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.

Source

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

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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.

Source

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

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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.

Source

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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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.

Source

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.

Source

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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.

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

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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.

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

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