Mitigating Risk of Investigational New Drug (IND) Development: From Concept To Practice

Several studies have shown that the drug development is very expensive and prices have risen sharply in recent years. There are many reasons for the cost of drug development, but the most important one is time and risk. As a result, the development phase over the past two decades has not contributed directly to the rapid development of drug research. However, as clinical studies become larger & more multifaceted, and the development process is faster than inflation, the “time costs” related with investing in drug production increases rapidly to the point of continuity. Even then drug development timeframe remains identical. In fact, there is evidence that the process of clinical trials has been complicated and intricate over the years. The context coincides with the context that threatens drug development. By increasing the risk, we mean the possibility of discontinuing treatment due to drug efficacy, safety or business problems. Drug failure are a major contributor to research and development costs, whether prices go up or not. Hence, the fact that pharmaceutical companies have successfully developed research methods to promote research by regulators is an important pointer of the efficiency of drug development process. Working with new technology to improve the likelihood of a new compounds can increase the output of new drug invention.

Zero Phase Clinical Studies are useful in Sponsor, volunteers, and the general public. Based on Phase 0 clinical trials, eliminating investigational drug candidate prior to the First phase increases the likelihood of using the diagnostic drug in the marketplace and decreases the time, cost, and availability of patients.

In the near future, the Zero Phase will be a huge benefit. It is also known as the exploratory Investigational New Drug (IND) or ” micro dosing method “. The purpose of IND study is to explain clinical studies:

• Conducted before first phase.
• Conducted on limited Subjects
• Has no therapeutic or diagnostic intent (e.g., screening studies, micro-dose studies).

This exploratory IND study is typically conducted prior to the traditional dose escalation, safety, and tolerance studies in patient.  The length of dosing is only seven days in an exploratory IND study. Early phase 1 clinical trials of IND & biological products are used to assess efficiency for further development of the medicinal product. The main purposes of zero phase is to assess the potential biomarker/target development of pharmaceutical or biological products and validate it in preclinical models. The clinical data obtained from zero phase is not only useful for prioritizing the promising compounds, but also helps modification of phase 1 study design before starting. Zero phase provide us essential human pharmacokinetics (PK) and pharmacodynamics (PD) data in the initial phase of drug production. With the help of zero phase clinical studies, only most promising compounds move to subsequent studies, where sponsor can reduce the extra cost, time and subjects.

Obsolete first phase approach

Stereotypically, amid pharmaceutical development, huge numbers of biomolecules are produced with the purpose of classifying the most promising candidates drug for further clinical development. These biomolecules are mostly structurally linked, but can diverge in imperative ways. Promising drug candidates are frequently selected by means of in vitro testing models that inspect binding to receptors, effects on enzyme activities, toxic effects, or other in vitro pharmacological limitations.

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These tests often require the most basic amount of drug. The candidate drugs that are not rejected amid these initial tests are equipped in greater sizes for in vivo preclinical testing for efficacy & safety. Usually, a single drug candidate is designated for an IND application & infused into human subjects, mostly healthy volunteers. If first phase shows good result then drug goes towards second phase & then third phase but if drug get rejected then over again take its analogue or other drug candidate & again repeat this procedure. Upto 250 drug candidates enter in preclinical study from that only 1-2 drug molecules get into market. Upto 74% fail in phase 1, 20% in phase 2 and 6% in phase 3. This percentage are on the source of those drugs which get passed from Preclinical models and are investigated in the clinical trials.

Need of phase ‘Zero’ clinical trials:

• To obtain information on pharmacokinetics (PK) and pharmacodynamics (PD) at the beginning of first phase, this can be helpful for further evaluation of drug candidate.
• Considering potential drug candidates for further study may shorten the duration.
• By investigating only the most promising drug candidate in subsequent studies, the cost of the new drug development process will be reduced.
• Effective drug Remain in the market as unwanted compounds are eliminated in zero phase clinical trial.

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Eligibility Criteria for Conducting zero phase trials:

• Before first phase study,
• Before Filling the exploratory IND application,
• Participating Volunteers are healthy subjects,
• Only 15 volunteers are recruited,
• Duration is for 7 days,
• Dosing 1/100^thor 100 µg or 30 nanomole,
• Only one dosing cycle for clinical study,
• In anti-cancer IND pre and post tumour biopsies done if required.

The purpose of the Zero Phase clinical study:

• Redefine the Mode of Action (MOA) in non-clinical models achieved in human,
• Determine of biomarker assay using human tumor tissue,
• Evaluate PK and PD of drug and its analogue for selecting most promising candidate,
• Provide PK and PD data for further study i.e. phase 1 and further.
• Evaluate PK and PD and their analogues to select the most effective drug candidate.

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Benefits:

• Reduced time by supporting the pre-test of pharmacological action of new drug candidate.
• Assistance in the selection of target compounds that promise further extensive clinical study prior to the regular first phase study.
• Help speed up the general drug development process by focusing only on the promising compounds.
• Avoid unnecessary exposure to healthy subjects.
• Pose a lower risk of human toxicity by testing at lower drug dose and shorter exposure times.
• Pre-clinical studies are safer than phase 1 clinical trials.
• Less quantity of animals is used.
• Reduce the drug development time.
• Most effective drug gets to market faster.
• A partial dose of drug candidate is needed.

Disadvantages:

• There is shortage of any therapeutic as well as diagnostic intention.
• It can be difficult to motivate volunteers to participate in an experiment as there is no therapeutic purpose.
• Participating in Phase 0 trials can reduce the overall burden of patient taking part in the more common first Phase trials having therapeutic intention.
• Very few validated biomarkers are available for evaluating cancer activity.
• Requirement of ultra-sensitive and high-performance devices like AMS and PET that are scarcely available.

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Closing Remarks

The FDA has taken several steps to reduce the time, cost, and other factors associated with developing a primary drug for a similar product that has the potential to be successful in the future. FDA has issued detail guidance ” Exploratory IND Studies” are research programs in the United States that meet current regulatory requirements, allowing sponsors to advance more proficiently for successful drug development of initial promising future drug candidate with needed human subject protections. The “zero phase” or exploratory IND clinical studies can be shorter and less expensive than conventional IND studies. This is due to the approaches described in this guide, which takes into account the potential of candidate drug at lower risk than traditional clinical trials. In the future, such micro-dosing studies will be important for the first time for the development of drugs in human experiments. Medically speaking, it is ethical to expose human subjects with small doses, which do not appear to be necessary for most drugs and PK / PD products that prevent side effects. The micro-dose approach used in IND studies makes a positive contribution to drug development by providing access to basic human information. As a result, the choice of drugs will be more accurate from a human point of view.