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.


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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.


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

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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.


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

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CircRNA as cancer biomarker and potential therapeutic target

CircRNA as cancer biomarker and potential therapeutic target

Circular RNAs (circRNAs) are class of long, non-coding RNAs, which are very tissue specific. Initially these circRNAs were thought to have no biological function. In the recent research there are more and more evidence that these types of RNA are present in mammalian cells and regulate gene expression by binding to microRNAs and other molecules to inhibit their function.

There also evidence that circRNAs may be involved in development of some diseases like atherosclerotic vascular disease, neurological disorders, prion diseases, osteoarthritis, diabetes, Parkinson’s, Alzheimer, multiple sclerosis, schizophrenia, colorectal cancer, hepatocellular carcinoma, breast cancer and pancreatic ductal adenocarcinoma.

A study shows that circRNAs synthesis is mediated by epithelial mesenchymal transition (EMT). EMT is known to be involved in cell invasion and metastasis. circRNAs have also showed to interact with cerebellar degeneration-related protein 1, which is expressed in the brain and may be connected with Parkinson’s, Alzheimer and brain development.

For example, circ_0067934, which is circRNA, is shown to be overexpressed in oesophageal cancer cells than in normal cells. It is also discovered that this circRNA is involved in tumor development – tumor progression is associated with higher expression of  circ_0067934. Similar case is observed with circ_002059, another circRNA, which is in lower concentrations in gastric cancer in comparison to normal tissue.

All these findings show a promise that circRNA could be used as biomarker and potential therapeutic target. However more research is required to clarify the exact functions of the circRNAs.


CircRNA: a novel type of biomarker for cancer


Published on 2 May 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

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Cancer Immunotherapy and Killer Cells

Cancer Immunotherapy and Killer Cells

Cancer immunotherapy is a promising field in drug development because it provides new treatment options for various cancers, especially in combination with standard of care.

Immune system can recognize and eliminate tumour cells and is responsible for targeting most cancers in initial phase. However, cancer cells can escape the immune system.

What are the cytokine-induced killer cells?

Cytokine-induced killer cells (CIK) are mix of activated lymphocytes, including natural killer T cells, cytotoxic T cells and natural killer cells.

Tolerability and Safety

CIK are studied in vitro and in vivo in some pre-clinical studies. Administration of CIK has shown so far minimal side effects and significant toxicity was observed in only small percentage of treated patients. Some of the most common side effects are: fever, headache, fatigue, fever-related chills and rash. Most of them are resolved spontaneously within 24 h or require only symptomatic treatment.

Clinical Trials

  1. Hepatocellular Carcinoma (HCC)

Immunotherapy with CIK cells used in combination with surgical resection or in patients not candidates for hepatectomy prevents recurrence and/or metastasis and increases overall survival.

  1. Renal Cell Carcinoma (RCC)

Current studies have shown that CIK treatment may prevent recurrence/metastasis and improve overall survival of patients with advanced RCC.

  1. Non-small Cell Lung Cancer (NSCLC)

Current data indicates that CIKA may significantly prolong time to progression in patients with late-stage NSCLC.

  1. Gastric Cancer (GC)

Current research shows that CIK could be used as adjuvant treatment to prolong the survival of patients with stage II – III gastric carcinoma.

  1. Other Solid Tumors

CIK were studied also in breast cancer, ovarian cancer and soft-tissue sarcomas. While the results in breast cancer and ovarian cancer are promising, the ones in soft-tissue sarcomas are inconclusive.

There is ongoing research in adoptive immunotherapy where patients are administrated tumor-specific cytotoxic T cells to stimulate patient’s immune system and the cells are able to recognize and kill tumors.

Challenges in CIK therapy

  1. There is no standardized protocol for generating CIK cells.
  2. Dosage is not determined yet.
  3. Current studies are too heterogenic to allow clear conclusions about outcome.
  4. CIK are generated under GMP conditions.

While current results are promising more studies are required to determine the safety and efficacy of CIK.


Cancer Immunotherapy with Cytokine-Induced Killer Cells

Published on 2 April 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

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