Innovative Clinical Trial Designs: overview

Innovative Clinical Trial Designs: overview

Those who have worked on clinical trials for many years probably remember the rigidity of the clinical protocols and how often clinicians complained that the study design is out of touch with reality. The new tendency of using innovative clinical trial designs shows that this message was heard. Clinical research has also changed during the years and now we know a lot more about the complexity of diseases like cancer.

What are the limitations of the standard randomized clinical trials?

In a standard study there will be 2-3 options to choose from, it will randomize 1-5% of the eligible patients who consent and in the next 5 to 10 years it will try to catch up with the recruitment that is falling behind and reduce the amount of protocol violations. Data and Safety Monitoring Committee could potentially request early termination. The data will be analysis according to Intent-to-Treat (ITT) principle – counting all outcomes according to randomization, regardless of changes in adherence. This, of course, will trigger long arguments around the data generated from the study its validity, if the correct group was selected, etc.

What innovative designs could be used in cancer clinical trials?

  1. Single-Arm Dose-Finding Studies

The purpose of these studies which are common in phase 1 clinical trials is to find the balance between determining the maximum toxicity dose (MTD) and safe treatment of patients where the dose will be close to the unknown MTD so they can have better chance to benefit from the treatment. Normally phase 1 oncology clinical trials involve small number of patients (20-30) and a model-based approach could be used to determine the most appropriate dose. In this case when the drug reaches phase 3 the researchers can used all data from phase 1 and phase 2 – response and toxicity data – to design phase 3 study. The standard settings do not use such approach.

  1. Biomarker-Based Personalized Therapies: Development and Testing

This approach involves identifying and using relevant biomarkers (for example, tissue samples from tumor – fixed, fresh or circulating tumor cells). The second step is to identify reliable method to assess these markers and the third set is to design clinical trials that support development and verification of personalized therapies.

  1. Seamless Phase 2-3 Randomized Clinical Trials

Small single-arm phase 2 cancer clinical trials cannot use big resources until there is more reliable data that the treatment has potential to be successful. In such cases it may be useful to include phase 2 study as an internal pilot of the confirmatory phase 3 trial.

  1. Comparative effectiveness research studies: Equipoise-Stratified Randomization

The authors of the paper discuss STAR*D study, which offers different treatment options for patients with depression. The study offered 7 possible treatment options and for those patients who did not achieve satisfactory results there were 4 switch options and 3 augment options which allowed clinicians to select the best option for their patients.

  1. Comparative effectiveness research studies: Sequential Multiple-Assignment Randomization (SMAR)

Using the same study as above for example the authors present another option for adaptive study design but in this case the treatment is adaptive. In order to improve the outcome of the treatment patients were randomized on different treatment options based on their medical history and response to previous treatments.

  1. Comparative effectiveness research studies: Embedded Experiments to Close the Knowledge-Action Gap

This approach supports the idea that patients are randomized on the treatment which is superior to the standard of care. One of the challenges of new treatments is that they are implemented in clinical practice very slow and the purpose of this approach is to provide clinicians with more reassurance that the treatment will offer better outcome for this patients.

There is a clear need for changes in protocol designs to align them with clinical practice and provide more flexibility for patients and clinicians.


Innovative Clinical Trial Designs: Toward a 21st-Century Health Care System

Published on 9 Jan 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

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Review: Is clinical trial design fit for purpose?

Review: Is clinical trial design fit for purpose?

It is not a secret that the research and development in the pharmaceutical industry is very costly, time-consuming, risky and not particularly efficient. According to estimates bringing new drugs on the market could cost between $800 million and $2 billion. Failure in late stages – phase 2 and phase 3 – contribute significantly for the increased expenses. Some of the big challenges of phase 2 studies are that there is no enough information regarding dose-response relationship and the relevance of the biological target.

All these challenges were the reason for initiatives to change the way clinical trials are designed.

What kind of new approaches could be used?

  • One of the new approaches involved combination of different types of modelling: biological modelling, pharmacological modelling and statistical modelling. This method allows to use external data in order to model and simulate your study. Later on simulation would allow selecting the best study design to achieve your goals.
  • Bayesian modelling – this method combine external baseline data to improve efficacy and safety signal detection in early development. An example of such approach is to use small cohorts with dose-escalation to assess efficacy and safety at the end of each cohort. Dose will be increased until maximum therapeutic dose is achieved or unacceptable toxicity. Each new cohort will start only if all safety parameters are assessed for the different doses from the previous cohorts. This will allow detecting safety problems which are observed in large population of patients and only relatively strong efficacy signals will be detected.
  • Adaptive designs – In this case interim data from a trial is used to modify and improve the study design, in a pre-planned manner and without undermining its validity or integrity. For example, a larger proportion of the enrolled patients can be assigned to the treatment arms that are performing well, drop arms that are performing poorly, and investigate a wider range of doses so as to more effectively select doses that are most likely to succeed. In the next stage this allows to identify early efficient treatment, drop poorly performing arms, stop the study early for meeting its primary endpoints or modify eligibility to include more patients.
  • Seamless designs – in this case single trial has objectives that are traditionally addressed by separate trials.
  • Sample size re-estimation methods – this allows to increase or decrease sample size at an interim point for the trial.

The way we run clinical trials is changing and while it becomes more flexible in drug development point of view it could also become more complex from research centres point of view.


The future of drug development: advancing clinical trial design

Published on 6 Dec 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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CAR T cells and the future of HIV therapy

CAR T cells and the future of HIV therapy

Chimeric antigen receptor (CAR) T cells have been studied for over 25 years and are very successful in some types of cancer. With more than 30 million people living with HIV infection there were great hopes that CAR T cells method can help achieve “cure” but unfortunately after 15 years of clinical trials they have not shown to be effective.

What are CAR T cells?

Chimeric antigen receptor (CAR) T cells are obtained from donor lymphocytes, and then they are genetically modified and transfused back to the donor. They are designed to redirect T cells that express specific cell-surface epitopes which induce Major Histocompatibility Complex (MHC) – independent cytotoxic T lymphocytes response.

When this method was used in relapsed/refractory leukaemia they have achieved 67% 6-month survival rate in comparison to less than 25% with best available chemotherapy. These results raised high hopes for the potential effect of CAR T cells in HIV treatment.

What are the potential advantages of CAR T cells to target HIV-infected cells?

  • CAR T cells are independent of MCH and can target HIV-infected cells that are not targeted by host cytotoxic T lymphocytes (CTLs). HIV nef downregulates MHC-I expression; immune exhaustion or immune tolerance;
  • CAR T cells can keep their cytotoxic activity for at least 6 months and CAR DNA has been detected in peripheral blood for up to 10 years, which could potentially provide protection of HIV-expressing cells and cells that reactivate in the future;
  • CAR T cells have been found to penetrate blood-brain barrier, where is an important HIV reservoir.

Clinical trials with first generation CAR T cells

First generation CAR T cells use CD4 cells to target HIV Env-expressing cells. There were 4 clinical trials using this approach and while the CAR T cells were detected at least 10 years and there were no adverse events, the treatment did not achieve statistically significant effect on viral load. This led to discontinuation of further research.

First generation CAR T cells were relatively ineffective in cancer too.

Clinical trials with second generation CAR T cells

Second generation CAR T cells use CD28 or 4-1BB which are important for lymphocytes activation and persistence. They have proved to be significantly more effective than first generation. This second generation is used in cell cultures and has shown promising results in reducing HIV-infected cells. However there are no in vivo results yet.

There are some positive signs in second generation CAR T cells testing and this is still exciting field to keep up to date with.


Quarter Century of Anti-HIV CAR T Cells

Published on 1 Nov 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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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

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B cell receptor targeting and cancer therapy

B cell receptor targeting and cancer therapy

B cell receptor is involved in the normal B cell development and immunity but also in supporting the growth and survival of malignant B cells in patients with B cell leukaemias or lymphomas. The expression of this receptor on the surface of the B cells is important for the immune response. It triggers antigen-antibody responses and B cells differentiation into plasma sells and membrane B cells.

B cells activation is mediated by activation of membrane-proximal kinases like spleen tyrosine kinase (STK), Bruton tyrosine kinase (BTK) and PI3K. In the recent years there are inhibitors which are developed to target these kinases as part of the treatment of leukaemias and lymphomas. For example, some of the approved inhibitors are: Ibrutinib (BTK inhibitor) and Idelalisib (PI3K inhibitor). However, these inhibitors are not specific to tumour cells only and they can influence other processes in the healthy cells. Currently there are in development more specific inhibitors.

The treatment responses to these inhibitors can vary depending on the B cell receptor signalling and its interaction with the microenvironment. Also the genetic background and the degree of genetic instability could activate mechanisms which could lead to resistance to these drugs.

The role of B cells in solid tumours is not established yet but B cells are discovered in solid cancers like breast, cervical, ovarian, non-small-cell lung cancer and pancreatic ductal adenocarcinoma. Tumour-infiltrated B cells and macrophages both express BTK and are targeted by BTK inhibitors.

While the kinases involved in B cell receptor activation are promising target more research is needed to develop specific inhibitors that will target cancer cells.


Targeting B cell receptor signalling in cancer: preclinical and clinical advances

Published on 3 Sep 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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DNA nanorobots and cancer treatment

DNA nanorobots and cancer treatment

A research team from National Center for Nanoscience and Technology, Beijing, China has reported an interesting and novel approach in targeting tumours. They have constructed autonomous DNA robots which were programmed to transport and deliver therapeutics directly to the tumours.

According to the research paper such DNA robots have already been studied in cell cultures and insects but not in animals.

One of the potential new methods to target solid tumours is vascular occlusion, which is a process of blocking the blood vessels (in this case the once that support tumour growth and spreading). The research team has decided to use this method and to target tumour cells with thrombin. Thrombin cannot exist for a long time on its own in the blood circulation and it is not specific when triggering coagulation processes.

The experiments were done with mouse models and Bama miniature pigs. They have picked Bama miniature pigs because their physiology is closer to humans. Also they have run experiments with different types of tumours with different level of vascularization. The final results have shown that the DNA nanorobots have successfully delivered thrombin to the tumours and have blocked the blood supplies to them without affecting surrounding cells.

According to the authors this is an important step forward in developing method which will allow targeting tumours and blocking formation of metastasis.

It is definitely a very promising field with great potential.


A DNA nanorobot functions as a cancer therapeutic in response to a molecular trigger in vivo

Published on 1 August 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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