This page lists correspondence with the National Institute for Health and Clinical Excellence. On 3 December 2012 BMJ editor in chief Dr Fiona Godlee wrote to NICE's chair, Professor Sir Michael Rawlins. In her letter she says: "Now that serious doubts have been raised about the evidence behind claims for oseltamivir’s effectiveness and safety, I am asking you to withdraw approval for oseltamivir until NICE has received and reviewed the full clinical trial data and those anonymised data are available for independent scrutiny."
All rapid responses
It has been my concern for the last year that General Practitioners are disadvantaged in their desire and need to help protect vulnerable children from abuse. Other agencies "share concerns " and have lower thresholds for reporting, whilst all the training for GPs seems to focus on "referrals". Not surprisingly, many doctors are concerned whether something they see before them crosses that threshold of referral, which they fear will precipitate action and jeopardise future relations with the family.
The complexities of presentations in our surgeries is not matched by a sophisticated system for dealing with our concerns. The separation of Health Visitors from the primary care team in most areas has deprived GPs of their ability to make soft referrals when they have concerns about a family, though this has never helped with the sexual abuse of older children.
We need to deploy more effective and proportional systems if we in Primary Care are to fulfill our role in genuinely protecting the vulnerable.
Competing interests: No competing interests
We congratulate Professor Jensen and Professor Bulova for their clinical review about patients with Down's syndrome, however, we believe that they should also have included in their review the ocular manifestations of the syndrome; firstly since they are very common and secondly they may seriously affect the quality of life of the patients. The improvement of healthcare, the increase of life expectancy in patients with Down's syndrome[1,2] has lead to significant increase in sequence and severity of ocular manifestations of the syndrome.
Down's syndrome is associated with ophthalmic disorders affecting all ocular structures . The prevalence of diagnosis of ophthalmic disorders in Down’s syndrome patients is estimated at 77%.
Anatomic comparison of anterior segment ocular structures between patients with Down’s syndrome and general population has revealed significant abnormalities among patients with Down’s syndrome, including pupil size, corneal thickness, corneal volume and corneal curvature, indicating a predisposition for developing ophthalmic disorders.
In patients with Down’s syndrome, significant refractive errors (defined as hypermetropia over 3 diopters and myopia more than 1 diopter) and strabismus are the most common ophthalmic disorders with estimated prevalence of 43% and 45% respectively. The treating physician and parents should be aware of these manifestations in young patients with Down’s syndrome since if these are overlooked they may lead to permanent visual impairment of the patients due to the development of amblyopia. More rare ocular manifestations of the syndrome include epiphora (35%) and nystagmus (16%). Keratoconus is another disorder presenting in 5-8% of patients with Down’s syndrome; patients should be closely monitored as in some instances keratoconus may cause hydrop (acute swelling and scaring of the cornea) with subsequent reduction of vision which may eventually lead to the necessity for corneal transplant surgery.
In adult patients, cataract is reported as the ophthalmic disease with the highest prevalence (42%), followed by significant refractive errors (25%), strabismus (21%), conjunctivitis (13%) and nystagmus (12%). Although cataract surgery is nowadays a safe and effective procedure, it may be more challenging in patients with Down’s syndrome due to the concomitant ocular diseases such as nystagmous, keratokonus and in most cases surgery has to be done under general anesthesia.
In conclusion, ophthalmologic evaluation must be included in periodical medical examination performed in every patient diagnosed with Down’s syndrome, since a delay in the diagnosis and prompt treatment of ocular disorders can lead to visual impairment and adversely affect their quality of life.
1. A. T. Berk, A. O. Saatci, M. D. Ercal, M. Tunc, and M. Ergin, “Ocular findings in 55 patients with Down’s syndrome,” Ophthalmic Genetics, vol. 17, no. 1, pp. 15–19, 1996.
2. Q. Yang, S. A. Rasmussen, and J. M. Friedman, “Mortality associated with Down’s syndrome in the USA from 1983 to 1997: a population-based study,” The Lancet, vol. 359, no. 9311, pp. 1019–1025, 2002.
3. R. A. Catalano, “Down syndrome,” Survey of Ophthalmology, vol. 34, no. 5, pp. 385–398, 1990.
4. Krinsky-McHale SJ, Jenkins EC, Zigman WB, Silverman W. Ophthalmic disorders in adults with Down syndrome. Curr Gerontol Geriatr Res. 2012;2012:974253.
5. Aslan L, Aslankurt M, Aksoy A, Gümüşalan Y. Differences of the anterior segment parameters in children with down syndrome. Ophthalmic Genet. 2014 Jun;35(2):74-8.
6. Stephen E, Dickson J, Kindley AD, Scott CC, Charleton PM. Surveillance of vision and ocular disorders in children with Down syndrome. Dev Med Child Neurol. 2007 Jul;49(7):513-5.
Competing interests: No competing interests
Professor Stockwell provides a very helpful synopsis which explains why health organisations throughout Europe support Minimum Unit Pricing (MUP) for alcohol. The political and legal processes mean that the implementation of the policy is complex and takes a long time and there is a risk that only those heavily involved can keep track. However it is important that the broad support the medical profession and other groups have shown for MUP is maintained. The opponents of MUP would be happy for the issue to disappear into the long grass.
He expresses surprise that the alcohol industry has opposed MUP in the UK. The position is more complex than that. There is considerable support for MUP within the alcohol industry particularly among the pub trade and smaller producers. The opposition comes from producers who operate globally and from large retailers, in particular supermarkets and it has been those large organisations which have dominated the perception of the diverse industry interests.
Last month Scottish Health Action on Alcohol Problems, a project of the Scottish Royal Colleges and Faculties, held an event where industry supporters of MUP spoke of the harm which the proliferation of cheap supermarket alcohol caused to UK business and growth. Health experts spoke of the health harm. A report of the event can be found here. http://www.shaap.org.uk/images/mup-event-summary.pdf
Regarding the significance of the current European Court of Justice consideration of the Scottish MUP legislation, our legal advice is that the ECJ considers the proportionality of each case individually. Action that is justified for alcohol in Scotland may not be justified for obesity in Greece. However, this will be a test of the priority which the European Union and its institutions gives to health considerations and a broad coalition of European health organisations is working to ensure the primacy of health.
Competing interests: Scottish Health Action on Alcohol Problems has been campaigning for Minimum Unit Price for Alcohol as part of a response to alcohol related harm since 2006.
Re: Adherence to healthy lifestyle and risk of gestational diabetes mellitus: prospective cohort study
Prevention is better than cure is a golden maxim for many ailments including gestational diabetes(GM). It is suggested in the present study that life style modifications - modifiable factors like diet, physical exercise and maintaining a proper body weight could reduce the risk of gestational diabetes a growing public health concern. The most important risk factor is considered to be body mass index (BMI). The reported BMI is found to be
Maintaining a healthy diet, doing regular physical exercise, avoiding alcohol and smoking help maintain a good health in every individual. GM is a growing health threat in obese subjects.. What about the lean mothers? Does GM affect lean mothers with poor nutrition? How many of these subjects included in the study had previous history of GM or there is GM reported in the family (Family history).
Yet with growing threat of childhood obesity, taking measures to prevent GM is one of the factors that could help prevent obesity in children.
Competing interests: No competing interests
Gillian Prue raises an important developing issue in her article BMJ2014;349:g4834 regarding vaccination of boys against Human papillomavirus (HPV). HPV types 16 and 18 are known to be oncogenic with significant risk factors related to the development of oro-pharyngeal cancers as well as other diseases such as oral and genital warts, with the incidence tripling in the past three decades. HPV is highly recognised in head and neck conditions known to be premalignant and malignant such as erythroplakia and epithelial dysplasia.
The successful introduction of the vaccination programme for 12-13 year old girls should be equally expanded to include boys. Head and neck cancers have a greater prevalence amongst the male population and the progression to include boys in a HPV vaccination programme would be a positive stride towards eliminating a known risk factor for which there are long-term benefits. The cost of management of patients with head and neck cancers runs into many thousands of pounds including extensive multi-disciplinary care with extended hospital admissions and outpatient care. The implication of widespread vaccination against HPV carries a significant cost benefit for long-term provision of healthcare resources and management of patients presenting with disease. This far outweighs the cost of management of patients subsequently presenting with head and neck cancers. The introduction of a vaccination for both sexes would be a significant progression in eliminating head and neck disease and a mandate supported by head and neck clinicians.
Zaman Mirza (SHO in Oral and Maxillofacial Surgery)
Bhavin Visavadia (Consultant in Oral and Maxillofacial Surgery)
Zur Hausen H. Papillomavirus infections – a major cause of human cancers. Biochem Biophys Acta 1996; 1288: F55–F78.
Shima K, Kobayashi I, Saito I, Kiyoshima T, Matsuo K, Ozeki S, Ohishi M, Sakai H. Incidence of human papillomavirus 16 and 18 infection and p53 mutation in patients with oral squamous cell carcinoma in Japan. BJOMS 2000; 35:5: 445-450
Miller CS, Johnstone BM. Human papillomavirus as a risk factor for oral squamous cell carcinoma: A meta-analysis, 1982–1997. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2001;91:622–35.
Competing interests: No competing interests
What is human life worth?
A medico-legal expert, usually called to make a valuation for insurance or compensation purposes, should be able to answer to the question.
Different types of assessment tools can help him: tables of guidance developed by Scientific Societies (1), guides enclosed to insurance contracts or to specific legislations, only used by some Countries and applied to limited fields (e.g. in Italy, lists relating to injuries caused by accidents at work or by road traffic), and the important support provided by court sentences (2).
However, despite our attitude to assign a precise economic value to people (3), taking into account their age, their gender, their social status, their ability to produce an income, after reading the discussion of Adams BD and Benger J (4), we are not able to find, so poor craftsmen of legal medicine as we are, a “fixed” answer to the question underlying the paper’s title.
Indeed, one thing is to evaluate the permanent impairment, applying an utilitarian-productivist parameter from a prospective in which, for compensatory or indemnity reasons, someone is required to pay the financial damages awarded to an individual who has suffered measureable physical or psychological loss following injury. Another thing is to reason in the same terms in order to guide the organizational options relating to health policy.
In view of a scientific evidence that seems to confirm the hypothesis of a very limited survival rate (not exceeding 10%) for those subjects who have suffered a cardiac arrest outside the hospital, does it make sense to ask ourselves if it is justified to guarantee next transport to the hospital for further assistance, in addition to the adequate intervention on site for cardiopulmonary resuscitation?
The question does not make sense, if we consider that such an organization, economically onerous, leads to a failure in 90% of cases, in a world that requires, at least, a balanced budget.
The question does not make sense, if we require the evidence demonstrating the efficacy of adrenalin administration during a cardiac arrest (5), scotomizing that “absence of evidence is not evidence of absence” (6).
The question does not make sense even if we follow the view that informed consent has the role of ultimate decision-maker: giving resuscitation and transport only to those people who have been informed about the risk to survive in a persistent vegetative state and have decided to accept such a scenario in advance (7).
Nevertheless, such an important choice could be modified over time, leaving the first aider, facing a man into cardiac arrest, in the dilemma: is the declaration of his desire, maybe done a year ago, still valid?
We need evidence based health policy rather than economic policy based evidence, rewording what Oliver D said (8).
Subtracting a 10% chance to survive in the long-term to a subject in cardiac arrest occurred outside the hospital, on the basis of economic calculations, means human capital is suddenly depreciated and it is worth less than an hospital bed.
If we accept this approach, the next step will be the proposal to close the Emergency Rooms, too much onerous structures compared with the goal to guarantee a long-term survival to all ESI level 1 patients, who are a small number compared to the totality of subjects admitted at ESI level 2-5, who could moreover benefit a different management of waiting lists.
Let us reverse the perspective and see the patient in cardiac arrest as a common patient to whom the maximum organising and logistical effort is to be made – avoiding to extend the agony at all cost with disproportionate treatments - because his human capital (9) is worth more than any utilitarian consideration.
After all, as a broadly acknowledged religious principle states, “whoever saves one life, saves the world entire”(10).
1. Cocchiarella L, and Andersson G B J. Guides to the evalutation of permanent impairment. First Ed, 2002 American Medical Association;
2. Saha K, and Shetty D. Are large compensation payouts for negligence good for medicine in India? BMJ, 2014; 349:g5229;
3. Gross E L. Impairment, disability, and work issues. In Legal Medicine, 6th ed. Mosby, 2004; 61: 585-594;
4. Adams B D, and Berger J. Should we take patients to hospital in cardiac arrest?. BMJ, 2014; 349:g5659;
5. Perkins GD, and Nolan JP. Early adrenaline for cardiac arrest. BMJ, 2014; 348:g3245;
6. Sedgwick P. Understanding why “absence of evidence is not evidence of absence”. BMJ 2014;349:g4751;
7. McCartney M. Adrenaline in cardiac arrest: it’s unethical for patients not to know. BMJ, 2014; 349: g5258;
8. Oliver D. Preventing hospital admission: we need evidence based policy rather than “policy based evidence”. BMJ, 2014; 349:g5538;
9. Amidon S. Human Capital: a novel. Picador, First Ed, 2005
10. Talmud Yerushalmi, Sanhedrin 4-12; The Quran, Surah V.
Competing interests: No competing interests
We would like to respond to comments made by Dr. Yui in three rapid responses to the BMJ article by Cohen  on 4, 11 and 16 September 2014.
The author raises questions about why dabigatran is marketed without monitoring of plasma dabigatran concentrations, about the nature of the exposure–response relationships for efficacy and safety of dabigatran, and whether an optimal plasma trough dabigatran concentration could be determined.
The most important reason why dabigatran etexilate is labeled without monitoring is the fact that no monitoring was undertaken in the pivotal RELY trial , which formed the basis for registration with over 18,000 patients. In RE-LY, superiority to well controlled dose-adjusted warfarin was achieved for efficacy with the dabigatran etexilate 150 mg twice daily dose, and reduced bleeding was achieved with the dabigatran etexilate 110 mg twice daily dose. Both doses reduced significantly the intracranial bleed rate compared to warfarin. Any putative additional benefit in clinical outcomes with adjusted dabigatran dosing, based on monitoring on the basis of retrospective analysis, would be speculative.
In a recent publication , cited by Dr. Yui, it has been hypothesized that, for patients above the 90th or below the 10th percentile of trough plasma dabigatran concentrations for the 150 mg twice daily or 110 mg twice daily doses, respectively, dose adjustment might improve their benefit–risk ratio. Multiple analyses have shown that patient characteristics (such as age [3, 4] and renal function  – both of which are correlated with dabigatran plasma level) are critical factors for the benefit–risk assessment of dabigatran. This is already reflected by the inclusion of such factors in treatment labels. The additional impact of plasma levels remains a hypothesis. The favourable clinical profile of fixed doses of dabigatran in comparison to warfarin was reaffirmed by the FDA in one of the largest real-world analyses of its kind, comprising 134,000 patients above 65 years .
We understand that the author concludes that BI could not identify a relationship between dabigatran plasma concentration and efficacy based on the logistic regression analyses. The respective analyses have been performed by the FDA and by Boehringer Ingelheim (BI) and indicate an exposure–efficacy relationship of borderline significance . The FDA analyzed the data using a Cox model which nearly reached significance. Although a relationship between exposure and efficacy was not identified when BI used a univariate logistic regression model (containing no explanatory variables beyond concentration), BI subsequently performed a multivariate logistic regression analysis which showed a significant relationship between exposure and efficacy (odds ratio 0.562, 95% CI 0.320, 0.987; P = 0.0448) .The minor difference between the P values is explained by the use of different methods. BI explored the data using several different methods. All analyses using different methods reached the same conclusion.
The relationship between exposure and safety and/or efficacy is well described in all submission documents provided to health authorities worldwide. BI never denied these relationships.
Based on decades of oral anticoagulation with vitamin K antagonists, with doses adjusted based on international normalized ratios (INRs), it may be attractive to define target plasma concentration ranges and adjust dosing based on plasma level monitoring for dabigatran. The author estimates the optimal concentration range of dabigatran for both efficacy and safety between 60 and 200 ng/mL. This may have been based on the concentration ranges where HR less than 1.0 in Figure 3 . However, the HR = 1.0 lines in Figure 3 are relative to the responses at median concentrations. Using median concentration as a comparator is somewhat arbitrary and therefore is not suitable for deriving an optimal therapeutic range. Furthermore, if this estimation is based on Figures 2 and/or 3 in reference , this estimated range must be limited to patients with the same characteristics as in the graphs, namely a 72-year-old male with prior stroke and diabetes (Figure 2) and a 71-year-old patient with CHADS2 score of 2 (Figure 3).
Extrapolation to other patient types is not warranted. As can be seen in Figure 1 from the same paper , differences in age alone have marked effects on both safety and efficacy, and identical concentrations correspond to different risks and benefit–risk balances depending on age. It is this observation that led Reilly et al. [3, 8] to conclude that there is no single plasma concentration range that provides optimal benefit–risk for all patients.
The author suggests that BI should compare the responses observed at a range of dabigatran concentrations against warfarin. However, such an approach is not possible as no adequate comparison group within the warfarin-treated patients can be defined. In order to ensure a fair assessment of the effect of, for example, high dabigatran concentration relative to treatment with warfarin, the warfarin comparator group would need to be sufficiently large and match the dabigatran-treated group. The fixed-dose trough level of dabigatran depends on age, creatinine clearance and other variables, whereas the dose adjustment of warfarin based on INR implicitly adjusts for several, even unmeasured, impacting variables. Therefore, no adequate comparison group within the warfarin-treated patients can be defined for treatment with certain trough levels of dabigatran within the RE-LY database.
Joerg Kreuzer, Therapeutic Area Head Medicine Cardiovascular, Boehringer Ingelheim GmbH, Ingelheim, Germany
Paul Reilly, Global Team Lead, Clinical Development Cardiovascular, Boehringer Ingelheim Pharmaceuticals Inc., Ridgefield, CT, USA
Hugo Maas, Pharmacometrician, Boehringer Ingelheim GmbH & Co. KG, Biberach an der Riss, Germany
Herbert Noack, Expert Statistician, Boehringer Ingelheim GmbH, Ingelheim, Germany
1. Cohen D. Dabigatran: how the drug company withheld important analyses. BMJ 2014;349:g4670.
2. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009;361(12):1139-51.
3. Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, et al. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014;63(4):321-8.
4. Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011;123(21):2363-72.
5. Hijazi Z, Hohnloser SH, Oldgren J, Andersson U, Connolly SJ, Eikelboom JW, et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation 2014;129(9):961-70.
6. FDA Drug Safety Communication: FDA study of Medicare patients finds risks lower for stroke and death but higher for gastrointestinal bleeding with Pradaxa (dabigatran) compared to warfarin – 13 May 2014. http://www.fda.gov/Drugs/DrugSafety/ucm396470.htm. Last accessed 17 September 2014.
7. Centre for Drug Evaluation and Research: Clinical Pharmacology Review NDA 22-512, Dabigatran. http://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/022512Orig1s000Cl.... Last accessed 30 September 2014.
8. Reilly PA, Connolly SJ, Yusuf S, Eikelboom JW, Ezekowitz MD, Wallentin L; RE-LY Investigators. Reply: regarding the effect of dabigatran plasma concentrations. J Am Coll Cardiol 2014;63(25 Pt A):2885-6.
Competing interests: Employees of Boehringer Ingelheim
As Jocalyn Clark outlines, the solutions for global health incontriversibly lie outwith healthcare. Then again, this is hardly surprising: so do the most pressing domestic health problems of today. The interplay of power, politics and health can be seen throughout debates from minimum alcohol pricing and e-cigarettes to healthcare rationing and NHS privatisation.
A firm conceptual understanding of public health, including the wider determinants of health, both on a national and international scale, have become fundamental attributes to the modern doctor's understanding of health. The post-2015 development agenda has great implications for health and medical professionals have an important voice in this debate.
The demand for global health education is there, yet here the content of current medical curricula falls considerably short; a set of Global health learning outcomes for medical students in the UK have been proposed which could form the framework for an adapted curricula.
Even as global health continues to attract cross-disciplinary contributors and collaborations, the medical profession continues to have an central role. Public health specialists may spearhead efforts, but population health is of relevance for all clinicians in order to best serve their patients. It is time all doctors were equipped with the skills they need to effectively tackle the great health problems of our day.
 Clark J. Do the solutions for global health lie in healthcare?. BMJ 349 (2014): g5457.
 Martineau F, et al. International health graduates—career path experience. The Lancet 379.9831 (2012): 2051-2052.
 Bhutta,A., et al. Education of health professionals for the 21st century: a global independent Commission. The Lancet 375.9721 (2010): 1137-1138.
 Johnson O, et al. Global health learning outcomes for medical students in the UK. The Lancet 379.9831 (2012): 2033-203
Competing interests: No competing interests
the authors start with observation about uk doctors feeling under continual change in regulation. I agree. But what is not stated is that regulation changes have to be proportional to our workload, the plethora of other regulations affecting health care organisations, and must have face validity for the profession. The latter I consider is severely lacking. I am concerned that employers are stakeholders in proposed changes. Employers have many agendas, some of which are not compatible with quality of care and doctors regulatory duties, but more related to profit and cutting costs, and have power over their employees as employers and therefore significant conflict of interests. In particular the response of a lot of Trusts in relation to whistle blowing is an example of employers response to doctors responding according to our regulatory duties.
Competing interests: No competing interests
We fully agree with Etminan that guidelines are important to support the reporting of high quality data from pharmacoepidemiological studies and their appropriate evaluation.1 Etminan writes that new reporting guidelines are urgently needed. However, several guidelines already exist.
In Europe, the ENCePP Guide on Methodological Standards in Pharmacoepidemiology2 offers public electronic access to internationally agreed guidelines, such as the key and widely-adhered to Good Pharmacoepidemiology Practice guidelines from the International Society for Pharmacoepidemiology. A specific chapter describes communication issues, including reporting of results. The guide is updated annually and amended as necessary in response to comments received. The ENCePP Checklist for Study Protocols stimulates researchers to consider important principles when designing a pharmacoepidemiological study and writing a study protocol including a section for communication of study results.3 The PROTECT project is issuing recommendations to reduce inconsistencies between results of pharmacoepidemiological studies by developing methodological standards applicable to different safety issues using a range of data sources.4,5 In addition, the Good pharmacovigilance practices provide a set recommendations for the format and content of the study protocols and study reports.6 In the United States, similar efforts are underway and the US Food and Drug Administration (FDA) released guidance on the conduct and reporting of pharmacoepidemiology safety studies that use electronic healthcare data.7 Therefore, with existing guidance and checklists for reporting of epidemiological studies, including STROBE, researchers have good resources to design, conduct and report results of pharmacoepidemiological studies.
Etminan states that absence of reporting guidelines for pharmacoepidemiological studies may lead to poor quality data with inconsistent findings. We suggest that it is the full recognition and application of existing guidance, together with its regular updating based on feedback and experience that is needed, rather than development of new guidance.
1 Etminan M. Reporting guidelines for pharmacoepidemiological studies are urgently needed. BMJ 2014;349:g5511 doi: 10.1136/bmj.g5511 (17 September 2014).
2 The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). Standards and Guidances. http://www.encepp.eu/standards_and_guidances/methodologicalGuide.shtml
3 The European Network of Centres for Pharmacoepidemiology and Pharmacovigilance (ENCePP). Standards and Guidances. http://www.encepp.eu/standards_and_guidances/checkListProtocols.shtml
4 The Pharmacoepidemiological Research on OuTcomes of Therapeutics by a European Consortium (PROTECT). http://www.imi-protect.eu/about.shtml
5 Abbing-Karahagopian V, Kurz X, de Vries F, van Staa TP, Alvarez Y, Hesse U, Hasford J, Dijk Lv, de Abajo FJ, Weil JG, Grimaldi-Bensouda L, Egberts AC, Reynolds RF, Klungel OH. Bridging differences in outcomes of pharmacoepidemiological studies: design and first results of the PROTECT project. Curr Clin Pharmacol. 2014 May;9(2):130-8.
6 European Medicines Agency. Guideline on good pharmacovigilance practices (GVP) Module VIII – Post-authorisation safety studies (Rev 1). http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guidelin...
7 US Food and Drug Administration. Guidance for Industry and FDA Staff: Best Practices for Conducting and Reporting Pharmacoepidemiologic Safety Studies Using Electronic Healthcare Data. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformati...
Competing interests: RR is an employee and shareholder of Pfizer, Inc. SP declares research grants, advisory roles and regulatory deliverables, mostly funded by pharmaceutical companies. XK, KB, LP, PA, OK and SP are members of ENCePP Steering Committe or working groups. XK, PA, OK and RR are members of PROTECT. XK, OK and RR are contributors to the ISPE Good Practice Guidance. RR was Member of FDA Panel that provided input for development of FDA Guidance. The views expressed in this letter are the personal views of the author(s) and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or one of its committees or working parties.