Circulating tumor cells and their future in oncology diagnostic

Circulating tumor cells and their future in oncology diagnostic

Circulating tumour cells (CTCs) are rare tumor cells that have been investigated for diagnostic, prognosis and predictive biomarkers for different types of cancer. CTCs have been described back in 1869. They are not used in clinical practice at the moment, however CTCs were explored in breast, lung, prostate and colorectal cancers.

How rare are CTCs?

There is approximately 1 circulating tumor cell per ml of blood released by primary tumors or metastases that can be detected in peripheral blood.

What types of circulating tumor cells exist in clinical practice?

  1. Treatment based on CTCs used as liquid biopsy: Biopsies are invasive, expensive, time-consuming and potential harmful so using CTCs is one way of avoiding this procedure.
  2. Treatment based on CTC count or CTC variations: This depends on technique used and volume of blood screened.
  3. Treatment based on CTC biomarker expression: Isolating single cell of CTCs could be challenging.

What are the challenges of using circulating tumor cells in cancer screening?

Usage of Cellsearch technique in early non-metastatic cancer have shown low CTC detection rates (5-30% depending on the cancer type). This method is limited to some circulating epithelial cells so it cannot be used wildly. Unfortunately other techniques have not shown better detection rates.

How could CTCs be used as prognostic value?

Analysis of 1944 patients with breast cancer using CellSearch has shown that patients with increased CTCs have poor prognosis and decreased progression-free survival. Also evaluating CTCs count at baseline allows better prognosis of survival. Similar results are observed in patients with metastatic colon cancer, castration-resistant prostate cancer and small cell and non-small cell lung cancer.

CTCs value as prognostic factor was also observed in non-metastatic cancers with similar correlation – the higher amount of CTCs means poor prognosis.

How could CTCs be used in monitoring treatment response?

Studies with patients with metastatic breast cancer have shown that women with high baseline CTC counts, which is reduced after one cycle of chemotherapy have better prognosis than patients where their CTC count is elevated.

While CTCs have great potential as prognostic factor and in monitoring therapy, there are still lots of challenges before their implementation in clinical practise with biggest among them – discovering new methods and techniques for detection of CTCs.

Source

Circulating tumor cells: clinical validity and utility

Published on 2 July 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

Paediatrics Clinical Trials: Children Are Not Simply Small Adults

Paediatrics Clinical Trials: Children Are Not Simply Small Adults

Children often have the same diseases as adults, however many of the approved drugs on the market are not tasted in children. Many rare and serious diseases affecting children have no treatment options and as a result clinicians are forced to use “off label” drugs (drugs not approved to be used in children population).

Undoubtedly clinical research involving kids have plenty of challenges. There are many initiatives from regulatory agencies, which are trying to encourage pharmaceutical companies to include children in clinical trials or to obtain information for the application of marketed drugs in children.

Why is important to have drugs tested for children?

  • Paediatricians could be denied access to potential beneficial treatment for children just because there is no data from that population.
  • Children are treated with medications based on adults’ data or empirical experience in children. This could increase the safety risk for the young patients.

Controlled clinical trials are the best way to provide children with access to new treatments and at the same time obtain relevant safety data.

What are the most common challenges in clinical research, which lead to exclusion of children?

  • The research topic is not relevant for children;
  • Laws or regulations that do not allow children to participate;
  • There is already some knowledge on the topic;
  • The condition is rare in children;
  • Limited number of children which does not allow enough data to be generated;
  • Not enough data about adults to judge the potential risks for children;
  • Children are not homogenous group and absorption, distribution, metabolism and excretion of the drugs depend of age and their current organs development;

Since 2000 in USA and Europe regulatory agencies require pharmaceutical companies to include paediatric data in all new drug application and licence extensions when there is an expectation that the drugs will be used in children.

Another initiative in USA and Europe is the “orphan” drug status which encourages development of drugs for rare diseases; however it is not expected to benefit paediatrics research significantly.

FDA Modernization Act which has similar regulations in Europe gives 6 month extension to drug licences or patents for drugs, which have paediatric data.

There are a number of ethical considerations which have to be observed when conducting research with children:

  • Children can be included in clinical trials after it was established that the drug could be beneficial.
  • Protocols involving paediatric population should be reviewed by Ethics Committee which includes members knowledgeable in ethical, clinical and psychosocial issues.
  • Informed consent is obtained from parent / guardian unless children are in intellectual maturity which allows them to make decision for themselves.
  • If the information can be obtained in less vulnerable population, it should be preferred to vulnerable population – for example, if the studies in adolescents that can be consented could be used for younger children, the study should include adolescents and not younger children who cannot consent.
  • Studies in handicapped or institutionalised paediatric populations should be limited to diseases found in this specific population or when it is expected the disease and the treatment to be affected in such population – for example, studies cannot include children with disabilities if they can use children without disabilities and will provide adequate data.
  • Paediatrics studies have to be conducted by experienced and trained clinician.
  • The design of clinical trials should try to minimise the amount of children involved and required procedures without affecting data integrity.
  • All measure to be taken to minimise the discomfort and distress that could be caused to the children.

While paediatric clinical trials have their challenges obtaining safety data for children is vital for providing adequate treatment.

Source

Clinical Trials in Paediatrics

 

Published on 1 June 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

Review: Clinical trials and restricted medications

Review: Clinical trials and restricted medications

During my recent work I came across 2 cases of usage of restricted medications in patients participating in clinical trials. In both cases restricted medications were prescribed by GP or physician at local hospital without realising that patients should not take these medications. Just to put your mind at rest both patients are well, but what happened is something that everyone in clinical research should be concerned about.
But let’s start with what is restricted medication and why such medications exist?
All medications are metabolised in specific parts in the human body (in most cases liver is involved) and sometimes some medications can influence (increase or decrease) the plasma concentration of other medications. This could be potential safety issue for the patient as they could be exposed to overdose or lower than the required therapeutic dose. So it is understandable that such medications would be considered “restricted”. This is, of course, the simplest explanation.
Why restricted medications are very important in clinical trials?
As we know clinical trials drugs are newly developed compounds and there are lots of unknown about them. While they are in clinical trials it is important that patients do not take “restricted medications”, which could affect the plasma concentration of the study medication because this could be significant safety issue.
Then how these 2 cases happened and patients were prescribed restricted medications?
The discussion below is relevant to UK and I have to admit I am not familiar how health care systems around the world operate. In a perfect world all health care providers will have access to patients’ electronic medical records and they will be able to obtain the most up to date information. Unfortunately the world is not so perfect and each health care provider in UK has their own EMR or paper records that other providers do not have access to. This means that, more or less, we rely on patients to provide adequate information to different health care providers. However this is not a solution to the problem because patients cannot be expected to be able to explain what medications they should not take.
How to avoid “restricted medications” to be prescribed to patients on clinical trials from third parties?
The only possible option that the research team has is to ask their patients to contact them if they have medications prescribed by GP or local hospital so that they can advise them if they can take them. Although this again puts the focus on patients communicating to different providers this is still less complicated solution to the problem.
What is the big safety issue?
While patients participating in clinical trials are monitored closely and although such cases are not unusual research teams are able to react adequately to guarantee patients’ safety. The question is who is monitoring all these licensed medications on the market that have restricted medications too?
Published on 
2 May 2017
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.
Preclinical data in clinical trials: Are participants Guinea pigs?

Preclinical data in clinical trials: Are participants Guinea pigs?

There have been several occasions when people hear that I work on clinical trials and their reaction is “Oh, you are using people as guinea pigs!” I have shared my experience with some of the clinical trials teams and they also confirmed that that this is unfortunately still quite common reaction among general public. This is also one of the main reasons for participants to decline taking part in clinical trials. In this review we will discuss some tips on how to educate participants about clinical trial and help them make the best decision for themselves.
What makes people feel they are guinea pigs?
  1. The “Research” feeling – It is not surprising that the word “research” gives that unease feeling in some people that it is not known what will happen to them.
  2. The “Placebo Myth” – Another common misconception is the “placebo” – majority of the people believe that all clinical trials include placebo and there is a 50% chance that they will not receive drug. It is true that some clinical trials use placebo but patients with medical condition are never left on placebo only and usually the placebo is given in combination of standard of care for the appropriate disease.
  3. The” drug is doing more good than harm” feeling – All potential participants are informed about possible adverse reactions but because it is regulatory requirement all possible adverse reactions to be listed in the informed consent that often represent an overwhelming list of scare reactions. On the other hand it is unlikely that people will read the medication brochure of a marketed drug (which also has an extensive list of adverse reactions) that leaves them with the impression that the clinical trials drugs are more dangerous.
How to educate potential participants about clinical trials?
I was explaining to a friend recently that all drugs on the market have been studied in clinical trials before obtaining marketing authorisation. He looked at me very surprised and said “You mean even aspirin?”
In order clinical trials teams to be able to educate their patients they need to understand themselves the preclinical data and what is known about the drug before reaching volunteers and patients.
Preclinical data is usually generated by using tissue cultures and animal models. The main purposes of preclinical data is to detect any harmful effects, to exclude any potentially harmful effects, to determine the dose and duration of the treatment and if possible to discover the mechanism of action. All this data allows clinicians and toxicologists to evaluate the risks of the new potential drug and to identify the unacceptable risks.
For example, in vivo models require sufficient amount of animals to be included in order to obtain the required pharmacological, toxicological and dose-response data. Based on these results is calculated not only the dose for human clinical trials but also the dose escalation scheme.
In conclusion during the different stages of drug development there are numerous preclinical drug safety studies, which are conducted in vivo or in vitro and provide the necessary safety information if the drug could be used in humans. All this data is generated to assure that clinical trials participants are not guinea pigs and their life and well-being is not put at risk.
Published on 
3 October 2016
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.
Analysis: How informed are participants from the Informed Consent Form

Analysis: How informed are participants from the Informed Consent Form

I was travelling in a taxi during the recent months and after I mentioned I work in clinical research the taxi driver decided to share with me that he has participated in a clinical trial once but he withdrew because he didn’t like the medication and he thought it did him more harm than good.
Unfortunately this is not the first case. Over the years I have met people who shared with me their experience in being approached to participate in clinical research and many declined after reading the informed consent form because they didn’t want to be guinea pigs.
All this just shows that we need a novel approach in informing participants about clinical trials and that the current inform consent process is failing people who not necessarily understand the ICF language.
It is known that majority of the participants in clinical trials are educated, have better connection with their health care provider and have interest in supporting research.
Over the years due to changes in the regulatory environment the ICF has become lengthy and overwhelming document, which not surprisingly push participants away. Although physicians and nurses are doing their best in explaining clinical research to potential participants, they are restricted by workload and resources and may not have the time needed for each individual person to understand the purposes of the research.
What could be changed in the informed consent process?
  • Video-assisted informed consent – This type of aid to the consent process is a video, which explain the simple steps of participation in the clinical trial. It has already been used in paediatric trials and it was successful.
Video could help approach low income participants who may struggle to understand the informed consent form. It could also be easily converted into different languages to break the language barrier.
  • Web site supporting consent decision – Web site dedicated to the clinical trial with consent support video and additional materials could benefit participants by providing much more information than the actual ICF in more use-friendly manner.
  • Booklets and support materials to help participants understand ethical considerations taken in research.
Supporting participants’ comprehension of research could provide long term benefit for everyone working in clinical research. It will improve general public understanding of research and will increase the level of satisfaction and positive experience from clinical trials. Moreover, it could help low income participants feel more comfortable with informed consent forms and participating in research.
Published on 
1 September 2016
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.