Thursday, 23 May 2013

Recently Launched US website makes clinical trials easy to find

A US doctor has Launched a website to make it easier for the world’s sickest people to connect with research that could potentially save their lives.

The non-profit endeavor known as aims to become "The Wikipedia of clinical trials," by allowing a quick and free search for studies at academic centers around the globe, said its founder Bruce Markowitz is “really a resource for everybody, worldwide,  for free,” said Moskowitz, a primary care physician in Palm Beach, Florida,  whose mobile patient population -many of whom migrate north for the summer  gave him the idea of finding better ways to share information.

Moskowitz hopes that the new website will improve the quality of research and also helps to identify how many clinical trials are duplicated.

The new web site is an open-source platform, so educational centers can send in their own information. It updates automatically and can send users alerts when a trial status changes or a new trial opens up.    It also allows patients to email a doctor in any country to find out about a clinical trial, Moskowitz said.

Thursday, 16 May 2013

Role of Preclinical Toxicology studies in Clinical Research


Preclinical studies are carried out on animal models prior to the onset of clinical trials in humans. Various parameters need to be considered in preclinical studies before the drug is actually tested on humans. Important factors include pharmacokinetics data, pharmacodynamics data, drug safety and toxicology data. The goals of preclinical studies include: predicting the safety, efficacy, toxic effects, dose dependence and further to extrapolate it for potential human outcome.


Preclinical phase is the stage of drug development process that begins before clinical trial actually starts during which the feasibility, iterative testing and drug safety data are collected. Other non clinical studies include pharmacology studies for safety assessment [safety pharmacology] and pharmacokinetic [ADME] studies. The above mentioned studies provide a myriad of information about the drug and how they might act during clinical trials. Drugs will undergo PK, PD and toxicity studies through animal testing.

Importance of Pharmacokinetics and Pharmacodynamics data:

Absorption [A]:
  • Helps to decide on routes of administration.
  • Helps to decide on dosage level.
Distribution [D]:
  • Helps to know the impact the drug has created
  • Helps to study the Bioavailability of the drug [rate of bound and unbound drug]

Metabolism [M]:

Conjugation Data ,Cumulative effect, Therapeutic effect, Toxic effect.

Excretion [E]:

Helps to know the excretion rate of the drug from the body.

Some other parameters which could be derived from PK/PD studies are efficacy, potency, drug concentration levels in plasma, cmax, tmax, bioavailability and t1/2 life. Secondary parameters include data on AUC [Area under the Curve] which is a measurement of how much drug is absorbed by the body and how easily it is eliminated. Pharmacodynamics studies also gives data about permeability of barrier, pH and binding capacity.

Preclinical toxicology studies:

Invitro tests are used to evaluate the long term safety of a drug. It helps to determine specific properties of a drug and also helps to assess mutagenic and carcinogenic effects leading to toxicity. Toxicological activity of the products can be determined using invitro and invivo assay methods which estimate the clinical relatedness of the toxicological effects of the drug.

(i) Invitro methods:

Objective: To study the action of the test drug in tissues and cells from different organisms. This helps to study the mutagenic and carcinogenic property of a drug.

Tissues from several species including man can be examined and it also helps to reduce the number of animal tests required for screening new drugs. These studies help us to know certain factors like genotoxicity and mutagenicity. Genotoxicity refers to the study of toxic effects of the drugs on genetic/molecular level. The methods used in genotoxicity studies are molecular profiling and whole genome analysis.

High throughput profiling of a gene or a protein could reveal if there are any potential changes in the chromosome and DNA activity in using a drug. For e.g.: In humans, SNP [single Nucleotide Polymorphisms] are observed in which a single gene / base pair differ from another human. Studies are carried out to see the effect of drug on SNP’s, Haplotype genes etc using marker analysis.

Other studies are conducted specifically on microorganisms. To determine antibacterial property of a drug, few assays used include: Bacterial Reverse Mutation tests [AMES test], E.coli Reverse Mutation Assay, Invitro mammalian chromosome aberration test, Invitro mammalian cell gene mutation test.

Assay studies are conducted on microorganisms like Salmonella typhymurium, Escherichia coli and yeast. Mammalian cells used are mouse myeloma cells, Chinese hamster ovary [CHO] cells and also fully sequenced organism like Drosophia melanogaster [fruit fly].

(ii) Invivo methods:

Objective: The main objective of carrying our invivo studies are to determine the qualitative and quantitative analysis of how the drug acts on a body and the prime determining factor being the drug safety. The studies that are carried out inside an animal model is referred to as invivo studies. The choices of animal model play a major role in these types of studies.

Choice of model organisms: Differences in gut enzyme activity and circulatory system makes certain models more appropriate based on dosage forms. For e.g., canines are good models for solid oral dosage forms because carnivore intestine is underdeveloped compared to omnivores and gastric emptying rates are high. Also rodents cannot act as models for antibiotic drugs because alteration of intestinal flora causes significant adverse effects.

Depending on the drugs functional group it may be metabolized in similar or different ways between species which will affect both efficacy and toxicology. Some commonly used traits are: those animals which breed faster, easily availability, low cost in growing and housing, and selecting animals for which biological profile information is already available and are already proven to be model animals.

Ethical issues: 

Invivo studies are carried out abiding to certain guidelines put forth by PETA [People for the Ethical Treatment of Animals] which states that animals should to be treated respectfully.

The invivo studies can be carried out to determine the following factors:

Objective: To determine the safest dose to be administered. The study gives the results for MTD [Maximum tolerated dose] and NOAEL [Non Observed Adverse Effect Limit].


Raji Radhakrishnan S (Student of ACRI)

Tejeswani (Academic Coordinator)

Dr Smita Singh (Head of Academics)

Thursday, 9 May 2013

It is Time to Make a Move! Ensure the Safety and Overall Wellbeing of the Human Subjects Involved in Clinical Research


Subject/Trial Subject is an individual who participates in a clinical trial, either as a recipient of the investigational product or as a control.

The clinical trial is incomplete without the participation of an eligible human subject. It is known that Clinical trial is the heart and soul of the modern drug development process. It has become the necessity to evaluate the safety and efficacy of the drug in the human participant.

Many events and incidents occurred in the past clinical trial processes have an impact on both the researcher and the participant involved in clinical trial. Therefore, the question remains, how can we ensure the safety and overall well being of the human subjects?

Ethical principles that guides safety in Clinical Research

There are established guidelines and processes that monitor and ensure the safety of the human volunteers.

 According to Belmonte there are 3 ethical principles that guides the clinical research
  • Respect for person
  • Beneficence
  • Justice
Patient autonomy or respect for the person is an important principle in the medical ethics; in actual practice, especially in the context of developing countries, this important principle is usually disregarded or misrepresented or only partially acknowledged.

Role of Investigator, Clinical Research Coordinator and Other staff;
  • The investigator should understand that clinical research is not only valuable for the society but it is also ethically challenging. It requires an able and adept handling of both the science and human values.

  • The investigator has to be aware of the tension that could arise as a result of balancing the science and protection to the subject.

  • The investigator has to inform subject accordingly.

  • Take an opinion from other members, physicians who are involved in the clinical trial to minimize the risk to the subject.

Responsibility of IRB/IEC in assuring the safety of human subjects

An IRB is defined as a committee which is responsible for the review, approval, disapproval, modification and suspension or termination of trial related to human subject

IRB is responsible for:-
  • Review of important documents like informed consent form, protocol.
  • Investigator brochure update, financial document and advertisement.
  • Review research to ensure that benefit outweighs the risk.
  • Review reports related to death, serious unexpected adverse event sent by the investigator.
  • Conducting periodic review of all the documents, benefits, risks and informed consents etc
Common Problems associated with IRB:-
  • Advertisement not reviewed and approved prior to conduct of clinical trial.
  • Investigator qualification like CV not reviewed.
  • Various document like protocol, Informed consent form not review prior to the conduct of clinical trial.
  • Informed Consent.
Informed consent is defined as “Subject willingness to participate in the clinical trial after being informed about all the aspects of the clinical trial’.

It demonstrates that
  • Person has freely given conformation without any coercion.
  • Person knows that this is research but not a treatment.
  • Person has been given all the important and relevant information related to the trial.
Must include important information:-
  • Objective and purpose of the research.
  • Benefit and risk associated with the research.
  • Duration of the research.
  • Any alternative treatment available.
  • Can withdraw from the treatment.
  • Compensation of unexpected injury.
Common Problems associated with Informed Consent
  • Consent may not correct.
  • Proper signatures are not obtained.
  • Poorly written consent form.
  • Missing required elements.
  • Amended form is not signed.
Subject protection in U.S:-

There are different methods which are followed in the U.S to protect the rights of the study subject:-

Office for Human Research Protections which came in existence in the year June18, 2000, has a considerable power over the conduct of clinical trials.

The Office for Human Research Protections (OHRP) provides leadership in the protection of the rights, welfare, and wellbeing of subjects involved in research conducted or supported by the U.S. Department of Health and Human Services (HHS).

OHRP helps ensure this by 
  • Providing clarification and guidance.
  • Developing educational programs and materials. 
  • Maintaining regulatory oversight.
  • Providing advice on ethical and regulatory issues in biomedical and social-behavioral research.
In addition to inaugurating the OHRP, Education and training of clinical investigators and IRB staff.

Improved monitoring to quickly detect problems in Patient’s  safety and penalties of up to $250000 per clinical investigator and up to $1 million per institution for violations of patient protection agreements.

Subject protection in developing countries

With a population of more than a billion of people and prevalence of disease like cancer and HIV, and excellent pool of investigator, CRA and CRC, makes India an attractive location for foreign companies. Nevertheless, the subject enrolled in India is more vulnerable .Why?

1.Poor public health and educational system in Developing countries:-

Due to which the participant may not fully understand about the rights while participating in the clinical trial.

2. Inadequate dissemination of information


The unemployed and people below poverty line choose to be part of clinical trials to get free treatment.

4.Corruption in the public and private sectors.

In the context of developing countries, informed consent was nonexistent till the Consumer Protection Act came into existence.

Informed consent is very important before any medical treatment. Such consent can be implied, as in the case of a general physician’s treatment, when physician is trying to administer any drug or to perform any surgical procedure. In developing countries, where informed consent is infancy, most important elements of the trials are hidden and particularly in hospitals they are expected to sign the Informed consent form with a rider stating that they are willing for any kind of treatment.
5.Lack of facility and coordination among regulatory agencies

In August 2008, according to a report there are: "Fewer than 40 ethics committees in India are properly constituted and functioning”.

Ironically there is no proper linkage between Director Control General of India and Ethics Committee which are the governmental and institutional level of regulatory respectively .The DCGI fully depends upon the EC to implement the ethical principles. The DCGI neither cares for the proper functioning of ECs nor take care of how the rules and regulations are implemented. It’s been 30 years of EC in India but still there is no effective review process in India.

This is the time to break the silence and improve the ethical challenges that India is facing today.