Biologic drug (recombinant drug) considerations
A recombinant drug (a biologic) is produced through the application of biological processes involving DNA technologies. Biologic drugs are intended to be used to treat and manage diseases and health conditions in patients. Clinical trials would be used to obtain answers about the pharmacological product (Chow & Liu, 2013).
However, they are carried out after approvals from relevant bodies in different countries. A clinical trial involves four stages, which must all be passed to prove that a biologic drug is safe to use and produces good biological effects (Chow & Liu, 2013). The clinical phases and considerations in each phase are summarized as follows:
Figure 1. A table with a summary of the 4 phases of clinical trials.
Phase I
Phase I considerations for a biologic drug would include the following:
- Safety
- Pharmacodynamics
- Pharmacokinetics
- Tolerability
Safety
Drug safety is an important aspect that is assessed in clinical trials. The goal of assessing the safety of a drug is to ensure that it does not cause more adverse reactions than expected therapeutic benefits in the human body. The safety of the chosen recombinant drug would be determined in cases of pregnancy and overdose, among others (Chow & Liu, 2013).
It will be important to determine the level of drug benefits in the scenarios because they may lead to adverse drug reactions. Although much information regarding the safety of the drug would be obtained from human subjects participating in the clinical trials, some information would be accessed from medical literature and pharmacovigilance agreements (PVAs).
The safety consideration would encompass some aspects that would greatly determine the overall assessment in terms of safety. Adverse drug reactions are undesirable side effects that are caused by a drug. The drug benefit is defined as a therapeutic good that is associated with a drug.
Efficacy is the level to which a pharmacological product produces good efficacy. Harm is the extent to which a drug causes tissue damage. Effectiveness of a drug is the extent to which a drug is metabolized. Drug metabolism determines how a drug produces good efficacy levels in the human body (Chow & Liu, 2013).
The safety assessment in human subjects will mainly focus on comparing the benefits and limitations of the drug. It has been shown that drugs that produce many benefits in patients have low levels of harm. Such drugs are adopted in the healthcare industry because they have more benefits than adverse drug effects.
Pharmacodynamics
The pharmacodynamics consideration would involve studying the physiological effects that the drug would have on human subjects (Chow & Liu, 2013). In other words, the consideration will focus on deciphering the changes that the recombinant drug will introduce to body tissues. To determine the effects of the drug on the body tissues, it would be essential to understand how the drug would act. It might act on the body through two processes (Chow & Liu, 2013).
First, it might inhibit standard physiological or pathological events in the body. Second, it might produce efficacy by hindering important processes of parasites and other disease-causing organisms. Although the above are the two processes of drug activity, the following seven (7) actions have been demonstrated to be initiated by several classes of drugs:
- Receptor agonism
- Depressing action
- Silent antagonism
- Stabilizing action
- Exchanging and replacing actions
- Destruction of cells
- Direct beneficial actions
The selected recombinant drug might produce a desirable biological activity by targeting the following components:
- Cell membrane
- Important chemical reactions in human cells
- Transport proteins
- Ion channels
- Enzymes
- Structural proteins
- Receptors and ligands
A deep understanding of the components to be targeted by the drug under investigation would be essential in anticipating the effects of the drug on the study subjects.
It would be important to assess the type and level of undesirable effects of the drug in the human body. The following undesirable effects would be studied:
- Carcinogenic activities
- Harmful drug interactions
- Abnormal chronic conditions
- A series of deleterious actions
An understanding of the above effects would be essential in redesigning the drug if it would be found to have more harm than benefits.
The pharmacodynamics consideration would also focus on the therapeutic window of the biologic drug. The therapeutic window refers to the average amount of a drug that produces the best efficacy (Chow & Liu, 2013). In other words, it is an effective dose of a drug. The amount of drug falls between an effective dose and the dose that produces adverse effects.
Drugs with small therapeutic windows are given to patients with a lot of care and control. The blood of patients needs to be assessed routinely to determine the amount of the drug circulating in the body because it has very high chances of losing effects or producing adverse effects.
Lastly, the pharmacodynamics consideration would involve the assessment of the duration of action of the drug (Chow & Liu, 2013). Duration is the period during which a drug produces therapeutic changes in the body. Determining the duration of time of the recombinant drug would be important in scheduling the times of the day when patients should take the drug. Ideally, patients would be advised to take the drug when its plasma concentrations would have dropped considerably.
Tolerability
Tolerability or drug tolerance is an important clinical trial phase I consideration. Drug tolerance refers to a state when a body’s reaction to a certain amount that causes desirable effects reduces significantly. For the drug to achieve its therapeutic effects, its dose must be increased (Chow & Liu, 2013). It would be important to determine the tolerability levels of the biologic drug so that to determine the rate at which human beings would develop resistance against the drug. It is characterized by the following:
- Reversibility
- Drug specificity
- Dosage
- Frequency of drug usage
If it would be established that the drug would have tachyphylaxis, then further studies would be conducted to determine the causes of the sudden cause of drug tolerance. In such a case, it has been demonstrated; the dose is not the culprit. Two mechanisms of drug tolerance exist. First, pharmacological tolerance could be experienced in patients when a decreased amount of drug arrives at the target within the body.
This could be caused by induction activities of various enzymes involved in drug metabolism, for example, CYP450 enzymes (Chow & Liu, 2013). Second, pharmacodynamic tolerance would occur when there is a downregulation of the number of receptors involved in pharmacodynamics or increased number of receptor antagonists.
The two events would have a basis on the genes contained in the DNA. Expression of the genes leads to an increase in the number of receptor agonists or antagonists. It will be important to assess the causes of tolerance with regard to the selected recombinant drug during phase I of the clinical trials.
Pharmacokinetics
Pharmacokinetics refers to a collection of processes that determine the destination and the form of a drug in the human body. In other words, pharmacokinetics helps to understand the impact of body reactions on administered drugs. The study of the biologic drug’s pharmacokinetics would help to determine the bioavailability. Bioavailability is the ratio of drug that reaches its target of the action. Drugs that have high values of bioavailability are characterized by excellent efficacy levels.
The bioavailability of the drug under investigation would be determined by several factors. First, the chemical form of the drug would impact the rate at which a pharmacological product would be metabolized and transported to sites of action. Second, drug metabolism will determine the amount of drug that would interact with the sites of actions. If drug metabolism would break down most of the drug’s chemical components, then only a small proportion of the drug would reach biological targets.
Third, the stability of the drug would influence the amount that would produce biological effects at the sites of action. If the drug would be quite stable, then a considerable proportion would interact with receptors at the sites of action. Fourth, the pharmaceutical form of the drug would contribute to the drug proportion reaching its target.
Five components are used to define processes that characterize the pharmacokinetics (Chow & Liu, 2013). First, drug liberation is used to imply the collection of events that help a drug to be released into the body. Second, absorption is used to describe the process of a drug gaining access into the circulatory system. This is essential because drugs are transported to their sites of action by the blood. If the drug under investigation would be highly soluble in blood, then it would be easily transported to the sites of action.
Third, drug distribution is the process of taking the drug to body organs through the circulatory system. Excellent drug distribution mechanisms would result in good efficacy levels of the drug (O’Neil, 2013).
Fourth, drug metabolism is the transformation of a drug by chemical components of the body. The process might result in biotransformation or inactivation of the recombinant drug under study. Fifth, drug excretion refers to the process of eliminating the drug from the body. This phase will determine whether the drug would accumulate in body tissues, or it would be removed from the body.
Healthy volunteers will be used in this phase of clinical trials, and they will be monitored at the first time of drug administration until many half-lives would have passed (De Angelis et al., 2005). At the end of this phase, the dose of the drug under investigation would be determined.
Phase II
Phase II trials will aim to assess whether the drug will have biological activities. They will be conducted on larger groups of subjects than those used in the phase I trials. Both healthy individuals and patients will be included in the trials. Phase II considerations for a biologic drug would include the following:
- Efficacy
- Toxicity
- Dosing requirements
- Patients and healthy individuals
Efficacy
The trials would adopt the approach of case series to assess the extent to which the recombinant drug produces desirable physiological effects that lead to improved health conditions of the study subjects. For example, the research team might hypothesize that the drug would have desirable biological effects in about 30% of the study participants.
If the researchers would find out that the biological effect is exhibited in less than 30% of the subjects, then they would conduct further studies on the drug that minimally tolerated drug doses. If they would obtain improved efficacy rates with the revised doses, then they would incorporate more subjects to calculate the estimate of the rates of response.
The drug would pass the phase II trials if it showed significant efficacy rates. Drugs with good efficacy rates are used in patients because of their good tested rates of biological activities (Chow & Liu, 2013).
Toxicity
If the drug will be confirmed to have significant efficacy rates, then researchers would observe and document the toxicity levels of the drug. It might be found that the drug would have higher toxicity levels at high doses than at lower doses (O’Neil, 2013). The study team would aim to correlate doses with efficacy levels. They would have to reduce doses too low levels that would not produce any toxic effects. However, lower doses should still be able to elicit desirable therapeutic activities (Chow & Liu, 2013).
Dosing requirements
Dosing requirements are important in the second phase of clinical trials. The levels of doses that would produce the best pharmacological effects would be determined by finding an estimate of the average doses that would be observed in the subjects. Also, dosing ranges and intervals would be established.
The ranges would be used to establish the best doses for adults and children. Dosing intervals would be based on the values of the half-life of the drug. It the drug’s half-life would be found to be short, then dosing intervals would be made short (Chow & Liu, 2013).
Patients and healthy individuals
The phase II trials will involve the use of the drug and placebos in both healthy individuals and patients. The drug activities will be assessed on the two groups of subjects. If there will be no difference in biological effects produced by the drug and placebos, then it will be established that the recombinant drug would have no significant efficacy rates. However, differences in physiological states of subjects given the drug and those given placebos would indicate that the pharmacological product would have significant efficacy levels.
In conclusion, phase II trials would be divided into phase IIA division that would determine dosing requirements, and phase IIB division that would involve the determination of the drug’s efficacy (Chow & Liu, 2013).
Phase III
This phase will aim to determine the effectiveness of the new drug as a new intervention. It will also aim to assess the value of the drug in clinical practice. In this phase, the efficacy of the drug will be compared to that of the ‘gold standard. It is an expensive phase that would involve randomized controlled trials on hundreds and thousands of patients. Phase III considerations for a biologic drug would include the following:
- Size
- Duration
- Expenses
- Approval
- Consumer response
Size
Phase III trials are large, and they may involve about 300 to 3,000 study subjects. The number of subjects is based on the complexity of the targeted disease and health condition. The phase III of the drug trials would adopt a significant number of subjects. The sample size to be used would be calculated using a statistical tool. Sample size with a statistical power would be selected (Wang et al., 2007).
Duration
It would be important to conduct phase III trials for some time long enough to understand all issues that would not have been detected and solved in phase I and phase II trials. The randomized controlled multicenter trials would allow sufficient time for patient follow-ups to assess the efficacy of the new drug intervention in comparison with the ‘gold standard’ treatment (Chow & Liu, 2013; O’Neil, 2013).
Expenses
Because trials are complex, it would be important to consider expenses to be incurred in this phase. If the cost estimates would be high, then sponsors would be sought to fund the ambitious project. The phase III trials would commence after the required funds will have been obtained.
Approval
Phase III trials require approval from relevant clearance bodies. The drug will have to meet standard norms and guidelines so that it would be approved (De Angelis et al., 2005; Chow & Liu, 2013; O’Neil, 2013).
The guidelines would specify manufacturing approaches and data that would have been collected during the pre-clinical and clinical trials. The rate at which the specified data would be availed to the approving body will greatly determine the speed at which the drug will be approved or rejected for clinical use.
Consumer response
The phase will also focus on marketing the drug to consumers, pending approvals from the relevant bodies. The responses from consumers about the pricing and side effects of the product will be studied. If a significant number of consumers would express safety concerns about the drug, then it would be essential to conduct further studies to assess the safety of the drug in patients (Chow & Liu, 2013). However, good responses from consumers would be an indication that the drug would have good sales in the future.
Phase IV
This phase would occur after the marketing phase. It would have the following considerations:
- Pharmacovigilance
- Technical support
- Drug interactions
- Aggressive marketing
Pharmacovigilance
When the drug is introduced into the market, it would be essential to continue conducting pharmacovigilance to assess whether it would continue providing patients with therapeutic benefits.
The study would be done in clinical fields and hospitals. Clinical data would be used to access important information about the safety of the drug. For example, if healthcare data will show that a significant number of patients would be found to have side effects associated with the drug, then it will be important to carry out studies to determine the causes of the undesirable effects.
Technical support
This consideration will focus on support in the manufacturing and distribution processes. Efficient manufacturing processes would lead to steady production that would ensure that the drug will always be available in the market for drug consumers. This consideration would also concentrate on how technical problems would be solved.
For example, the period that would be required to troubleshoot faulty equipment would greatly determine manufacturing efficiency. If long periods would be required to solve such technical problems, then it would imply that the drug might be out of stock, and its sales would be affected negatively.
Drug interactions
It is not possible to conduct drug-interactions involving all drugs in vitro. Therefore, the drug would be expected to interact with different drugs in patients. Some drug interactions could produce undesirable effects, which might be lethal. It would be essential to document the adverse effects that would be produced as a result of drug interactions (O’Neil, 2013).
The documentation would help to include the information in the drug product information. Thus, users of the drug would be advised about the different classes of drugs that would not be used together with the recombinant drug.
Aggressive marketing
Pharmaceutical companies manufacture drugs so that they would sell them and make profits. Aggressive marketing will be launched to promote sales of the product. Different approaches will be utilized to market the biologic drug. Medical representatives will be hired to raise awareness of the drug among physicians and clinicians who would prescribe the drug to be used by their patients.
Medical representatives will also convince pharmaceutical distributors to purchase the drug in anticipation that its sales would increase significantly. Aggressive marketing will facilitate the rate at which the product will be sold and used by healthcare consumers. The marketing personnel will important in explaining the biological importance of the drug to clinicians, physicians, and consumers when conducting continuous medical education.
A critical appraisal
A critical appraisal on Wallentin, L., Becker, R. C., Budaj, A., Cannon, C. P., Emanuelsson, H., Held, C.,… & Harrington, R. A. (2009). Ticagrelor versus clopidogrel in patients with acute coronary syndromes. New England Journal of Medicine, 361(11), 1045-1057.
Coronary syndromes have been shown to cause many deaths across the world every year. The study aimed to assess the efficacy of ticagrelor in treating coronary syndromes. Specifically, a comparison was made to an established drug in the market that was being used to treat coronary syndromes.
The study findings will contribute greatly to the proposed study, which aims to understand and carry out clinical trials on ticagrelor. The study used 18,624 study participants who were enrolled in 43 countries in 2008. Important results were reported (Wallentin et al., 2009).
The group of patients that were treated with the new drug demonstrated lower endpoint than the group that was treated with clopidogrel. The difference was found to have statistical significance. This shows that the new drug showed better treatment levels because it treated the health condition through the application of a relatively smaller amount of the drug.
It was established that the two drugs showed a significant difference in physiological effect in the first month of treatment, a trend that continued throughout the study (Wallentin et al., 2009). The continued difference implies that it did not happen by chance, but due to pharmacological benefits associated with the two drugs.
In studies involving drug comparisons, it is always essential to show that one drug is superior to another by calculating the statistical significance of treatment variations. About adverse effects like death and recurrent ischemia, the new drug showed low chances of patients experiencing the effects (P<0.001). The following are the other conditions that were found to originate from vascular causes:
- Stroke
- Myocardial infarction
- Transient ischemic attack
- Arterial thrombosis
The rate at which patients in the two treatment groups suffered from stroke did not show significant variations. However, the group treated with ticagrelor exhibited more cases of hemorrhagic strokes (Wallentin et al., 2009). It could have been important to assess the causes of stroke in the treatment group by conducting more studies. Although the difference in the cases of stroke did not show statistical significance, it could raise concerns about the new treatment in the future.
It might be that the drug would cause more stroke cases in the future if it would be used continuously by patients. The assumption could be true because the period was not long enough to assess long-term effects of ticagrelor about strokes. It would be critical to conduct lengthy studies in the future that would determine the effects of the drug about hemorrhagic strokes.
The two drugs were also assessed in terms of efficacy in patients who were planning to undergo invasive treatment. The results showed that the group treated with ticagrelor was marked by lower rates of endpoint. Therefore, the results implied that ticagrelor could be used to save the lives of patients who were in danger following coronary complications. Hence, the drug could be recommended as an excellent treatment option for treating severe cases of vascular diseases (Wallentin et al., 2009).
The study established that the group that was treated with ticagrelor showed lower rates of thrombosis than the group that was treated with clopidogrel. That was an important observation because thrombosis is a common complication of the vascular system that affects people of different ages (Wallentin et al., 2009). The therapeutic benefit of the new drug could be assumed to prevent high blood pressure that is caused by the accumulation of fats on the inner walls of blood vessels.
The rigorous assessment of the 33 subgroups demonstrated that ticagrelor was attenuated in patients characterized by weight that was less than the recommended weight about their sex. The same observation was made for patients who were not taking drugs that could lower lipids at randomization, those who were recruited in North America (Wallentin et al., 2009).
Bleeding was another aspect that was studied in the two treatment groups. The bleeding that was defined in the clinical trial did not differ significantly with any of the two drugs. Also, in terms of major bleeding, the two drugs did not have a significant difference that could have resulted in myocardial infarction and thrombolysis. Another important observation that was documented was that all the 33 subgroups did not show differences in major bleeding.
Thus, the results were characterized by a high level of consistency. Such a level of consistency of observations is essential in clinical trials because it shows that a study is not characterized by confounding factors that introduce bias. Study findings that are not consistent cannot be used by researchers to impact evidence-based practices in the healthcare industry. On the other hand, findings marked by a high level of consistency can be repeated by independent researchers to produce the same results (Wallentin et al., 2009).
It was demonstrated that the two treatment groups exhibited the same rates of bleeding that would require transfusion of erythrocytes, but the ticagrelor group showed higher cases of bleeding that could not require transfusion. That was an important observation because the two drugs caused bleeding that could not require the replacement of red blood cells. However, it would be critical to assess the effects of bleeding associated with the use of ticagrelor. It could be that continued use of the drug would result in health conditions that would require a blood transfusion.
It was noted that ticagrelor (13.8%) produced more side effects than clopidogrel (7.8%). Adverse drug effects in the group treated with the new drug made study participants discontinue from the study (Wallentin et al., 2009). That was a recommended approach so that the observed adverse drug effects could not cause more harm to patients.
In conclusion, the use of ticagrelor appeared to have more therapeutic effects than clopidogrel. The new drug showed better rates of preventing death caused by coronary syndromes and myocardial infarction. Also, the drug did not cause bleeding that could require transfusion. Therefore, ticagrelor could save the lives of thousands of patients suffering from coronary syndromes. Further studies will need to be conducted in the future to assess the long-term efficacy and safety levels of the drug.
References
Chow, S. C., & Liu, J. P. (2013). Design and analysis of clinical trials: concepts and Methodologies. Hoboken, NJ: John Wiley & Sons.
De Angelis, C. D., Drazen, J. M., Frizelle, F. A., Haug, C., Hoey, J., Horton, R.,… & Weyden, M. B. V. D. (2005). Is this clinical trial fully registered?—A statement from the International Committee of Medical Journal Editors. New England Journal of Medicine, 352(23), 2436-2438.
O’Neil, M. J. (Ed.). (2013). The Merck index: an encyclopedia of chemicals, drugs, andbiologicals. London, United Kingdom: RSC Publishing.
Wallentin, L., Becker, R. C., Budaj, A., Cannon, C. P., Emanuelsson, H., Held, C.,… & Harrington, R. A. (2009). Ticagrelor versus clopidogrel in patients with acute coronary syndromes. New England Journal of Medicine, 361(11), 1045-1057.
Wang, R., Lagakos, S. W., Ware, J. H., Hunter, D. J., & Drazen, J. M. (2007). Statistics in medicine—reporting of subgroup analyses in clinical trials. New England Journal of Medicine, 357(21), 2189-2194.