Phase I clinical trials

Original medicinal product:
the first experience of clinical use (phase I).
Modern requirements

A.Y.Savchenko, K.S.Davydova, G.V.Ramenskaya, V.G.Kukes
Branch "Clinical Pharmacology" NC BMT RAMS, Moscow
Remedium Magazine www.remedium.ru N 9-2011

The development of new and more advanced medicines plays a crucial role in the health care of all countries. The main stage in the study of potential drugs are phase I studies in which the drug is used for the first time by healthy volunteers or patients. The first phase is the link between scientific research and clinical practice. Phase I studies can be attributed to experimental studies related to clinical practice. These studies require comprehensive knowledge, the result of the study depends on the correctly set goals and objectives and the quality of the study. At the same time, the safety and well–being of research subjects – both healthy volunteers and patients - should always be in the first place.

Over the past 3 years in the Russian Federation, phase I studies account for about 10% of all studies allowed in the country (Table 1).

Table 1

Tasks in phase I studies include: finding methods for evaluating the activity and effectiveness of new drugs, exchanging safety data; calculating the initial dosage; developing protocols with increasing doses; and – in the interests of the well–being and safety of research subjects - consistently paying close attention to risk reduction and management issues during the study.

However, before a potential drug can be given to people, the developers of the drug are required to conduct full-scale animal studies. The main objectives of such preclinical studies are as follows:

• identification of the effect of the drug on the body systems (pharmacodynamics);
• determination of the drug content in the blood, mechanisms of absorption, distribution, metabolism and excretion after ingestion (pharmacokinetics);
• assessment of the toxicity of the range of doses of the drug for animals, many times higher than planned for humans, and in the case of toxicity, determination of the affected organs and safety limits expressed: a) at a dose at which no undesirable effects (NOAEL) are observed, relative to body weight and b) in the effect of the drug – the concentration of the drug in the bloodstream during 24 hours (toxicokinetics) [1];
• development of the optimal dosage form of the drug.

Only after a thorough study of the potential drug on animals and obtaining promising and safe results, they begin phase I studies. Most phase I studies are conducted with healthy volunteers. However, for ethical and safety reasons, some studies involve only patients with the disease for which the drug is being developed.

In successful cases, phase I–III studies can be carried out for up to 10 years, but many products are withdrawn from development mainly for the following reasons:

• poor tolerability or insufficient safety of drugs for people;
• unsatisfactory pharmacokinetic or pharmacodynamic profile;
• inefficiency or insufficient effectiveness for the treatment of the target disease.

A ten-year analysis of studies of new drugs showed that only in 60% of cases, phase I studies passed into phase II and only 11% of medicines were on sale [4]. Phase I studies make it possible to identify drugs with the potential for success, as well as to weed out ineffective drugs without involving a large sample of patients.

Currently, the fundamental documents regulating the conduct of clinical trials, including Phase I in the Russian Federation are:

• Federal Law No. 61-FZ of April 12, 2010 "On Circulation of Medicines";
• National Standard of the Russian Federation GOSTR 52379-2005 "Good clinical practice";
• Decree of the Government of the Russian Federation No. 714 of September 13, 2010 "On Approval of the Standard Rules for Compulsory Life and Health Insurance of a Patient Participating in Clinical Trials of a Medicinal Product";
• Order of the Ministry of Health and Social Development of Russia dated August 31, 2010 No. 774n "On the Ethics Council".

When planning a phase I study, the origin of the drug is taken into account, for example:

• chemical structural elements,
• biotechnological preparations,
• cell therapy preparations,
• gene therapy drugs,
• plasma-derived drugs,
• other extractive agents,
• herbal preparations;
• homeopathic medicines,
• radiopharmaceutical compounds.

Biotechnological drugs (also called biological drugs) are recombinant proteins, hormones, cytokines, monoclonal antibodies, genetically modified microorganisms (GMOs) and genetic drugs. Currently, we have no differences in the regulation of research on biotechnological drugs, unlike world practice, where the examination of experimental high-risk biological drugs differs from the procedure for other drugs (the duration of consideration of such studies has been increased, clinical studies of genetic drugs must be authorized by the Advisory Committee on Genetic Therapy (GTAC)).

Additional requirements for the researcher are provided for conducting studies of preparations of protein origin and monoclonal antibodies. For example, he should be able to stop immune reactions, including anaphylactic ones [11]. Many proteins are characterized by a long half-life and require rare intake by patients. Therefore, in order to obtain an exhaustive picture of the pharmacokinetic profile and a reliable assessment of the immune response, it is necessary to provide a sufficient follow–up period of 3 months or even longer.

Potential drugs of biological origin are classified as drugs with a higher risk than other studied drugs.

• Biological medicines of increased risk include:
• any compounds that can cause severe disruption of vital body systems;
• drugs with agonistic or stimulating effect;
• new drugs or mechanisms of action for which there is no prior experience of use;
• species-specific drugs that make preclinical risk assessment complicated or impossible;
• potent drugs, for example, compared to natural ligands;
• multifunctional drugs, for example, divalent antibodies;
• cell-related targets;
• targets that bypass normal regulatory mechanisms;
• targets of the immune system;
• targets in systems with the potential for significant biological enhancement in vivo.

The term "increased risk" implies that the assessment of drugs should be even more thorough and qualitative than usual, and does not mean that the risk for subjects may be higher than the minimum.

As a rule, in the first phase I study, single doses are examined with increasing in order to assess the tolerability, safety, pharmacokinetics and, if possible, pharmacodynamics of the drug under study, as well as comparing the results with the conclusions of preclinical studies. Subsequent phase I studies are studies of multiple increasing doses. Other types of Phase I studies include assessment studies:

• the effects of potential influencing factors, such as food, gender of the subject, age and genetic differences, on the activity of the drug;
• dependence of the response on the dose or concentration of the drug (for example, using biomarker studies [5] or the administration of stimulant drugs (allergens, serotonin, histamine, etc.);
• possible interaction of the drug with registered drugs;
• absorption, distribution, metabolism and excretion of the drug labeled with a radioactive isotope;
• bioavailability or bioequivalence of the drug [6];
• the effect of the investigated product on the QT interval on the electrocardiogram (ECG) [7].

It is possible to combine in one study both a study with the study of a single dose, and a study with the study of multiple doses of a drug. If necessary, studies on the effects of food or age are included, so a study with the first inclusion of people is just the first stage in a large complex of studies.

Before starting any phase I study, in addition to risk assessment and justification of such an assessment, it is necessary to develop a strategy that guarantees minimal risk throughout the study. The choice of the initial dose is the most important aspect of risk management in the study.

The methodology for calculating the safe initial dose proposed by the FDA [8] uses a step-by-step approach:

• first, the dose at which no undesirable effects are observed, obtained from toxicological studies (NOAEL) [1], is converted to an equivalent human dose (HED) based on the body surface area;
• then the HED is selected from the most suitable individuals;
• after that, a safety factor (10-fold) is applied to obtain the maximum recommended initial dose (MRND);
• The MRND is adjusted taking into account the expected pharmacological effect of the drug.

This technique is simple and is confirmed by extensive previous experience of application. However, the emphasis is not on choosing a dose with minimal pharmacological effect in humans, but on a dose with minimal risk of toxicity, taking into account NOAEL. In addition, the goal is the dose, not the effect of the drug [2]. Thus, a complementary method for determining a safe initial dose can be a calculation based on the expected dose at which a minimal biological effect is observed. This method takes into account all relevant data and takes into account: novelty, activity, mechanism of action, degree of species specificity, data on the dependence of dose and response in human and animal cells in vitro, data on the dependence of dose/concentration and response in animals in vivo, the results of pharmacokinetic and pharmacodynamic simulations, calculated involvement targets depending on the concentration and concentration of the target or target cells in humans in vivo. If different calculations are obtained by different methods, the minimum value is taken and the actual initial dose must be set to a safety limit. If there is a possibility that preclinical data will serve as an unreliable guideline for the response in humans, the calculated initial dose decreases and increases with a small step so that the dose–response curve is not steep.
In phase I studies with increasing doses, the dose, as a rule, doubles with each increment, and this practice is confirmed by a logarithmically linear dose–response curve. However, an increase in the dose should be carried out only after a thorough analysis of all available data on the experience of using previous doses. Consistent measurements of the drug content in the blood during the study allow increasing the dose based on the effects of drugs [2]. Researchers (doctors, clinical pharmacologists, analysts) should consider all available data, including from preclinical studies, before deciding to increase the dose. In case of concerns about the tolerability and safety of drugs or exceeding the dose at which undesirable effects are not observed, it is necessary to use an intermediate dose, provided that this is provided for by the protocol. The reasons for all decisions to increase the dose should be recorded in the documents.

Also, the most important aspects of risk management in phase I studies are the number of patients receiving the drug at a certain point in time, the time interval between doses by individual subjects, the composition of groups that depend on the drug, the method of administration and the type of study. So, at the very first appointment of a high–risk drug, the drug is prescribed only to one subject, and if the method of administration is intravenous, the drug is administered by slow infusion for several hours, and not in the form of a rapid injection, if there is no reason to use the second method. Conversely, if the studied low-risk agent is used internally, groups of subjects can receive the drug simultaneously and at short intervals, for example, every 5-10 minutes. It is also necessary to take into account the possibility of providing emergency medical care if necessary.

It is believed that drug studies with the first inclusion of people are associated with a higher risk than later phase I studies. However, the risk at the stage of transition from preclinical studies to a study with the first inclusion of people may not be higher than in other cases. For example, when switching from a single dose to multiple doses, when changing young to elderly volunteers, when switching from monotherapy to combined use with registered drugs during drug interaction studies. It should be noted that the analysis of the results of phase I studies indicates good safety indicators [9-10]. In general, the incidence of serious adverse events associated with the studied drug was about 0.02%. The risks are assessed by a team of researchers by studying the protocol, the researcher's brochure, the dossier of the tested drug, correlate predictable risks and inconvenience with the expected benefits for a single subject and for future patients with the corresponding disease. Each patient receives explanations in the patient's information sheet. Permission to conduct a study is issued by an authorized federal body on the basis of state scientific, ethical and legal expertise, comprehensively assessing the validity and safety of the upcoming Phase I clinical trial.

In the next article, we will continue to talk about the basic requirements for clinical centers participating in phase I studies.

Literature

1 Non-clinical safety studies for clinical trials. CPMP/ICH/286/95.
2 Toxicokinetics and exposure in toxicology studies. CPMP/ICH/384/95.
3 Pharmaceutical innovation. Br J Clin Pharmacol 1988; 25: 387-96.
4 Kola I., Landis J. Can the industry reduce attrition rates? Nature Rev Drug Disc 2004; 3: 711.
5 Lesko L., Atkinson A. Use of biomarkers and surrogate endpoints in drug development. Ann Rev Pharmacol Toxicol 2001; 41: 347-366.
6 Bioavailability and bioequivalence. CPMP/EWP/QWP/1401/98.
7 Shah R. QT interval in drug development. Br J Clin Pharmacol 2002; 54: 188-202.
8 Estimating the safe starting dose for healthy volunteers. FDA, 2005.
9 Declaration of Helsinki. World Medical Association, 1996.
10 Sibille M., et al. Is phase 1 still safe? Br J Clin Pharmacol 2006; 62: 502-503.
11 Resuscitation Council (UK). Guidelines, 2005.

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