COMPARISON BETWEEN PAPER CRF AND eCRF

ABSTRACT

Now-a-days every field Business, Banking, Transport, Government sector.. and so on has moved from manual to on-line services, to gain huge efficacy for suppliers and potential financial value to the company. Suppliers that have failed to modernize their business strategies have slowly vanished from the market place.

In this decade, going digital can improve the quality of clinical trials in many ways. The present paper is a narrative review of comparison on the percentage of clinical trials performed using the simple pen and paper to record the data with the trials that are performed by smart data entry us electronic case report forms (or eCRF)

“ Source or eSource – is the grapevine of this era clinical trials ”

INTRODUCTION

One of the core documents in clinical trials is the case report form (CRF). A case report form (or CRF) is a paper or electronic questionnaire specifically used in clinical trial research. The Case Report Form is the tool used by the sponsor of the clinical trial to collect data from each participating site. All data on each patient participating in a clinical trial are held and/or documented in the CRF, including adverse events.

According to FDA

On page 11, the FDA adds: "The eCRF is the electronic document containing all data elements on a study subject that the investigator has reviewed prior to release to parties in Tier 3 (e.g., the sponsors, CRO, institutional review board)." The word "all" is used again.

On page 3, the guidance states: "The eCRF is a vehicle used to assemble all the data from different electronic- and paper-based systems and makes it possible to capture and organize these diverse data in a manner that satisfies the study protocol and that enables the data to be systematically reviewed and analyzed." Got it? The key word there is "all." Are all of your organization's eCRFs "vehicles"?

 In the past decade, the classical paper case report forms are surprisingly entrenched against the digital age. As clinical trials are considered as business process, the sponsor’s main objective will be to compare pros and cons of paper CRF and eCRF so as to estimate the values of data quality parameters and performed cost calculations for a sample clinical trial.

Paper CRF Vs. eCRF

Many of the studies have shown that electronic subject data collection yielded higher quality then the simple paper collection with great study compliance. The studies have also proved that electronic data capture has significantly reduced the overall expenses of the trial. Hence it is no wonder that companies have an interest in cost cuttings.

However, some clinical researchers argue regarding the “flexibility”. According to them Paper CRF is a flexible tool that can record the free-form information using pen and paper at any point of time. Whereas in case of eCRF, it is very hard to predict in advance the kind of data that needs to be captured. Paper CRF can never fail to accommodate the data but what happens to the eCRF if there is a power break up or short circuit goes down?

But if the digital tools are properly managed, the above mentioned lack of flexibility also become s the greatest strength of the electronic case report forms. eCRF can be a truly inter-responsive tool that can provide information to the investigators as soon as the data is entered and with very less frequency of errors.

“An intellectual eCRF – is like acquiring brainy scientist at the clinical site”

ADVANTAGES OF eCRF

Lowered Chances Of Errors: Electronic case report forms are designed in such a way that it will send an “ALERT” to the investigator, if any wrong entries are made. In this way eCRF provide a check to the investigators and prevents errors before it happens.

Reduced Data Entry Time: Increasing EDC computerization has enabled a paperless environment where key study variables based on protocols and electronic querying are directly entered into the clinical trials application.

Eliminating Duplicate Data Entry: In eCRF the repetitive data in clinical trials such as- Subject ID, Study Number, Site ID, Date - are automatically replicated from the first form to the last form. Hence eliminating duplicates.

Accurate Data: Since eCRF are configured to check for and prevent errors and omissions, data collected is accurate.

Facilitate Analysis: Data collected in eCRF are linked with one form to another from for analysis.

Improved Document Management: Advanced electronic record-keeping systems with basic features like document version control, full text indexing, metadata templates, data storage, security access etc., have improved the document management system.

Dashboards: Electronic case report forms provide features such as color-coded dashboards for each subject visit that provide information to the clinical investigator at a glance. Hence dashboards remain the outstanding as well as user-defined options to display the data that can be visualized and identified with an ease imagination.

CONCLUSION

Although EDC technology and e-clinical systems have been implemented to enhance various aspects of the data management process, implementation not been without difficulty nor has it been improved as rapidly as many has anticipated. But, EDC acceptance seems, strong and there are few instances where sponsors have gone back to PDC studies when they have had the experience of EDC.

However, competitive pressure in today’s market place is forcing the CRO’s to seek better ways of reducing drug development times and increasing productivity. Electronic case report forms that are shortening the clinical trial lifecycle by collecting quality data more quickly and accelerating the availability of data are solutions to a critical path bottleneck that the industry has been working on for many years.

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Written by
Vanitha
vanitha.archana@clinzen.com

                                         

Things To Know Before Participating In A CLINICAL TRIAL

Deciding to take part in a clinical trial can be hard, but it’s your choice to make. A lot has changed over the past few decades, and many people want to know as much as possible about all of their treatment options before they make up their minds. People should learn as much as possible about the clinical trials that interest them. They should also feel comfortable discussing their questions and concerns with members of the health care team. Prospective participants should understand what happens during the trial, the type of health care they will receive.

Some of the basic Questions that one should answer themselves before participating

•      Why do I want to take part in a clinical trial?
•      What are my goals and expectations if I decide to take part?
•      How realistic is the trial?
•      The chances of benefit versus risk?
•      What is being studied during the trial?
•      What are the possible interventions that I might receive during the trial?
•      What tests and procedures are involved?
•      Will hospitalization be required?
•      How could the study treatment affect my daily life?
•      How long will the study last?
•      Who will pay for my participation?
•      Will I be reimbursed for other expenses?
•      What type of long-term follow-up care is part of this trial?
•      Will results of the study be provided to me?
•      What are my options if I am injured during the study?
•      Is there patient confidentiality in the trial?

Potential Benefits

Participating in well-designed and well-executed clinical trials is one approach for eligible patients/volunteers to:

• Get actively involved in their health care.
• Gain access to potentially new research treatments
• Have access to expert medical care for the condition being studied, since investigators are often specialists in the disease area being studied.
• Help others by contributing to medical research.

Possible Risks

There are generally known and unknown risks associated with clinical trials, such as:

• There may be unpleasant, serious, or even life-threatening side effects resulting from the treatment.
• The treatment may not be effective for the participant.
• The protocol may require more of the participant's time and attention than a standard treatment. (Participants may need to visit the study site on a regular basis, be subjected to additional tests, get more treatments than are normally necessary, stay in the hospital and/or follow complex dosage requirements)

Safeguards

Several levels of safeguards are in place to help protect the people who take part in clinical trials. There are still risks involved with any study, but these safeguards try to reduce the risk as much as possible.

Three basic principles, as outlined in the Belmont Report from the late 1970s, provide the basis for research involving humans:

• Respect for persons: Recognizing that all people should be respected and have the right to choose what treatments they receive
• Beneficence: Protecting people from harm by maximizing benefits and minimizing risks
• Justice: Trying to ensure that all people share the benefits and burdens of research equally

Having an idea of what you can expect from taking part in a study can help relieve some of your concerns and make things go more smoothly. The first thing you will need to do is give your informed consent to take part in the study.

Informed Consent

The people running the study are required to get your written, informed consent before you take part in any way (often even before you have any needed tests to see if you are eligible for the study). In the informed consent process, the researchers (doctors or nurses) will explain the details of the study to you and answer your questions and concerns.

Before you sign the consent form, ask questions. Be sure someone from the research team goes over the form with you in detail. Consent forms are not all easy to understand, and there may be words or ideas that seem confusing. You may want to bring someone along with you to the meeting to help make sure all your concerns are addressed.

Taking Part in Study

Once you’ve signed the consent form, you will be ready to take part in the study. You’ll probably need to have blood tests or imaging tests done before you start treatment (if you haven’t had them recently). A full medical history and physical exam are also usually done. The results are needed before you start the actual study to be sure that you meet the eligibility criteria and to help ensure your safety.

How to leave the study early

You may quit taking part in the study for any number of reasons:

• You completed treatment on the study
• The treatment does not appear to be working for you
• You have serious side effects while in the study
• The study itself is stopped early because the treatment either has proven to work, has proven to not work as well as the standard treatment, or it’s been found to be too harmful
• You decided to leave the study

There are different groups that can provide guidance for people before participating in clinical trial

• American Cancer Society
• Emergency Care Research Institute (ECRI)
• National Institute of Mental Health
• American Association of Health Plans
• Food and Drug Administration
• National Multiple Sclerosis Society
• National Institute of Health

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Written by
Harisha Kothapalli
harisha.kothapalli@clinzen.com

What’s the therapeutic window of your drug?

Did we anytime think how a drug shows the effect? Why should you take not more than 25 mg of Atenolol or not more than 4000 mg of paracetamol (1000 mg per dose) or 10 mg of Cetirizine (once) per day? Why can’t we not increase or decrease the dose? Why few drugs are taken as once daily and others could be broken down to two or more times a day? These questions will be answered in this article.

When a molecule is discovered, we do not know how much of the drug gives optimal effect against the disease, how much amount of the drug precipitates to show adverse effects. For this, we carry out studies to determine the optimal amount needed to show the desired effect. This optimal range of the drug or medication is termed as therapeutic window.

Therapeutic window or pharmaceutical window is the drug concentration range in which the drug shows the desired effect. It is the range of drug dosages which can treat disease effectively while staying within the safety range. In other words, it is the dosages of a medication between the amount that gives an effect (effective dose) and the amount that gives more adverse effects than desired effects. For instance, medication with a small pharmaceutical window such as Carbamazepine must be administered with care and control, e.g. by frequently measuring blood concentration of the drug, since it easily gives adverse effects such as agranulocytosis.

But how do we determine this window? For this, the study goes back to the phase I of clinical trials. In this phase, from the data and results obtained from the preclinical or non-clinical studies, we determine the maximum concentration of the drug that can be administered to a healthy volunteer without the precipitation of adverse event. The dose is slowly increased in the volunteers and is checked for the effects. From this we get the maximum safe concentration (MSC). Next moving to phase II clinical trials which are conducted in patients with the disease for which the drug is being tested for here, we determine the minimum dose of the drug enough to show effect against the disease. This concentration of the drug that starts to fight against the disease is called as minimum effective concentration (MIC).

Let us take an example of a drug X. An immediate release dosage form of this medicament was administered to a subject orally. The amount of the active ingredient initially in the dosage form was 3 mg. The drug seemed to show no effect. Then the amount of the medicament was increased to 5 mg which was found to be good. The amount was then increased and it was found that the drug was safe till 10 mg. Therefore, the minimum amount of drug that can show effect is taken as 5 mg and the maximum safe amount was taken as 10 mg as per the experiment.

Therapeutic ratio or therapeutic index:

The therapeutic index (also known as therapeutic ratio) is a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes death (in animal studies) or toxicity (in human studies). Quantitatively, it is the ratio given by the lethal or toxic dose divided by the therapeutic dose. In animal studies, the therapeutic index is the lethal dose of a drug for 50 % of the population (LD₅₀) divided by the minimum effective dose for 50 % of the population (ED₅₀).

Therapeutic index or therapeutic ratio = Toxic dose₅₀ / Effective dose₅₀

Lethality is not determined in human clinical trials; instead, the dose that produces toxicity in 50% of the population (TD₅₀) is used to calculate the therapeutic index. Lethal dose is important to determine in animal studies, there are usually severe toxicities that occur at sub-lethal doses in humans, and these toxicities often limit the maximum dose of a drug. A higher therapeutic index is preferable to a lower one: a patient would have to take a much higher dose of such a drug to reach the lethal/toxic threshold than the dose taken to elicit the therapeutic effect.

A drug or other therapeutic agent with a narrow therapeutic range (i.e. having little difference between toxic and therapeutic doses) may have its dosage adjusted according to measurements of the actual blood levels achieved in the person taking it. This may be achieved through therapeutic drug monitoring (TDM).

The therapeutic index varies widely among substances, for example, opioid analgesics like Remifentanyl has a therapeutic index of 33,000 : 1 and Tetrahydrocannabinol, a sedative and analgesic of herbal origin has a safe therapeutic index of 1000:1, while Diazepam, and skeletal muscle relaxant has a lower therapeutic index of 100:1. Less-safer drugs such as Digoxin, cardiac glycoside has a therapeutic index of approximately 2:1. Other examples of drugs with a narrow therapeutic range given by FDA which may require drug monitoring both to achieve therapeutic levels and to minimize toxicity are Dimercaprol, Theophylline, Warfarin sodium, Valproic acid, lithium carbonate Clindamycin etc. Most antibiotics, such as the β-lactams, macrolides and quinolones have a wide therapeutic index and therefore do not require therapeutic drug monitoring. Some antibiotics like Gentamycin, Vancomycin, Amphotericin B and Polymyxin B require monitoring to balance efficacy with minimizing adverse effects as they could be irreversible. Other drugs such as Teicoplanin, Flucloxacillin and the antifungal agents like Itraconazole, Flucytosine and Fluconazole are monitored in certain circumstances.

Therefore, it is very important to determine the therapeutic index of the drugs for better administration of the drug minimizing the side effects. It is also important to measure the plasma drug levels as a part of therapeutic drug monitoring to avoid the unnecessary administration of the drug and administration of drugs with narrow therapeutic index with maximum efficiency.

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Written by

Vindhya Marpalli

vindhya.marpalli@clinzen.com

SURVIVAL OF THE FITTEST - Struggle for life

“Survival of the fittest” as coined by the British philosopher of the Victorian era, Herbert Spencer, explains the evolutionary trend of life, which can also be seen even in our man defined world of medicines. In order to treat a disease, several molecules are created after identifying the target. These discovered molecules have to be tested before bringing it into the market for human use.

“Don't count your chickens before they hatch” - These discovered molecules cannot be as such prescribed to the needy without enough evidence that the molecules show enough efficacy in parallel with its safety. Hence, to prove this, the molecules are made to go through a lengthy process of verification. This process is termed as Clinical trials.

What led to the birth of stringent clinical trials? To understand this we have to go back to early 1900s. Sulfanilamide, a drug used to treat streptococcal infections (bacterial infections), had been shown to have a promising curative effect in tablet and powder form. In 1937, there was a demand for the drug in liquid form. On experimentation it was found to dissolve in diethylene glycol, a solvent, which was lab tested for flavor, appearance, and fragrance giving satisfactory results. Immediately, the drug was compounded in liquid form using diethylene glycol without testing for its toxicity. At that time the food and drugs law did not require safety studies to be done on new drugs. Selling toxic drugs was, undoubtedly, bad for business and could damage a firm's reputation, but it was not illegal. Because no pharmacological studies had been done on the new Sulfanilamide preparation, one characteristic of the solution was left unnoticed. Diethylene glycol, a chemical normally used as antifreeze, is a deadly poison. At least 100 deaths were blamed on the medication. This led to the passage of the 1938 Food, Drug, and Cosmetic Act, which increased FDA's authority to regulate drugs.

Another example is the unforgettable Thalidomide tragedy. Thalidomide first entered the German market in 1957 as an over-the-counter remedy, the only non-barbiturate sedative known at the time, gave the drug massive appeal. Sadly, tragedy followed its release, catalyzing the beginnings of the rigorous drug approval and monitoring systems in place at the United States Food and Drug Administration (FDA) today. The product was advertised as “completely safe” for everyone, including mother and child, “even during pregnancy,” as its developers “could not find a dose high enough to kill a rat.” By 1960, thalidomide was marketed in 46 countries, with sales nearly matching those of aspirin. Around this time, the drug was also found to be a possible curative for morning sickness. In 1961, this so-called harmless compound showed severe birth defects in the babies whose mothers took the drug during pregnancy. The drug interfered with the babies' normal development, causing many of them to be born with phocomelia, resulting in shortened, absent, or flipper-like limbs. A German newspaper soon reported 161 babies were adversely affected by thalidomide, leading the makers of the drug—who had ignored reports of the birth defects associated with the it—to finally stop distribution within Germany. Other countries followed suit and, by March of 1962, the drug was banned in most countries where it was previously sold.

Clinical trials can be defined as a set of medical research and drug development that generate safety and efficacy data (or more specifically, information about adverse drug reactions and adverse effects of other treatments) for health interventions (e.g., drugs, diagnostics, devices, therapy protocols). These studies are conducted only after sufficient satisfactory information has been gathered from the nonclinical studies on safety and grant of approval from the health authority/ethics committee in the country where approval of the drug or device is sought.

Clinical trials are of five types – prevention, screening, diagnostic, treatment, and quality of life. Trials can also be comparative type which has come up in recent times to prove the molecule as an alternative to an already existing marketed molecule. These trials are initiated by the sponsor(s) and he is the one who is answerable about the outcome of the trial to the regulatory authorities. The sponsor has to select an experienced, qualified investigator having the capability of recruiting the subjects and site where the study can be conducted. For a given study, the number of sites can range from one to many spreading across many countries and races.

The road-map to success for the trial which is the protocol has to be prepared by the sponsor carefully taking care of the trial design. This document gives information on the objective, methodology and statistical analysis for the procedures used in the trail. In order to void bias, randomization, blinding technique is used so that the values are not altered. Prior to the start of the study, this prepared document, the protocol needs to have an approval from the regulatory bodies.

The clinical trial of new drugs is commonly classified into four phases. Each phase is treated as a separate study for its approval. The patient population is directly proportional to the type of product and the stage of its development – small scale, pilot (medium) and large scale. In order to determine the therapeutic window (the effective safe and effective drug range) of the molecule, phase one and phase two trials are conducted separately (the later is conducted only after success of former). In the phase one the safety the molecule is tested in healthy volunteers of population size of less than 100. After gathering enough positive data the study is taken to the next level of phase two where less than 500 subjects, both healthy and diseased, are taken for determining the safety and efficacy respectively. Only after the success of the phase two, phase three is conducted by increasing the population size to about 10,000. Here, in this phase, the efficacy of the molecule is studied closely keeping an eye on the side effects or the adverse events of the molecule. Once the trial is said to have achieved its goal, NDA i.e New Drug Application is sent to the regulatory bodies such as US FDA along with the data that was obtained from the trial for obtaining the approval of marketing the molecule.

The molecule is all set to enter the market. Post marketing surveillance or phase four is carries out in order to keep a check on the treatment’s benefits and risks and optimal use. This phase is mainly helps us in understanding or discovering the long term side effects, if any seen.

In the struggle for success, initial molecules of around 10,000 get filtered to less than 250 in preclinical study, out of which less than 5 molecules enter the clinical study. From a group of less than five, one molecule could be given an approval by the health authorities for human usage.

Hence, in this scientific world of medicine, a drug with benefits clouding the risks is the one rewarded as the fittest!!!

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Written by

Vindhya Marpalli

vindhya.marpalli@clinzen.com

INTERNET RECRUITMENT

“Clinical trials now have the potential to conduct research study using World Wide Web… [the Internet] that have the ability to recruit people themselves, enter their data into our computers, and provide fast and convenient electronic recruitment process”

ABSTRACT

“Recruitment-the key for a successful clinical study”

Recruitment is a dialogue that takes place between an investigator and a potential participant prior to the initiation of the informed consent process. It begins with the identification and enlistment of volunteer subjects or controls for the clinical trial. The use of the Internet in randomized controlled trials has grown tremendously in recent years. In order to reach a large target population of study subjects, an effective mechanism for recruitment is needed. To generate results on time and complete trials, completion of recruitment on time is essential. A small delay in recruitment leads to delay in completion, and thus a financial loss for the sponsor.

INTERNET RECRUITMENT 

“To market the product immediately, sponsors must explore new subject recruitment techniques”

“Time to market” is one of the important quote in clinical trials. The faster the study gets the approval, the more financial value it will have for the company. Delays in study will be very costly to the CRO’s. It is therefore easy to understand why patient recruitment has been called “the most important and challenging aspect of clinical trials,” with pitfalls in recruitment process is one of the main reasons for the failure of clinical studies.

Less number of subject enrollment into study will have many negative implications, such as highly expensive with extra resources and longer duration of clinical trials. In addition, poor recruitment process not only impede the successful evaluation of new and existing interventions, but it will also prevent greater efficiency in clinical development. Thus it is very clear that subject recruitment is a key phase in the clinical trials. If the subject enrollment period in clinical trials could consistently be reduced, it would cause a major advancement in optimizing clinical study process and improving economic health of the company.

ONLINE RECRUITMENT OF PATIENTS

The internet is playing the major role in recruiting subjects. Prior to internet most subject were recruited for studies through their physicians or perhaps through mass media advertising. Although this form of recruitment has enjoyed a degree of success, it has limitations that can affect how quickly a site meets its recruitment targets. The US Food and Drug Modernization Act of 1997 required the Department of Health and Human Services to establish a registry of clinical trials for both the government and the private sector. As a result a new trial enrollment was launched and with the home page banner as “linking patients to medical research.” The site was launched in Feb 2000 and currently contains approximately 11300 clinical studies sponsored by the National Institutes of Health, other US government agencies, and the pharmaceutical industry in over 90 countries. The website provides basic information on clinical trials and information for people considering to participate in a trial.

SPEED, EFFICIENCY AND COST-EFFECTIVE

The advantages to using internet for recruitment are many. With the push of a button, a sponsor can potentially be in numerous homes or doctor's offices across the globe. There is nothing to print out and physically mail. In the world of clinical trials, time is of the essence. Every hour saved translates into the potential to complete the trial on time or ahead of schedule, thereby getting a product to market faster.

ACCESSIBLE, CONVENIENT TO COMMUNICATE 

       Website can be used as a powerful means of communication for trial personnel (investigators, monitors, sponsors and committee members). The clinical trial website can be used for the following tasks: providing information to study subjects, and investigators listing contact information; and globalization of data handling for patient registration, randomization and data collection.

INTERACTIVE CAPABILITIES

In this era of advanced communications technology, if people have questions they do not have to wait for a longer time for an answer. Clinical website enables to respond quickly to the subject queries. Thus this will speed up the process of recruitment. The faster the sponsor completes the recruitment process the sooner trial can move forward. In addition, faster recruitment process will save money in the long run and minimize the time to market.

CONFIDENTIALITY CONCERNS

Security is a central issue when considering the Internet for sensitive information exchange. Although internet provides many options and opportunities to sponsor are in recruitment process, there are also challenges to be aware. As more and more information is exchanged through the website, there is a risk of hacking the confidentiality of the subjects. However the risk of people hacking into the website can be reduced by applying 21 CFR part11 compliance, encryption is also available for email communications and a well-defined quality assurance process to maintain the integrity and confidentiality.

ETHICAL AND REGULATORY CONSIDERATIONS

Regardless of different strategies used in the subject recruitment process, ethical and legal issues must be considered. Each clinical study has its own unique inclusion and exclusion criteria. Ethical committees and regulatory bodies will ensure that safety is of the highest priority.

CONCLUSION

        As competition for clinical trial subjects continues to intensify, sponsors and investigators need to broaden their strategies for recruitment and retention. Internet can be used in each and every step of the clinical trial including protocol development, identification of funding opportunities, recruitment, registration, randomization, data collection, analysis, publication and communications. Internet can enhance the clinical studies in such a way that multi-centered trials are more manageable, less expensive, easier to administer, and less time-consuming. The major pitfall of online trials is the security and integrity of the documents that are collected and transmitted electronically. Hence in future we can look forward to internet technologies that enhance the security to the electronic data. 

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Written by
Vanitha Paloju
vanitha.archana@clinzen.com

PHASE 0

Introduction

Currently, Preclinical trials using animal models, cell culture methods and bioinformatics methods takes up to 18 months and the typical development for investigation of new drugs takes between ten to fifteen years and associated with high cost and low rate of approval, which explains us that magnitude of resources being wasted on investigating Non-promising molecules. This clearly indicates that some grievances exist in the traditional drug development model.

Identifying the compelling need for re-evaluation of and an innovative paradigm shift in the traditional drug development model, FDA, as part of its critical path initiative, established task Force on Methodology for the Development of Innovative Cancer Therapies (MDICT) comprised of experts from National Cancer Institute (NCI), academia, industry, and FDA and held multiple discussions with pharmaceutical industry.  In January 2006, as an outcome, FDA issued guidance on Exploratory IND studies.

Micro dosing (or micro-dosing)

It is a technique for studying the behavior of drugs in humans through the administration of doses so low they are unlikely to produce whole body effects, but high enough to allow the cellular response to be studied. This helps to know the pharmacokinetics of the drug with almost no risk of side effects.  This is called a Phase 0 study and is usually conducted before clinical Phase I to predict whether a drug is viable for the next phase of testing. Human micro dosing aims to reduce the resources spent on non-viable drugs and the amount of testing done on animals. 

Phase 0 clinical trials

Exploratory IND studies, often called as Phase 0  clinical trials, are conducted prior to traditional phase I dose escalation, safety and tolerability studies with very limited human exposure(<30 patients) and have no therapeutic or diagnostic potential. These studies assess feasibility for further clinical development of a drug or biological product regulated by Center for Drug Evaluation and Research (CDER). Bridging the gap between traditional preclinical studies and clinical development, Phase 0 trials provide an opportunity to assess pharmacokinetics (PK) and pharmacodynamics (PD) of new molecules early in humans with reduced preclinical testing.

Designing Phase 0 trials:

By design, Phase 0 trials portend lower risks to human subject than traditional phase I trials. As such, fewer preclinical supporting data are required prior to conducting a Phase 0 trial. The initial agent dose depends in part on the stated trial objectives, but should not be greater than 1/50th of the no-observed-adverse-effect level (NOAEL) estimated from animal toxicology testing. Validated pharmacodynamics assays, ideally with low variability in the molecular target, are suitable for application to Phase 0 trials if the investigational agent can reasonably be expected to demonstrate target modulation at a non-toxic dose. Standard operating procedures should be defined in advance and revised as necessary based on results of the Phase 0 trial.

The biggest difference between Phase 0 and the later phases of clinical trials is that there’s no chance the volunteer will be helped by taking part in a Phase 0 trial.
Because drug doses are low, there’s also less risk to the patient in Phase 0 studies compared to phase I studies. Phase 0 studies help researchers find out whether the drugs do what they are expected to do. If there are problems with the way the drug is absorbed or acts in the body, this should become clear very quickly in a Phase 0 clinical trial. This process may help avoid the delay and expense of finding out years later in phase II or even phase III clinical trials that the drug does not act as it was expected to basing on lab studies.

Ethics of Phase 0 trials

Proponents argue that Phase 0 clinical trials have the potential to expedite the development of new oncology drugs while exposing fewer research subjects to the risks of experimental treatments. At the same time, Phase 0 oncology trials raise important ethical concerns that have received little attention.  In particular, there is a question of whether it is ethical to enroll individuals in research that offers them no potential for clinical benefit. Further concern focuses on the inclusion of terminally ill and consequently vulnerable cancer patients in these trials. There is a need to evaluate the concerns of Phase 0 clinical trial.

Merits/Advantages of Phase 0 trials

• Due to their design, Phase 0 trials can be conducted in less time with fewer patients than Phase I trials.
• By conducting a Phase 0 trial on a particular drug, the process for Phase I and II trials on that drug is accelerated.
• Phase 0 trials could facilitate rational drug selection, identify therapeutic failures early, and compress timelines for anticancer drug development.
• Phase 0 trials provide initial rationale and guiding principles for further drug development based on studies in humans.
• Phase 0 trials help to evaluate the effects of the drug at the molecular level and   identifies the lead agent from the group of compounds in order to optimize the starting dose of subsequent phases of the trial

Demerits of Phase 0 trials

• Sometimes the results obtained from Phase 0 trials are not relevant to the results of later phases.
• Since micro dose evaluation is conducted in Phase 0 trials researches have to depend on BA (Bioavailability)/BE (Bioequivalence) labs as parameters are limited and expensive.

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Written by
Harisha Kothapalli
harisha.kothapalli@clinzen.com