Pharmaceutical R+D

What is a drug?

In Pharmacology, a drug is a natural or synthetic substance able to produce biological or functional effect in a living organism. A medication is a drug used for the treatment, cure, prevention, or diagnosis of a disease as well as in some condition to enhance physical or mental well-being.

Preclinical phase

After the drug discovery, its biological activity is analysed in computational models, cell cultures or animals (from less to more sensitive according to their phylogenetic scale) following the 3 R's principle of Russell and Burch. The protocols must be submitted and approved by the Ethical Committee of Experimental Animal Research of the university or research centre where the research is going to be carried out. 

Preclinical studies are also required to determine the efficacy of the medicament via the pharmacokinetic (the response of the organism to the drug) and pharmacodynamic (how the drug acts in the organism) analyses. In addition, the security of the drug needs to be evaluated by toxicological studies after chronic and acute exposure.  An improper testing of the efficacy or security of the drugs can cause serious health problems in the clinical stage, as happened in the middle of the XX century with Thalidomide, a drug prescribed as a sedative and antiemetic for morning sickness. Thousands of pregnant women took Thalidomide to relieve their symptoms. In the late 50's and early 60's reports of children born with deformities such as phocomelia (rare congenital disorder involving malformations of the limbs, see picture in the right) as a consequence of Thalidomide use saw the light. The effects of Thalidomide raised the issue of safety of pharmaceutical drugs with testing and approval of toxins becaming more important.

After preclinical testing, the drug can progress to the clinical phase following the positive evaluation of the National (AEMPS: Agencia Española de Medicamentos y Productos Sanitarios in Spain), European (EMA: European Medicines Agency) or American (FDA: Food and Drug Administration) authorities.

Clinical phase 

The clinical phase includes a serial of tests to ensure the efficacy and security in humans as well as to generate data of the adverse drug reactions or adverse effects with other treatments. All the investigations must conform to the Declaration of Helsinki and the protocols must be submitted and approved by the Ethical Committee of Clinical Research. The clinical developmental phases are:

• Phase I: the drug is administered, for the first time, to 20-100 healthy individuals in order to evaluate the safety of the dosage and how the drug should be given. Usually this stage lasts from 6 to 12 months.
• Phase II:  the biological activity and the optimal dosage of the drug is tested in 100-200 patients and healthy individuals involved in blind clinical trials. Information about the drug's safety, side effects and potential risks are also collected. This phase of the clinical trial lasts between 1-2 years.
• Phase III trials enroll a large number of individuals (1,000-3,000 patients) in order to compare the efficacy of the new drug with other existing medicaments in a double-blind, randomized study. Additional information about the safety and side effects of the drug is gathered during a period of 2-3 years. Once the drug has been proven succesful in the Phase III clinical trial, the researchers can submit an application to AEMPS, EMA or FDA approval. If data from the clinical trial meet the AEMPS's, EMA's or FDA's standards of safety and efficacy, the drug is approved for a specific use.
• Phase IV or post-marketing surveillance: the safety surveillance is designed to detect any rare or long-term adverse effects over a large population. Harmful effects can result in a drug being withdrawn or restricted to certain uses. A recent example include rofecobix (Vioxx), a nonsteroidal antiinflammatory drug used for the treatment of osteoarthritis, acute pain and dysmenorrhoea, that was withdrawn from the market because it caused serious secondary cardiovascular effects.

The entire process of a drug from the lab to this point may take approximately 12-18 years. In the following video, you can see a summary of the 4 stages of the clinical phase:

You will have to know all the phases of the pharmaceutical R&D process as well as their main characteristics:

 

Types of research

Clinical trials

Clinical trials are sets of tests in medical research that generate information on health interventions (e.g., drugs, diets, diagnostics, devices, therapy protocols).

Clinical trials often involve patients with specific health conditions. In early phases, participants are healthy volunteers who receive financial incentives for their inconvenience. In coordination with a panel of expert investigators, the sponsor decides what to compare the new agent with (one or more existing treatments or a placebo), and what kind of patients might benefit from the medication or device.
During the clinical trial, the investigators: recruit patients with the predetermined characteristics, administer the treatment(s), and collect data on the patients' health for a defined time period. These patients are volunteers and they are not paid for participating in clinical trials. 

Classification of clinical trials can be done by the way the researchers behave:
- In an observational study, the investigators observe the subjects and measure their outcomes.
- In an interventional study, the investigators give the research subjects a particular treatment (pharmacological, dietary or surgical). Usually, they compare the treated subjects to subjects who receive no treatment or standard treatment. Then the researchers measure how the subjects' health changes.

Taking into account their purpose five different types of trials can be organized:
- Prevention trials look for better ways to prevent disease in people who have never had the disease or to prevent a disease from returning. These approaches may include medicines, vitamins, vaccines, minerals, or lifestyle changes.
- Screening trials test the best way to detect certain diseases or health conditions.
- Diagnostic trials are conducted to find better tests or procedures for diagnosing a particular disease or condition.
- Treatment trials test experimental treatments, new combinations of drugs, or new approaches to surgery or radiation therapy.
- Quality of life trials (supportive care trials) explore ways to improve comfort and the quality of life for individuals with a chronic illness.
- Compassionate use trials provide partially tested, unapproved therapeutics to a small number of patients who have no other realistic options. Usually, this involves a disease for which no effective therapy exists, or a patient who has already attempted and failed all other standard treatments and whose health is so poor, he does not qualify for participation in randomized clinical trials.

The following videos show the importance of randomization and blinding.

The classification algorithm shown below can help you to identify the main types of clinical trials being carried out by researchers.

Translational research

The traditional categorization of research identifies two main categories: basic research (also termed fundamental or pure research) and applied research. While basic research often leads to breakthroughs or paradigm-shifts in practice, it usually takes a long time to be applied in any practical context. On the contrary, applied biomedical investigation often represents an incremental improvement to current knowledge rather than a radical breakthrough, however, it has the advantage of exerting a potential direct impact on clinical practice in a relatively short time period. As mentioned by Albani & Prakken in their very comprehensive article published in the 2009 September issue of Nature Medicine, translational medicine encompasses the continuum of activities that extend from the conception of an idea to advanced clinical testing and, ultimately, to the development of a new medical technology or drug. Translational research refers to making findings from basic science useful for practical applications that improve human health and well-being. With a focus on multidisciplinary collaboration, translational research aims to move “from bench to bedside” or from laboratory experiments through clinical trials to point-of-care patient applications. However, translational research is bidirectional and also encompasses “from bedside to bench” approaches.

Compartmentalization within science together with the cultural separation between different scientific fields makes it difficult to establish the multidisciplinary teams that are necessary to be successful in translational research. Additional challenges for translational research arise in the traditional roadblocks encountered in academia, industry and government to successfully move an idea from its conceptual stage to early clinical development and final application. To flourish, translational research requires a knowledge-driven system that establishes a feedback loop to accelerate the translation of data into knowledge whereby the complex and underlying causes and outcomes of disease can be unravelled, to design either effective prevention processes or early detection and personalized treatment strategies. Thus, translational research entails two distinct domains, namely the enterprise of translating knowledge from the basic sciences into the development of new treatments at the same time as translating the findings from clinical trials into everyday practice.

• Study the different classification possibilities of research studies together with their main characteristics, advantages and disadvantages.

• This information will enable you to decide which is the most appropriate type of research in each case.
• You need to know and understand what "translational research" means. 

Go to ADI to see the assignment of topics for the team work!