WHERE DRUGS AND MEDICINES COME FROM A BRIEF ACCOUNT OF THE DEVELOPMENT OF PHARMACEUTICALS

Summary

According to data from the pharmaceutical industry, of every 10,000 molecules evaluated for transformation into some kind of medicine, only one to three of them will make the grade. The development of pharmaceuticals is a continuous and changing process, with different byways and nuances whereby the search for a molecule or substance with pharmacological potential, whatever its origin, goes through various phases of testing for safety and effectiveness, leading finally to a drug for human consumption.

Introduction

A probability of one in ten thousand would be acceptable to almost no one. In simple human terms (and not mathematical ones) it would mean possibly waiting almost twenty-seven years to find a solution to a problem, if you tried out a new solution every day. You might have to read 9,999 books before finding your favorite author or the precise quotation that describes your emotions. The same number of television series might be necessary for you to say you like one of them. And yet this is the kind of probability that a drug or medicine has of eventually being marketed. According to data from the pharmaceutical industry, of every 10,000 molecules evaluated for transformation into some kind of medicine, only one to three of them will make the grade. During the process, some of them will lose viability in the first stage, and others perhaps when they are nearly ready for sale to the public. Still others will achieve their goal of being marketed, but in real-life circumstances they will end up being withdrawn for reasons of safety or owing to various commercial considerations. 1

Our children may ask us (or we ourselves may have asked, as children): “What tree do medicines grow on, or where are they found? Are they all created in laboratories?” As adults, our questions may circle about the seemingly inexhaustible capacity of the pharmaceutical industry to create new medications. What strategies are employed by “laboratory scientists” to ensure that there is always some new pharmaceutical in line, waiting to be transformed into a medicine?

Definition and Organization

The development of pharmaceuticals is a continuous and changing process, with different byways and nuances (by no means as rigid as one might imagine), in which the search for a molecule or substance with pharmacological potential (preventive, palliative, curative, diagnostic), whatever its origin (vegetal, animal, mineral, synthetic), goes through various phases of testing for safety and effectiveness, leading finally to a drug for human consumption. 2 The stages or phases may differ in number, depending on the regulatory agency in question, but they generally include at least three stages:

1.Chemical development or characterization stage

2.Preclinical stage

3.Clinical stage: Ex perimentation on human beings

Chemical Development or Characterization Stage

The chemical development stage involves the discovery, characterization, and final formulation of molecules with pharmacological potential. In practical terms, during this stage, researchers explore and examine “nature” (with a touch of serendipity, on occasion) with a view to discovering and extracting chemical candidates which, by their effect either on their organism of origin or on their external environment, modify a biological variable or entity.

To take an example, in order to make this more clear: a researcher working in a laboratory may attempt to find a substance (let us assume the term “antibiotic” does not yet exist) that inhibits or eliminates the growth of bacteria that generate deadly diseases in human beings. By chance or serendipity (or a combination, perhaps, of serendipity and curiosity), the researcher has to leave the laboratory for a few days and forgets his (or her) Petri dish on the worktable. On returning, before throwing away the contents of the dish, he notices something strange. He takes his microscope and observes that the bacteria have not proliferated, owing to a fungus introduced from outside of the dish. With the help of other member of the laboratory, he identifies the culprit: a fungus of the Penicillium family. The rest is history.

Following the discovery of the substances with biological effects, it is necessary to continue with their characterization, that is, to identify and reconstruct the active principle of the substance, the molecule capable of modifying a physiological variable. Once this has been achieved, it is important that the molecule in question be stable in actual conditions, and above all that it be easy to extract or synthesize, without any loss of its pharmacological characteristics. In general terms, a pharmaceutical can be of vegetal, animal, mineral, or synthetic origin. It may be an extract from some part of a plant (as for example arrow poison curare, extracted from Chondodendron tomestosum), or the secretion from an animal (protamine, for example, extracted from the sperm of certain fishes), or a substance derived from a metal (such as iron fumarate), or simply generated in the laboratory from an animal extraction (as in the case of insulin). In short, the range of “possible” pharmaceuticals is enormous.

The goal of this stage is to generate stable active principles with a potential for being transformed into a medicine.

Preclinical Stage

During this stage, the toxic effects of the molecule obtained in the characterization stage is evaluated at different levels. These trials tend to be performed in organoid and/ or animal cell cultures. It is currently possible to run predictive mathematical models on a computer in order to examine the possible outcomes of the interaction of the active principle with a living organism or with a system or organ thereof. The exploration of this contact may result in the union of the pharmaceutical with a certain protein, yielding data on the strength and time of union, among other factors. Nevertheless, these results do not yield sufficient evidence to be used as a sole source of information.

Organoids are relatively new, consisting of threedimensional cultures that imitate the structure and function of an organ. Put more simply, they are organs in miniature. Experimentation of this type can be performed during the preclinical stage or later. The objective is to reproduce the effect of a pharmaceutical on an “organ” without the intervention of other physiological variables that may exist in the case of an organism as a whole. The evaluation of this effect can be very useful.

In spite of the foregoing, the most traditional way of carrying out this stage is through animal models. These can be either small (inferior) species or large (superior) species, depending on the size and complexity of the living being. The choice of model, that is, of species to be used generally depends on the active principle, its effect (mechanism of action), and its similarity to a human being. Such models can be evaluated wholly or partially (limited to a single organ).

For example, let us suppose a researcher wishes to understand the effect of seawater as a possible ocular lubricant. He may choose a white rabbit as an animal model, since the eyes of this species are very similar to human eyes. But if the researcher wished to evaluate the effect of the same active principle on the heart (since certain rabbits show an accelerated heartrate), the best animal model might be a pig. Be that as it may, many experiments are performed on different strains of rats and mice, simply because they are so easy to handle.

It is also possible to use animal models to carry out trials of the active principle that has been extracted on the conditions for which it is intended. There are two options here: generating the model itself, or acquiring it. In the first case, it is possible to “create” a sick rat in order to imitate humanlike physiopathological phenomena. In the second case, it is possible to acquire a genetically manipulated animal model (known as a knockout) that shows a physiological defect. Another example to illustrate this: let us suppose a researcher wishes to undertake trials of a new kind of insulin. A laboratory mouse is created and injected with streptozotocin, a substance that destroys the beta cells of the animal’s pancreas, which produce insulin. In the other case, the researcher will purchase a knockout mouse for the insulin gene.

The goal of this stage is to evaluate general and specific toxicity (that is, whether the pharmaceutical affects the entire organism or only certain tissues), relative efficacy (the mechanism of action and its effect are corroborated), and certain pharmacokinetic parameters (how and where the substance is absorbed, stored, transformed, and eliminated).

Clinical Stage: Experimentation on Human Beings

This stage tends to be the most crucial of all in the development of pharmaceuticals, since, if the potential harm exceeds the benefits, however slightly, it is very probable that the regulatory authorities will reject continuation of the trials through the following phases, owing to the fact that, as the involvement of human subjects grows, both costs and required supervision tend to increase. This stage is usually subdivided into four phases, although there are sometimes further subdivisions. These are the phases commonly referred to as clinical trials.

Phase 1 or Pharmacokinetics (PK)

During this phase, which tends to involve few participants (~5-30) and last from anywhere from a few days to several months, the subjects are usually in good health. The volunteers who participate in this phase are often hospitalized or interned in some way so that the great majority of variables can be evaluated and the number of intervening or confounding variables that might modify expected results can be diminished. Among all these variables, the goals to be controlled include: feeding, laboratory proofs, physical activity, exposure to environmental and emotional factors, and others. The most controlled factor, however, is strict adherence, whereby the participant ingests the trial drug or has it applied in some other way (intravenous, intramuscular, etc.). No placebo or any comparable substance is necessary to contrast results.

The objective of this phase is to determine safety and pharmacokinetics. The endeavor to identify all the possible adverse effects the pharmaceutical may have on a human being requires a large number of laboratory and consulting room tests. It also includes coming to understand how and where the substance is absorbed, stored, transformed, and eliminated.

Phase 2 or Safety Over Efficacy

In this phase, which normally lasts several months, the number of participants tends to increase to anywhere from ten to a hundred, approximately. Trial participants are usually sick, diagnosed either with the illness for which the pharmaceutical is being evaluated or with some similar condition. The experimental treatment or intervention may be administered in the context of ambulatory care or hospitalization. Since strict safety is the goal, laboratory and consulting room testing is frequently done. It is recommended that a second group be given a placebo or a medicine of proven efficacy, already in use, for the purposes of comparison.

The goal of this phase is to evaluate safety and certain aspects of efficacy. As in the prior phase, the main adverse effects are monitored through repeated laboratory and consulting room testing.

Phase 3 or Efficacy Over Safety

This is considered one of the most important phases, since the pharmaceutical being tested must show its superiority (or at least a modification of the response variable) with respect to whatever it is being compared to. In this phase, participants can increase to anywhere from hundreds to thousands, though this will depend on the prevalence of the illness and the budget available. This phase tends to last several years. In order to sustain and corroborate results, numerous clinical trials, with different outcomes and comparisons, tend to be held. As in the previous phase, participants have been diagnosed with the condition the pharmaceutical is designed to “treat.” It is recommended that a control group, whose members have been administered a placebo or a drug of proven efficacy, also be employed.

Unlike the previous phase, the goal here focuses mainly on effectiveness and, to a lesser degree, safety.

Phase 4 or Past-Marketing

During this phase, clinical trials are no longer performed. Rather than experimentation with human subjects, an evaluation is performed of all the data accumulated on the actual use of the medication, including reports of adverse effects or reactions that have appeared during the period of its marketing and reallife circulation. There is no recommended or approximate number of participants, but since the drug is already being marketed, they can be expected to number in the thousands. The duration of this phase tends to be by periods of anywhere from two to five years, or even up to ten years. It includes participants suffering from the condition for which the drug is specifically prescribed, but also offlabel prescriptions. Comparison groups are not normally employed.

The main goal is safety, though new hypotheses may be generated from the use and effects of the substance in real life conditions.

Final Comments

Few of us ever ask ourselves where the drugs and medicines come from that we use in our everyday lives. But with the advent of the SARS-CoV-2 pandemic, we have all been given a crash course in pharmaceutical research in real time. We have gone from discovering a few cases of an untypical illness to the development of a vaccine, moving from the identification of risk factors to clinical trials with human subjects. More than ever before, we have paid attention to the development of pharmaceuticals. This process that we are experiencing in accelerated motion ―from discovery to clinical trials― usually lasts about ten years. It tends to cost billions of dollars and have a relatively low success rate. In the case of success, however, those costs can be quickly and significantly recovered. As in Maurice Sendak’s book, Where the Wild Things Are, the time span for the development of drugs and medicines may seem long, but it is very short if considerations of safety are taken into account.

Conclusion

Thanks to these development, safer and safer drugs have been created and tragedies like that of the thalidomide babies have been avoided. There is still much to improve, however, in areas such as animal experimentation, human exposure to risk, and long-term safety. We need to speed up certain stages of the process, but without compromising strict attention to safety.

Further Reading

By “real life” we mean simply everyday life, excluding the controlled environment, in terms of almost all variables, generated not only in research on plants and animals, but also in experimentation with human subjects.

For the purposes of this article, we use the term pharmaceutical for a substance which does not yet have a definitive form and has not been marketed. A substance with a final pharmaceutical form, which can be marketed, is referred to as a drug or medicine. But either kind of substance may have potential uses in the context of the health sciences.

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Arieh Roldán Mercado Sesma

is a surgeon and obstetrician graduated from the Universidad de Guadalajara. He studied at the Centro Universitario from 2000 to 2006, earning a master’s degree and doctorate in pharmacology. He has been an associate professor and researcher at the Centro Universitario de Tonalá (Universidad de Guadalajara) since 2012 and is a member of the Sistema Nacional de Investigadores (Level 1).