How do we know if drugs are carcinogenic?

How do we know if drugs are carcinogenic?

We often see in the news headlines information of some drug being potentially carcinogenic or contaminated with substance that is potentially carcinogenic. But what that means and how do we test drugs for carcinogenicity?

Carcinogenicity testing of substances is preformed on nonhuman species at some quite high doses or exposure levels in order to predict the occurrence of tumorogenesis in humans at much lower levels.

Generally now we have good understanding of most of the mechanisms of chemical and radiation induced carcinogenesis. There is a list of know human carcinogens and you can find more details here

How do these carcinogenic substances work?

There are several mechanisms and theories of chemical carcinogenesis:

  1. Genetic (all due to some mutagenic event)
  2. Epigenetic (no mutagenic event)
  3. Oncogene activation
  4. Two-Step (induction/promotion)
  5. Multistep (combination of above)

Another way to classify them is based on the four major carcinogenic mechanisms:

  1. DNA damage
  2. Cell toxicity
  3. Cell proliferation
  4. Oncogene activation

How do we assess carcinogenicity?

The most simple approach is to design bioassays and evaluate if cancer occur or not in animal models. However, the complexity of oncology diseases require more sophisticated models and testing which is why now is taken in consideration time-to-tumor, pattern of tumor incidence, effects on survival rate and age of first tumor.

There are 3 aspects of organ responsiveness that have to be tested too:

  1. Those organs with high animal and low human neoplasia rates – In this group below animal cancer data in liver, kidney, forestomach and thyroid gland.
  2. Those organs with high neoplasia rates in both animals and humans – In this group are animal cancer models in mammary gland, hematopoetic, urinary bladder, oral cavity and skin.
  3. Those organs with low animal but high human neoplasia rates – There are lots of discussions about this group but some of the organs that are believed to belong here are prostate gland, pancreas, colon and rectum, cervix and uterus.

One of the limitations is lack of assessment of low neoplasia rates in both animals and humans.

As probably expected the carcinogenicity bioassays are the longest and most expensive part of toxicology studies. Often there are more controversial in terms of results.

According to the regulatory requirements 3 or 4 doses of the substance have to be tested to determine carcinogenicity. Usually are used 2 control groups of equal size and each group has minimum 50 animals of each sex. In the studies are normally used the maximum tolerated dose, the lowest dose and mid-dose, which often is geometric mean of the 2 other doses. The duration of the exposure to the dose is usually 2 years. Extended duration is often not suitable in rat and mice models because with the age it is increased the chance of spontaneous tumorgenesis.

While there is a room for improvement in carcinogenic studies there is lots of safety research going on before new therapeutics reach patients in later stages of drug development. Another important point to remember is that carcinogenicity of substances is not black and white and often more data is needed to determine if they really are carcinogenetic.


Drug Safety Evaluation

Published on 29 Nov 2019

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

Could response-based dose be the future of patient care?

Could response-based dose be the future of patient care?

FDA report showed that most drugs are effective in only 25-62% of the patients. That probably make you wonder why they are approved and prescribed to patients? The answer to this question is not simple. Many approved drugs have a range of therapeutic dose which could be prescribed to the patients which allows clinicians to adjust the dose based on patient response and toxicity.

This variation of efficacy is another argument in support of precision medicine where patients are assessed based on their medical history, genetic background and other information in order to be provided with the optimal dose and the most adequate treatment for their condition.

What are the disadvantages of current clinical trial designs when it comes to dose individualisation?

Some small size clinical trials in specific indication like blood pressure, blood sugar, pain, seizure and coagulation could use different dose titration models to identify the best dose for the patients. However, large clinical trials often use fixed dose in their research.

Statistical model using data from clinical trials shows that in large clinical trials with fixed dose the response rate can vary between 20 and 80% while clinical trials with individually adjusted dose have much higher response rate.

Why cannot we simply use individualised dose instead of fixed dose?

While no doubt having option to adjust doses as per individual response would be the best solution to the problem there are some complications that prevent this.

  • For example if the drug is eliminated by kidneys and patient has renal function impairment they should be treated with lower dose to reduce the toxicity. And while this sounds like a logical decision the risk of giving the patient sub-optimal dose should also be considered.
  • This could not be done in oncology trials because the dose calculated is the maximal tolerated dose which is selected to maximise the effect.
  • Dose reduction is not an option for HIV drugs because of the high risk of drug resistance.
  • Drugs for slow progressing disease which require extended treatment also cannot be assessed adequately for efficacy.
  • Acute conditions which require one-off treatment cannot use dose titration.

There are several considerations for cases where dose titration is possible:

  1. The condition has to be stable to allow efficacy assessment.
  2. The drug should rapidly achieve steady pharmacokinetic and pharmacodynamics state otherwise the clinical trial will be very long considering the patients have to take more than 1 dose.
  3. Efficacy and toxicity should be quantifiable and relevantly stable once steady state is reached.
  4. The response to the drug should have quick onset and offset to avoid washout period.
  5. There should be an upper limit of dose-escalation to ensure patient safety.
  6. Subtracting the response of placebo – for example, patients could expect better response at higher doses and this could increase the efficacy of placebo arm.
  7. The treatment duration will be longer because patients will need more than one dose and this could increase the risk of drop out.

While dose titration has its challenges it has future in precision medicine and it is a logical option when assessing patients’ treatment.


The remarkable therapeutic potential of response-based dose individualisation in drug trials and patient care

Published on 1 Aug 2019

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

Adopting orphan drugs in different therapeutic areas

Adopting orphan drugs in different therapeutic areas

What happens if a newly developed drug fails in the tested indication?

Very often such drugs are abandoned if the developers think they will not be able to be used for different indications or therapeutic areas. In such cases these drugs are classified as ‘orphaned drugs’.

Where the term ‘orphaned drug’ comes from?

The focus of drug development is shifting towards diseases that affect smaller amount of the population, also known as rare or ‘orphan’ diseases. In USA a disease is considered ‘orphan’ if affects less than 200 000 people or roughly 1 per 1500 people. The term ‘orphan drug’ refers to drugs used to treat orphan diseases and its derived from legislation like Orphan Drug Act of 1983.

Not surprisingly oncology is viewed as one of the major therapeutic area where orphan drugs are used because more and more evidence suggest that cancer is a collection of orphan diseases.

Vicus Therapeutics has developed a model which allows adoption of such orphan drugs for new cancer indications.

Step 1:  Hierarchical Network Algorithm (HiNET) – This is an algorithm that allows modelling of the disease by evaluating tissue energetics, homeostatic control and biochemical pathways.

Step 2: Drug Selection: In this step it is used a data base which contains information for off-patent drugs, their target and human efficacy data in similar diseases, potential adverse events and pharmacokinetic profiles.

Step 3: Due to the complexity of cancer rarely one single drug could be used, therefore the model created potential treatment regimens.  Then the suggested regimens are evaluated for their potential safety and efficacy.

The use of such models in repurposing the orphan drugs is a novel and smart way of speeding up drug development process and identifying new therapies for rare diseases which in many cases have no treatment options.


Adopting orphan drugs: developing multidrug regimens using generic drugs

Published on 4 July 2019

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

Can we predict adverse reactions?

Can we predict adverse reactions?

One of the big challenges in drug development is our limited ability to identify potential adverse reactions associated with new therapeutics. Pharmacogenomics provides a great opportunity in understanding the mechanisms of action of drugs and predict not just their adverse reactions but also their efficacy. But as all opportunities it has some limitations too. In this review we will discuss the usage of pharmacogenetics in drug development and adverse reactions prediction.

But let’s start with what is adverse reaction and why it is important in drug development. Adverse drug reactions include a range of expected (and unexpected) toxicities to therapeutic failures and rare, severe reactions. Monitoring and preventing these reactions is top priority in drug development. How much we can predict the adverse reactions depends on various factors. In some cases where the nature of the studied drug is known there are some anticipated adverse reactions; similarly if the metabolic pathway of the drug is known there are some expected adverse reactions.

How could pharmacogenomics contribute in monitoring drug safety?

For example, codeine is activated to morphine by liver enzyme CYP2D6, however if the patient has multiple copies of active CYP2D6 gene they may be exposed to higher doses of morphine. If the enzyme is with low activities, on the other side, patients will have lower levels of active drug. This same enzyme is responsible for activating one of the cancer therapeutics – tamoxifen – and patients with low activity of the enzyme could be exposed to lower doses of tamoxifen. So why is this important? Patients with active CYP2D6 could be at risk of overdose when taking codeine; cancer patients who do not metabolise well tamoxifen will have lower doses of active drug and this could affect their treatment.

In some cases the consequences are quite drastic – for example, data from clinical trials with patients with metastatic colorectal cancer show that if the tumor cells active mutation in KRAS gene this leads to lack of effect of the anti-cancer drugs, cetuximab and panitumumab.

All these examples show the importance of genetic information when treating different medical conditions, which is why some clinical trials are collecting biogenetic markers for analysis.

What are the challenges in using pharmacogenetics information?

  • There is still limited data regarding many drugs – sometimes this is result of patent protections, in other cases just lack of data or unknown drug action mechanism or metabolic pathway.
  • In cases of very limited treatment options for the patients there is an ethical dilemma is patients have to be excluded from treatment because of unfavourable genetic profile.
  • Genetic testing is expensive and adds cost to patients’ treatment.
  • Collecting information after drug approval is out of drug developers’ control.

While there are challenges in using pharmacogenomics methods in identifying adverse reactions, it will have its place in the future of drug development.


Pharmacogenomic strategies in drug safety

Published on 1 May 2019

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

Clinical trial design and patients with brain metastases

Clinical trial design and patients with brain metastases

The most common spread of metastatic solid tumours in central nerve system (CNS) is as parenchymal brain metastases or as leptomeningeal disease (metastases in brain membrane or spinal cord). Because the brain is protected by blood-brain barrier many drugs in standard dose will not achieve the required concentrations to be effective in CNS. Some anti-cancer drugs, however, do not cross blood-brain barrier at all but activate lymphocytes that can penetrate to CNS; while other drugs do not have effect on CNS.

For many experimental anti-cancer therapeutics there may be not sufficient information regarding their activity on CNS. As a result if the studied drugs do not have effect on CNS patients with brain metastases will progress quickly and this may affect the overall outcome of the clinical trials. On the other hand if the anti-cancer drugs have CNS activity and patients with brain metastases are excluded from the clinical trials there will be no information on drug activity on CNS and patients will miss new treatment option.

What types of clinical trial designs are possible for patients with CNS disease?

Design 1 – if the drug is considered unlikely to have CNS activity or efficacy

There are 2 possible designs to overcome the challenges above:

  • Exclude patients with CNS disease
  • Exclude patients with untreated or unstable CNS disease – CNS disease has to be either asymptomatic on stable dose of corticosteroids or off corticosteroids.

Design 2 – if the drug is considered likely to have CNS activity or efficacy

  • Permit untreated CNS metastases
  • If untreated CNS disease is measurable, mandate that these lesions be captured as target lesions
  • Define whether a growing CNS lesion previously treated with radiotherapy is permissible as a target lesion
  • Standardise CNS imaging frequency
  • Define if symptomatic, or if steroids or anticonvulsants permitted initially, or later
  • Specify bicompartmental endpoints and action if progression is observed in one but not both compartments
  • For randomised studies, stratify according to:
  • Whether CNS disease is present or absent
  • Whether CNS disease is treated or untreated
  • If treated, whether CNS progression has occurred

Design 3 – if there is minimum information on drug activity on CNS

Appropriate for phase 1 studies

This model includes dose escalation until the optimum dose is achieved. Then it is followed by molecularly or histologically defined efficacy expansion cohorts; food effect and drug-drug  interaction sub-studies and CNS metastases sub-study.

Appropriate for phase 2 and 3 studies

  • Initially permit only absent or treated and non-progressing CNS metastases in general trial population
  • Permit separate single-arm early CNS cohort with defined number of patients with measurable untreated or progressing CNS disease with separate early efficacy analysis such as CNS objective response
  • Minimise risk in this early CNS cohort by only allowing in asymptomatic cases
  • Modify protocol (as either amendments or following pre-written decision pathways) as data emerge to be like either scenario A or scenario B

CNS progression is a big challenge in treating patients with metastatic solid tumours. New approaches are required to assess when patients with CNS disease could be appropriately included or excluded from clinical trials.


Clinical trial design for systemic agents in patients with brain metastases from solid tumours: a guideline by the Response Assessment in Neuro-Oncology Brain Metastases working group

Published on 1 Oct 2018

Author: Olga Peycheva, Director at Solutions OP Ltd. 
Olga has been working in clinical research since 2005 and has extensive experience in Eastern and Western Europe

FDA legislation changes and clinical trials: July 2018

FDA legislation changes and clinical trials: July 2018

FDA extends access to experimental drugs

FDA extended access program started back in 2009 and it allowed patients with life-threatening diseases who have exhausted all other options to try experimental drugs, which are not on the market yet. After the implementation the program for the period between 2009 and 2014 FDA has approved almost 6000 requests for experimental treatment, however some view the current process as ineffective.

The new legislation ‘Federal Right to Try Act’ will further increase the access to experimental drugs and change the pathway to obtain approvals. However, the agency remains committed to protect patients’ safety and provide more treatment options to patients with life-threatening diseases.


FDA prepares guidance on including adolescent in adult oncology clinical trials

It is known that cancer in young paediatric patients may differ from adults and therefor needs new approaches and treatments; there is an acute demand for treatment options for paediatric cancer patients. It was established that in some type of cancers there is similarity in paediatric and adult cancer histology and biological behaviour – for example, some soft tissue and bone sarcomas, central nervous system tumours, leukaemia, lymphomas and melanomas.

Often paediatric clinical trials are conducted long after adult trials and this could lead to delay in access to potentially effective therapies.

In June 2018 FDA released guidance on inclusion of adolescents (age between 12 and 17 years) in clinical trials. The guideline outlines appropriate criteria for inclusion of adults and adolescents at different stages of drug development; recommendations regarding dosing, pharmacokinetics, safety, monitoring and ethical considerations.

According to the guide doses have to be selected based on whether the adult dose is fixed or based on body size; dosing should be supported by pharmacokinetic characteristics of the drug, the therapeutic index of the drug and dose- and exposure-response relationships. Pharmacokinetic samples for adolescents should be collected according to the drug development programme to verify exposure in adolescents and adults. In case of body size-adjusted dosing adolescents should receive the same body size-adjusted dose as adults; however if it is fixed dose then a minimum body weight threshold should be defined to prevent adolescents with a lower than average body weight from exceeding adult exposure. While in early drug development long term safety follow up may not be possible the guide recommends sponsors to develop plan for long term safety evaluation where feasible. Under the federal regulations, IRBs reviewing adult oncology clinical trials that allow for the enrolment of adolescents must ensure that the provisions of 21 CFR Part 50, Subpart D (‘Additional Safeguards for Children in Clinical Investigations’) and 21 CFR 50.52 (‘Clinical Investigations involving Greater than Minimal Risk but Presenting the Prospect of Direct Benefit to Individual Subjects’) are satisfied before approving the trials.