Preclinical research including in vivo and in vitro studies are a part of R&D activities at TRPHARM.
In vivo and in vitro studies
Studies that are in vivo are those in which the effects of various biological entities are tested on whole, living organisms usually animals including humans, and plants as opposed to a partial or dead organism, or those done in vitro, i.e., in a laboratory environment using test tubes, petri dishes etc. Ex vivo refers to experimentation or measurements done in or on tissue from an organism in an external environment with minimal alteration of natural conditions.
Animal Models as well as ex vivo and in vitro preparations can be used as test systems. Ex vivo and in vitro systems can include, but are not limited to: isolated organs and tissues, cell cultures, cellular fragments, subcellular organelles, receptors, ion channels, transporters and enzymes. In vitro systems can be used in supportive studies (e.g., to obtain a profile of the activity of the substance or to investigate the mechanism of effects observed in vivo).
For more information please refer to ICH Harmonised Tripartite Guideline (Safety Pharmacology Studies for Human Pharmaceuticals S7A).
Safety Pharmacology Studies for Human Pharmaceuticals
The objectives of safety pharmacology studies are:
1) to identify undesirable pharmacodynamic properties of a substance that may have relevance to its human safety
2) to evaluate adverse pharmacodynamic and/or pathophysiological effects of a substance observed in toxicology and/or clinical studies and
3) to investigate the mechanism of the adverse pharmacodynamic effects observed and/or suspected.
The investigational plan to meet these objectives should be clearly identified and delineated.
Clinical trial (also called clinical study) is essential for the development of medicines and without them patients cannot gain access to new potentially life-saving medicines.
TRPHARM works to discover and develop innovative, safe, and effective ways to prevent or treat most challenging diseases.
We are committed to the well-being of patients who take part in our trials, and uphold the highest ethical standards in all of our research initiatives. The approval and conduct of clinical trials is within the remit of the relevant authorities. Guidelines are in place to ensure that clinical trials are conducted as safely as possible. All of clinical researches sponsored by TRPHARM are reviewed by an Independent Ethics Committee.
What is clinical trial?
Any investigation in human subjects intended to discover or verify the clinical, pharmacological, and/or other pharmacodynamic effects of an investigational product(s), and/or to identify any adverse reactions to an investigational product(s), and/or to study absorption, distribution, metabolism, and excretion of an investigational product(s) with the object of ascertaining its safety and/or efficacy.
What are phases of clinical trial?
Clinical trials are conducted in a series of steps, called phases – each phase is designed to answer a separate research question.
- Phase I:
Researchers test a new drug or treatment in a small group of people for the first time to evaluate its safety, determine a safe dosage range, and identify side effects.
- Phase II:
The drug or treatment is given to a larger group of people to see if it is effective and to further evaluate its safety.
- Phase III:
The drug or treatment is given to large groups of people to confirm its effectiveness, monitor side effects, compare it to commonly used treatments, and collect information that will allow the drug or treatment to be used safely.
- Phase IV:
Studies are done after the drug or treatment has been marketed to gather information on the drug’s effect in various populations and any side effects associated with long-term use.
First in Human (FIH) clinical trials are part of the exploratory phase of drug development and represent a significant milestone in the clinical development of new medicines. When only preclinical data are available to guide dose-selection, population, study design, safety monitoring and appropriate expertise are all critical to maximise the safety of the study subjects and the quality of the data.
** If you are looking for information about TRPHARM studies in your area, you can begin your search below. All our studies in patients are registered at www.clinicaltrials.gov, which lists the locations of study sites.
(ClinicalTrials.gov Identifier: NCT02760368)
(ClinicalTrials.gov Identifier: NCT02760433)
(ClinicalTrials.gov Identifier: NCT02667639)
Levels of Evidence for Clinical Studies
Level I: High quality randomized trial or prospective study; testing of previously developed diagnostic criteria on consecutive patients; sensible costs and alternatives; values obtained from many studies with multiway sensitivity analyses; systematic review of Level I RCTs and Level I studies.
Level II: Lesser quality RCT; prospective comparative study; retrospective study; untreated controls from an RCT; lesser quality prospective study; development of diagnostic criteria on consecutive patients; sensible costs and alternatives; values obtained from limited stud- ies; with multiway sensitivity analyses; systematic review of Level II studies or Level I studies with inconsistent results.
Level III: Case control study (therapeutic and prognostic studies); retro- spective comparative study; study of nonconsecutive patients without consistently applied reference “gold” standard; analyses based on limited alternatives and costs and poor estimates; sys- tematic review of Level III studies.
Level IV: Case series; case control study (diagnostic studies); poor refer- ence standard; analyses with no sensitivity analyses.
Level V: Expert opinion.
03/Therapeutic Research Areas
3.1. Research in Oncology
Cancer represents a significant, and growing, burden on healthcare systems. Biosimilars are currently available for use in oncology in the supportive care setting; the focus of biosimilar development is likely to switch to agents such as monoclonal antibodies. Available evidence indicates that biosimilars approved by regulatory authorities offer a safe and effective alternative to originator biological therapies. They also offer potentially significant cost savings to healthcare payers.
Our original and biosimilar portfolio in oncology, drug discovery infrastructure, and experience in drug development make us partner for translational research, whether you’re in academia or industry. At TRPHARM, we translate today’s science into tomorrow’s medicine.
3.2. Research in Inflammation
Autoinflammatory diseases area group of clinical conditions other than autoimmune diseases, characterized by recurrent inflammatory episodes. We are proud to develop biotherapeutics for Behcet’s Disease, Familial Mediterranean Fever (FMF) and other diseases in collaboration with Academicians in the world including Turkey.
The academic, pharmaceutical and biotechnology sectors trust us to realise the full potential of their research. This is why we are the partner of choice for early phase anti-inflamatory drug development. Ethical conduct is the foundation for all our decisions. We would like to have a clear confidence when patients use our drugs.
3.3. Research in Rare Diseases
Rare diseases, when taken together, are not that rare at all.
In fact, according to the National Institutes of Health (NIH), 30 million Americans have one of the nearly 7,000 diseases that are officially deemed “rare” because alone they each affect fewer than 200,000 people in the United States. Sometimes, only a few hundred patients are known to have a particular rare disease. More than 450 medicines in development for rare diseases in the world.
Patients often need advocates, and that can be especially true for people with a rare disease, who have unique problems and may have little or no support or available treatment. TRPHARM is committed to helping patients and advancing rare disease therapies through the development and marketing of “orphan” medical products.
04/Biotherapeutic and Biosimilars
An active ingredient is any component that provides therapeutic value of a drug. Many drugs combine multiple active ingredients and interactions between these substances may be critical for drug activity.
Biotherapeutics are those drugs of which active substances are produced by proteins (growth hormone, insulin, antibodies etc.) or living organisms (cells, viruses and bacteria) or drugs composed by these substances. These are larger and more complex molecules that chemically derived drugs. For instance, monoclonal antibodies (MABs) were discovered in 1972 and for which their discoverer was awarded with a Nobel Prize. These therapeutic molecules specifically bind to specific molecules and prevent these molecules from causing a specific disease. Furthermore, they prompt the immune system of the body to target disease-causing agents. These diseases include genetic disorders such as Familial Mediterranean Fever, infectious diseases, oncological diseases such as ovarian carcinoma and autoinflammatory diseases such as rheumatoid arthritis.
Biosimilars are proven to be similar to an already licensed biotherapeutic product regarding product quality, efficacy and safety based on direct comparisons (or head- to-head comparisons) and these are similar versions of originator biotechnology products that may offer affordable and quality solutions compared to originators. Currently, many international company develop biosimilars and this allows each individual patient to access to treatment options that were inaccessible previously due to their high costs.
Biosimilars also follow the same product development steps as biotherapeutics and are only licensed and becomes available by prescription after being approved by Regulatory Authorities as effective and safe as their originator products.
Significant economic burden of biotechnology products compels health authorities to shift towards biosimilars. After the patent exclusivity of originator products had expired, the first five biosimilars were approved in 2006 and 2007. The lack of long-term safety data for biosimilars, forced health authorities to issue various regulations. European Medicines Agency (EMA) issued necessary regulations and published product-specific guidelines and subsequently granted first approvals for biosimilars. In Turkey, registration criteria for biosimilars have been defined in the “Guidelines on biosimilar medicinal products” issued in 2008.
In conclusion, generic drugs (equivalent) are chemically synthesized, stable and small-molecules while biosimilars are biotechnology products and are produced by living organisms. They are very large and complex molecules. Therefore, biosimilars cannot be accepted as generics and different methods are used to carry out comparisons between biosimilars and originators. Increasing number of generics and biosimilar will eventually reduce treatment costs and increase access to treatments for patients.
Below are some of the links to Access regulatory guidance for biosimilars:
US Food and Drug Administration (FDA) Guidance for Industry on Biosimilars
European Medicine Agency (EMEA) Guidelines on Biosimilar Medicinal Products
Turkish Ministry of Health, Medicines and Medical Devices Agency Guidelines on Biosimilar Medicinal Products
1.Biotherapeutics –Understanding Novel Therapies, International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) – 2012. www.ifpma.org (accessed 26.07.2016).
2.Biosimilars – Alper B. İSKİT XXXVIII. National Hematology Congress, Antalya, 2014. http://www.thd.org.tr/thdData/Books/547/biyobenzerler-alper-b-iskit.pdf (accessed 26.07.2016) .
3.WHO Expert Committee on Biological Standardization Sixtieth report. Annex 2. Guidelines on evaluation of similar biotherapeutic products (SBPs) – WHO Technical Report Series No. 977, 2013. http://www.who.int/biologicals/expert_committee/TRS_977_60th_report.pdf (accessed 26.07.2016).
4.Erwin A. Blackstone, PhD; Joseph P. Fuhr, Jr, PhD. The Economics of Biosimilars. Am Health Drug Benefits. 2013;6(8):469-478.
05/Good Practices (GxP)
Good Laboratory Practice (GLP) is a quality system concerned with the organizational process and the conditions under which non-clinical health and environmental safety studies are planned, performed, monitored, recorded, archived and reported. GLPs are regulations published in the Code of Federal Regulations (21CFR part 58). GLPs are not guidelines, they have the force of law.
Good Manufacturing Practice (GMP) is the part of quality assurance which ensures that products are consistently produced and controlled to the quality standard appropriate to their intended use and as required by the Marketing Authorization or product specification. GMP is concerned with both production and quality control.
Good Clinical Practice (GCP) is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve the participation of human subjects. Compliance with this standard provides public assurance that the rights, safety, and well-being of trial subjects are protected, consistent with the principles that have their origin in the Declaration of Helsinki, and that the clinical data are credible.
We are committed to the well-being of patients who take part in our trials, and uphold the highest ethical standards in all of our research initiatives.
T.R. Ministry of Health
Turkish Medicines and Medical Devices Agency
Clinical Trials Portal
Turkish Medicines and Medical Devices Agency Head of Clinical Trials Department
International Council for Harmonisation
European Medicines Agency (EMA)
U.S. Food and Drug Administration (FDA)
Association of Clinical Research Professionals
Clinical Research Association
Turkish Association of Contract Research Organizations (SAKDER)
National Institutes of Health Clinical Trials Database