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Purpose of Non-Clinical and Clinical Studies

The procedure of developing a drug involves two processes: clinical and non-clinical studies. Clinical studies are performed on people and are aimed at examining a behavioral, medical, or a surgical intervention. It is the primary technique used by researchers to test the safety of a new drug, diet, treatment, or medical device. Basically, the study helps to know the effectiveness of the drug and if its side effects are less harmful than the existing drugs. On the other hand non-clinical studies refer to studies conducted on animals and cells but not humans. The purpose of the test is to examine the safety of the new substance being studied. The non-clinical testing investigates any harmful impact of the substances on a body caused by the pharmacology of the new substance, including genetics, toxicity, and carcinogenicity, amongst others. The information from non-clinical studies aids in clinical studies planning, in which the information is used in deciding the starting dose and range of doses in the clinical studies. Similarly, it suggests the clinical signs to be looked for to identify any harmful effects (Sacaan et al., 2020).

Various protocols are used when conducting non-clinical trials (Sarkar et al., 2019). The protocols usually follow GLP (Good Laboratory Practice) regulations. In the initial preclinical process, also referred to as Go/No-Go decision, the substance under test must go through various steps, like pharmacokinetics (to determine availability of drug) and ADME (absorption, distribution, metabolism, and elimination) as well pilot studies whose objective is to investigate the safety of the candidate drug including general toxicology, mutagenicity, safety pharmacology, and genotoxicity (Mustonen et al., 2017). The preliminary studies are not subject to mandatory compliance with the regulations of GLP. The studies aim is to investigate the safety of the candidate drug to acquire the first-hand data about its admissibility in various systems appropriate for advance deliberations.

Nonetheless, there are other compulsory studies that need to be conducted with respect to the GLP standards due to safety exposure to human beings. The mandatory tests include safety pharmacology, genotoxicity, and dose toxicity, and should be performed prior to the process of IND (Investigational New Drug). The non-clinical studies set usually must cover information required for safe switch of medicine to humans from test animals, basically on the basis of NOAEL (Non-Observed Adverse Effect Level) acquired from the research of general toxicity (Iansante et al., 2021). Following IND approval, are other GLP experiments used to evaluate chronic toxicity, genotoxicity, developmental and reproductive toxicity, and carcinogenicity, which are carried out during the phase of clinical development (Ulrich et al., 2018). Nevertheless, the need to perform the studies relies on the clinical application purpose of the candidate drug.

In this report, a critical evaluation of non-clinical data for a new drug (QMU1221) developed to treat transient liver disease in adult women, for a period of half a year (6 months) has been done. Phase 1 studies were successfully conducted on healthy volunteers, and results given. The next step is phase 2 studies that will involve patients and will go for a period of 3 months. The drug had been tested on rats and dogs for up to 4 weeks. Similarly, a 1-week drf study was done in NHPs. In the rats, the target organs were the ovaries and testes.

Protocols in Non-Clinical Trials

The goals of conducting non-clinical tests of drugs before rolling them out for human use are, characterization of potential adverse effects of the drug, characterization of pharmacokinetic profile, characterization of essential pharmacodynamic effects or proof of principle, guidance towards safe application in clinical studies in humans by determining a safe starting dose and providing monitoring guidelines for the study, and provision of enough data for concluding that users/patients are not exposed to any risk during use (Hoogendoorn, 2019; Wallis et al., 2018; Sacaan et al., 2020).

Usually, in phase 1 studies, the steps involved are toxicology, reproductive toxicology, and ADME. In this study, all the above mandatory steps in phase 1 were conducted, albeit for the minimum recommended period due to the tight budget.

The main target organ for the study was the liver. Consequently, it was imperative to know the effect of the substance on the livers of the rats used in the study.

For reproductive toxicology, the testes and ovaries were the reproductive organs picked for analysis after the test.

The preliminary ADME studies were performed under the metabolite 1, metabolite 2, and NOAEL for human, rat, dog, and NHP. The test results were recorded and are shown in the results section. The NOAEL was done in mg/kg/day.

In all the species tested, the liver was affected in the following ways

  • Increased enzymes in the liver
  • Increased weight
  • Increased hepatocyte hypertrophy
  • High doses led to cell neurosis
  • However, reversibility was not investigated

The early ADME studies results are shown below.

The preliminary QSAR analysis done for the parent and metabolite 1 yielded the following results:

  • Mixed inconclusive results for genotoxicity was recorded, in spite of being negative for bacterial reversion
  • The parent showed to possess much shorter half-life of elimination than the metabolite 1
  • Further, the metabolite 1 indicated ability to inhibit angiogenesis

The other test data showed the following results;

  • The bacterial reversion (Ames) test turned negative
  • There was a positive result on in vitro in mouse lymphoma cells
  • The preliminary developmental drf indicated effects observed without maternal toxicity in rats
  • Rabbits were not evaluated
  • No further studies were conducted

Despite having gone through phase 1 so far, it appears most pre-clinical trials were left out in the steps to fit the tight budget. Crucial steps of preclinical studies including GLP, IND, NDA (new drug application), and ADME were seemingly not carried out properly (Motoyama et al., 2018).

In addition, there is insufficient data concerning observation of both macroscopic and microscopic observations.

Due to the tight budget, the execution of phase 1 was insufficiently done. Phase 1 of non-clinical studies must involve both general toxicology and reproductive toxicology studies. Similarly,

Reversibility in the effect of the drug on the liver was not investigated. Investigating the reversibility was crucial for knowing whether the adverse effects on the liver were reversible or permanent. If reversible, then include the remedy in the non-clinical study test.

Why rabbits were not evaluated.

The mandatory tests include safety pharmacology, genotoxicity, and dose toxicity, and must be performed prior to the IND (Harris & Rhodes, 2018). The non-clinical studies package usually must contain data required for safe switch of medicine to human beings from test animals, basically on the basis of NOAEL acquired from the studies of general toxicity. Following IND approval, are other GLP experiments used to evaluate chronic toxicity, genotoxicity, developmental and reproductive toxicity, and carcinogenicity, which are carried out during the phase of clinical development (Ventrella et al., 2019). Nevertheless, the need to perform the studies relies on the clinical application purpose of the candidate drug.

In the preliminary and phase 1 part of the non-clinical study, the drug was tested in rats and dogs and the test lasted for 4 weeks. Also, a 2-week drf study was done in NHPs, albeit no to GLP.

Mandatory GLP Tests in Preclinical Process

Further toxicity testing should be conducted on all the species to further study the toxicity of the drug on the liver as well as the reversibility of the toxicity of the drug on the liver.

Also, further toxicity testing should be done on more rats to test for the effects seen in the preliminary developmental dwarf in the absence of maternal tox.

In addition, since rabbits were not evaluated in the previous tests, they should be subjected for further toxicity tests and evaluation to enrich the tests database and increase variety of data.

Phase 2 of the studies is conducted for the non-clinical studies during human clinical trials. The studies needed to support phase are reproductive toxicology, chronic toxicology, and carcinogenicity

The reproductive toxicology tests are conducted in the clinical studies, together with teratogenic potential evaluation. It is the most difficult test applied by the regulatory bodies and it is a precondition for authorization of new drugs (Rahalkar et al., 2018). The reproductive test is necessary because the drug is capable of affecting the reproductive system and activities in the following ways:

  • Effect on fertility as well as initial development of embryo to fetus.
  • Effect on the final development of embryo to fetus (teratogenicity)
  • Effect on development of pre-birth and post-birth, including maternal function.

After given a green flag to commence clinical studies, other non-clinical toxicity tests such as chronic and non-chronic studies should be carried out. The evaluation of toxicity is usually classified according to a chronological scale, like the acute studies which are conducted for verifying the effect of the medicine with the aid of single or repeated-dose for a day. Normally the chronic studies are regarded as studies that consume more than 90 days (Lahn, 2020).

Carcinogenicity studies are normally conducted in phases 2 and 3 on non-clinical studies during human clinical development, with the help of a rodent species, more so rats. Additionally, the study is recommended for performing other in vivo assays that are capable of providing more data on the carcinogenic substance’s sensitivity, like a shortened duration test on transgenic rat/mouse or a long duration carcinogenicity test in other species of rodents (Paul, 2017). The long duration carcinogenicity study in rats is normally carried out for a minimum of 2-year treatment period with 3 or 4 doses of the control and the test article. Basically, in these non-clinical studies, the least dose is the highest dose commended for human beings, whereas the maximal dose is the MTD acquired in the initial safety tests (Fung, 2020).

The carcinogenicity test requires use of 50 to 80 animals per gender/group. Regulations and rules of this test requires that the performance of the study to be done in harmony with the principles of GLP, with spf (specific pathogenic-free) animals as well as the histopathological analysis, in which in excess of 50 types of tissues are analyzed by a professional veterinary pathologist who has a vast experience in carcinogenesis.

The in vivo pharmacokinetics assay enables the quantifiable assessment of ADME of a new drug. The information is significant as it helps in predicting the most suitable dosage and the most desirable posology protocol to be applied. The in vitro tests are developed and authenticated to enable safety assessment for discovering the probability of the substances being toxic. Nonetheless, in most cases, these assays complement the in vivo tests. ADME is carried out in phase 2 of the non-clinical studies as well as in other phases and preclinical tests (de Almeida et al., 2020).

Evaluation of Non-Clinical Data for a New Drug (QMU1221)

Preliminary Ames tests aid in evaluating a probable genotoxicity effect as well as to detect genetic modifications and changes in organisms subjected to the drug. In this study, preliminary Ames test was conducted but he results were not detailed. Therefore, in the new studies the Ames tests should be intensively conducted to attain its full benefits. Further toxicology tests should be included in the new studies to investigate the toxicity profile. The additional safety tests include mutagenicity tests, local tolerance and safety pharmacology, and acute toxicity (Martínez Muñoz, 2018). Similarly, reversibility should be included in the new studies. Investigating the reversibility is crucial for toxicity profile investigation.

In this critical evaluation of QMU1221, several safety steps and phases of non-clinical studies have been reviewed. Within the review several classifications of toxicology (safety steps) have been specifically looked at. The non-clinical safety steps include the general toxicology that should be conducted in the first and second phase, sand lasts for 3 to 4 months. The second one is the reproductive toxicology which spans across phase 1, phase 2, and phase 3 of non-clinical studies of human clinical trials. Carcinogenicity is the other non-clinical safety step that is carried out in the phase 2 and phase 3 of non-clinical studies during clinical human trials.

Phase 3 of the studies is conducted for the non-clinical studies during human clinical trials. The studies needed to support phase 3 include reproductive toxicology and carcinogenicity.

The reproductive toxicology tests are conducted in the clinical studies, together with teratogenic potential evaluation. It is the most difficult test applied by the regulatory bodies and it is a precondition for authorization of new medicine.

Besides reproductive toxicology and general toxicology, the carcinogenicity study is always needed for medicine proposed for constant treatment spanning 6 or more months. In these instances, the carcinogenicity tests must be conducted prior to the market entry of the substances, but never prior to the commencement of clinical tests (Paul, 2017). The carcinogenic assay could be needed whenever there are substances known to belong to known groups of carcinogens or when chronic toxicology shows indication of carcinogenic probability, or when there is convincing indication that the substances and/or their corresponding metabolites get retained in the organism for an extended duration.

The in vivo pharmacokinetics assay enables the quantifiable assessment of ADME of a new drug. The information is significant as it helps in predicting the most suitable dosage and the most desirable posology protocol to be applied. The in vitro tests are made and certified to enable safety assessment for discovering the probability of substances being toxic. Nonetheless, in most cases, these assays complement the in vivo tests. ADME is carried out in phase 3 of the non-clinical studies as well as other phases including the preclinical step.

References

de Almeida, A. A. C., de Oliveira Ferreira, J. R., de Carvalho, R. B. F., dos Santos Rizzo, M., da Silva Lopes, L., Dittz, D., ... & Ferreira, P. M. P. (2020). Non-clinical toxicity of (+)-limonene epoxide and its physio-pharmacological properties on neurological disorders. Naunyn-Schmiedeberg's Archives of Pharmacology, 393(12), 2301-2314.

Fung, V. S. C. (2020). Integrating traditional Chinese (herbal) medicines into risk-based regulation-With focus on non-clinical requirements to demonstrate safety. Journal of Traditional Chinese Medical Sciences, 7(2), 88-94.

Harris, M., & Rhodes, T. (2018). Caring and curing: Considering the effects of hepatitis C pharmaceuticalisation in relation to non-clinical treatment outcomes. International Journal of Drug Policy, 60, 24-32.

Hoogendoorn, K. H. (2019). Advanced therapies: clinical, non-clinical and quality considerations. In Pharmaceutical Biotechnology (pp. 357-402). Springer, Cham.

Iansante, V., Brooks, A., & Coney, L. (2021). Considerations in the Design of Non-Clinical Development Programmes to Support Non-Viral Genetically Modified Mesenchymal Stromal Cell Therapies. Pharmaceutics, 13(6), 823.

Lahn, M. (2020). The Development of a Drug: A Pharmaceutical Drug Development Perspective. Phase I Oncology Drug Development, 1-15.

Martínez Muñoz, L. (2018). Non-Clinical Contribution to Clinical Trials during Lead Optimization Phase. Behavioral Sciences, 8(1), 17.

Motoyama, S., Takeiri, A., Tanaka, K., Harada, A., Matsuzaki, K., Taketo, J., ... & Mishima, M. (2018). Advantages of evaluating γH2AX induction in non-clinical drug development. Genes and Environment, 40(1), 1-7.

Mustonen, E. K., Palomäki, T., & Pasanen, M. (2017). Oligonucleotide-based pharmaceuticals: Non-clinical and clinical safety signals and non-clinical testing strategies. Regulatory Toxicology and Pharmacology, 90, 328-341.

Paul, G. R. (2017). Defining dosimetry and implications for aerosol presentation for non-clinical development of respiratory drugs (Doctoral dissertation, Cardiff University).

Rahalkar, H., Cetintas, H. C., & Salek, S. (2018). Quality, non-clinical and clinical considerations for biosimilar monoclonal antibody development: EU, WHO, USA, Canada, and BRICS-TM regulatory guidelines. Frontiers in pharmacology, 9, 1079.

Sacaan, A., Hashida, S. N., & Khan, N. K. (2020). Non-clinical combination toxicology studies: strategy, examples and future perspective. The Journal of Toxicological Sciences, 45(7), 365-371.

Sarkar, C., Jamaddar, S., Mollick, B., Akter, M., Ahmed, T., Mahir, M. I., & Islam, M. T. (2019). Importance and the unique aspects of modalities for conducting non-clinical and pre-clinical studies of compartmental and non-compartmental analysis. Pharmacologyonline, 3, 1-15.

Ulrich, P., Blaich, G., Baumann, A., Fagg, R., Hey, A., Kiessling, A., ... & Weir, L. (2018). Biotherapeutics in non-clinical development: Strengthening the interface between safety, pharmacokinetics-pharmacodynamics and manufacturing. Regulatory Toxicology and Pharmacology, 94, 91-100.

Ventrella, D., Forni, M., Bacci, M.L. and Annaert, P., 2019. Non-clinical models to determine drug passage into human breast milk. Current pharmaceutical design, 25(5), pp.534-548.

Wallis, R., Benson, C., Darpo, B., Gintant, G., Kanda, Y., Prasad, K., ... & Valentin, J. P. (2018). CiPA challenges and opportunities from a non-clinical, clinical and regulatory perspectives. An overview of the safety pharmacology scientific discussion. Journal of pharmacological and toxicological methods, 93, 15-25.

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