New Drug Classes for the Treatment of Type 2 Diabetes

BY: Jane Moran 13. November 2012 14:20

Pharmacologic therapy has traditionally targeted the primary defects in type 2 diabetes including insulin resistance, impaired insulin release and abnormal gut glucose absorption. New drug therapies for type 2 diabetic patients are needed to keep pace with this growing population, the majority of which are failing to achieve recommended glycemic control. Several novel classes of drugs with unique mechanisms of action are being evaluated for anti-hyperglycemic effect with a lower risk of hypoglycemia and other common complications.

Sodium-dependent glucose transporter (SGLT2) inhibitors

One of the most promising new anti-hyperglycemic drug classes is the sodium-dependent glucose transporter (SGLT2) inhibitors. (dapaglifozin, canaglifozin) Glucose reabsorption occurs in the kidney via a sodium-dependent transporter termed SGLT2, selective inhibition of which suppresses reabsorption. Beneficial non-glycemic effects include promotion of weight loss, reduction in arterial blood pressure1 and reduced glomerular filtration rate, in the setting of diabetic hyperfiltration.2

The lack of hypoglycemia makes the safety profile attractive in spite of small increases in a kidney function test and hematocrit as well as an increase risk for genitourinary infections.3

Glycogen phosphorylase inhibitors

Glycogen phosphorylase is the enzyme that catalyzes the process of glycogenolysis, the release of glucose from its polymeric liver storage form glycogen. By inhibiting glycogen phosphorylase, hepatic glucose output can be lowered. Further research is needed to determine if these drugs will become a treatment option for type 2 diabetes.

Glucagon-receptor antagonists

In patients with type 2 diabetes, inappropriate levels of glucagon persist in the presence of hyperglycemia and hyperinsulinemia. By interfering with glucagon action, glucagon-receptor antagonists potentially lower both fasting and post-prandial glucose levels. Concerns regarding this class of drug include glucagon hypersecretion, risks of alpha cell hyperplasia, possibly leading to tumors and a major threat of hypoglycemia.4

Glucokinase activators

Glucokinase responds to increased blood glucose by increasing release of insulin by the pancreatic β-cells. In the liver, glucokinase acts to promote hepatic glucose uptake while suppressing hepatic glucose production.

Phase 2 studies have shown dose-dependent glucose lowering with Glucokinase activators (GKAs). Despite concerns for hypoglycemia and the development of fatty liver, several GKAs in development show potential to advance to long term trials. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors.

11-beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) inhibitors have reached Phase 2 development. 11beta-HSD1 regulates local availability of glucocorticoid (GC) by catalyzing the conversion of active GCs from inactive 11-keto forms augmenting local GC action. An inhibitor of 11beta-HSD1 has the potential to lower intracellular GC concentrations and thereby attenuate the adverse impact on glucose control.

Protein tyrosine phosphatase 1B inhibitors

A key regulator of the insulin signal transduction cascade is protein tyrosine phosphatase1B (PTP1B) which acts as a negative control leading to attenuation of insulin action.5

Inhibitors of PTP 1B would increase insulin sensitivity by blocking the PTP 1B-mediated negative insulin signaling pathway. Challenges to development have included selectivity against non-metabolic actions and identification of a bioavailable formulation.6

G-protein-coupled receptor (GPR) 119 agonists

G-protein-coupled receptor (GPR) 119 is a member of a major class of receptors which functions to translate extracellular messages into intracellular signals. GPR119 agonists can promote increased insulin secretion directly through actions on the β-cell. Additionally, GPR119 indirectly increases insulin through enhanced release of incretin hormones.7 The ability to activate these complementary pathways in glucose homeostasis is an attractive aspect of this drug class.

1 Wilding J, 2008
2 Brenner B, 2007.
3 The Kidney. Abdul-Ghani M. Curr Diabetes Res. 2012; 12:230-238.
4 Bagger JI et al. Diabetes Obesity and Metabolism. 2011;13:965-971.
5 Taniguchi CM et al. Nature Reviews Molecular Cell Biology.2006; 7: 85–96.
6 Koren S, Fabtus GI. Best Prac and Res Clin Endocrin and Metab. 2007;21(4):621-640.
7 Chu ZL et al. Endocrinology.2008; 149(5)2035-2037.

Elderly patients: an increasingly relevant patient population.

BY: Simonetta Alvino 9. October 2012 09:19

It is likely that the Europe Union (EU) will face major challenges in relation to population ageing brought about by low fertility levels, improved medical and social care leading to longer life expectancy, and the baby-boomers entering the age of retirement. The number of elderly people in the EU – defined as those aged 65 years or over – is expected to grow from around 84 million (or 17% of the total population) in 2008 to around 141 million (or 29.9% of the total population) by 2050. The growth of the population aged 80 or more will be even more pronounced as more people are expected to live longer. The proportion of people over 80 is projected to almost triple in the EU and will account for a double-digit share of the total population by 2050 with more than 50 million people (Eurostat yearbook 2008).

As the proportion of this vulnerable population in society rises, it becomes increasingly important to ensure that their special needs are taken into consideration when developing, approving. and using new medicines. In fact, there is a perceived need for more systematic acquisition and assessment of clinical-trial data relating to the benefits and risks of medicines intended for use in the elderly. The World Health Organization (WHO) (November 2004), in the study “Priority Medicines for Europe and the World” concluded “The elderly are still unjustifiably excluded from clinical trials. Laws and guidelines should be developed that include the participation of the elderly”.

In 2006, the Committee for Medical Products for Human Use (CHMP) evaluated the adequacy of guidance on the elderly medicinal products and identified areas of improvements regarding:

1. The number of elderly patients participating in the clinical development programs.
2. The minimum requirements for two different age classes: elderly and very elderly.
3. The adequate representation of the elderly in the efficacy and safety database for integrating and completing the pharmacokinetics (PK) requirements. Ensuring that medicines are labelled appropriately for the elderly is important and this means that they should be included in clinical studies where special ethical, safety, and efficacy issues may arise.

In early 2011, the European Medicine Agency (EMA) published a “Geriatric Medicines Strategy” and established a Geriatric Expert Group, which will establish numerous regulatory actions, spanning from scientific advice to European Public Assessment Report (EPAR) template changes as well as post-marketing pharmacovigilance.

In parallel with the launch of EU Commission Pilot Innovation Partnership on Active and Healthy Ageing and the revision of the Clinical Trials Directive, we might see an increased political debate on the needs to ensure adequate representation of older patients in clinical trials, which could potentially lead to legislative initiatives (e.g. paediatric legislation). Currently, the European Forum for Good Clinical Practice (EFGCP) Geriatric Working Party is finalizing a document (guidance) which provides recommendations primarily on ethical aspects, on clinical trials performed in older people who may belong to a vulnerable patient population.

The pharmaceutical industry need to clarify their thinking and willingness on the matter of clinical development for older adults to face and proactively shape the discussions ahead and address the needs of this growing population.

Rheumatoid Arthritis: New Definition of Remission

BY: Anna La Noce 21. September 2012 10:59

It is widely recognized and recommended that current treatment of rheumatoid arthritis should be targeted to disease remission or, if this is not achievable, to minimal disease activity. In agreement with such recommendation, evaluation of remission and low disease activity are always included among efficacy end points of confirmatory trials of novel anti-rheumatic agents. However, this raises the problem of using a shared definition of remission that is stringent but achievable and could be applied uniformly as an outcome measure in clinical trials.

Remission has been commonly defined as a DAS28 lower than 2.6. However, in theory, this goal can be achieved even if more than 10 joints are swollen. Apparently joint erosion can continue progressing even when the DAS28 remission definition is met. In the last few year, the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) have focused on a definition of remission that reflects a state of absence of disease activity. In 2011, The ACR/EULAR proposed two options for assessing remission in clinical trials, a Boolean or an index based definition (Felson et al, Arth Rheumatism 2011;63:573-86). The Boolean definition requires that all following criteria show a score £ 1: swollen and tender joints, serum C-reactive protein (CRP) (mg/dl), patient global assessment (0 to 10). The index based definition requires a Simplified Disease Activity Index (SDAI) score £ 3.3. The ACR/EULAR have requested that both definitions are tested in future clinical trials and validated in observational datasets. Interestingly, the ACR/EULAR recommendation has been included in the revised European Medicines Agency (EMA) guidance on clinical trials in rheumatoid arthritis (CPMP/EWP/556/95 rev. 2, draft 2011), where remission or low disease activity are indicated as potential primary study end points, with remission in particular representing an optimal primary end point for trials in early rheumatoid arthritis. The EMA guidance also makes reference to the definitions of remission proposed by the ACR/EULAR.

In agreement with the ACR recommendation, data from previous clinical trials have been re-evaluated to compare the remission outcome based on the different definitions. For example, results from the TAMARA phase IIIB study (tocilizumab in patients with active disease despite stable dose of conventional or biological disease-modifying anti-rheumatic drug (DMARD) were analyzed to assess remission according to the new ACR criteria and to compare the results with the original analysis of DAS28-erythrocyte sedimentation rate (ESR) remission (Ilking-Konert et al, Ann Rheum Dis 2011;70:1986-90). At week 24, while nearly 50% of patients (47.6%) had achieved a DAS28 < 2.6, only 20.3% had attained the Boolean defined remission and 25.2% the index based remission (SDAI £ 3.3). As expected, the more stringent criteria of Boolean remission led to a considerable reduction of remission rate, that was consistent with the SDAI and with the Clinical Disease Activity Index (CDAI) remission (24.1% with CDAI < 2.8). This result indicates that Boolean criteria represent a remission model closer to what is to be intended as remission in the clinical practice, as compared with DAS28. A similar comparison was conducted in patients with early rheumatoid arthritis, for whom remission should be the primary therapy goal. Again, Boolean remission was attained by less than half of the patients compared to those that achieved a DAS28-CRP < 2.6. The new remission criteria are also being evaluated in observational or cohort studies, like the BRASS (Prince et al, Arthr Res Ther 2012;14:R68), the ESPOIR (Zhang et al, Arthr Res Ther. 2012;14:R156), early rheumatoid arthritis cohort studies (Kuriya et al, J Rheumatol. 2012;39:1155-8; Vermeer et al, Rheumatol. 2012;51:1076-80) and others. Data so far tends to confirm that the new Boolean and the SDAI remission criteria are better predictors of stability of joint damage progression compared with DAS28. Due to ACR/EULAR Boolean stringent criteria, remission may not be an achievable goal for many patients, with a number of swollen and tender joints as well as patient global assessment £ 1 being the main limiting factors.

New criteria are being evaluated in recently initiated clinical trials, in addition to DAS28, SDAI or CDAI criteria. Results from these studies may provide useful information on the performance and feasibility of the new ACR definition of remission and, most important, on the possibility of using this definition as a primary end point in future clinical trials, particularly in very early or early rheumatoid arthritis.

In the future, imaging may be included among the criteria for remission. In fact there is evidence that synovitis can still be found in patients in clinical remission and may lead to adverse functional and clinical outcome. Many questions concerning use of imaging for evaluating remission are yet to be answered, for example: the type of imaging method, the joints to be evaluated, the acceptable level of inflammation, and the impact of imaging remission on patient’s outcome.

Hormone Replacement Therapy in Menopause: 10 Years Post Women’s Health Initiative

BY: Simonetta Alvino 6. September 2012 13:42

The past decade has seen marked fluctuations in opinions concerning the merits and risks of postmenopausal hormone replacement therapy (HRT). In July 2002, menopause management faced a major turning point when the first data from the Women’s Health Initiative (WHI) trial were released (JAMA 2002;288:321-333). This study was categorized as a primary prevention trial for coronary heart disease (CHD).

However, the mean age at recruitment was 63 years, when menopausal symptoms have usually finished and HRT is rarely started, but this important difference from common clinical practice was not acknowledged at that time. Instead, WHI investigators concluded that HRT was not cardioprotective and that its risk/benefit ratio did not favor the use of postmenopausal hormones for prevention of chronic diseases. As a result, there was dramatic change in prescription habits following recommendations to reserve HRT for symptomatic women and to limit its use to the ‘shortest duration needed’ and to ‘the lowest effective dosage’. The results of the WHI changed the perception of the risk/benefit of HRT.

During the ten years which followed the publication of the WHI results, additional outcomes from subsequent analysis and new studies have kept alive the scientific debate: the increased risk for breast/uterine cancer and cardio-vascular disease found in the WHI have been increasingly viewed with scepticism and the focus of the research is now on other unresolved issues:

Critical window for starting HRT and treatment duration
Based on more than 40 observational studies on HRT, the total relative risk for CHD was 40-50% lower among current or previous users of HRTcompared to those who never had used it (p < 0.001). The key differences between the design of the WHI and the following observational studies on HRT were the timing of the initiation and the duration of HRT therapy and time since menopause. HRT administered around menopause, when there are still vascular estrogen receptors responsive to exogenous HRT, appears to reduce progression of atherosclerotic plaque. However, if HRT is administered many years after menopause, it is not beneficial and may sometimes disrupt established plaque with adverse effects.

The optimal treatment’s duration
The latest data on HRT do not warrant the fear and ultra-conservative approach adopted in 2002. Longer-term therapy is appropriate for women with long-term symptoms who are aware of the potential risks for their regimen in their personal circumstances. Individualised regimens can reduce the incidence of adverse outcomes.

HRT can be offered to informed women for as long as they have debilitating symptoms but the data are not yet strong enough to advocate it for chronic disease prevention (except perhaps for osteoporosis prevention near menopause with the option of other effective fracture prevention treatments at a later age). However, some women have continuing symptoms even into their seventh decade and they should not be denied HRT if their therapy and risks are individualized, understood, and not exaggerated.

The best formulations for minimizing breast/uterine cancer risks
Although the risks of HRT have been inflated by the popular press, there are potential side effects and risks that must be individualized and reduced by tailoring the therapy. Emerging data suggests fewer side effects with:

  • lower HRT doses
  • minimal use of systemic progestogens
  • use of non-oral routes in some women and the use of HRT in symptomatic women from near menopause

HRT remains the most effective therapy for vasomotor symptoms and urogenital atrophy. By 2030, an estimated 47 million women will be undergoing menopause each year. Quality of life is an important end point in women’s health research. We should not forget that a woman’s prolonged life expectancy has resulted in an extended postmenopausal lifetime, which could be longer than the woman’s entire reproductive age.


Writing Group for the Women's Health Initiative Investigators: Risks and benefits of estrogen plus progestin in healthy postmenopausal women, principle results from the Women's Health Initiative randomized controlled trial. JAMA 2002; 288:321-333

Kim JK et al. Changes in Postmenopausal Hormone Therapy Use Since 1988. Womens Health Issues 2007;17(6):338–341

MacLennan AH, Hormone replacement therapy: a 2008 perspective. OBSTETRICS, GYNAECOLOGY AND REPRODUCTIVE MEDICINE 2008;19:13

Greiser CM, Greiser eM, Doren M. Menopausal hormone therapy and risk of breast cancer. A meta-analysis of epidemiological studies and randomized controlled trials. Hum Reprod Update 2005; 11:561–573.

Nedrow A, Miller J, walker M, Nygren P, Huffman LH, Nelson HD. Complementary and alternative therapies for the management of menopausal symptoms. A systematic evidence review. Arch Intern Med 2006; 166: 1453–1465.

Palacios S. Advances in hormone replacement therapy: making the menopause manageable. BMC Women's Health 2008, 8:22

Grodstein F, Stampfer MJ The epidemiology of coronary heart disease and estrogen replacement in postmenopausal women. Prog Cardiovasc Dis 1995, 38:199-210.

Canonico M et al. BMJ 2008;

Renoux C et al. Transdermal and oral hormone replacement therapy and the risk of stroke: a nested case-control study BMJ 2010;340:c2519

Sturdee TW and Pines A. Updated IMS recommendations on postmenopausal hormone therapy and preventive strategies for midlife health. CLIMACTERIC 2011;14:302–320

Santen RJ et al. Executive Summary: Postmenopausal Hormone Therapy: An Endocrine Society Scientific Statement J Clin Endocrinol Metab, July 2010, 95(Suppl 1):S1–S66

Closing in on Residual Cardiovascular Risk

BY: William T. Garland, MD 27. July 2012 10:49

From 1970 to the present, the death rate from cardiovascular disease (CVD) has remained essentially unchanged in the USA and other developed countries. Since the general population has aged over this span of time, age-adjusted CVD death rates have correspondingly declined during this period. This age-adjusted reduction in CVD mortality has occurred notwithstanding a growing obesity epidemic with attendant growing prevalence of diabetes.

The decline in age-adjusted CVD mortality is due to a decline in cigarette smoking as well as many improvements in CVD therapeutics, including better methods for achieving revascularization and better control of blood pressure. Widespread use of statins (beginning in 1987 with the approval of lovastatin) has also played an important role in this success story. However, analysis of many CV outcomes trials (4S1, CARE2, AF-CAPS/TexCAPS3, LIPID4, HPS5) has revealed that statins fail to prevent two thirds of major adverse CVD events (MACE)6. Accordingly, a major effort has been underway for many years to identify additional therapies that could be added to statins to reduce or eliminate this residual risk.

Recently published CVD outcomes trials reveal how challenging it will be to eliminate residual CVD risk. AIM HIGH7 showed that while niacin therapy (added to background statin therapy) increased HDL by > 15% compared to placebo, there was no reduction in MACE. More recently the ORIGIN trial showed that an omega-3 fatty acid preparation (1 gm per day; background statin therapy was used in a majority of patients) failed to reduce MACE notwithstanding a significant reduction in triglyceride levels. Finally, in May 2012 the dal-OUTCOMES trial was halted due to absence of therapeutic benefit from dalcetrapib, a CETP inhibitor that increased HDL by about 30%.

The effort to identify new therapies that will reduce or eliminate residual CVD risk is ongoing. HPS2 THRIVE is a massive trial (over 25,000 patients) which will show conclusively whether niacin added to statins offers benefit; study completion is expected in 2013. SOLID TIMI 52 (13,000 patients, completion expected 2014) and STABILITY (15,828 patients, completion expected 2013) are designed to see if addition of darapladib to statins reduces MACE (darapladib reduces lipoprotein phospholipase A2, a pro-inflammatory enzyme associated with increased CVD risk in epidemiological studies). REVEAL (30,000 patients, completion expected 2017) is designed to show whether anacetrapib will reduce MACE when added to a statin (anacetrapib is a CETP inhibitor which increased HDL by 138% in the DEFINE trial, and also significantly reduced Lp(a) and LDL). Finally, the 8000 patient REDUCE IT trial will show whether addition of 4gm per day of AMR101 will reduce MACE when added to statin therapy (AMR101 is a highly purified ethyl ester of EPA known to reduce triglyceride levels; study completion is expected in 2016). Meanwhile, earlier phase trials with novel therapies designed to reduce residual CVD risk are also underway. It is probable that before long we will be able to meaningfully reduce residual CVD risk.

1 Lancet 1994;344:1383-9
2 NEJM 1996;335:1001-9
3 JAMA 1998;279:1615-22
4 NEJM 1998;339:1349-57
5 Lancet 2002;360:7-22
6 JACC 2005;46:1225-8
7 NEJM 2011;365:2255-67
8 Published online June 11, 2012; 10.1056/NEJMoa1203859 NEJM 2010;363:2406-15

Proactively Documenting Requirements for Quality in a Clinical Quality Agreement

BY: Pamela Strobel 17. July 2012 18:17

Biopharmaceutical companies are under increasing pressure to bring new drugs to market quickly and efficiently while adhering to the highest quality standards. Working with experienced strategic partners who can help improve the quality of the study and data is a key to success.

Ensuring subject protection, data integrity and that the study is conducted in compliance with relevant laws and regulations are key objectives in achieving quality from the perspective of regulatory authorities. So, how do you confirm that you have achieved these objectives?

It’s vital that sponsors and their outsourcing partners proactively implement a defined governance structure and document the quality expectations of each partner before the clinical trial begins. A best practice includes the creation of a Clinical Quality Agreement. Quality agreements may be composed for use at the project level, program level, or relationship level.

A Quality Agreement describes the standards, expectations, and respective responsibilities of the sponsor and outsourcing partner with respect to quality risk management, quality control, and quality assurance. The jointly-owned agreement ensures adherence to local, regional and international regulations, ICH/GCP guidelines and relevant standard operating procedures (SOPs), as well as promotes consistency, transparency, and open communication among the partners to aide in effective management of clinical trial quality and compliance.

The partners must review and agree on key quality indicators (KQIs) to be included in the Quality Agreement. These metrics are different from the project-specific metrics that study teams utilize to assess trial progress and quality of deliverables. The KQIs are based on compliance risk, probability, impact, and detectability. Following are a few key examples of KQIs that should be considered whem creating a Clinical Quality Agreement:

  • Governance and process improvement
    • Number of repeat audit findings/issues after corrective actions and preventive actions (CAPAs) are implemented
  • Selection and training of personnel
    • Percent of personnel passing GCP compliance and CRO/sponsor SOP and protocol testing prior to being assigned to a project
    • Turnover rate for key personnel (positions turned over/total positions)
  • Risk Management
    • Number of protocol amendments due to inadequate risk assessment/poor feasibility
  • Audits and issue resolution
    • Number of critical and major audit findings per site or function
    • Percent of CRO CAPAs completed on time
    • Percent of site CAPAs completed on time

For each KQI agreed upon, specific criteria for threshholds and trends should be set, monitored and reported on throughout the study. By proactively documenting the mutual responsibility for delivering quality by sponsors and outsourcing partners, we can bring about new strategies for improving the quality of studies and data in clinical trials.

Patient Retention: A Customized Approach

BY: Julie Ross 11. July 2012 09:49

Industry insiders are aware that patient retention is becoming one of the most critical components of planning a successful study. More often than not, study planning is so focused on study start-up and getting patients enrolled, that retaining patients can be easily overlooked. The key to recruiting and retaining patients is understanding a person’s needs and maintaining a consistent dialogue to ensure these needs are met.

As humans we have fundamental needs, which are said to be common across all cultures and despite all things that change over time, these needs remain the same. These needs are subsistence, protection, affection, understanding, participating, leisure, creation, identity and freedom. In most cases patients state that they remain in a clinical trial for the altruistic aspect or the sense that they’re doing something for the greater good. So the essentials of patient retention are all about caring. This includes making patients feel special, understanding their physical and emotional needs, their motivations, how to keep them engaged and most importantly an approach to the patient themselves and the overall patient population being retained.

With this in mind, today’s patient retention programs need to focus on the most important aspect of the study — the people. People of different cultures, ethnicities, and ages all have one thing in common; they want to feel engaged, respected and appreciated. There are many tactical solutions that can successfully be employed, traditional and non-traditional, that are effective. The key to any tactic is to ensure the patient has a choice in how they are engaged. Taking advantage of early opportunities to engage a patient is absolutely critical, this can be as early as the first attempt of study approach. Some patients may prefer to receive their appointment reminders via email or text rather than via phone. Some patients may need to go back to work after a study visit and will be appreciative to get in and out of the office fast. Others may want to spend extra time in the office to chat if they are going home to an empty house. A few preference and lifestyle questions upfront will engage patients early on.

All are aware of regulatory restrictions with providing patients expensive gifts and these regulations vary greatly depending on the country. That being said, items that relate to the study and those that some may deem necessary need to be thought through and be made available.  For example, if study medication is dispensed in volume, ensuring patients have a bag to carry it will show them they were considered during the planning process.

Overall, there is not one approach, item, or service that will retain all patients; however, focusing the effort on the patient to ensure they get what they want out of the trial is the key. In the business of running trials, timelines, deadlines and budgets, it's necessary to pause during planning to ensure those that make the trial successful, the patient, are part of the planning and shown the appreciation for their participation even for those things that seem everyday.


Global Pediatric Research

BY: Philippa Smit-Marshall 30. March 2012 09:46

Regulatory and non-governmental initiatives prioritized pediatric drug research to address unmet clinical needs and to improve the accessibility to the pediatric population of innovative and safe medicines. In return, prolongation of patent protection has been offered by the regulators as an incentive and a reward. However, the execution of pediatric clinical studies present unique challenges in terms of the requirement for specific designs, technical issues. and ethical considerations.

Increasing competition for patients has resulted in the globalization of trials, sometimes into emerging territories with associated need to address ethical and experience issues. The increase in complexity of clinical studies in children and the need to invest in solutions to solve these challenges have driven up the cost of pediatric clinical research. Managing these costs to ensure a return on investment is critical if the goal of improving the health of children through ethical and scientifically sound drug development is to be achieved.

Pharmacovigilance = (Effective + Safe) Therapeutics

BY: Sarah Rondeau 12. December 2011 10:12

Security has become increasingly important in all aspects of modern life, and clinical trials are no exception. In addition to close monitoring by investigators and pharmaceutical company sponsors, clinical trials are autonomously reviewed by Independent Review Boards (IRBs), Ethics Committees (ECs), and drug safety firms. This is where pharmacovigilance fits into the drug development process: to provide an extra level of security to ensure safe and effective products reach patients.

Pharmacovigilance, simply put, is drug safety. It is the science of understanding the adverse effects caused by a drug and assessing whether the drug benefits outweigh the risk. This includes detecting adverse events (AEs) during the clinical trial and post-marketing, monitoring and updating the risk-benefit ratio based on relevant findings, preventing and/or minimizing AEs, and, most importantly, harmonizing, and communicating findings to the relevant regulatory authorities in a timely way.

If at any time during the clinical development process the drug developer decides the risks associated with a compound outweigh its benefits, development may be discontinued altogether. By detecting safety signals early in the process, a strong pharmacovigilance system can help minimize the costs of discontinuing clinical development at a later phase.

The principle of vigilant pharmacovigilance in a clinical trial is well served by the establishment of strict eligibility criteria, which can help target the effect of a drug on a disease process with minimal interaction from comorbidities or concomitant medications. Such criteria can produce highly focused data that can be extrapolated to cover larger patient populations with a vast array of medical conditions. If the product receives marketing approval, it will be used in a far less controlled environment. One serious AE may not be statistically important in an arena with 8000 patients, but in a clinical trial of 150, it can change the course of the drug’s future.

Another benefit of pharmacovigilance is enhanced communication with IRBs, ECs, and regulatory authorities around the world. In addition to decreasing the potential for bias, global communication allows the results of a limited trial to be collated and compared to similar trials or similar drugs. Massive computer databases can be used to monitor safety signals that may not be apparent within the pharmaceutical company’s own database. As a result, the company gets a broader picture of a drug’s potential than that provided by a single trial. Such information also allows the company to lay the groundwork for a new trial without duplicating efforts from previous trials, thereby saving costs as well as time.

In today’s pharmaceutical marketplace, patients expect a medication’s benefits to outweigh its risks. Pharmacovigilance can help ensure that those expectations are met. Indeed, a robust, well-defined pharmacovigilance system, actively employed throughout the clinical development process, is the single most important process available to provide safe and effective drugs to patients around the world.


CATEGORIES: Quality | Regulatory | Safety

Principles in Quality Assurance: the “Grip/Build/Engage” (GBE) Model

BY: Anthony Jones 9. December 2011 15:27

Today’s quality challenge is how to implement a comprehensive quality program that ensures sustainable regulatory compliance and continual improvement, while contributing to improvements in business process, profitability, and customer satisfaction. Quality Assurance (QA) has a key role to play in achieving the transformation from an approach based on point-solutions to arising compliance issues, to having a harmonized, aligned quality system and culture. To become a valued partner in this transition, QA must adopt a strategic model that provides demonstrated value and constantly improving positive impact. A model that is engaging in its simplicity while retaining the key elements of more complex quality systems is the “Grip/Build/Engage” (GBE) model [1,2]. The system is designed based on the attributes of true effectiveness as demonstrated in various arenas, not just in the professional realm. An example of true effectiveness and impact is visually represented by looking at Tiger Woods’ golf swing, []. To achieve his undeniably remarkable results Tiger Woods: • Maintains a solid grip on the ground and on the club at all times • Pulls the club away from its target, building a tension in his body while aiming and aligning • Engages effortlessly by releasing the tension and following through completely This is a powerful analogy for an effective quality system and business approach – the delivery of consistent high-impact results through aligned processes with an elegant simplicity that delights the customer. To translate this GBE approach to QA, an analogy can be made both to Tiger Woods’ golf swing and established quality models such as the Plan-Do-Study-Act (PDSA) cycle used by W. Edwards Deming [3], to describe the three overlapping phases.

Stage 1: Grip Foundations come first! A solid base is established by defining overall vision, strategy, principles, and values. This is most powerfully expressed by defining story, a narrative description of desired achievements and way of working. Balance is attained, monitoring and control activities are put in place to check results and systems, and mechanisms for taking effective corrective action are instituted. This “Grip” stage equates to the “Study” and “Act” sections of the PDSA cycle, studying first before acting to improve.


Stage 2: Build Developing people, process and structure, by taking actions that do not necessarily lead directly toward the desired goal. This stage is comprised of “important but not urgent” activities such as training and education, planning, determining strategy, and process improvement. This phase is especially critical to the eventual outcome as it will produce the acceleration and momentum needed to hit the target, minimizing the risk of unanticipated impediments or resistance. In PDSA terms, this is the “Plan” portion of the cycle; ensuring that the details have been studied, instruction and training are available and problems are anticipated.


Stage 3: Engage Engaging with people, tasks, challenges and opportunities to produce results, the “Do” part of PDSA. The overriding principle of successful engagement is to get better results with less effort through using the following principles: • Reduce waste and cut all elements that do not contribute to story and goals, or do not relate to the GBE steps. This generates time that can be re-invested more profitably. • Focus on results by identifying and concentrating on the “elusive 10%” [1, 4] of activities that will provide 90% of results. This includes maintaining efforts to achieve stated objectives in-line with the QA story, and taking care to balance activities around the different steps of the GBE cycle. • Economy of effort: by not using more resource than is necessary to achieve a given outcome, goals can be achieved more rapidly and with less resource expended. • Pro-reactivity: using reactive, routine tasks to contribute to longer-term goals, not just completing the task, but also building something bigger at the same time. Identifying and capitalizing on high-leverage activities that create the largest effect per given input. • Simplification: compliance tends to be inversely related to complexity [5]; a more complex procedure will potentially have a higher occurrence of non-compliance and will require more resource. This is a commitment to using the minimum level of complexity necessary for comprehensive solutions.


By adopting this model and striving to balance activities around the three stages of GBE, a more powerful approach to attaining results is realized. Extending the golf analogy, this prevents repeated ineffective hacking at the ball using a lot of effort (expending resource inefficiently on tasks that do not provide value) and facilitates constant improvements in quality, compliance and profitability. The GBE model is a framework to make QA more rational, principle-based, efficient, and effective. As the workplace becomes increasingly complex, adopting a structured approach allows QA to remain a focused, balanced, and valued partner in making a positive impact on our business and the customers we serve.



1. Principles in Quality Assurance, Part 3: Making an Impact. Jones AB. Qual Assur J, 2009; 12, 132–138 (

2. Principles in Quality Assurance, Part 4: Putting it all Together. Jones AB, Quality Assurance Journal, Qual Assur J 2011; 14, 18–26 (

3. See:

4. Drucker PF. Managing for Results. New York: Harper and Row; 1964.

5. Get to Market Now! Turn FDA Compliance into a Competitive Edge in the Era of Personalized Medicine. John Avellanet, Logos Press, May 2010 (