Medicines Regulatory Authorities Research Articles

The Belgian commitment to pharmaceutical quality: a model policy to improve quality assurance of medicines available through humanitarian and development programs

Today, a combination of globalization of pharmaceutical production, lack of regulatory harmonization, and weakness of Medicines Regulatory Authorities, creates the “perfect conditions” for poor-quality medicine to circulate in the global market and to penetrate the less-regulated countries. Medicines regulation is the responsibility of the national regulatory authorities in the recipient country, but in the poorer countries, in practice, the responsibility of supply of quality-assured medicines is often taken by Non-Governmental Organizations and other implementers. But with some notable exceptions, many donors lack a pharmaceutical procurement policy with adequate quality requirements; and many implementers lack the skills and expertise needed to orient themselves in the complex web of global pharmaceutical supply. Thus, patients served by humanitarian or development programs may remain exposed to the risk of poor-quality medicines.When public money is used to purchase medicines for medical programs to be carried out overseas, adequate policies should be in place to assure that the same quality requirements are set that would be required for medicines marketed in the “donor” country.We will describe here a policy recently adopted in Belgium, i.e. the “Commitment to Quality Assurance for Pharmaceutical Products”, signed in October 2017 by the Vice Prime Minister and Minister for Development Cooperation and 19 Belgian implementing agencies. By signing the new policy, the counterparts committed to ensure quality of medicines in the programs funded by Belgium’s Official Development Assistance, and to build quality-assurance capacity in the recipient countries. Implementers are requested to integrate in their financing applications a section for pharmaceutical quality assurance, with a justified budget. They are also invited to consider how costs could be rationalized and mutualized by aligning the strengths of the various implementers. This model policy has the potential to be considered for adoption by other donors, to help to reduce the current multiple standards in pharmaceutical quality, and to contribute to protect vulnerable communities from the plague of poor-quality medicines.

Real-world effects of medications for chronic obstructive pulmonary disease: protocol for a UK population-based non-interventional cohort study with validation against randomised trial results

IntroductionChronic obstructive pulmonary disease (COPD) is a progressive disease affecting 3 million people in the UK, in which patients exhibit airflow obstruction that is not fully reversible. COPD treatment guidelines...

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Editorial introductions

Pre-Surgical Metformin in Uterine Malignancy (Premium): A Multi-Centre, Randomised Double-Blind, Placebo-Controlled Phase 3 Trial

Background: Endometrial cancer is strongly associated with obesity and insulin resistance. Metformin, an insulin sensitizer, reduces endometrial tumour growth in vitro. Pre-surgical window studies allow rapid in vivo assessment of anti-tumour activity. Previous window studies found short-term metformin treatment reduced endometrial cancer proliferation but these lacked methodological rigor, particularly control arms for comparison. PREMIUM was designed to definitively determine the anti-proliferative effect of metformin in vivo using a robust window study design. Methods: A randomised, double-blind, placebo-controlled phase 3 trial was conducted in five hospitals in England. Eligible women had biopsy-proven atypical endometrial hyperplasia or endometrioid endometrial cancer and were not receiving anti-diabetic medication. Women were computer-randomised (1:1) using the permuted block method (block size 30) to metformin (850mg daily for three days, increased to twice daily thereafter) or placebo for 1-5 weeks, until the evening before surgery. Participants and researchers were blinded to treatment group allocation. The primary outcome was post-treatment immunohistochemical expression of Ki-67 in the hysterectomy specimen; a modified intention-to-treat analysis included all women taking at least one dose of study drug and undergoing tumour biopsy within 72 hours of treatment discontinuation. Safety analysis included all women receiving at least one dose of drug. Findings: Between February 2015-2017, 93 women were randomised to metformin (n=47) or placebo (n=46), with five withdrawals (four without taking any drug and one because of no post-treatment biopsy). Eighty-eight women were included in the final analysis (metformin n=45, placebo n=43). There was no overall difference in post-treatment Ki-67 between the metformin and placebo arms, in an ANCOVA analysis adjusting for baseline Ki-67 expression (mean difference -0·57%, 95% CI -7·57% to 6·42%, p=0·87). Women receiving metformin reported significantly more adverse events than those receiving placebo (37 [82·2%] vs. 25 [58·1%], p=0·001), especially nausea and vomiting (17 [37·8%] vs. 6 [13·6%], p=0·015), diarrhoea (23 [51·1%] vs. 6 [13·6%], p=0·0003) and anorexia (9 [20·0%] vs. 0 [0·0%], p=0·003), but did not discontinue treatment.. Interpretation: Short term treatment with standard diabetic doses of metformin does not reduce tumour proliferation in women with endometrial cancer awaiting hysterectomy. This study does not support a biological effect of metformin in endometrial cancer and casts doubt on its potential application in the primary and adjuvant treatment settings. Future studies should focus on primary and secondary prevention of endometrial cancer and pursue longer treatment windows. Clinical Trial Number: The study was registered on UK and European clinical trials databases (ISRCTN 88589234, EudraCT number 2014-000991-25) and is closed to recruitment. Funding Statement: National Institute for Health Research Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: All participants provided written, informed consent. The trial was approved by the North West Research Ethics Committee (14/NW/1236), Medicine and Healthcare Products Regulatory Authority (MHRA, reference 21387/0232/001-0001) and local Research and Development departments.

Adeno-Associated Virus Vectored Immunoprophylaxis to Prevent HIV: A Phase 1 Randomized Controlled Trial in Healthy Adults

Background: A preventive vaccine for HIV is a critical public health need. Adeno-associated virus (AAV) mediated antibody gene delivery could be an alternative to immunization to induce sustained expression of neutralizing antibodies to prevent HIV. We conducted a first-in-human, phase 1 study of rAAV1-PG9DP, a recombinant AAV1 vector encoding the gene for PG9, a broadly neutralizing antibody against HIV. Methods: The trial was a phase 1, randomized, blinded, placebo-controlled, dose-escalation study at a single center in the UK. Healthy, HIV-uninfected men aged 18-45 were randomly assigned (3:1) to intervention or control in one of four dose-escalating cohorts (4x1012 vector genomes(vg), 4x1013 vg, 8x1013 vg or 1·2x1014 vg). Volunteers received intramuscular injection with rAAV1-PG9DP or placebo in the deltoid or quadriceps and were followed for 48 weeks. The primary objective was safety and tolerability. A secondary objective was to evaluate PG9 expression in serum and related HIV neutralization activity. This trial is registered with ClinicalTrials.gov, number NCT01937455. Findings: 21 volunteers were enrolled between February 10, 2014 and February 28, 2017 and completed 48 weeks follow-up. Reactogenicity was generally mild or moderate and self-limited. There were no probably or definitely related adverse events and no serious adverse events. We detected PG9 by HIV neutralization in serum of four volunteers, and by RT-PCR in muscle biopsies of four volunteers. We did not detect PG9 by ELISA in serum. PG9 anti-drug antibody was present in 10 volunteers in the higher dose groups. Both anti-AAV1 antibodies and AAV1 specific T-cell responses were detected. Interpretation: Intramuscular administration of rAAV1-PG9DP in healthy men was safe and well-tolerated. Antibody expression was detected directly in muscle and indirectly in serum, and anti-drug antibodies were induced, indicating PG9 expression. Future studies should explore higher doses of AAV, alternative AAV serotypes and gene expression cassettes, or other broadly neutralizing HIV antibodies. Trial Registration number: This trial is registered with ClinicalTrials.gov, number NCT01937455. Funding: International AIDS Vaccine Initiative, United States Agency for International Development (USAID), Bill & Melinda Gates Foundation, US National Institutes of Health Declaration of Interest: Jim Ackland reports receiving consulting fees from International AIDS Vaccine Initiative during the course of the study. Fraser Wright reports grants from National Institutes of Health during the conduct of the study. In addition, Dr. Wright has a patent US 9,408,904 licensed to Spark Therapeutics. Ethical Approval: The protocol was approved by the University of Surrey Ethics Committee, the NRES Bristol Research Ethics Committee and the UK Medicines and Healthcare products Regulatory Authority and conducted in compliance with Good Clinical Practices and the Declaration of Helsinki guidelines.

Safety assessment of concurrent statin treatment and evaluation of drug interactions in China.

Objectives:Acute muscle injury and potentially fatal rhabdomyolysis may occur with the use of statins and certain enzyme inhibitors, but data on this topic from China are quite limited. This study aimed to measure the concomitant exposure of patients to different statins and their enzyme inhibitors or interacting medications in 76 hospitals in six Chinese cities.Methods:Prescription database was retrieved from Hospital Prescription Analysis Cooperation Project from January 2015 to December 2015, covering 76 tertiary facilities in six cities in China. Every evidence-based enzyme inhibitor was included, and labeled enzyme inhibitors and other relevant information were identified and obtained using the Drug Safety Update from the UK Medicines and Healthcare Products Regulatory Agency. The proportions of different statin types among all patients and those co-medicated with their inhibitors were examined.Results:A total of 296,765 patients exposed to statins were included in this study. 80% of patients (n = 144,863, 80.5%) were concomitantly prescribed a CYP3A4-metabolized statin with an interacting drug during the study period. Among those prescribed a non-CYP3A4-metabolized statin, 40.0% of patients were concomitantly given an interacting drug, and approximately 20% of patients were concomitantly given a labeled inhibitor, predominantly calcium channel blockers, other statins, and fibrates. Rates of co-prescription were higher in patients aged over 65 years and in patients taking high-dose statins.Conclusion:Statins were frequently co-prescribed with metabolic inhibitors in China, where drug safety strategy on highlighting warnings and contraindications of statins are still lacking. For high-dose statins patients who are over 65 years and co-administered with any metabolic inhibitors, prescribers and pharmacists should be more concerned in order to prevent adverse drug reactions.

Predicting prostate cancer progression: protocol for a retrospective cohort study to identify prognostic factors for prostate cancer outcomes using routine primary care data

IntroductionProstate cancer is the most common cancer in men in the UK, with nearly 40 000 diagnosed in 2014; and it is the second most common cause of male cancer-related...

The African Medicines Regulatory Harmonization Initiative: Progress to Date

The African Medicines Regulatory Harmonization Initiative (AMRH) has contributed to reduce marketing authorization timelines in East African Community and the Southern African Development Community member states. Challenges still exist in using the outcome of the regional joint dossier review processes for national decision making processes by the national medicines regulatory agencies. Progress in domestication of the African Union Model Law on Medical Products Regulation by twelve countries provides basis for improving regulatory systems. This is coupled by the designation of eleven regional centers of regulatory excellence which will ensure sustainable training programmes and subsequent increase in Africa’s regulatory workforce. The Biennial Scientific Conferences on Medical Products Regulation in Africa is a strategic platform for knowledge and ideas exchange among key stakeholders in the pharmaceutical sector. The ongoing alignment of the African Vaccines Regulators Forum, the Network of Medicines Control Laboratories in Sub-Saharan Africa, Pan African Harmonization Working Party on the regulation of medical devices and diagnostics, the planned establishment of a forum for blood and blood with AMRH serves as a solid foundation for establishment of the African Medicines Agency (AMA). AMA will be a key driver to remove technical barriers for trading among the region countries by contributing to the continental socio-economic development agenda.

Drooling Reduction Intervention randomised trial (DRI): comparing the efficacy and acceptability of hyoscine patches and glycopyrronium liquid on drooling in children with neurodisability

ObjectiveInvestigate whether hyoscine patch or glycopyrronium liquid is more effective and acceptable to treat drooling in children with neurodisability.DesignMulticentre, single-blind, randomised controlled trial.SettingRecruitment through neurodisability teams; treatment by parents.ParticipantsNinety children...

Medicines Regulation in Africa: Current State and Opportunities.

Sound regulatory systems are critical for protecting public health against use of medical products which do not meet international standards of quality, safety and efficacy. This review provides a summary of the current status of National Medicines Regulatory Authorities (NMRAs) in Africa, and various initiatives that have been established to improve their performance. All countries in Africa (except Sahrawi Republic), have NMRAs but their organizational set-up and functionality is variable. Some are located within Ministries of Health and others are semi-autonomous. There is progressive improvement in regulatory capacity, particularly in quality control and post-marketing surveillance, pharmacovigilance and clinical trials oversight. The African Vaccines Regulatory Forum, African Medicines Regulatory Harmonization Initiative, Network of Official Medicines Control Laboratories and WHO Prequalification Scheme have helped countries strengthen their regulatory capacities. The potential establishment of the African Medicines Agency (AMA) in 2018 is an opportunity to improve NMRAs’ capacity in Africa.

Use of driving-impairing medicines by a Spanish population: a population-based registry study

ObjectiveTo assess the use of driving-impairing medicines (DIM) in the general population with special reference to length of use and concomitant use.DesignPopulation-based registry study.SettingThe year 2015 granted medicines consumption data...

Incidence of shoulder dislocations in the UK, 1995–2015: a population-based cohort study

ObjectiveThis cohort study evaluates the unknown age-specific and gender-specific incidence of primary shoulder dislocations in the UK.SettingUK primary care data from the Clinical Practice Research Datalink (CPRD) were used to...

Optimized Medical Product Regulation in Mexico: A Win-Win for Public and Economic Health.

Medicines regulators, while performing a vital public health activity, are often perceived as both negative cost centers for governments and as impediments to innovation and economic development. The Mexican government recently undertook a regulatory optimization program focused on transforming the Mexican medicines regulatory pathway into one that is efficient, value-added, aligned with international norms, resource accountable, and one that protects and promotes public health, while also facilitating economic development. To facilitate the implementation of a new national access to medicines policy, the national government and the Mexican medicines regulatory agency instituted a multifaceted series of regulatory and legal reforms, which are described in this paper. These reforms encompassed multiple aspects of the regulatory oversight of medicines: administrative processes, clinical trials oversight, reliance on market authorization information and reports (ie, "work products") of other trusted regulators, and validation of activities by both Pan American Health Organization (PAHO) and WHO. These reforms have resulted in a marked positive impact on the availability of safe, effective, quality medicines at lower costs for Mexicans, both in the private and public sectors, while simultaneously facilitating expansion of the Mexican pharmaceutical industry. The regulatory optimization approach undertaken by Mexico could be a useful model for other countries that are trying to provide appropriate public health protection to their citizens, facilitate access to needed quality medicines, and encourage local economic development.

The cost of entry: An analysis of pharmaceutical registration fees in low-, middle-, and high-income countries.

BackgroundAdvances in pharmaceuticals offer improved health outcomes for a wide range of illnesses, yet medicines are often inaccessible for many patients worldwide. One potential barrier to making medicines available to all is the cost of product registration, the fees for regulatory review and licensing for the sale of medicines beyond the cost of clinical trials, if needed.Methods and findingsWe performed a cross-sectional analysis of pharmaceutical registration fees in low-, middle-, and high-income countries. We collected data on market authorization fees for new chemical entities and for generic drugs in 95 countries. We calculated measures of registration fee size relative to population, gross domestic product (GDP), and total health spending in each country. Each of the 95 countries had a fee for registering new chemical entities. On average, the ratio of registration fees to GDP was highest in Europe and North America and lowest in South and Central America. Across individual countries, the level of registration fees was positively correlated with GDP and total health spending, with relatively few outliers.DiscussionWe find that, generally speaking, the regulatory fees charged by medicines regulatory authorities are roughly proportional to the market size in their jurisdictions. The data therefore do not support the hypothesis that regulatory fees are a barrier to market entry in most countries.

Direct oral anticoagulants: analysis of worldwide use and popularity using Google Trends.

Four direct oral anticoagulants (DOACs) have been approved for clinical use by many medicines regulatory agencies around the world. Due to increasing use of these drugs in routine practice, we planned an original study to investigate their worldwide diffusion using a popular Web-search engine. Two electronic searches were performed using Google Trends, the former using the keywords "warfarin" AND "heparin" AND "fondaparinux", and the latter using the keywords "warfarin" AND "dabigatran" AND "rivaroxaban" AND "apixaban" AND "edoxaban", both using the search criterion "prescription drug". No language restriction was applied, and the searches were carried out from the first date available in Google Trends (January 1st, 2004) to present time (June 1st, 2017). The median Google Trends score of warfarin (i.e., 86) was consistently higher than that of heparin (54; P<0.001), fondaparinux (6; P<0.001), dabigatran (11; P<0.001), rivaroxaban (5; P<0.001), apixaban (1; P<0.001) and edoxaban (1; P<0.001). Specific analysis of the trends shows that the score of warfarin exhibits a highly significant decrease over time (r=-0.40; P<0.001), whilst that of heparin has remained virtually unchanged (r=0.12; P=0.127), and that of fondaparinux has marginally increased (r=0.16; P=0.038). As regards DOACs, the scores of these drugs significantly increased during the search period (dabigatran, r=0.79; rivaroxaban, r=0.99; apixaban, r=0.98; edoxaban, r=0.78; all P<0.001). When the analysis was limited to the past five years, the dabigatran score significantly decreased (r=-0.57; P<0.001), whereas that of the other DOACs exhibited an even sharper increase. Most Google searches for DOACs were performed in North America, central-eastern Europe and Australia. The results of our analysis suggest that the popularity of DOACs is constantly increasing around the world, whereas that of warfarin has exhibited a constant and inexorable decline.

Decrease in Switches to 'Unsafe' Proton Pump Inhibitors After Communications About Interactions with Clopidogrel.

In 2009 and 2010 medicines regulatory agencies published official safety statements regarding the concomitant use of proton pump inhibitors and clopidogrel. We wanted to investigate a change in prescription behaviour in prevalent gastroprotective drug users (2008-2011). Data on drug use were retrieved from the Out-patient Pharmacy Database of the PHARMO Database Network. We used interrupted time series analyses (ITS) to estimate the impact of each safety statement on the number of gastroprotective drug switches around the start of clopidogrel and during clopidogrel use. After the first statement (June 2009), significantly fewer patients switched from another proton pump inhibitor to (es)omeprazole (-14.9%; 95% CI -22.6 to -7.3) at the moment they started clopidogrel compared to the period prior to this statement. After the adjusted statement in February 2010, the switch percentage to (es)omeprazole decreased further (-4.5%; 95% CI -8.1 to -0.9). We observed a temporary increase in switches from proton pump inhibitors to histamine 2-receptor antagonists after the first statement; the decrease in the reverse switch was statistically significant (-23.0%; 95% CI -43.1 to -2.9). With ITS, we were able to demonstrate a decrease in switches from other proton pump inhibitors to (es)omeprazole and an increase of the reverse switch to almost 100%. We observed a partial and temporary switch to histamine 2-receptor antagonists. This effect of safety statements was shown for gastroprotective drug switches around the start of clopidogrel treatment.

Post Marketing Surveillance of Anti-malarial Medicines in Tanzania

Background: Presence of substandard and falsified anti-malarial medicines is a major concern in countries with high prevalence of malaria. Systematic assessment and monitoring of anti-malarial medicines circulating on the market is critical to National Medicines Regulatory Authorities (NMRAs) in ensuring quality of these products in the fight against the burden of malaria disease. Objectives: This survey was conducted by Tanzania Food and Drugs Authority (TFDA) with the aim of monitoring the quality of registered anti-malarial medicines circulating on the market in Tanzania Mainland. Methodology: Purposive sampling method was used in obtaining the samples of anti-malarial medicines from 21 out of 26 regions of Tanzania Mainland between 2012 and 2015. These medicines were collected from ports of entry, domestic manufacturers, Medical Stores Department (MSD), wholesalers, hospitals, health centres, dispensaries and retail pharmacy outlets. Samples were subjected to product information review and quality screening using Global Pharma Health Fund® (GPHF) Mini-Lab kits. Samples failing or yielding doubtful results and ten percent (10%) of passed samples were subjected to tier two confirmatory testing using full pharmacopeial monographs at TFDA-WHO prequalified quality control laboratory. Results: A total of 1,444 samples of oral solid formulations from different types of anti-malarials were sampled. Out of these, 132 (9.1%) failed labelling product information requirements. A high percentage of samples passed identification test by TLC (97.9%) and disintegration test (99.8%). A 4.8% (7/145) failure rate was observed in confirmatory testing of which one of the failed samples namely quinine sulphate 300 mg tablets was confirmed to be falsified. Conclusion: These results indicate the importance of post marketing surveillance as an additional measure of assuring the quality of medicines by Regulators following marketing authorization and as a way of detecting falsified medicines circulating on the market.

The Current Status of Sakigake Designation in Japan, PRIME in the European Union, and Breakthrough Therapy Designation in the United States.

Following the Breakthrough Therapy Designation system in 2012 in the United States, the Sakigake Designation was introduced in 2015 in Japan, and PRIME (PRIority MEdicines) was started in 2016 in the European Union. Each system aims at giving patients better access to innovative drugs and regenerative medicine products by providing product developers with generous regulatory and scientific support from an early development stage. So far, the designation systems have operated independently in each region, and no products with the same indication have been designated commonly under the 3 designation systems. However, no designation system excludes a product designated under another system, which allows the possibility of an applicant to seek all 3 designations; this may happen in the near future. Therefore, an understanding of the current situation under each designation system will contribute to effective operation of each system as well as identification of further collaborative activities between the European Medicines Agency; Japan's Ministry of Health, Labour and Welfare/Pharmaceuticals and Medical Devices Agency; and the United States Food and Drug Administration. Such collaborations can be successful because these organizations have already established a close relationship through international activities such as the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) and the International Coalition of Medicines Regulatory Authorities (ICMRA).

Medicines Counterfeiting in Africa: A View from Zimbabwe

With the sprouting of unregulated outlets on the streets of Zimbabwe, common questions that are raised include: (i) what is the Medicines Control Authority of Zimbabwe (MCAZ) doing about these street vendors? and (ii) is the law against unregulated markets and proliferation of substandard and falsified (SF) medicines being actively enforced? There is no doubt that this is a new challenge for MCAZ because of the risks involved with SF medicines. Notwithstanding the rather strong regulatory framework for the regulated market that the MCAZ has major control over, and its demonstrable regulatory prowess over the last 20 years as a National Medicines Regulatory Authority (NMRA), MCAZ is increasingly challenged to take a leading role in addressing this rising phenomenon. MCAZ has attempted to address the problem through collaboration with the Zimbabwe Republic Police (ZRP), public education and inspections by port officials at ports of entry. However, the problem still persists. A general lack of concrete qualitative and quantitative data on the commonly encountered SF medicinal products on the Zimbabwe market is another major issue. This is evidently a multi-layered problem and as the Shona adage goes “chara chimwe hachitswanye inda” (loosely translated “one thumb cannot crush all lice”), there is need for engaging local and regional partners in a bid to fulfil the MCAZ's mandate of protecting public health by ensuring medicines and medical devices intended for sale and distribution in Zimbabwe, are safe, effective and of good quality.

Polyelectrolyte coating on superparamagnetic iron oxide nanoparticles as interface between magnetic core and biorelevant media

Nanoparticles do not exist in thermodynamical equilibrium because of high surface free energy, thus they have only kinetic stability. Spontaneous changes can be delayed by designed surface coating. In biomedical applications, superparamagnetic iron oxide nanoparticles (SPIONs) require an optimized coating in order to fulfil the expectation of medicine regulatory agencies and ultimately that of biocompatibility. In this work, we show the high surface reactivity of naked SPIONs due to ≡Fe-OH sites, which can react with H+/OH- to form pH- and ionic strength-dependent charges. We explain the post-coating of naked SPIONs with organic polyacids via multi-site complex bonds formed spontaneously. The excess polyacids can be removed from the medium. The free COOH groups in coating are prone to react with active biomolecules like proteins. Charging and pH- and salt-dependent behaviour of carboxylated SPIONs were characterized quantitatively. The interrelation between the coating quality and colloidal stability measured under biorelevant conditions is discussed. Our coagulation kinetics results allow us to predict colloidal stability both on storage and in use; however, a simpler method would be required to test SPION preparations. Haemocompatibility tests (smears) support our qualification for good and bad SPION manufacturing; the latter 'promises' fatal outcome in vivo.