Executive Summary
Type 2 diabetes is an escalating global health problem further driven by the epidemic in obesity. Worldwide, type 2 diabetes aff ects 198 million people and is increasing at a rate of 3% annually. Obesity aff ects nearly one third of the United States population and is on the rise throughout the developed world.
Th erapeutic advances are emerging from new class-es of anti-diabetclass-es agents including DDP-4 inhibi-tors and GLP-1 analogs, third-generation therapies with potential to provide better control of blood sugar levels and reduce risk for kidney disease and retinopathy. But today’s promising pipeline must be delivered in an environment of increasing regula-tory requirements for cardiovascular safety.
Th e leading cause of death among diabetics is heart disease. Prompted by growing concerns that anti-diabetes drugs may increase cardiovascular risk the Food and Drug Administration’s 2008 guidance requires larger and longer clinical trials. Th e trend is toward clinical databases of 3,000 to 5,000— roughly twice the size of previous development pro-grams. Regulators are seeking more data on safety and durability of drug eff ects in populations that are more refl ective of real-world treatment.
To address growing challenges in study design and patient recruitment, sponsors who are developing anti-diabetes drugs will require more scientifi c exper-tise and greater operational capabilities. A case study of a Phase II DDP-4 inhibitor trial is presented to il-lustrate both the research challenges and the value of partnering to expand critical development resources.
Introduction
Th e future of diabetes clinical research is being shaped by two urgent needs: to improve therapy for an escalating global epidemic and to ensure acceptable levels of safety for these interventions in a treatment landscape complicated by evolv-ing standards of care. Today’s biopharma pipeline holds hundreds of new agents with the potential to advance treatment, but rising regulatory require-ments to demonstrate cardiovascular safety demand clinical trials that are dramatically larger, longer and more complex.
Mary Parks, PhD, director of the Food and Drug Administration (FDA) Division of Metabolic and Endocrine Drug Products for the Center for Drug Evaluation and Research (CDER), gave this assessment of what this means for anti-diabetes drug developers:
“We are informing companies that, given the chronic and complex nature of diabetes, they should aim for larger and longer exposures that would inform us about safety and durability of drug eff ects,” she noted in a recent interview. “It’s also important for them to enroll a patient popula-tion that may be more refl ective of the populapopula-tion the drug will be marketed towards.”1
Th e trend is toward clinical databases of 3,000 to 5,000—roughly twice the size of past programs. New agents will have to be evaluated in many diff erent combinations, with insulin and other approved thera-pies. In addition, clinical drug evaluation will have to be more refl ective of a real-world treatment experi-ence. Th ese increasing demands are putting intense pressure on development resources, making partner-ing a vital strategy for diabetes drug development.
Type 2 Diabetes: A Growing and Under-treated Epidemic
Type 2 diabetes has reached pandemic levels, aff ect-ing more than 198 million people worldwide and increasing at a rate of 3% each year. 2,3 In type 2
diabetes, the body’s ineff ective use of insulin results in a daunting list of life-threatening co-morbidi-ties—heart attack, stroke, kidney failure, blindness, vascular damage, nerve damage and numerous tertiary diseases. Th e World Health Organization (WHO) calculates that nearly 3 million deaths worldwide are attributable to diabetes each year; by 2030, that fi gure is expected to double.4
Th e rising prevalence of type 2 diabetes is driven by an alarming epidemic in obesity that aff ects approxi-mately one third of the United States (U.S.) popula-tion and is on the rise throughout the developed world.5 WHO estimates that more than 1 billion
adults are overweight worldwide and at least 300 million are obese.6 Obesity increases risk for
diabe-tes: about 85% of type 2 diabetics are overweight; about 55% are obese.7 Th e cohort of conditions
com-mon to both disorders has been dubbed “diabesity.”
An important trend in diabetes clinical research is the epidemic in childhood obesity and the ac-companying increase in childhood type 2 diabetes. Since 1980, obesity has tripled among U.S. school-age children and adolescents. A 2010 study reports that 17% of U.S. children aged two to 19 years
were at or above the 95th percentile of weight-for-recumbent-length growth charts.8 Type 2 diabetes
is diffi cult to diagnose in children, but the Centers for Disease Control reports that the disease now af-fects 151,000 U.S. children and adolescents.9 Th ere
will be a growing need for pediatric clinical tri-als, which involve special considerations related to safety and recruitment.
While there have been notable treatment advances, the International Diabetes Federation reports that optimal management to improve immediate and long-term quality of life is not reaching many, “per-haps the majority,” of patients due to the complexity of the disease, lack of proven, cost-eff ective resources and diverse standards in clinical practice.10
30 Years of Progress in Diabetes Th erapy
Progress is being made in diabetes treat-ment by combining old and new therapies to control blood sugar levels with increas-ing eff ectiveness. Statins, Angiotensin Converting Enzymes (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs) also helped to reduce risk for heart and kidney disease in diabetics. Th e U.S. Centers for Disease Control (CDC) reported a decline of 3.9% in the age-adjusted death rate for diabetes in 2007.
Treatment Landscape: Diverse Targets, Issues in Standard of Care
Th e diverse mechanisms that underlie control of glucose levels and weight gain off er diverse targets for intervention. Advancing research has generated nine classes of anti-diabetes drugs—six in the past 20 years.11 Although a wide range of factors and
pathways have been implicated, there is still no unifying explanation for pathogenesis. Th e result-ing uncertainties impact both clinical care and drug development.
Th e leading cause of death among diabetics is cardiovascular disease. Th e relationship between re-duced blood sugar levels and cardiovascular disease remains unclear. Th ere is confl icting evidence about the overall cardiovascular benefi t of lowering blood glucose levels, together with growing concern about the cardiovascular risks posed by glucose-lowering drug therapies. Standards of care are evolving, and measures of eff ectiveness are expanding beyond the endpoints of glucose levels and body mass index to address a constellation of diabetes- and obesity-related complications, including cardiovascular out-comes, nephropathy and retinopathy. Th ese trends impact both clinical care and drug development.
Standard of Care: HbA1c Targets
Th ere is continuing debate regarding the optimal target for glycosylated hemoglobin levels (HbA1c), the traditional biomarker for glycemic control and
drug effi cacy. Th e American Diabetes Association calls for maintenance of HbA1c levels at <7%.12 Th e
International Diabetes Federation and the American Association of Clinical Endocrinologists recommend a more intensive target of ≤ 6.5%.13,14 As therapeutic
advances make it possible to reduce HbA1c levels further, there are questions regarding the benefi ts of more aggressive therapy.
Results from major studies have found benefi ts in reducing HbA1c levels, but eff ects on macrocar-diovascular events remain ambiguous. Th e 10-year UK Prospective Diabetes Study (UKPDS) pub-lished in 1998 compared outcomes for control at 7.9% and more intensive control at 7% with either sulfonylureas or insulin. UKPDS found that more intensive control substantially reduced risk for microvascular disease but not for macrovascular disease or overall mortality.15
Th e ADVANCE (Action in Diabetes and Vascular Disease) study compared outcomes for control at 7% and at 6.5% using a gliclazide in 11,140 pa-tients. Results published in 2008 at the fi ve-year point showed that intensive control at 6.5% reduced the combined rate of cardiovascular death, nonfatal stroke, nonfatal MI, nephropathy and retinopathy by 10%. However, there was no benefi t for macro-vascular events or for overall mortality.16
Current Th erapy
At present, the goal of therapy is to maintain HbA1c glucose levels at a 7% or 6.5% target—long term and without weight gain—to protect against heart attack, stroke, kidney disease and retinopathy. A combination of drugs off ering diff erent mecha-nisms of action usually is required to achieve these targets. Metformin remains the fi rst-line treatment for type 2 diabetes. Th is older therapy, favored because it does not promote weight gain, typically is used in combination with newer agents. Th ese include thiazolidinediones (TZDs), DPP-4 inhibi-tors and GLP-1 analogs.
TZDs reduce peripheral insulin resistance, primar-ily by their eff ect on adipose tissue. Th ey have been shown to provide better maintenance of glucose levels over time,17 and there is some evidence that
TZDs may protect insulin-producing beta cells.
Th e newest anti-diabetes agents, DPP-4 inhibitors and GLP-1 analogs, are interventions based on the hormone GLP-1 (glucagonlike peptide 1). GLP-1 plays a major role in regulating blood glucose levels by stimulating insulin secretion, suppressing glu-cagon levels and slowing gastric emptying. DPP-4 inhibitors act to prevent the enzyme dipeptidyl peptidase 4 from inactivating GLP-1, while GLP-1 analogues are synthetic versions of the hormone that increase GLP-1 activity.
Mechanisms of Action in Current Th erapies
Key strategies of current anti-diabetes drugs include:
• Stimulating the pancreas to release more insulin: sulfonylureas (Diabeta, Amaryl) and meglitinides (Prandin, Starlix) • Reducing “insulin resistance”—that is, making cells more sensitive to insulins: Biguanides (fi rst-line therapy metformin) and TZDs (Avandia, Actos)
• Reducing absorption of glucose and carbohydrates in the intestine: disaccha ride inhibitors (Acarbose) and glucosidase inhibitors (Precose, Glyset)
• Blocking the inactivation of GLP-1, which stimulates insulin secretion and regulates glucose levels: DPP-4 inhibitors (Januvia, Onglyza, alogliptin)
• Enhancing action of GLP-1: GLP-1 analogs (Syncria, in Phase III)
DPPIV-inhibitors include sitaglyptin (Januvia) and saxaglyptin (Onglyza), introduced in 2006 and 2009, and alogliptin, expected to reach market in 2014. Th ese new agents reduce blood glucose levels as eff ectively as existing therapies but with less risk of hypoglycemia and weight gain. Th ey are used in combination with either metformin or a TZD and can also be used as monotherapy; developers usually design trials to evaluate candidates for both uses.
Research Landscape: Promising Pipeline, Growing Safety Issues
Th e biopharma pipeline currently holds more than 500 anti-diabetes agents.18 In addition to DPP-4
inhibitors and GLP-1 analogs, a new class of sodium glucose co-transporter-2 (SGLT-2) inhibitors is advancing. Other novel mechanisms in development include glucokinase activators, glucagon antagonists, and sirtuins. Among the most promising are the FGF-21 agonists, potent activators of glucose uptake on adipocytes; candidates are in various stages of development from preclinical to Phase II trials.
Th e number of clinical diabetes trials has increased dramatically. At the same time, the development path of new diabetes drugs has become longer, more complex and increasingly expensive due to increasing requirements to demonstrate cardiovas-cular safety.
2008 FDA Guidance on Cardiovascular Risk Evaluation
Safety issues surrounding the TZD rosiglitazone (Avandia) intensifi ed concerns about cardiovascular risks associated with anti-diabetes drugs. In 2007, a meta-analysis of 42 clinical trials, most comparing rosiglitazone to placebo, found an increased risk for myocardial ischemia.19 In 2009, fi ndings from the
long-term RECORD study of rosiglitazone safety also showed an increased cardiovascular risk.20 Th e
rosiglitazone issue raised serious questions about whether longer clinical trials should be required to evaluate cardiovascular outcomes in anti-diabetes drugs seeking market approval.
In 2008, the FDA updated its guidance for dia-betes drug and biologic development. Th e new recommendations were intended to ensure that anti-diabetes drugs do not add unacceptable risk for cardiovascular disease. Major provisions address cardiovascular endpoints in Phase II and III, study designs to support meta-analysis and requirements for postmarketing safety trials.21 Th e additional
requirements are having a profound impact on in-creases in research costs and timelines.
FDA 2008 Guidance:
Evaluating Cardiovascular Risk in New Antidiabetic Th erapies
Summary of Recommendations for Sponsors18
• Establish an independent cardiovascular end points committee to evaluate cardiovascular events, in a blinded fashion, during Phase II and III studies
• Ensure that Phase II and III trials are designed and conducted so that a analysis can be performed to appropriately account for important study design features and patient- or study-level covariates
• Provide a protocol describing the statistical methods for the proposed meta-analysis. Studies will need to be longer—e.g., a minimum of two years rather than the typical length of three to six months—in order to obtain enough events and provide data on longer-term cardiovascular risk for chronically used therapies
• Perform a meta-analysis of the important cardiovascular events across Phase II and III trials; explore similarities and diff erences in subgroups (age, sex, race) if possible
• Compare the incidence of important cardiovascular events that occur with the investigational agent to the incidence of the same types of events that occur in the
control group to show that the upper bound of the two-sided 95% confi dence interval for the estimated risk ratio is less than 1.8. Th is can be accomplished using the meta-analysis, or by conducting an additional single, large safety trial, either alone or added to other trials • If the premarketing application includes clinical data that show the upper bound of the two-sided 95% confi dence interval for the estimated increased risk is between 1.3 and 1.8, and the overall risk-benefi t analysis supports approval, a postmarketing safety trial generally will be necessary to show that the upper bound of the two-sided 95% confi dence interval for the estimated risk ratio is less than 1.3. Th is can be accomplished by conducting a single trial or by combining the results from a premarketing safety trial with a similarly designed postmarketing safety trial • If the premarketing application contains clinical data that show the upper bound of the two-sided 95% confi dence interval for the estimated increased risk is less than 1.3 and the overall risk-benefi t analysis supports approval, then a postmarketing cardiovascular trial generally may not be necessary
Design Challenges for Clinical Trials
Sponsors face major challenges both in study design and implementation. In order to meet the increas-ing requirements for cardiovascular safety, sponsors must collect data for 15,000 exposures for a mum of six months, and 400 exposures for a mini-mum of one year. Th is standard of safety requires studies of 3,000 to 5,000 patients maintained on the experimental drug for as long as three years. A comparator group of the same size must be re-cruited and followed as well. Sponsors must decide how much data is suffi cient, given the trend toward increasing safety requirements. Th ey may choose to meet approval requirements as quickly as possible, or they may take a more conservative approach and collect data that could address additional regulatory questions and safety issues.
Comparator Drugs
According to FDA’s Mary Parks, the choice of com-parator drug will be increasingly important. With many therapies available, companies cannot avoid the question of what it means to be “better.” Will new agents have to show better effi cacy; better safety and effi cacy; or some middle ground, given that the drug is likely to be used in combination therapy?
“Standards for approval do not require that a drug show that it’s superior or comparable in eff ect to other therapies,” she notes “Companies (are going
to be asked): what does this new drug off er to pa-tients?” Th ere is more and more scrutiny about what a new drug has to off er beyond glycemic control.1
Multiple Endpoints
According to Richard Gregg, MD, chief scientifi c offi cer for Vitae Pharmaceuticals, the future points to increasing focus on the interrelated co-morbidities of diabetes and obesity.22 In the past, the focus was
almost exclusively on the hard end point of HbA1c. Moving forward, there will be greater emphasis on a drug’s impact on the co-morbidities of hypertension, dyslipidemia and atherosclerosis. Evaluation will include measurements of changes in blood pressure and lipoproteins in addition to HbA1c.
“Going forward, it’s going to be about the overall disease pathophysiology—being able to focus on multiple end points,” Gregg says.
Gregg predicts that sponsors will need partners who can provide increasing expertise and capabilities. Th ere will be growing needs to do biomarker studies in Phase I where a primary goal will be to under-stand drug actions at the molecular level. In Phase II, there will be increasing use of new technologies, including new imaging technologies, to establish that the drug is hitting those targets—for example, that a DPP-4 agent is impacting GLP-1.
Inclusion/Exclusion Criteria
Traditionally, diabetes clinical trials excluded patients with pre-existing cardiovascular disease. Now these at-risk patients are included in studies to provide more real-world evaluation of drug eff ects and to speed accrual of cardiovascular event obser-vations. Sponsors must decide on the number of at-risk patients to enroll and the severity of illness acceptable for inclusion. A larger sample of patients with higher risk for cardiovascular events can speed event accrual, but it becomes more diffi cult to attribute an event in these patients to drug eff ects as opposed to pre-existing disease. Another design issue is the event window—the time during which a study subject must have experienced a cardiovas-cular event in order to be eligible for enrollment. Timeframes range widely, from 60 days before enrollment to six months.
Retrofi tting Studies for Compliance
For agents in Phase III trials when the 2008 guid-ance came into eff ect, developers have been re-quired to initiate additional studies to demonstrate cardiovascular safety. For agents in earlier stages of development, sponsors had to consider ways to retrofi t research programs to comply with the addi-tional requirements. Such retrofi tting is an ongoing challenge as new safety issues emerge from drug use in medical practice. Sponsors must devise ways to capture more information in the course of an ongo-ing study to address unexpected safety concerns.
Impact on Marketed Drugs
For marketed drugs, the impact of emerging safety issues unfolds on a case-by-case basis. A major safety fi nding prompts reevaluation of an entire class, but not all drugs in a class will have the same safety pro-fi le. In some cases, new studies may be required for sponsors to bring their marketed drugs into compli-ance; in others, sponsors may already have suffi cient data to address an emerging safety issue.
Recruitment Challenges: Competition for Patients
Sponsors are engaged in fi erce competition to fi nd, enroll and retain appropriate study subjects to conduct larger and longer trials. ClinicalTrials.gov lists more than 2,250 clinical trials for type 2 diabetes drugs in progress worldwide.23 Despite the
prevalence of type 2 diabetes, there is a scarcity of treatment-naïve patients needed for clinical trials and increasing competition for trial sites capable of enrolling large numbers of subjects. It is not un-usual for type 2 diabetics who qualify for research participation to “shop” for studies that off er com-pensation, dropping out of one trial and enrolling in another.
Quest for Research-naïve Patients
In the major research venues of North America and Western Europe, type 2 diabetes is treated at early stages of the disease with a combination of oral anti-diabetes drugs, and in some cases with insulin as well. Th is makes the pool of treatment-naïve pa-tients in developed regions very small. Treatment-naïve patients also tend to be underserved by the health care system and to have additional problems in trial participation, such as workday availability and transportation.
Treatment-experienced patients are diffi cult to en-roll for diff erent reasons. In developed regions, the majority of patients receive treatment that provides good control; neither patients nor physicians have incentives to change regimens to participate in a trial. Recruitment eff orts are further strained by increasing requirements for evaluation in specifi c subpopulations based on gender, age and ethnicity.
To access larger, treatment-naive patient popula-tions, sponsors are conducting more trials in emerg-ing nations where type 2 diabetes is prevalent and where patients are less likely to receive early and aggressive treatment. Type 2 diabetes is becom-ing more prevalent in the emergbecom-ing nations of Asia and South America where obesity is also increasing along with improving economies. In these regions there are more incentives for patients to enter studies to access treatment that is not otherwise available.
Retaining Subjects is Crucial
Th e increasing length of diabetes trials means that patients must participate in studies that last three years and longer. Th is puts additional pres-sure on drop-out rates. Drop-out rates as high as 67% have been reported for clinical trials that last for a year or more.24 Compliance also becomes a
bigger issue, since protocols can involve diet and exercise regimens.
Sponsors are building retention plans into studies and educating sites to implement a variety of ef-fective strategies. Nurse educators and nutritionists can increase compliance with dietary and exercise regimens; messaging services off er text, email and phone reminders for dosing and visits and help address transportation needs. It will be increas-ingly important to identify potential drop-outs and retain them. One successful approach is to design a sub-study that enrolls patients who have withdrawn from a trial; the sub-study is modifi ed in ways that make it easier for patients to continue.
Conclusion
As diabetes clinical research study size, duration and complexity increase, it is clear that the development of new diabetes therapies will be slower and far more costly. In the balance between acceptable safety and therapeutic advance, safety issues dominate the cur-rent environment. Delivery of today’s rich pipeline of diabetes agents requires drug sponsors to expand their resources through partnerships that can pro-vide greater levels of regulatory and design experi-ence and greater access to global patient populations.
References
1. Parks, Mary. Biggest challenges sponsors face in diabetes trials. Interview in Applied Clinical Trials Online Podcasts. Accessed Feb 16, 2009 at http:// appliedclinicaltrialsonline.fi ndpharma.com/applied-clinicaltrials/article
2. WHO. “Diabetes.” Accessed Feb 18, 2010, at http://www.who.int/mediacentre/factsheets/fs312/en/
3. McGarty, T. P. Type 2 diabetes: a control-lable epidemic. Th e Telmarc Group, Notes No 61, March 2009.
4. WHO “Diabetes Facts & Figures.” Accessed Feb 18, 2010, at www.who.int/diabetes/facts/en/
5. Cowen and Company. Sep 2009. Th erapeutic Categories Outlook.
6. WHO Global Strategy on Diet, Physical Activ-ity and Health. 2010. ObesActiv-ity and overweight. Ac-cessed March 22, 2010, at www.who.int/dietphysi-calactivity/publications/facts/obesity/en/
7. MMWR Morbidity Mortality Weekly Report.
Prevalence of overweight and obesity among adults with diagnosed diabetes—United States, 1988-1994 and 1999-2002. 2004. Nov 19; 53(45): 1066-1068.
8. Ogden, C.L., Carroll, M.D., Curtin, L.R., et. al. 2010. Prevalence of high body mass in-dex in US children and adolescents, 2007-2008.
JAMA,303(3):242-249.
9. Centers for Disease Control. Diabetes projects. Accessed April 19, 2010 at
http://www.cdc.gov/diabetes/projects/cda2.htm
10. International Diabetes Federation. Global guide-line for type 2 diabetes. Accessed Mar 8, 2010 at http://www.idf.org/Global_guideline
11. Gale E. A. 2009. Collateral damage: the conun-drum of drug safety. Diabetologia, 52:1975-1982.
11. American Diabetes Association. 2004. Standards of medical care in diabetes, Diabetes Care 27 (Suppl 1):S15-S35.
12. International Diabetes Federation. 2005. Clini-cal guidelines task force: Global guideline for type 2 diabetes. Available at www.idf.org/home/index. cfm?unode=B7462CCB-3A4C-472-80E4-710074-D74AD3
13. American Association of Clinical Endocrinolo-gists. 2002. Medical guidelines for the management of diabetes mellitus: the AACE system of intensive diabetes self-management, 2002 update. Endocr Pract 8(Suppl.1): 40-83. 2002.
14. UK Prospective Diabetes Study (UKPDS). 1998. Intensive blood glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. Lancet, 352:837-853.
15. ADVANCE Collaborative Group.2008. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. NEJM, 358:2560-2572.
16. Rendell, Marc. 2004. Advances in diabetes for the millennium: drug therapy of type 2 diabetes.
Medscape General Medicine v 6(3 suppl).
17. Pharmaprojects. Update May 2009.
18. U.S. Food and Drug Administration. Safety: Avandia (rosiglitazone maleate) Tablets November 2007. Posted 11/19/2007. Available at
http://www.fda.gov/Safety/MedWatch/SafetyInfor-mation/SafetyAlertsforHumanMedicalProducts/ ucm150820.htm
19. U.S. Food and Drug Administration. Safety: Avandia (rosiglitazone): Ongoing Review of Car-diovascular Safety. Posted 02/22/2010. Available at http://www.fda.gov/Safety/MedWatch/SafetyInfor-mation/SafetyAlertsforHumanMedicalProducts/ ucm201446.htm
20. U.S. Food and Drug Administration. CDER 2008. Guidance for Industry: diabetes mellitus. Evalu-ating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. Available at http://www.fda. gov/downloads/drugs/GuidanceComplianceRegula-toryInformation/Guidances/ucm071627.pdf
21. Gregg, Richard. Obesity drugs and co-mor-bidities. Interview in Applied Clinical Trials Online Podcasts. Accessed Feb 16, 2009 at http://applied-clinicaltrialsonline.fi ndpharma.com/appliedclinical-trials/article
22. ClinicalTrials.gov. Accessed March 8, 2010: http://www.clinicaltrials.gov/ct2/search/ browse?brwse=cond_cat_BC18
23. Dal-Re, R., Luque A., et al. 2001. Irritable bowel syndrome: attrition rates of patients identifi ed at primary care centers during a 50-week period ver-sus those identifi ed in hospitals in a phase II clinical trial. Int J Clin Pharmcaol Res, 21 (3-4): 127-136.
Case Study
Background
Th is was a full-service, Phase II DPP-IV
inhibitor trial. Th e original specifi cations for this trial included:
• Subjects experiencing inadequate glycemic control on current regimen of metformin and pioglitazone • 300 sites across 22 countries
• Global enrollment target – 760 subjects • Enrollment period – January 2007 through June 2008
Challenges
PPD faced a challenging start-up timeline and regulatory delays in several countries. Th e start-up delays were primarily due to:
1. Delays in obtaining appropriate insurance certifi cates
2. Review cycle for sponsor approval of informed consents customized to meet local requirements 3. Delays in site contract and budget negotiations 4. Delays in ethics committee and ministry of health approvals due to numerous regulatory agencies requesting a protocol amendment to exclude subjects with New York Heart Association criteria Class I-IV heart failure
Strategy
PPD recognized the critical nature of the clinical trial application negotiation process and capitalized on existing relationships with sites by using previously negotiated language to expedite the contract negotia-tion process and activate sites as quickly as possible.
With client collaboration and approval, the number of sites in the United States was increased to miti-gate delays in regulatory approvals in the Europe/ Middle East/Africa and Asia-Pacifi c regions, and put the timelines back on schedule. Secondly, sites were asked to identify potential subjects ahead of initiation to ensure interested subjects were screened immediately following site activation.
During the pre-study site visits, PPD leveraged our experience in this indication by selecting an appro-priate mix of sites that had performed well on previ-ous type 2 diabetes studies with less experienced sites that showed evidence of the patient population in their practice. For less experienced sites, PPD focused additional site management eff orts on con-tinual training, education and support to ensure the quality of the data was comparable with the most experienced sites.
Additionally, the PPD project team recognized the enrollment developed recruitment plans and strate-gies to continuously engage sites and motivate them to exceed their original enrollment commitments. Th ese plans were customized on a country and site level to ensure all possible risks were mitigated. Site contracts were also amended to off er competitive fi nancial reimbursement to those sites that met their targets.
Results
Despite the start-up challenges, PPD met the target for the fi rst patient-in date of 30 January 2007 and reached the global enrollment goal of 760 patients two weeks ahead of schedule.
Case Study: The Role of Partnering in Successful Diabetes Research Programs
Th e development of the DPP-4 inhibitor alogliptin off ers valuable perspective on the scope and chal-lenges of current diabetes research. It also illustrates the vital role partnering plays in the design and implementation of successful research programs.
Alogliptin pre-registration studies were completed in record time using a highly effi cient design that provided for simultaneous rather than sequen-tial studies. Submitted in September 2008, the alogliptin new drug application (NDA) was in review when FDA’s 2008 guidance came into ef-fect. Alogliptin became the fi rst diabetes agent to undertake an additional study in order to comply with the guidance-specifi ed cardiovascular safety parameters; this bellwether trial indicates the cur-rent regulatory viewpoint.
PPD, Inc. began development of alogliptin in 2004 after purchasing rights from the compound’s origi-nator, Syrxx Inc. As sole sponsor, PPD designed double blind, placebo-controlled studies to evalu-ate alogliptin as a monotherapy, and completed fi rst-in-human and proof-of-concept trials. PPD had designed fi ve Phase III studies and enlisted the study sites when Takeda Pharmaceutical Company Ltd. acquired Syrxx in 2005. Takeda and PPD then entered into a partnering agreement in which PPD would collaborate on all development work and
downstream services. In addition to monotherapy, the partners developed a combination therapy using alogliptin together with Takeda’s approved anti-diabetes drug, pioglitazone (ACTOS).
Effi cient Design
Th e fi ve studies were conduced globally in Europe, Asia and Latin America. A total of 2,239 patients were randomized; one of the fi ve studies required treatment-naïve patients. Th e trials were conducted simultaneously, with each site running as many of the fi ve trials as possible. As a result, the partners were able to take alogliptin from lead optimization to NDA submission in a record 49 months.
“Our strategy meant that most diabetes patients treated at a given site would qualify for one of the studies,” explained Paul Covington, former execu-tive vice president of development, PPD, Inc. “It also meant that sites were conducting few, if any, competing trials. We designed feeder studies to roll into long-term extension studies.
“We’ve seen a dramatic increase in the number of diabetes studies and competition for patients,” Covington notes. “We were able to enroll some treatment-naïve patients in North America. But our most effi cient sites were in Latin America (Brazil, Peru and Mexico) and in Eastern Europe (Russia, Ukraine and Romania). Th is kind of global reach is just essential now.”
Long-term Safety Study
Th e successful development program faced a new hurdle when FDA required that a single long-term cardiovascular safety study be completed to earn ap-proval for the alogliptin and alogliptin/pioglitazone NDAs. Working closely with FDA, Takeda and PPD designed a safety study that will enroll 5,400 patients globally and collect data for 4.7 years. En-rollment criteria pose the greatest challenge. Patients must not only have type 2 diabetes and participate in a study lasting nearly fi ve years; they must also have experienced acute coronary syndrome within 15 to 60 days prior to enrollment. If alogliptin suc-ceeds in the massive safety study, the new diabetes therapy will reach patients in 2014.
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