R&D blog-min

Role of Research and Development in Modern Pharmaceutical Industry


In a life cycle of a drug from its discovery till launch, a series of crucial steps are involved in order to comply with regulatory requirements as per respective local regulatory authority. These steps from discovering a new drug to its launch in the market contributes to research and development in the pharmaceutical industry. The process is time consuming and may take several years for completion.

Steps involved in research and development in the modern pharmaceutical industry are as follows, i) early drug discovery, ii) preclinical studies, iii)clinical development, iv) review and approval by applicable regulatory bodies, v) post marketing surveillance.

Identifying a potential target-

Early drug discovery involves target identification and validation, hit discovery, assay development and screening, high throughput screening, hit to lead and lead optimization. Target identification begins with identifying the function of potential therapeutic agents and its role in the disease. It can be approached by direct biochemical methods, genetic interactions or computational interface. However, a combined approach may be required to fully characterize on-target and off-target interactions in order to understand molecular action mechanisms. Main motive of hit discovery is to identify molecules with potential interactions with drug targets.

Assay development-

Different types of assays can be used for assay development and compound screening, ranging from biochemical to cell-based assays. The choice of the assay depends on the biology of the drug target protein, scale of the compound screen, the equipment infrastructure, etc. Factors required for assay development are; i) Pharmacological importance of the assay– ability to identify compounds with the desired mechanism of action, ii) Reproducibility– is readily reproducible across assay plates, screen days and the length of the drug discovery programme, iii) Quality– pharmacology of the standard compounds falls within predefined limits, iv) Effects of compounds in the assay– should not be sensitive to the concentrations of solvents used in the assay.

Screening methods-

High throughput screening, (HTS) involves screening of the entire compound library against the drug target. Knowledge-based screening is a method of selecting from the chemical library smaller subsets of molecules with potential activity at the target protein. Fragment screening is making very small molecular weight compound libraries which are screened at high concentrations. Physiological screening is a tissue-based approach with the response more in direction with the desired in vivo effect.

Lead optimization-

Drug-like molecules must go through different phases to identify the hit lead molecule and optimization with a potency of 100nM – 5mM at the drug target. The refinement process involves generating dose-response curves in primary assay for each hit. Followed by examining the surviving hits in a secondary assay. Generation of rudimentary structure-activity relationship, SAR data and identifying the essential elements in the structure linked with the activity. Lastly, in vitro assays providing significant data with regards to absorption, distribution, metabolism and excretion (ADME) properties as well as physicochemical and pharmacokinetic (PK) measurements. Overall, the aim is to achieve a lead compound optimized with desirable effects on the target that can provide therapeutic benefits within an acceptable safety window. Average time required for this step is 2-6 months.

A glance at preclinical trials-

Preclinical studies or non clinical studies, carries out testing on animals to accurately model the desired biological effect of a drug in order to predict treatment outcomes in patients determining its efficacy, and to identify all toxicities associated with the drug to predict adverse effects for safety assessment. There are two types of preclinical studies, i) in vitro, ii) in vivo, iii) ex vivo assay and iv) in silico. In compliance with good laboratory practices, GLP, in vitro studies are carried out outside of living organisms in a test tube, glass or petri dish. On the other hand, in vivo studies are those which involve living organisms, including animal studies and human clinical trials. Ex vivo assay refers to a medical procedure in which an organ, cell or tissue are taken from the living body for treatment testing such as skin biopsies or isolated samples from tumor biopsy. In silico studies refers to using computer simulations to predict the reaction of a compound with specific proteins or pathogens. 

Goal of preclinical studies involve determination of pharmacokinetics, proof of concept, formulation, optimization & bioavailability, establishing safe dose, therapeutic dose, lethal dose and maximum tolerated dose. The compound from drug discovery is modified through preclinical studies and becomes Investigational New Drug, IND. IND application is filed for review and approval as per guidelines and standards of local and national regulatory authority. On an average the time required for this phase is approximately ranging from 1-6 years.

A complete overview of Clinical trials-

Clinical development of drug discovery begins after approval of IND for further testing. Clinical trials are conducted for testing of the new drug classified into several phases.

Phase 0 and Phase I-  Phase 0 is known as human micro dosing studies, which involves 10-15 individuals who are administered with small amounts of sub therapeutic dose mainly to determine pharmacokinetics, oral bioavailability and half-life of the drug. Phase 0 trials are often skipped to direct Phase I trials unless some of the data is inconsistent from previously conducted preclinical studies. Phase I studies are conducted amongst healthy volunteers to test the safety, tolerability, pharmacokinetics & pharmacodynamics, side effects & adverse effects, optimum dose, half-life and formulation method for the drug. In circumstances when testing for diseases like cancer or HIV, the treatment for which is likely to make healthy individuals ill, clinical patients are selected as an exception. Phase I trials are not randomized and hence are vulnerable to selection bias. This phase involves 20-100 individuals. Phase I trials can be further divided into, i) Single ascending dose, Phase I (a) in which a small number of participants are entered sequentially at a particular dose while monitoring them for a period of time to confirm safety. If no adverse effects are noted, then dose is escalated for newer groups. It is continued until pre-calculated pharmacokinetic safety levels are achieved or intolerable side effects are noted, it is the point where drug reaches at maximum tolerated dose, MTD; ii) Multiple ascending dose, Phase I (b) in which group of participants receives multiple low doses of the drug, which is subsequently escalated for further group of participants up to a predetermined level. It helps in determining pharmacokinetics and pharmacodynamics of multiple doses of the drug along with its safety and tolerability.

Phase II- Phase II trials are performed on larger groups (50–300) and are designed to assess biological activity and effect of the drug. Trial design of Phase II trials are either as case series, which demonstrates safety and efficacy in a selected group of participants, or as randomized controlled trials ,RCT, where some participants receive the drug/device and others receive placebo/standard treatment. Phase II studies are divided into Phase II (a) and Phase II (b). Phase II (a) studies are pilot studies designed to demonstrate clinical efficacy or biological activity of the drug. Phase II (b) studies determine the optimal dose at which the drug shows biological activity with minimal side-effects. It is also known as maximum effective dose, MaxED.

Phase III- Phase III trials are conducted in a large patient population of 300-3000 individuals determining the efficacy of the new drug in comparison to existing standard treatment. They are time consuming and expensive with complicated trial designs such as Randomized controlled multicentre trials with single, double or triple blinded factors in order to avoid bias and clean results. Phase III (a) studies are trial designed and executed to obtain statistically significant data for new drug approval by regulatory authority. Phase III trials that continue while awaiting regulatory approval in order to provide life-saving drugs to patients until the drugs are available in the market are categorized as Phase III (b) studies. Label expansion studies by the sponsor also fall under this category.

Phase IV- If the new drug successfully passes through Phase I, II, and III, with desirable outcomes, the manufacturing, preclinical and clinical data is then submitted as a new drug application, NDA, for review and marketing approval by national applicable regulatory authority. Post approval the new drug is marketed and Phase IV trials begin, which is post marketing surveillance of the new drug and lasts for up to 5 years. The entire process from developing a drug from preclinical research till marketing can take approximately 12-18 years. A Phase IV trial is a drug monitoring trial to assure long-term safety and effectiveness of the drug, vaccine, device or diagnostic test. These trials involve the safety surveillance, i.e, pharmacovigilance and ongoing technical support of a drug after it receives regulatory approval to be sold. Phase IV studies may be required by regulatory authorities or may be undertaken by the sponsoring company for competitive reasons, such as finding a new market for the drug, or other reasons, for example, the drug may not have been tested for interactions with other drugs, or on certain population groups such as pregnant women, who are unlikely to subject themselves to trials. The safety surveillance is designed to detect any rare or long-term adverse effects over a much larger patient population and longer time period than was possible during the Phase I-III clinical trials. Harmful effects discovered by Phase IV trials may result in a drug being withdrawn from the market or restricted to certain uses; examples include cerivastatin (brand names Baycol and Lipobay), troglitazone (Rezulin) and rofecoxib (Vioxx).


Thus Research & Development is essential when it comes to the pharmaceutical industry, since R&D services not only generate income for the companies involved in the research but it often saves lives. Reliable Pharmaceutical R&D services allow for companies to have technical and manufacturing procedures, quality control measures and production scope aspects as per required standards.

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.