Drug Discovery Blog-min

How we test safety and efficacy of new drugs.


The concepts of efficacy and safety have been with mankind since ages. In native sense, an efficacious and safe medical intervention is one that works and causes no undue harm. A drug should be used only when it will benefit a patient. Benefit takes into account both the drug’s ability to produce the desired result (efficacy) and the likelihood of adverse effects (safety). For a major portion of the history of medicine, efficacy and safety were measured by that native standard, which till today lies at the heart of medical practice, but the meaning and measurement of those concepts have evolved with increased sophistication and advancement of scientific methods in medicine. This article introduces the concepts of efficacy, effectiveness and adverse effects. It also throws light on patient oriented and surrogate outcomes along with their comparison and correlation in safety assessment of new drugs. Lastly concluding with the importance of long term monitoring and assessment of benefit to risk ratio for new drugs.

How does efficacy & effectiveness differ from eachother?

Efficacy is the capacity to produce an effect (e.g., lower blood pressure, lower or control high blood sugar). Efficacy can be assessed accurately only in ideal conditions (i.e., when patients are selected by proper criteria and strictly adhere to the dosing schedule). Thus, efficacy is measured under expert supervision in a group of patients most likely to have a response to a drug, such as in a controlled clinical trial.

Effectiveness differs from efficacy because the former takes into account the overall performance of the drug to real world use. Often, a drug that is efficacious in clinical trials is not very effective in actual use. For example, a drug may have high efficacy in lowering blood pressure but may have low effectiveness because it causes undesirable adverse effects which makes it difficult for patients to adhere to it. Effectiveness also may be lower than efficacy if clinicians inadvertently prescribe the drug inappropriately (e.g., giving a fibrinolytic drug to a patient thought to have an ischemic stroke, but who had an unrecognized cerebral haemorrhage on CT scan). Thus, effectiveness tends to be lower than efficacy.

Patient-oriented outcomes & Surrogate outcomes-

Patient-oriented outcomes should be used rather than surrogate or intermediate outcomes to judge efficacy and effectiveness. Patient-oriented outcomes are those that affect a patient’s well-being. They involve prolongation and better quality of life, improve function or prevent disability, and provide relief from symptoms. Surrogate or intermediate outcomes are factors that do not directly involve the patient’s well-being. They are features such as physiologic parameters (e.g., blood pressure) or test results (e.g., concentrations of glucose or cholesterol, tumour size on CT scan) that are thought to predict actual patient-oriented outcomes. For example, clinicians typically presume that lowering blood pressure will prevent the patient-oriented outcome of uncontrolled hypertension (e.g., death resulting from myocardial infarction or stroke). However, it is conceivable that a drug could lower blood pressure but not decrease mortality, perhaps because it has fatal adverse effects. Also, if the surrogate is merely a marker of disease (e.g., HbA1C) rather than a cause of disease (e.g., elevated blood pressure), an intervention might lower the marker by means that do not affect the underlying disorder. Thus, surrogate outcomes are less desirable measures of efficacy than patient-oriented outcomes.

On the contrary, surrogate outcomes are more feasible to use, for example, when patient-oriented outcomes take a long time to appear (e.g., kidney failure resulting from uncontrolled hypertension) or are rare. In such cases, clinical trials would need to run for a long time unless a surrogate outcome (e.g., lowered blood pressure) is used. In addition, the main patient-oriented outcomes, death and disability, are binary (i.e., yes/no), whereas surrogate outcomes are often continuous, numerical variables (e.g., blood pressure, blood glucose). Numerical variables, unlike binary outcomes, may indicate the magnitude of an effect. Thus, use of surrogate outcomes can often provide much more data for analysis than can patient-oriented outcomes, allowing clinical trials to be done using limited patients for a certain amount of time.

Correlation of patient-oriented and surrogate outcomes- 

However, surrogate outcomes should ideally be proved to correlate with patient-oriented outcomes. There are many studies in which such correlation appeared reasonable but was not actually present. For example, lowering blood glucose to near-normal concentrations in patients with diabetes in the intensive care unit resulted in higher mortality and morbidity (possibly by triggering episodes of hypoglycaemia) than lowering blood glucose to a slightly higher level. Some oral antihyperglycemic drugs lower blood glucose, including HbA1C concentrations, but do not decrease risk of cardiac events. Some antihypertensive drugs decrease blood pressure but do not decrease risk of stroke.

Factors that help in assessing safety index of drugs-

Adverse Effects are clinically relevant undesirable effects that are patient-oriented outcomes, such as, death, disability or discomfort. Surrogate adverse effects (e.g., alteration of concentrations of serum markers) are often used but, as with surrogate efficacy outcomes, should ideally correlate with patient-oriented adverse effects. Clinical trials that are carefully designed to prove efficacy, can still have difficulty identifying adverse effects, if the time needed to develop an adverse effect is longer than the time needed for benefit to occur or if the adverse effect is rare. For example, cyclooxygenase-2, COX-2 inhibitors relieve pain quickly, and thus their efficacy can be shown in a comparatively brief study. However, the increased incidence of myocardial infarction caused by some COX-2 inhibitors, such as Rofecoxib marketed as Vioxx, occurred over a longer period of time that was not apparent in shorter, smaller trials. Hence, clinical trials may exclude certain subgroups and high-risk patients, adverse effects may not be fully known until a drug has been in widespread clinical use for several years. Post marketing surveillance or pharmacovigilance is one way to test for safety of new drugs in long term.

Another factor that ensures safety and efficacy of new drugs is benefit to risk ratio. Known or expected benefits vs. unknown or unexpected risks is when the efficacy of a new drug is tested, a specific type of benefit is expected. Other benefits are usually additional to the outcome sought. While assessing risk, the negative outcomes are often unknown or unexpected, and, unlike the additional benefits, the significance of these adverse effects must be considered to the extent practicable before the drug is considered for acceptable risk. When thalidomide was tested as a sleeping pill, no major negative effects were discovered. Its effects upon the fetus were not tested, and thalidomide was marketed as a safe drug. The birth defects that resulted, vividly demonstrates the need to consider risks from many perspectives. 


The drug safety concept has earned a lot of attention during the last century due to the fact it plays a direct role in a patient’s health. Recent regulatory laws, stresses that drug safety should be included in the process of new medication’s approval and continued conduct of post-marketing drug evaluations, i.e., pharmacovigilance. Benefit–risk assessment should be considered by all health care professionals when they prescribe specific drugs to specific groups of patients. Hence, drugs with a high risk profile should be avoided unless their benefit outweighs the risk. Drug safety has gone through different stages from the last century till now, with several unfortunate tragedies that incline us to protect our patients from all aspects. All patients should be protected; however, specific groups of patients demand paramount care, such as pregnant women, children, and the elderly, since they are identified as vulnerable populations.