Drug Trials

Function

Drug development refers to the process of introducing a new pharmaceutical agent to the market following the discovery, synthesis, or modification of a compound. It includes pre-clinical research as well as drug trials involving human subjects.

Pre-clinical investigations are non-human studies that involve testing the drug in microorganisms and animal subjects to generate data on its toxicity, pharmacokinetics, and pharmacodynamics. If further studies will take place in human subjects in the United States, this data requires submission to the U.S. Food and Drug Administration (FDA) for approval of an investigational new drug (IND) application. Other countries typically have a similar approval process. Once the IND application gets approved, the investigational drug undergoes various phases of human drug trials. If the drug tests as safe and efficacious during phases I to III of the drug trials, the drug sponsor can submit a New Drug Application (NDA) to the FDA. The national drug regulatory authority then reviews the application to determine whether the drug can receive final approval for marketing.[3]

Drug trials in human subjects are generally subdivided into five phases, with each phase comprised of at least one distinct clinical trial. The drug is usually approved for use in the general population by the national regulatory authority if it successfully passes through drug trial phases I, II, and III. The entire drug development process usually takes several years to proceed through all the phases.

Phase 0 trials are optional, exploratory, first-in-human trials that are designed to determine whether the drug affects human subjects as expected from earlier pre-clinical investigations. These trials involve the administration of low, nontherapeutic doses of the study drug to a small number of participants (typically 10 to 15) and help gather preliminary data on the pharmacokinetics and pharmacodynamics of the drug in human subjects.[4][5]

Phase I drug trials screen the investigational drug for safety. These trials help determine a safe dose range and identify any side effects associated with the new drug. Drug testing occurs over a few weeks or a month in a small group of healthy volunteers (usually 20 to 80).[6]

In phase II clinical trials, the experimental drug testing takes place within a larger group of participants (typically 100 to 300) to determine its efficacy and to further evaluate its safety. Phase II trials usually last for months and involve participants with the target disease or condition.[7]

Once preliminary evidence from phase II trials establishes the efficacy of the drug, phase III trials are conducted to obtain final confirmation of its safety and effectiveness. This phase involves a complete examination of the risk/benefit profile of the drug, usually comparing it to commonly used treatments in a broader population (typically 1000 to 3000 subjects) over a longer period (often six months).[8]

Phase IV drug trials take place following the approval of the drug to be sold in the market and provide additional evidence regarding the risks, benefits, and optimal use of the drug. Of the phase IV studies, those non-interventional studies that are mandated by the regulatory authority to verify the tolerability, safety, and effectiveness of a marketed drug in the real-world setting are termed post-marketing surveillance (PMS) studies. Post-marketing safety surveillance helps detect any long-term or rare adverse effects over a longer period of time and in a much larger patient population than is possible in any of the other phases of drug trials. In addition to safety monitoring, post-marketing surveillance studies also help in the planned collection of clinical data related to the use of a drug in a varied spectrum of patients, thus, yielding data that researchers may not have gathered during phase III studies.[9]

Investigator-initiated or academic clinical trials are clinical studies initiated and conducted by a non-pharmaceutical company researcher, who could be an individual investigator, a collaborative study group, or an institution. The key premise in this type of clinical trial is that the responsibility of being the sponsor as well as the investigator may lie with the person who designs and conducts the study, though sponsors sometimes fund these trials, especially if they think it may lend support for a new indication. Investigator-initiated trials help generate data on the safety and effectiveness of a drug in the real-world setting. They are largely driven by questions that remain unanswered from phases I to III of drug trials.[10][11]

Issues of Concern

Participation in a drug trial carries an increased level of risk as compared to ordinary medical care, especially due to the potential of being exposed to the unexpected effects of a new drug. Drug trials also encompass several ethical dilemmas. These dilemmas generally stem from the fact that those who bear the burden and risk of participation in the trials are not the same as those who stand to gain from them.

Current research ethics place significant weight on the informed consent process. However, the notion of informed consent is sometimes questionable due to the difficulty in determining the adequate level of information that should be provided to the participant for the consent to be valid, especially in a new compound that has not been tested before and which may be associated with unknown risks. Either too little information is given, or in some cases, too much information is provided in a language that is too technical for the participant to comprehend.[12][13]

Placebos are commonly used in drug trials. An issue of concern associated with using a placebo is the possibility of harming the participating subjects, who, instead of receiving active treatment, are receiving a placebo. If the participant is not receiving active treatment, this may expose the subjects to an aggravation of their conditions, increased levels of pain, or even the risk of death. Therefore, the use of placebos is acceptable only if it does not subject the participant to any risk of serious or irreversible harm.[14][15]

Randomization is an essential component used to reduce bias in clinical trials. However, randomization between the two arms of a drug trial may raise serious ethical concerns. By participating in a randomized controlled trial, the participants may receive a treatment that eventually turns inferior. This is particularly problematic if the experimental drug is found to be worse than the standard treatment available outside of the trial or the participant is assigned to a placebo. Participants may thus be denied the best-proven standard of care available.[16]

Publication bias occurs when only clinically or statistically significant results of drug trials are published. Unfavorable results are often not publicized or published, thus generating a false impression of the effectiveness of a medication. For instance, a pharmaceutical company sponsoring a drug trial typically has the right to review the research results prior to publication and may withhold the publication of unfavorable results. Thus, the research findings remain unavailable to the scientific community and make it difficult for healthcare providers to ascertain if a particular drug is appropriate for their patients or not.[17][18]

Sponsorship bias or funding bias is another issue of concern that may arise during drug trials. Funding for a trial is often provided by a pharmaceutical company that has manufactured or sponsored the drug. This produces a conflict of interest, as the company is inherently biased towards favorable research outcomes and would help enhance the sale of its product.[19][20][21]

Clinical Significance

Pre-clinical investigations answer basic questions regarding a drug's safety; however, they are not a substitute for studies that evaluate the effects of a drug on the human body.[22] Well-conducted clinical drug trials are widely accepted as the principal source of evidence on the safety and effectiveness of medical interventions.

The drug development process' ultimate goal is to introduce a new or significantly improved/altered compound, with proven therapeutic effect, to the market. Hence, the transition from pre-clinical research to clinical phases marks a critical juncture, as many potential medications do not progress beyond this point. Trials of first-in-class drugs are also helpful in providing the most rigorous testing of causal mechanisms in human disease.[2] Post-marketing surveillance helps monitor a drug once it reaches the market and is used by individuals under different circumstances and in real-life situations instead of carefully controlled laboratory conditions, typical of pre-approval drug trials. This ongoing work aids in detecting previously unrecognized positive or negative effects of the drug.[23]

Enhancing Healthcare Team Outcomes

Drug trials provide the best evidence of the efficacy and safety of a drug in human subjects. However, this is only true if the trial activity is transparent, discoverable, and high quality. The responsibility for the transparency of a drug trial and the safety of the research participants rests with the sponsor, the local site investigators, the various Institutional Review Boards (IRBs) that supervise the trial, and the national drug regulatory agency. All stakeholders need to understand the various ethical and moral issues commonly encountered in clinical trials and carry out their responsibilities in conducting high-quality research to produce the best and most accurate information possible to inform clinical decisions and practice. It is also of great significance that all parties fully understand the results of drug trials so that findings are applicable in clinical practice in an appropriate, relevant, and ethical manner.[24][25]

All interprofessional healthcare team members bear a responsibility to remain current on clinical trials, so they can use the latest data-driven models to direct patient care and question practices that are not supported by the latest research. This responsibility will, of necessity, be specialty-driven, so the focus on trials will be on studies that pertain to the discipline of the provider; physicians will exhibit a great interest and need for knowledge on trials that deal with their specialty area. Likewise, pharmacists will be more inclined to look into drug trials that line up with their specialties if they have them. Nurses (again, especially within specialty certifications), PTs, even chiropractors, and other ancillary medical providers should be aware of the latest pertinent research and be willing to share this knowledge with other healthcare team members where needed and/or appropriate. Only through open collaboration and communication can everyone on the interprofessional team drive patient outcomes optimally. [Level 5]