EU Drafts Research Guidance for Diabetes Treatment

The EUs Committee for Proprietary Medicinal Products describes the process clinical investigations should follow.

The European Union is treading delicately into new territory with draft guidance on developing diabetes products. The EUs senior scientific body for medicines, the Committee for Proprietary Medicinal Products, has just released the text for consultationuntil January 2002. It acknowledges that it is operating in a complex area with this guideline, and, unusually, it even includes a section on endpoints that it openly admits is almost speculative in nature.

The Note for Guidance on Clinical Investigation of Medicinal Products in the Treatment of Diabetes Mellitus (CPMP July 2001; www.emea.eu.int/ pdfs/human/ewp/108000en.pdf) describes the type of clinical development program that should support the registration of new medicines for the treatment of diabetes mellitus.

Prevention of diabetes and fixed combinations of oral antidiabetic agents are not covered by this guideline because, the CPMP says, there is only limited experience in this field. The note is intended to assist applicants during the development phase, offering guidance rather than binding rules. Even so, any deviation from the advice should be explained and discussed in the expert report, the CPMP insists.

The overall view is that global treatment of diabetes mellitus should aim not only at lowering blood glucose to near normal levels but also at correcting metabolic abnormalities and cardiovascular risk factors. Although several international trials have shown that any decrease in the level of blood glucose monitored by the glycated fraction of hemoglobin (HbA_1C) reduces the risk of microangiopathy, multiple cardiovascular risk factor intervention is the key issue in type 2 diabetes, it says.

Study design
For developing oral antidiabetic agents for type 2 diabetes mellitus, study design recommendations include a washout period of up to three months for subjects already treated with oral antidiabetic agents who are starting therapeutic exploratory studies with a treatment period up to around three months, in order to decrease the influence of previous treatment on the parameters of blood glucose control, which could last for a large part of short-term studies. For therapeutic confirmatory studies with active control of at least six months duration, a washout period is not considered necessary for previously treated subjects, because the final HbA_1C level will not be influenced by the former therapy.

Placebo-controlled trials are necessary to get relevant information on the hypoglycemic effect of the investigational drug, the guideline says. But, for ethical reasons, controlled trials of three to six months should be reserved for subjects at an early stage of the disease who are not already on treatment with other oral antidiabetic drugs. And protocols will need to stipulate that subjects will be withdrawn from the study if their glucose control consistently deteriorates.

The guideline endorses the current clinical practice of titrating a new oral antidiabetic agent until an optimal effect is seen, or until maximal tolerated or allowed dose is reached. But it stresses that the hypotheses on doses made at the early stages of development should be carefully tested, and the dossier should contain well-designed, dose-finding studies to justify the dosage used in confirmatory clinical trials and claimed in the Summary of Product Characteristics. Titration steps should in most cases last for at least four weeks unless a different duration is justified.

Study design should also aim to determine if there are demographic, genetic, metabolic (such as C-peptide or other measure of beta-cell function), or other factors that may predict response to a particular class of oral antidiabetic agents.

The guideline also says it is important to determine whether the pharmacokinetic behavior of the drug in elderly people is different from that in younger adults, particularly as related to hypoglycemia. A reasonable number of subjects over 65 years and possibly over 75 years should be included in therapeutic confirmatory studies, and specific efficacy and safety trials in this population may be needed. Type 2 diabetes might tend to become prevalent in obese adolescents, so trials in older adolescents are also recommended.

In respect of associated cardiovascular risk factors, any claim for improvement in lipids will require evidence of efficacy over and above the reversion to normal of hypertriglyceridemia that usually occurs with good glycemic control. Similarly, improvements in hyperglycemia related to weight loss in obese diabetics is certainly desirable and could potentially be a labeled indication, but will not be accepted as the sole basis for approval unless the glucose lowering effect of the antiobesity agent has a clear pharmacologic rationale, and is sustained and clinically relevant over and above that explained by effects on weight.

Positive effects on long-term macrovascular and microvascular complications can be evaluated properly only in large scale and long-term controlled clinical trials, which will be required only when specific claims are made or when there are suspicions of a detrimental effect of the tested drug.

Efficacy assessment
In the assessment of efficacy, the primary purpose of therapeutic confirmatory studies is usually to demonstrate an improvement in blood glucose control, the guideline states. Because glycohemoglobin (HbA_1C) is the most widely accepted measure of overall, long-term blood glucose control in type 1 and type 2 diabetes, and reduction of HbA_1C is directly related to a reduced risk of development of vascular complications, it is an appropriate primary endpoint. The primary analysis of HbA_1C should evaluate the difference in change from baseline HbA_1C between the test compound and the active comparator/placebo. But as the goal of treatment is to reduce the risk of complications, not just to lower HbA_1C, a new agent could not be approved based on a reduction in HbA_1C if there is evidence that the agent directly increased the risk of diabetic complications.

Changes in fasting plasma glucose is an acceptable secondary measure of outcome, and in some situations a reduction of postprandial glucose levels can be used as an endpoint. Future use of devices allowing continuous blood glucose management is also encouraged.

A reduction in insulinemia in subjects treated with oral hypoglycemic agents, or a reduction in insulin dose itself in insulin-treated type 2 diabetic subjects, is not considered a measure of efficacy unless accompanied by improvement in HbA_1C. But the elimination of the need for insulin entirely, or a reduction in insulin dose accompanied by a clinically significant improvement in the evolution of body weight, could be considered a measure of efficacy in insulin-treated subjects, provided that studies had appropriate controls.

Serum lipids (LDL and HDL cholesterol, triglycerides) levels should be documented regarding short and long-term effects, as available evidence supports benefit of reduction of LDL and increase in HDL.

Body weight should be documented regarding short- and long-term effect. If a novel agent causes weight increase in association with a decrease in HbA_1C it should be established that beneficial effect on HbA_1C is maintained long term in spite of the weight increase, and the nature of the weight increase should be addressed.

Development strategyThe proposed mechanism of action should be described in relation to preclinical data obtained in animal models, because the mode of action of candidate antidiabetic drugs for type 2 diabetes may indicate in which type of subject the drug may be most recommended, and may suggest different approaches for combination therapy.

Although there are no specific requirements for pharmacodynamic testing of oral antidiabetic agents in humans, the mechanism of action of the drug should be evaluated in relation to drugs already available. When possible, the direct pharmacodynamic effect should be evaluated independently of the effect on blood glucose level.

It may not be assumed that the pharmacokinetic properties observed in healthy subjects will be the same in diabetics. Factors such as delayed gastric emptying due to autonomic neuropathy can be expected to complicate drug absorption and disposition in a significant number of type 2 diabetic patients.

In the clinical studies themselves, the subjects enrolled must be representative of the target population in terms of demography, co-morbidity, and severity of the disease; and groups should be sufficiently balanced with respect to age, gender, body weight, and severity and duration of disease.

Dose-ranging studies should thoroughly assess the lower end of the effective dose range, as well as the optimal dose. At least three dosages should be studied with a total therapy phase of at least eight weeks and usually up to three months.

Parallel group, randomized, double-blind, placebo and comparator-controlled studies are necessary for therapeutic confirmatory studies. Results of confirmatory dose-finding studies can also be supportive for the proof of efficacy. Therapeutic confirmatory trials should normally aim at demonstrating superiority over placebo (where appropriate) and noninferiority to an active comparator. Criteria for equivalence/noninferiority must be predefined and well discussed. In respect to the noninferiority design of the pivotal studies, the guideline notes that it has recently been confirmed that even an apparently small reduction in HbA_1C is considered clinically relevant in terms of risk reduction of diabetic complications. It is therefore necessary to balance the degree of potential inferiority against some other clinical advantage such as safety, tolerability, or compliance. The applicant should demonstrate that this advantage can be equated to the loss of efficacy in some sense.

The overall duration of therapeutic, confirmatory, comparator-controlled, monotherapy studies should be no less than six months, including a maintenance period of at least 16 weeks. For oral antidiabetic agents with an original mechanism of action, a 12-month controlled overall duration may be required. For confirmatory studies, a run-in period (usually two weeks) is generally sufficient, during which the investigator must carry out baseline evaluation of subjects, including full clinical and laboratory assessment.

If the product is intended for use as an add-on therapy for subjects insufficiently controlled despite therapy with an established treatment, a study comparing the established agent as monotherapy against the combination of the new agent and the established agent is mandatory. Usually, a 16-week duration of the maintenance period is sufficient to demonstrate efficacy.

It is necessary to demonstrate a statistically significant and clinically relevant additional HbA_1C reduction (or improvement in blood glucose control) and, optimally, improvement in responder rates with the combination in subjects who did not respond sufficiently to therapeutic doses of monotherapy. For combination with insulin, efficacy on glycemic control should be documented against placebo. For monotherapy, add-on therapy, and combination with insulin, continuation or extension of the studies to at least 12 months is desirable to assess the maintenance of efficacy and safety in the long term.

Safety
Blood, liver, and skin disorders should be carefully monitored and documented. Special efforts should be made to assess potential adverse events characteristic of the class of products being investigated, depending on the mechanism of action and pharmacodynamic properties. Add-on studies alone do not allow a definitive assessment of the safety of a new compound. However, it is necessary to show that any additional safety concerns do not outweigh the additional benefit of the combination.

The applicant should establish a definition for less severe episodes of hypoglycemia, including a set of symptoms and self-monitored blood glucose. A high level of specificity is needed to make claims, so the definition needs to be more rigorous than in clinical practice. A detailed analysis of hypoglycemic episodes noted in clinical trials should be provided (broken down by age and by diurnal distribution), and the severity of symptomatic episodes graded according to the need for external assistance.

Because cardiovascular disease is the main cause of morbidity and mortality in type 2 diabetes, any new product in this area must have well-documented data regarding effects on blood pressure, hyperlipidemia, and clinical indicators of cardiac function. The total clinical experience must generally include long-term safety data on a large and representative group of subjects. The applicant should justify the duration of trials.

Insulin preparations
For insulin preparations with novel pharmacokinetic and pharmacodynamic properties, such as insulin analogues, long-term efficacy and safety data are essential. Clinical studies in type 1 diabetic children are mandatory, a reasonable number of geriatric patients should be included in the therapeutic confirmatory studies, and attention should be paid to hypoglycemia with long-acting insulin preparations in elderly subjects.

Due to the wide intra- and intersubject variability in the response to insulin in type 1 diabetes, pharmacodynamic data are of primary importance to demonstrate therapeutic equivalence or differences between insulin preparations, including their use in mixtures. For the pharmacokinetic evaluation of a new insulin or insulin analogue, the comparator drug should be an insulin or an analogue with a similar pharmacological profile. Comprehensive data should be provided on the insulin bioavailability based on peak insulin concentration and area under the insulin-time curves.

Efficacy endpoints
The draft guideline also contains a section on efficacy endpoints relating to the complications of diabetes, which the CPMP itself says should be considered with caution because experience of clinical development in this domain is limited, particularly with regard to neuropathy. Its starting point is that an antidiabetic agent or an agent acting independently of a hypoglycemic effect may seek to slow the progression of diabetic complications. Overall, a clearly documented and clinically significant change in the natural history of a diabetic complication would be considered as a primary measure of efficacy, says the guideline. It adds that unfortunately valid intermediate markers of most of the long term complications of diabetes which could be used in clinical trials are currently lacking. So before undertaking such studies, sponsors are invited to seek scientific advice from the CPMP.

Hard endpoints in terms of morbidity/mortality trials are still required for macrovascular disease. For retinopathy, endpoints based on the progression of diabetic retinopathy documented on well-validated grading scales are considered clinically meaningful. For nephropathy, hard endpoints are time for doubling plasma creatinine and the evolution to chronic renal failure defined as need for maintenance dialysis or transplantation or sustained increase in plasma creatinine to greater than 250 mol/L. As an intermediate endpoint, microalbuminuria is considered highly predictive of subsequent progression to manifest diabetic nephropathy and eventual chronic renal failure, especially in type l diabetes. Delay in onset of microalbuminuria, definite and sustained reduction of microalbuminuria, or delay of progression to microalbuminuria are relevant measures, but should be supported by long-term data (of at least 24 months) indicating a favorable evolution of glomerular filtration rate.

Send comments to the EMEA (fax +44 20 74 18 86 13) by January 2002.