noted the recentUSFDA interest in biosimilars, the creation of an FDA transparency initiative and the half-time score in the match between the FDA and Congress over the exclusivity period for biological products. Generic products had begun to sustain the same sort of strictliability lawsuits that innovators have had to face for decades. The US congressional budget was unapproved and many months late. In the UK, the National Institute for Health and Clinical Excellence (NICE) was flexing its muscles with guidances on therapeutic algorithms, and the European Medicines Agency (EMA) had just withdrawn rosiglitazone without a shred of evidence of its inferiority to sulfonylurea drugs in type II diabetesmellitus. The world wallowed in economic recession, although some small company financing had started to happen towards the end of the year. Some of the issues of 2010 have obviously continued into 2011. The FDA has stated that, in spite of the rosiglitazone debacle, cardiovascular outcomewill not be a primary endpoint for hypoglycaemic agents. Meanwhile, the USDepartment of Justice and various US states have now issued subpoenas relating to rosiglitazone; it is not clear what these investigations are about exactly, and, so far, not much seems to have come of them. From the point of view of the regulatory sciences, 2011 has probably seen less turmoil than most years. The FDA was reorganized just after last year’s review went to press. There is now a newOffice of Science and Innovation (OSI), reporting to the Office of the Chief Scientist. The task of OSI will be to track outcomes, and manage the Agency’s collaborations and partnerships (one could be forgiven for thinking that this should have already been happening). This OSI will also be equipped with its own, new advisory board. In terms of fundamental applied science, how to deal with follow-on biological products is probably the largest regulatory problem at the moment. The term ‘biosimilar’ has become accepted for a drug that ostensibly has the same properties as another biological product; this neologism can be used as a noun or as an adjective. The reason to avoid the descriptor ‘generic biological’ is because absolute identity of two fermented polypeptides can never be proven when they come from different manufacturing processes. But meanwhile, the FDA still struggles to produce a guidance describing what its review criteria for biosimilars might be. The innovators of biological products are entirely opposed to biosimilars, of course, and welcome perceived scientific complexity and consequent delay of regulations that would disturb the status quo, i.e. all biological drugs have to be developed as if they are new products (with the consequential expensive and time-consuming clinical trials). Here, the FDA seriously lags the Europeans. Not only did the EMA actually approve a biosimilar last year, but they have now provided a new guideline applicable to biosimilar monoclonal antibodies. Guidelines for biosimilar insulin, low molecular weight heparins, somatotropin, some growth factors and recombinant erythropoietins already exist in Europe; indeed, many in this suite of guidelines are a few years old and already entering revision and reissuance cycles. Unfortunately for the progress of regulation based upon science, biosimilars have now also attracted the attention of American politicians. Both FDA’s competency in general, and the period of exclusivity for innovator biological products in particular, became political football this year. Congressman Henry Waxman (Democrat, West Los Angeles, CA, USA) began by criticizing the existing 12-year exclusivity period. Meanwhile, the Representatives who authored the Patient Protection and Affordable Care Act (Anna George Eshoo, Democrat, CA, USA; Jay Inslee, Democrat, WA, USA; and Joe Barton, Republican, TX, USA), wrote to the FDA claiming that the Agency misunderstood the law, and were wrong to introduce the 12-year exclusivity period for biologicals in the first place. The President then stepped in with the draft financial year 2012 budget. This came, hilariously, while the unadopted financial year 2011 budget was by now 5 months overdue. In any case, the 2012 budget included a reduction in exclusivity for biological products to just 7 years, a proposal that was reportedly promptly ‘blasted’ by former Congressman COMMENTARY Pharm Med 2012; 26 (1): 1-3 1178-2595/12/0001-0001/

The Pharmaceutical Year That Was, 2013

49.95/0

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

Last year ended with Europe wallowing in its Euro-crisis, the United States (US) Congress wrangling over its budget (eventually unresolved, leading to a legislative ‘sequestration’), the promise of a Pharmacovigilance Risk Assessment Committee (PRAC) within the European Medicines Agency (EMA), a European initiative towards publication of clinical trials data, and an unremarkable number of truly new product approvals on both sides of the Atlantic [1]. Much of that carried on this year, while the economic situation continues to stagger and stutter. As mentioned last year, 2013 has seen the PRAC getting into its stride at the EMA [2]. The PRAC advises the Committee for Medicinal Products for Human Use (CHMP), the Co-ordination Group for Mutual Recognition and Decentralised Procedures-Human (CMDh), the EMA secretariat and the European Commission on all aspects of pharmacovigilance and risk management. The PRAC is comprised of: a Chairperson, a member (or alternate) from every member state, six members ex officio and technically qualified from the European Commission (EC), and another two EC members (with alternates) for public calls of interest for healthcare professionals and patients. They all have 3 year terms, renewed easily the first time, and after competition thereafter. The PRAC aims to review all Product Licence Applications (PLAs) from the point of view of proposed pharmacovigilance and risk management activities. These are all Module 1 components of the electronic Clinical Trials Dossier (eCTD), and thus are restricted to the European marketplaces. In addition, the PRAC will be reviewing Periodic Safety Update Reports (PSURs; these now require formal risk-benefit assessments), Post-Assessment Safety Studies (PASS), as well as doing general signal detection and making ‘for cause’ pharmacovigilance inspection decisions. For licensed products, these responsibilities differ little between centralised process and other approvals. Lastly, the PRAC is empowered to take urgent action on its own initiative in cases of serious threats to the public health. Flexing its muscles, in January 2013 PRAC recommended the withdrawal of three products from the entire EU, and most recently (September 2013) is recommending against short-acting beta-agonists in pregnancy [3]. A slang has developed in the United Kingdom: purity, efficacy and safety come first, and then the National Institute for Health and Care Excellence (NICE) has become known as a ‘fourth hurdle’. The PRAC might yet become known as the fifth hurdle. A new distraction this year is that the US Food and Drug Administration (FDA) doesn’t quite know whether it can regulate ‘electronic cigarettes’ [4]. In ordinary parlance, these breath-actuated inhalational devices deliver vaporized nicotine, and are shaped like a cigarette. The amusing angle of this regulatory uncertainty is that the FDA is, however, now attempting to regulate tobacco itself. The Family Smoking Prevention and Tobacco Control Act (2009) gave the FDA the authority to regulate products containing tobacco. A regulatory pathway for tobacco products has been contrived, based upon the notion of ‘‘substantial equivalence’’. On this basis, there have been two new product approvals and at least four rejections [5]. The two approvals so far (‘‘Newport Non-menthol Gold Box 100s’’ and ‘‘Newport Non-menthol Gold Box’’) had A. W. Fox is the Consulting Editor for Pharmaceutical Medicine.

Safety Pharmacology in Drug Discovery and Development

Evaluation of: Derosier F, Sheftell F, Silberstein S et al. Sumatriptan–naproxen and butalbital: a double-blind, placebo-controlled crossover study. Headache 52(4), 530–543 (2012). 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.