Phase I Studies: From First Drug Design To First-In-Human Studies

Patricia de Cock, MD, Head of Investigators; Annick van Riel, Director CPU ; SGS Clinical Pharmacology Unit, Antwerp

The start-up and conduction of a phase I study is a process which needs much planning, and numerous aspects and parameters need to be taken into consideration. These include, but are not limited to, the investigational medical product (IMP) dose to be delivered, how many volunteers are needed, and what kind of a study design will fit the objectives of the trial best. It is also necessary to assess the potential risks and how these may be prevented, as well as challenges in monitoring specific parameters during the trial.

History in this field of human testing takes us back over two hundred years. In 1796, English physician Edward Jenner, tested his hypothesis that milkmaids were generally immune to smallpox because the pus present in the blisters they received from cowpox (which is much less virulent) protected them from smallpox. He did this by inoculating James Phipps, the eight-year-old son of his gardener, with pus scraped from blisters on the hands of a milkmaid who had contracted cowpox. This created an immunity to cowpox, which in turn, caused smallpox to create an immunity to itself. After this, he started to inoculate others, and in fact, Jenner performed his own basic phase I study. Nowadays, it would be necessary to provide an Informed Consent form, a study protocol and a safety plan; and there would be a requirement to monitor how the product was manufactured and provide an SOP on the administration of it. Additionally, every step would need to be documented, and a statistical analysis performed on every data point generated.

These steps are now necessary to adhere to good laboratory practice (GLP), good manufacturing practice (GMP), and to ensure the use of accurate and credible data and standards to guarantee patient safety. All these practices together guarantee that drugs are developed in accordance with good clinical practice (GCP), and are both effective and safe to use.

Although the primary objective has not changed greatly – the industry still aims to bring new and innovative treatments to the market, and to close the gap with existing medical needs. But the drug development environment has changed greatly in recent years and is now highly regulated. The bio/pharmaceutical market is both global and very competitive, and is based on a complex research and development process which is much improved in terms of its performance, and is wider reaching, safer and quicker to market. However, the motivations and business goals of companies developing drugs have not changed, and as a consequence, to continue to be successful, new ideas need to be developed and executed.

These challenges and goals make phase I clinical trials crucial to the drug development process. In phase I research humans are exposed to a new drug substance for the very first time. The trials are usually performed in healthy volunteers, or in patients who are not expected to benefit from the IMP. The studies are designed to provide the answers to some very important questions including:

• Is the IMP safe in humans?
• What does the body do to the IMP: what are the drug’s pharmacokinetics?
• What does the IMP to do the body: what are the drug’s pharmacodynamics?
• Will the IMP work in patients?

 

Thus, Phase I is often seen as the gateway between scientific research and clinical medicine, and the outcome of the trials have a major impact on the next steps of any prospective drug.

First-in-human (FIH) and subsequent trials: the trend towards the first ‘bundle’ of studies

The primary objectives of a phase I study are to provide information on the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of an IMP. Subsequently, further studies are designed to measure potential interaction effects of different substances on the metabolism of the new drug, and to evaluate the effect of food, gender and any genetic differences between study subjects. Studies are also undertaken to determine the relationship between the dose and the effect of the drug on certain parameters, as for example, specific biomarkers. If more information is needed on the exact distribution of the IMP throughout the body, the use of radiolabelled active ingredients is warranted. It is also important to investigate whether there are any unforeseen effects, such as cardiological effects. Sometimes investigation of the concentration of the IMP in specific organs is needed, such as the skin (by performing skin biopsies), cerebrospinal fluid (by lumbar puncture), the cervix (by cervical biopsy), the lungs (by broncheoalveolar lavage), and so on.

There is an increasing trend within research to include all of these sub-studies into the first clinical trial to generate the maximum amount of data, as early as possible.

Designing an effective clinical trial protocol

There are a number of actions that have to be completed when an initial idea for a new medicine is translated into an effective clinical trial protocol. A risk and safety assessment includes the evaluation of all aspects of the IMP that are captured in the Investigators Brochure. All preclinical information, including the drug’s mode of action, toxicity, potency etc. has to be evaluated, as well as the specific procedures that need to be performed, as well as the specific patient populations. It should also be recorded whether the IMP is a high-risk one and, rather obviously, whether it is small-molecule new chemical entity (NCE) or a biologic therapy. The application of proper risk management procedures allows the prediction and prevention of possible side effects and identifies whether there is a need for extra safety measurements, either through extra patient visits to the clinic, the use of more laboratories, or the employment of telemetry, spirometry or other analytical techniques. An often overlooked requirement is the need to identify an antidote to the drug to minimize any potential harm. A procedure needs to be in place to deal with serious adverse event (SAE) and medical emergencies, including 24/7 access to a physician.

Finding the correct drug dosage

The next stage to be implemented is to define the correct starting dose of the drug, first by becoming familiar with the ‘no observed adverse events’ level (NOAEL), and converting this to the human equivalent dose (HED). This is based on the selection of the HED of the most appropriate pre-clinical animal model, and applying a safety factor (at least 10-fold) to get the maximum recommended starting dose (MRSD), and adjusting the MRSD to the predicted IMP action.

Dose escalation requirements also have to be determined. Normally, a study would start with a single ascending dose design: different groups of subjects receive sub sequential higher doses but each subject will only get the drug once. Later on, this can be altered to a multiple ascending dose design, where one subject will receive a specific dose several times (for example each day for 7 consecutive days). In between dosing, safety meetings are arranged to ensure that it is safe to step up to the next (higher) dose. Finally, and crucially, the conditions under which the trial must be stopped need to be specified (the so-called ‘stopping rules’).

From study proposal to execution and data collection

Having completed the protocol, which describes in detail how the study needs to be performed, the next stage is its execution. This obviously requires the recruitment of volunteers in advance – and the selection of those that fit the selection criteria of the study - each of them must complete an Informed Consent Form before the IMP can be administered. Once all the steps of the study have been executed, and there are no unexpected findings, no serious adverse effects and no protocol amendments - the database can be closed and the data collected. The findings can then be submitted into the Clinical Study Report, and an abstract of the report written and circulated. The investigation is now ready to move on to the next phase.

This is all assuming that everything goes as planned. However, there are many unexpected findings or problems that may arise. What happens if there is an SAE, or if elevated laboratory tests or abnormal ECG findings are seen during the study? What if the principal investigator (PI) becomes unintentionally unblinded? Or PK data shows results that are not as predicted? It may also be that a genetic profile may appear to influence absorption, or that an allergic reaction may occur during the trial. There are a number of potential outcomes and by planning, it is hoped these are minimized, however staff conducting trials must be prepared to add extra examinations during the execution of the trial, or seek specialist advice if necessary. In phase I research, it is paramount to always be prepared to expect the unexpected, as this is the first time a product has been given to humans.

Case Study: If an SAE occurs...

In a study with a biological agent, the first phase of the study was a single ascending dose (SAD) and the second was a multiple ascending dose (MAD). In the first cohorts of the first phase there were no problems, but at the higher dose there were quite severe reactions (but no SAE), with elevated C-reactive protein (CRP) observed, as well as muscle pain/shivering. In the second phase of the study, the first cohort again showed no problems, but in the second cohort a SAE occurred. A volunteer presented in the middle of the night with a clinical image that was suspicious for a myocardial infarction. Due to the agitation of the volunteer it was not possible to conclude on the exact nature of the event in the unit and the volunteer was very anxious. After consulting the physician on call, an emergency was declared, and the emergency physician arrived in 3 minutes. The volunteer was hospitalized.  As a next cohort was scheduled to receive a higher dose the next day, it was decided to stop the study until it was clear what had happened. After investigation it was concluded that it was no infarction and that the event was unlikely to be related to the IMP. The study restarted with an amended study protocol (extra safety measurements were implemented) and no further problems occurred.

Case Study: If an unexpected finding occurs...

In a study with a NME, again the first phase of the study was a SAD design followed by a MAD one. For the first phase, the first two cohorts showed no problem, and at the safety meeting the PI gave the go-ahead for dose escalation. For the third cohort, again there were no problems but there was an unexpected PK finding: the drug had a longer-than-expected half-life, and produced a significant active metabolite that had a very long half-life. The second phase was then implemented but with other doses and other design/other dose escalation steps, extra follow-up visits were implemented so that all volunteers were monitored until all the IMP and its metabolites were not detectable in blood samples any more. Thus, the study was implemented with an amendment and no further problems occurred.

If the PI doesn’t seem to be blind anymore...

It is possible that when a study is performed, various PD findings will be seen in the lab results, such as the concentration of glucose in the blood caused by glycemic lowering agents, or the effect of anti-coagulants.

The PD of a drug may produce reactions in the trial that are very specific and are recognized by the PI, thus leading to the ‘unblinding’ of the PI. This raises questions on whether this then could impact the PI’s judgement and the integrity of the data.

There are a number of solutions to the problem: if the effects were predicted, an open label trial can be considered. If they were unpredicted, an extra physician can be employed to judge specific values, and an evaluation of adverse effects completed even before the laboratory results are available. The problem is inherent for Phase I first-in human research, in-vitro testing does not give the same information as in-vivo testing, which in turn, does not give the same information as first-in-human studies.

Conclusions

Phase I studies provide the bridge to bring scientific data into clinical practice. Such studies are, in most cases, the first trials of a drug to be conducted in humans, and therefore it is important to expect the unexpected and plan as much as possible to be prepared for unforeseen events. Good execution of a Phase I study requires a strong partnership between the sponsor and CRO and a dedicated PI with supporting study staff. The solution to unexpected problems lies in a continuous dialog and thorough investigation.

 

Sources

•  ICH-GCP guidelines
• www.fda.gov:  The drug development process
• From Idea to Market: The Drug Approval Process Martin S. Lipsky, MD, Lisa K. Sharp, PhD, Department of Family Medicine, Northwestern University Medical School, Chicago; J Am Board Fam Med. 2001;14(5)