On April 11, 2022 Simbec-Orion reported that research is one of the most commonly investigated areas of clinical study. Oncology research has accelerated the development of advanced chemotherapy drugs, which are now generally less toxic as a result (Press release, Simbec-Orion, APR 11, 2022, View Source [SID1234611929]).
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Conventional chemotherapy drugs once primarily used cytotoxic compounds to target cancerous cells, which would also damage surrounding cells as a result.
Now, with an improved understanding of the underlying processes involved with different forms of tumorigenesis (tumour development), drug development research has resulted in non-toxic chemotherapy drugs that only interfere with specific cancer cells.
This has resulted in significant improvements in cancer patient care, with chemotherapy treatment options that have significantly less negative impact on the patient’s health and wellbeing.
Whilst there have been significant advancements in chemotherapy drug development, there is still further progress to be made. There are several issues surrounding the development of chemotherapy drugs that require careful attention from investigators and sponsors.
These issues are present across the full scope of chemotherapy drug development. From initial understandings of cancer, to the clinical pharmacology, patient care and ethical processes.
Understanding cancer as many diseases
As cancer research has progressed, our understanding of cancer as a disease has improved significantly. Insights into the processes involved in tumour development have provided researchers and medical professionals with a deeper understanding of the molecular and genomic mechanisms involved in tumorigenesis.
Such insights have proven that there are further variations of cancer types than were initially understood. For instance, lung cancer was once recognised in two different forms: non-small cell and small cell lung cancer.
Now, research has shown that there are a variety of lung cancer types, developed through different molecular and genomic processes.
These can include ALK-positive, EGFR-positive, ROS1-positive and other characteristic formations of lung cancer, all of which involve different genomic methods of tumorigenesis:
ALK-positive lung cancer is developed through the rearrangement of the ALK (anaplastic lymphoma kinase) gene and EML4 gene.
EGFR-postitive lung cancer is developed through the mutation of EGFR (epidermal growth factor receptor) proteins in cells, that when grown too much can cause cancer.
ROS1-positive lung cancer is developed through rearrangements in the ROS1 gene, whereby the gene fuses with nearby cells.
Research has shown that not all subtypes of cancer respond to the same chemotherapy treatment in the same way, making it necessary to develop targeted chemotherapy drugs. This is especially important since generalised chemotherapy treatments are significantly more damaging to patients than targeted treatments.
Developing targeted therapies
Since cancer is not simply one form of disease, patients cannot be effectively treated by generalised chemotherapy drugs. Instead, targeted chemotherapy drugs are needed.
Targeted therapies are drugs that treat the specific subtype of cancer in a specialised manner, targeting the specific molecular profiles of cells rather than damaging cells in a generalised manner.
For example, chemotherapy drugs for ALK-positive lung cancer use a different molecular compound to EGFR-positive lung cancer chemotherapy drugs.
The development of targeted chemotherapy drugs requires an individualised approach, whereby patients with specific molecular profiles are studied in order to develop specialised chemotherapy drugs for that particular subtype of cancer.
An individualised approach is essential for developing more effective targeted chemotherapy drugs, although this does come with several complexities and challenges, with many implications on clinical trial design and ethical procedures.
Limited sample groups
With many specific molecular profiles to study, this can make it difficult to find a reliable patient sample group with matching molecular profiles for clinical trials. And without successful clinical trials, chemotherapy drugs cannot proceed to market.
For instance, ROS1-positive molecular profiles occur in just 1-2% of non-small cell lung cancer (NSCLC) formations. This can present challenges with recruitment for clinical trials, since rarer molecular profiles will only be present across smaller sample groups.
For even rarer targets, there may simply not be enough patients to substantially test new development chemotherapy drugs, making it particularly difficult to enrol and retain patients for clinical trial research.
The issue of limited sample groups in chemotherapy drug development means that regulatory authorities, such as the FDA, have to approve the drug based on a limited number of trial participants.
To help overcome this issue, clinical research organisations such as Simbec-Orion take a tailored approach to clinical trial design, applying effective patient engagement and recruitment strategies to ensure the trial proceeds with a reliable sample size.
Toxicity issues in cancer drug development
Cancer chemotherapy drugs were considered cytotoxic in the earliest years of development, having potentially life-threatening side effects. Past chemotherapy drugs originally damaged or killed cancer cells in a generalised manner, having negative effects on surrounding healthy cells.
Thanks to advanced cancer drug development research, treatments are now substantially less toxic and treat the cancer in a targeted manner.
While newer chemotherapy drugs have proven to be more efficacious and much less toxic than conventional drugs, toxicity can still not be fully determined until clinical trial stages. This presents the issue of safety and toxicity risks, since this often involves testing unproven therapies on patients.
At the beginning of the clinical pharmacology process, chemotherapy drugs are tested using cell culture and animal model systems. Although, these initial testing methods are not able to provide a reliable prediction of the drug’s full toxicity.
In order to determine the chemotherapy drug’s full safety profile, it must be tested in human volunteers and patients in clinical trial research. Phase 1 will generally limit the number of cancer patients participating in the trial in order to test the safety in healthy volunteers first, and then administered to patient groups in later phases using dose escalation techniques.
The full safety profile and toxicity of newly developed chemotherapy drugs cannot be reliably determined until tested in cancer patient groups, meaning patients may be exposed to potentially toxic treatments.
Ethical issues in chemotherapy drug development
There are several ethical issues to consider surrounding the development of chemotherapy drugs. Many of these ethical concerns regard how the clinical trial process is managed in oncology research.
Risk to benefit ratio
Throughout the chemotherapy clinical trial process, the risk to benefit ratio is always an important consideration for researchers. Development chemotherapy drugs are unproven interventions, meaning it is vital that the risks and impacts on patient lives are well-understood by investigators.
Alongside understanding the potential risks, it is important to weigh up the prospective benefits. The intervention may benefit patients directly, or benefit scientific advancement generally. Although in either case, investigators must have a sufficient understanding that the drug is beneficial in order to outweigh the potential risks posed to patients.
Chemotherapy drug trials can also involve taxing procedures on patients, including biopsies, imaging and clinic visits. These procedures can be onerous and potentially distressing for patients, especially for those who are particularly unwell.
The chemotherapy drug may also prove to be ineffective, or even toxic during later stages of the trial, meaning already potentially vulnerable patients may have undergone burdensome processes for little direct benefit.
The risk to benefit ratio is a challenging ethical issue for researchers to weigh up. Because of this, it is important that patients fully understand the risks and benefits when consenting to taking part in chemotherapy drug development research.
Patient consent, communication and care
Not only should the risks and benefits be well-understood by researchers, they must also be well-understood by volunteers and patients. This raises the ethical question of whether the patient fully understands the risks and benefits of enrolling in chemotherapy drug research.
It is vital to ensure that the patient has a good understanding of the risks and benefits of taking part. Patients typically receive an informed consent document that details the potential risks, procedures and benefits involved.
This is not always the most reliable method of ensuring the patient has fully understood what’s involved. A more effective way of ensuring fully informed consent and communicating the risks and benefits is for patients to participate in a discussion with their physician. This should be encouraged across several discussions, whereby patients have time to consider the pros and cons between conversations.
This way, the patient is able to ask questions regarding any areas that are unclear, and the physician should encourage an open discussion to ensure the expectations are clear.
Patient sensitivity
Cancer can be a highly debilitating and life-threatening disease. Patients with advanced cancer, or patients who have sadly received a terminal diagnosis may be more likely to see chemotherapy drug trials as the only remaining treatment option.
This highlights the issue of patient sensitivity in chemotherapy drug development. Advanced or terminal cancer patients may feel desperate to explore new treatment options, and willing to take substantial levels of risk with unknown prospects of the benefits.
It can feel especially upsetting for patients in cases where chemotherapy drugs have proven unsuccessful or unsafe in clinical trials, making effective communication and engagement from the offset extremely important.
This issue surrounding chemotherapy drug development becomes especially complex in cases where the patient does not meet the eligibility criteria to participate in trials, although the physician may believe that the patient may benefit by taking part.
As a result of unguaranteed benefits and the chance that patients may not be eligible to participate in chemotherapy drug development trials, it is important for physicians to explain the alternative options to taking part. These may include standard therapies, or palliative care.
Addressing chemotherapy drug development challenges in clinical trial design
There are several challenges in the development of chemotherapy drugs that investigators and research organisations have to consider. From individualised approaches to targeted chemotherapy drug development, toxicity issues, sample sizing and ethical concerns, issues arise across the full scope of the drug development process.
This makes it important for research organisations to deliver a suitable clinical trial design that overcomes these challenges. There are several ways to do this, and the design will depend on the aims and type of chemotherapy research.
At Simbec-Orion, we take a tailored approach to clinical trial management, with therapeutic expertise in oncology and rare disease. Our trial designs have carefully overcome challenges using effective patient engagement strategies and centralised project management to ensure that the research meets the needs of sponsors and patients.