Implementation

Introduction

Our project this year is a type of targeting drug which can be used in cancer treatment. However, there are many more steps and problems we should consider before a drug can actually be used clinically.

What we did this summer is the very first step in a whole drug developing process, which is the new drug discovery and design.

Next we have to find a professional company to evaluate our idea and look for investment as it is significant to have financial support. It is impossible conducting the actually useful drugs by our own. As our drug can also be applied with other aptamers to detect the unknown receptors on cancer cells, therefore it is a better implementation as a combination therapy to treat cancer since aptamer is our trigger. For example, the drug can detect triple-negative breast cancer using suitable aptamer, hence our drug provides an alternative way to treat those patient who suffer from the triple negative breast cancer. Besides, the whole drug delivery system is simply editable. Therefore if a new antigen is detected, the whole system can trigger that as well with no change, except aptamer, in any condition while utilizing in reality. If our system is used, less experiment needs to be carried out when doing the expansion process due to the characteristic of the drug delivery system is unchanged.

If we got the investment, we can do the following task...

Figure 1. An overview of the drug development process.

Process development

The first step is designing the expansion process with the platformed method. We can also design the protocol by ourselves but it is difficult and easily fail which will lead to the loss of the funds. Therefore we have to search and cooperate with the pharmaceutical company that produce this kind of chemical based drug aiming for producing safe, effective and quality controllable drugs with high quantity producing process.

How can we do the expansion, for example, the expansion the production of the liposome? As the production of liposome is in the unit of ml, it is not enough for industrial production. This process mainly carried by chemical reaction, hence the reaction is only occurs in a larger environment. Doing the experiment under a larger environment area after analyzing the physical and chemical condition in this environment, ensures the product obtained is the same as that carried out in the laboratory.

Above all, all the other products in our process can be designed based on this idea: carry out in small environment, transfer it into a larger environment, analyze the physical and chemical difference between two environment, design the different amount of reactant and condition, compare the result after several experiment, find the lack in the whole process, finally gain the similar quantity of products.

Purification and preparation is using the chemical and physical properties of the drug to get the pure drug and developing a method to stop it from decomposing over a period. Which is easy and normally will be developed by the end of process development.

Developing analysis methods

As our drug is built up by different parts, after every expansion we have to use different and combined analyzing methods to determine the quantity and quality of the product produced. This process is extremely important as we have to identify exactly we we produced. The methods for identify physical and chemical structure includes mass spectrum, HPLC and so on; for identify its active like ELISA and ELONA, have to be utilized and repeated to gain exact data.

For example, we have an experiment to produce liposomes encapsulating doxorubicin with a larger system; after this step, we have to analyze the structure and the size of the liposome and the amount of doxorubicin each of it carried.

Besides, the products of each experiment must be analyzed and record the data for comparison. In order to control the variable, the content and method must be kept the same for each product at different steps.

Clinical trails

This is a long period that usually goes across 4-6 years if it is a commercial one. During the period we will compare our process and its yield, modifying our protocol to gain a higher yield. Evaluate the adaption of the process developing. CQA evaluates the risk and potential. Besides, the pharmacokinetics value and the amount of drug used per dose is determined in this stage.

pre-clinical trial tests

Pre-clinical trials are necessary to see if the drug or treatment really works safely on humans. It also decides whether the drug or treatment can be applied in clinical trails ultimately. Pre-clinical trials usually test the safety and efficacy of drugs, carrying out on animal subjects, such as mice, and monkeys. There are certain types of trials that have to be done, such as toxicology studies and other trials that are specific to the particular study compound or question.

Usually the pre-clinical trails ofIn vivo test will be carried out on the animals to prove the security of the drug. An animal test is usually held on mice and monkeys.

A valid in vivo test would require us to prove its:

Bioavailability

Bioavailability is usually assessed by determining the area under the plasma concentration-time curve (AUC—see figure). The most reliable measure of a drug’s bioavailability is AUC. AUC is directly proportional to the total amount of unchanged drug that reaches systemic circulation. Drug products may be considered bio-equivalent in extent and rate of absorption if their plasma concentration curves are essentially superimposable.^[1]

Figure 2 The graph of drug concentration in blood over time.

Safety

We will have to include more results on its side effects, median lethal dose, and other health issues caused by different dosages. At last, we will have to propose a dosage for humans. The consideration of the safety test is shown below. Besides, to ensure safety, the methods of analysis are also important. The purpose of in vivo test is to decide the amount of the drug we should use to ensure safety when we utilize the drug to treat patients. We should also focus on immunogenicity, as our project doesn't consider the effect on the immune system, hence before every preparation we need to do more research and experiment to see how the immune system will treat our drug and whether the modification we had to make to adapt the immune system.

Pharmacology

The propose of the pharmacology should be like what shown below.

1. Identify the unexpected pharmacodynamic properties of the test substance that may be related to human safety.

2. Evaluate the adverse pharmacodynamic and/or pathophysiological effects of the test substance observed in toxicological tests and/or clinical trials.

3. Study the mechanism of the observed and suspected adverse pharmacodynamic effects.

The research plan that meets the above research objectives should be clearly stated.^[2]

Stability

Figure 3. An overview of what stability tests include.

Stability testing is an important experiment that runs through the entire drug research and development, clinical, marketing, and post-marketing quality research. It is the basis for the formulation of product expiration dates and provides a basis for drug production technology, formulations, packaging materials, storage, and transportation conditions. It is also the basis for the formulation of product quality standards. Biological products are more sensitive to environmental factors such as temperature, humidity, and light. In order to ensure their safety and effectiveness, and avoid inactivation or degradation, corresponding stability tests must be carried out according to the characteristics of the products.

Construct the stability test. By building the environment in the human internal environment to find the half-life of the drug.

IND application

Figure 4^[4] The FDA.

The purpose of IND application is during a new drug's early preclinical development, the sponsor's primary goal is to determine if the product is reasonably safe for initial use in humans and if the compound exhibits pharmacological activity that justifies commercial development. When a product is identified as a viable candidate for further development, the sponsor then focuses on collecting the data and information necessary to establish that the product will not expose humans to unreasonable risks when used in limited, early-stage clinical studies.

For an IND application usually contains two categories: commercial and research. We will first give our experiment results out to the government which normally simply contain three parts: Animal pharmacology and toxicology studies, manufacturing information and clinical protocols, and investigator information.

If we pass the IND application we can do the clinic test. However, a huge amount of tests still need to be carried out. The tests for such as pharmacology, stability, pharmacokinetics, toxicology, and light safety are required to be done again and again.

Phases of clinical trials

Clinical trials are usually conducted in phases. Each phase is designed to answer certain questions.

1) Phase 0 clinical trails involve exploratory, first-in-human (FIH) trials that are run according to FDA guidelines. This phage explore if the drugs do what they’re expected to do.

2) Phase I trials are the first tests of a drug with a small number of healthy human subjects. This phage explore i find the highest dose of the new treatment that can be given safely without causing severe side effects.

3) Phase II Phase II trials are performed on larger groups of patients and are designed to assess the efficacy of the drug and to continue the Phase I safety assessments. Most importantly, Phase II clinical studies help to establish therapeutic doses for the large-scale Phase III studies.

4) Phase IV trials are also known as post-marketing surveillance trials involving safety surveillance (pharmacovigilance) and ongoing technical support after approval.

Conclusion

It is a long path for our drug to be carried in the reality as you can see, our project is just at the beginning. More researches are required to be done like do the market research for the condition of this kind of drug in market at the present, by this research we can determine, for example, which producing efficiency is acceptable and which chemical package is better; providing us a limit in process development.

Besides the commercial effect, the drug delivery system is an epochal design, in our standpoint. When our design got a process to be expanded, we can target it to any antigen we found and only need to modify the aptamer, there is no need to change the parameters like temperature or amount of chemicals to be added in the expansion process. This is a much rapid and efficiency method than using the monoclonal antibody.

There is also problem need to be changed, like the binding affinity is low compare to the antibody, the toxicity is too high and it may cause damage to the heart, but also these problem can be fixed after we got the investment.

Reference

1. Manuals. (n.d.). Drug Bioavailability. MSD Manual Professional Edition. https://www.msdmanuals.com/professional/clinical-pharmacology/pharmacokinetics/drug-bioavailability#v6524385
2. ICH指导原则 - S9抗癌药物的非临床评价 - 蒲标网. (n.d.). 蒲标网. http://db.ouryao.com/ich/content.php?lang=cn&id=60
3. Aucamp, M., & Milne, M. (2019). The physical stability of drugs linked to quality-by-design (QbD) and in-process technology (PAT) perspectives. European Journal of Pharmaceutical Sciences, 139, 105057. https://doi.org/10.1016/j.ejps.2019.105057
4. Center for Drug Evaluation and Research. (2021, February 24). Investigational New Drug (IND) Application. U.S. Food and Drug Administration.https://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-applicationhttps://www.fda.gov/drugs/types-applications/investigational-new-drug-ind-application
5. Types and Phases of Clinical Trials.The American Cancer Society medical and editorial content teamhttps://www.cancer.org/treatment/treatments-and-side-effects/clinical-trials/what-you-need-to-know/phases-of-clinical-trials.html#written_by