Human Preclinical Studies and Phase 0 Clinical Trials

The drug development process includes various steps from discovery (discovery of a new compound or biological product) to preclinical research (measuring the safety, toxicity, and efficacy in animal models), and then to clinical trials (testing the safety and efficacy in humans - either healthy volunteers or patients). The clinical trials are phased from phase 1 & 2 (early phase trials) to phase 3 (pivotal, confirmatory, late-phase trials), and to phase 4 (post-marketing clinical trials). A diagram indicates various stages of drug development. With innovative clinical trial designs, the clinical trial phases are blurred, for example, seamless phase 1/2 trial and seamless 2/3 trial. In rare disease areas, the drug development process may not have all phases of clinical trials. The adequate and well-controlled study may be phase 3, phase 2, or phase 1 (for example, expansion cohort studies).

Preclinical development, also called preclinical study or nonclinical study, is a stage of research that begins before clinical trials (testing in humans) and during which important feasibility, iterative testing and drug safety data are collected, typically in laboratory animals. Traditionally, the phase 1 study may be the first-in-human trials with the purpose of studying the drug's:

• pharmacokinetics (ADME: absorption, distribution, metabolism, and excretion) and pharmacodynamics (enzyme, protein,...) 
• toxicity, safety and side effects associated with increasing doses
• maximum tolerable dose
• early evidence of effectiveness

There are now two new steps that may be utilized in drug development: Preclinical human studies and phase 0 clinical trials. A revised drug development diagram is as follows: 

Human pre-clinical studies are those pre-clinical studies utilizing the human subjects (either utilizing the specimens collected from human subjects or performing testing in human decedents). Human pre-clinical studies are 'pre-clinical' because they are not conducted under IND (investigational new drug) and they are conducted for collecting the data to support the IND-enabling studies. 

In a paper by Abdallah et al, "A novel prostate cancer immunotherapy using prostate-specific antigen peptides and Candida skin test reagent as an adjuvant", they described a human pre-clinical study where peptides based on the prostate-specific antigen amino acid sequences were evaluated in terms of their recognition by peripheral immune cells from prostate cancer patients using interferon-γ enzyme-linked immunospot assay. A sample size of 10 patients with prostate cancer was selected for the study. The authors concluded: 

"We described a human preclinical study of a novel prostate cancer immunotherapy consisting of PSA peptides and Candida skin test reagent as an adjuvant. As solubility and formulation have been developed, it would be feasible to further evaluate the utility of this new therapy particularly when a proportion of prostate cancer patients seem to have immune cells with the ability to recognize these PSA peptides already. Therefore, whether this immunotherapy may enhance immune responses to PSA leading to tumor regression should be examined."

Dr. Locke's team in UAB recently conducted pioneer xenotransplantation of a gene-modified pig kidney. The study was described in the paper by Porrett et al "First clinical-grade porcine kidney xenotransplant using a human decedent model". The pig kidney was transplanted to a human decedent (brain dead patient). The purposes of this human preclinical study were stated as the following:

"Xenotransplantation is arguably the most pragmatic solution to the organ shortage crisis, but safety and efficacy concerns have limited advancement into humans. In preparation for a phase I clinical trial of porcine renal xenotransplantation at the University of Alabama at Birmingham, we asked what gaps in knowledge must be filled before such a clinical trial could be ethically offered to research subjects. We thus aimed to develop a human preclinical model which would permit the in vivo evaluation of critical safety and feasibility tenets of the pig-to-NHP model without risk to a living human. Our study was designed to test five central questions: (1) Is the current suite of porcine genetic modifications sufficient to avoid hyperacute rejection in humans? (2) Would prospective flow-based crossmatching correlate with graft survival free of hyperacute rejection? (3) Would life-threatening intraoperative complications occur during a renal porcine xenotransplant? (4) Would porcine cells and/or pathogens be detected in the blood of a human recipient? (5) Could porcine renal xenotransplantation be safely performed under the conditions necessary for a clinical trial? To this end, we designed and performed this experiment under clinical-grade conditions which included the transplantation of 10-GE porcine kidneys designed specifically for human transplantation into the conventional anatomic position using processes and facilities in compliance with multiple regulatory agencies."

In human preclinical studies, while human subjects are involved, there is no IND needed. Consents by the patients (in the first example) or by the relatives (in the second example) are needed. 

Phase 0 Clinical Trial: the concept of phase 0 clinical trial came from the FDA's guidance for industry "Exploratory IND Studies". The term 'phase 0 clinical trial' was not used in the guidance, but was used for exploratory IND studies. Phase 0 clinical trial may now be called 'early phase 1' clinical trial, for example, in NIH.gov website and in clinicaltrials.gov:

According to the FDA guidance "Exploratory IND Studies", the exploratory IND studies (therefore phase 0 clinical trials or early phase 1 clinical trials) are defined as the following:

"Exploratory IND studies usually involve very limited human exposure and have no therapeutic or diagnostic intent. Such studies can serve a number of useful goals. For example, an exploratory IND study can help sponsors

• Determine whether a mechanism of action defined in experimental systems can also be observed in humans (e.g., a binding property or inhibition of an enzyme)
• Provide important information on pharmacokinetics (PK)
• Select the most promising lead product from a group of candidates5 designed to interact with a particular therapeutic target in humans, based on PK or pharmacodynamic (PD) properties
• Explore a product’s biodistribution characteristics using various imaging technologies

 Whatever the goal of the study, exploratory IND studies can help identify, early in the process, promising candidates for continued development and eliminate those lacking promise. As a result, exploratory IND studies may help reduce the number of human subjects and resources, including the amount of candidate product, needed to identify promising drugs. The studies discussed in this guidance involve dosing a limited number of subjects with a limited range of doses for a limited period of time.

Existing regulations provide more flexibility with regard to the preclinical testing requirements for exploratory IND studies than for traditional IND studies. However, sponsors submitting the kinds of studies described in this guidance have not always taken full advantage of that flexibility. Sponsors often provide more supporting information in their INDs than is required by the regulations. Because exploratory IND studies involve administering either subpharmacologic doses of a product, or doses expected to produce a pharmacologic, but not a toxic, effect, the potential risk to human subjects is less than for a traditional phase 1 study that, for example, seeks to establish a maximally tolerated dose. Because exploratory IND studies present fewer potential risks than do traditional phase 1 studies that look for dose-limiting toxicities, such limited exploratory IND investigations in humans can be initiated with less, or different, preclinical support than is required for traditional IND studies.  "

In cancer.org website,"Types and Phases of Clinical Trials", Phase 0 clinical trials were specifically mentioned: 

Phase 0 clinical trials: Exploring if and how a new drug may work

Even though phase 0 studies are done in humans, this type of study isn’t like the other phases of clinical trials. The purpose of this phase is to help speed up and streamline the drug approval process. Phase 0 studies may help researchers find out if the drugs do what they’re expected to do. This may help save time and money that would have been spent on later phase trials.

Phase 0 studies use only a few small doses of a new drug in a few people. They might test whether the drug reaches the tumor, how the drug acts in the human body, and how cancer cells in the human body respond to the drug. People in these studies might need extra tests such as biopsies, scans, and blood samples as part of the process.

Unlike other phases of clinical trials, there’s almost no chance the people in phase 0 trials will benefit. The benefit will be for other people in the future. And because drug doses are low, there’s also less risk to those in the trial.

Phase 0 studies aren’t widely used, and there are some drugs for which they wouldn’t be helpful. Phase 0 studies are very small, often with fewer than 15 people, and the drug is given only for a short time. They’re not a required part of testing a new drug.

Phase 0 clinical trials are mainly conducted in the oncology area and there are quite some phase 0 (or early phase 1) studies are listed in clinicaltrials.gov. An example of a phase 0 study was published in JCO (Kummar et al 2009 "Phase 0 Clinical Trial of the Poly (ADP-Ribose) Polymerase Inhibitor ABT-888 in Patients With Advanced Malignancies").

FDA's Priority Review Voucher for COVID-19 Vaccine

 To spur drug development in the under-developed area, FDA relies on various policies and programs to incentify the biotech and pharmaceutical companies. The most famous one is the orphan drug development. In the last 10 years or so, a program called 'priority review voucher' become popular. If the biotech and pharmaceutical companies develop a drug in certain underdeveloped areas, once the drug is approved (not emergency user authorization), FDA will issue the marketing authorization holder a priority review voucher. The priority review voucher can be redeemed for future NDA/BLA applications to shorten the review time by four months. The priority review voucher can be a commodity to be sold or transferred to another company for monetary gain. 

• FDA's Priority Review Voucher Programs

• RAPS: Regulatory Explainer: Everything You Need to Know About FDA’s Priority Review Vouchers
• Endpoints: Priority review voucher updates: Who's won PRVs, who's bought them, and how much they're selling for

FDA currently has three priority review voucher programs and each has its own guidance to industries:

• Tropical Disease Priority Review Voucher Program and its guidance
• Rare Pediatric Disease Priority Review Vouchers
• Material Threat Medical Countermeasure Priority Review Vouchers 

To qualify for a PRV for tropical disease, a sponsor’s application must be for a drug or biological product for the prevention or treatment of a “tropical disease,” where a list of tropical diseases are listed by FDA and additional tropical diseases may be added by FDA. For example, Ebola was not in the original list but was added in 2019.

To qualify for a PRV for rare pediatric disease, a sponsor's application must be for a drug or biological product for the prevention or treatment of a "rare pediatric disease," where the rare pediatric disease is defined as:

The 21st Century CuresAct (Cures Act) Section 565A of the FD&C Act was designed to encourage development of new drug and biological medical countermeasures (MCMs), by offering additional incentives for obtaining FDA approval of certain MCMs. While there are existing incentive programs to encourage the development and study of drugs and biologics that may also be applicable to MCMs, section 565A of the FD&C Act provides an incentive specifically for development of certain MCMs, which may be used alone or in some cases in combination with other incentive programs. Other FDA incentive programs include: orphan-drug designation and the associated benefits under the Orphan Drug Act for rare disease drugs; programs to encourage study of drugs used in pediatric populations; various programs to facilitate and expedite development and review of new drugs to address unmet medical needs in the treatment of serious or life-threatening conditions; and programs for certain tropical disease products and antibacterial products. 

Last week (Jan 31, 2022), Moderna obtained the final approval (not emergency user authorization) for its Covid-19. After the approval, a brand drug name or proprietary name - SPIKEVAX - is approved. In the approval letter, FDA granted Moderna a material threat medical countermeasure priority review voucher (PRV).

Endpoints had an article "Exclusive: The curious case of the BioNTech priority review voucher" indicating that for Pfizer/BioNTech's Covid-19 vaccine (brand name Comirnaty) approval, the priority review voucher was not included at the time of the BLA approval. After the approval, BioNTech (as the market authorization holder) received a MCM priority review voucher even though the company did not announce it publicly. 

A priority review voucher can be worth hundreds of millions if transferred. however, the monetary awards from the MCM priority review voucher are trivial compared to the sales of the Covid-19 vaccines - PRV is just a nice-to-have incentive.  

Randomization, Re-Randomization, and Micro-Randomization

 I recently saw a Twitter post mentioning "Micro-Randomized Study Design Example - Maryland Alcohol-Dependent Moms Abstinence (MAMA) Study" and found the term 'micro-randomization' interesting and prompted me to compare the concept of randomization, re-randomization, and micro-randomization. Based on the number of times that a subject can be randomized in a study, we can differentiate the studies as randomized, re-randomized, and micro-randomized trials. 

Randomization is the process of assigning subjects (patients, clinical trial participants) by chance to groups that receive different treatments. In the simplest trial design (parallel-group design), the investigational group receives the new treatment and the control group receives standard therapy. At several points during and at the end of the clinical trial, researchers compare the groups to see which treatment is more effective or has fewer side effects. Randomization helps prevent bias. Bias occurs when a trial's results are affected by human choices or other factors not related to the treatment being tested.

ICH Topic E 9Statistical Principles for Clinical Trials has an entire section discussing randomization as the key design technique to avoid biases:

"2.3.2 Randomisation

Randomisation introduces a deliberate element of chance into the assignment of treatments to subjects in a clinical trial. During subsequent analysis of the trial data, it provides a sound statistical basis for the quantitative evaluation of the evidence relating to treatment effects. It also tends to produce treatment groups in which the distributions of prognostic factors, known and unknown, are similar. In combination with blinding, randomisation helps to avoid possible bias in the selection and allocation of subjects arising from the predictability of treatment assignments.

The randomisation schedule of a clinical trial documents the random allocation of treatments to subjects. In the simplest situation it is a sequential list of treatments (or treatment sequences in a crossover trial) or corresponding codes by subject number. The logistics of some trials, such as those with a screening phase, may make matters more complicated, but the unique pre-planned assignment of treatment, or treatment sequence, to subject should be clear. Different trial designs will require different procedures for generating randomisation schedules. The randomisation schedule should be reproducible (if the need arises).  

......"

In typical clinical trials, the study participants will be randomized only one time whether to different treatments or different treatment sequences. For clinical trials with parallel-group design, subjects are randomized to receive one of two or more treatments. For clinical trials with cross-over design, subjects are randomized to follow one of two or more treatment sequences. Once the treatment sequence is determined, subjects will follow the sequence to receive multiple treatments (for example, treatment A then treatment B or treatment B than treatment A,...)

The vast majority of randomized clinical trials are falling into this category and this includes:

• randomized double-blind trials: randomization + blinding 
• randomized open-label trials: randomization without blinding
• randomized cross-over trials: randomization to the sequence of treatments
• adaptive randomized trials: adjust the randomization ratio
• "N of 1" clinical trials: can be considered as a high order crossover, once the sequence is decided, the treatments at various stages are decided

Re-randomization is the process describing a situation where each patient can be randomized more than one time in the same study.  There are two types of re-randomization:

re-randomization in SMART trial design framework - SMART stands for Sequential Multiple Assignment Randomized Trial. In a trial with SMART designs, the same subject may be randomized more than once depending on the response to the initial assigned treatment after the initial randomization. According to the paper by Kidwell et al "Sequential, Multiple Assignment, Randomized Trial Designs in Immuno-oncology Research", A SMART is a multistage, randomized trial in which each stage corresponds to an important treatment decision point. Participants are enrolled in a SMART and followed throughout the trial, but each participant may be randomized more than once. Subsequent randomizations allow for unbiased comparisons of post-initial randomization treatments and comparisons of treatment pathways. The goal of a SMART is to develop and find evidence of effective treatment pathways that mimic clinical practice.

In a review paper by Wallace at el "SMART Thinking: a Review of Recent Developments in Sequential Multiple Assignment Randomized Trials", the following general diagram was given for SMART design:

We saw that SMART design with re-randomization was used in clinical trials in different therapeutic areas:

In a paper by Almirall et al "Introduction to SMART designs for the development of adaptive interventions: with application to weight loss research", the following diagram was used to illustrate a SMART design for weight loss research. After the initial randomized treatment period, the responders and non-responders are identified. The non-responders were re-randomized to different treatments. 

Ruppert et al described a study with SMART design in CLL "Application of a sequential multiple assignment randomized trial (SMART) design in older patients with chronic lymphocytic leukemia" where patients with complete response after stage 1 were re-randomized to receive two different treatments at stage 2. 

We conducted an ICE study - a registration study with IGIV-C in CIDP (a rare neurology disease) "Intravenous immune globulin (10% caprylate chromatography purified) for the treatment of chronic inflammatory demyelinating polyradiculoneuropathy(ICE study): a randomised placebo-controlled trial". We did not explicitly state the SMART design but did employ the re-randomization in the study. The subjects who were responders (to the blinded treatment) were re-randomized to receive either IGIV-C or Placebo in additional six months follow-up period. The re-randomized portion of the study was to compare the relapse rate between two treatment groups - a key secondary efficacy endpoint. 

With the re-randomized portion of the study, we built in two randomizations in the same study and demonstrated the treatment effect of IGIV-C in the primary efficacy endpoint of improving the responder rate and also the treatment effect of IGIV-C in preventing the relapse in the additional follow-up period - essentially two studies in one. This was used as a rationale for a single pivotal trial (two studies in one) to provide substantial efficacy for effectiveness. 

Re-randomization is also discussed for use in different settings where the subjects who complete the initial randomized period are put back to the randomization pool. Subjects were re-randomized to the study as if they are new to the study. In other words, the same subject was re-used and re-randomized into the study. Kahan et al described this type of re-randomized trial as the following: 

This type of re-randomized design is very rarely used and may be used in clinical trials with ultra-rare diseases that patient recruitment is extremely challenging. 

A Micro-randomized trial (MRTs) can be considered as an extension of the SMART design. The same subject can be randomized and re-randomized many times to different interventions. The time scale is much more frequent and short (for example several times in a day). The term 'micro-' can be confusing, but it is used to differentiate this type of randomization from the classical setting where randomization can not be too frequently. The term 'micro-' is used to describe a setting where the randomization/re-randomization needs to be conducted more frequently on a much short time scale - almost continuous time points. A Micro-randomized trial is good for the interventions that are delivered through mobile devices (such as push notification) and is good for interventions that are intended for changing subjects' behaviors. 

Here is a website describing what the micro-randomized trial is:

In micro-randomized trials (MRTs), individuals are randomized hundreds or thousands of times over the course of the study. The goal of these trials is to optimize mobile health interventions by assessing the relative effect of different intervention options and assessing whether the intervention effects vary with time or the individual's current context. With MRTs we can gather data to construct optimized just-in-time adaptive interventions (JITAIs).

Intervention options can include either or both engagement strategies and therapeutic treatments. Consider the Heartsteps MRT (described below) that is designed to promote physical activity among sedentary people. Heartsteps includes phone notifications with tailored activity suggestions to encourage physical activity; these are therapeutic in focus. On the other hand the SARA MRT (also described below) is designed to promote engagement by young adults in substance abuse research. SARA includes rewards for participants who complete assessments; these are engagement strategies. The design of both of these projects can be seen in the “Projects Using MRTs” section, below.

In an MRT, each participant can be randomized many times. For example in the Heartsteps project, the researchers identified five times throughout the day when people are mostly likely to be available to take a brief walk. At each of the five time points, the application randomizes between delivering a phone notification containing a tailored activity suggesion or to not deliver anything; as a result over the course of the 42 days, each participant is randomized 210 times. This sequence of both within-participant and between-participant randomizations comprises the MRT.

The MRT data can then be used to assess the effectiveness of the tailored activity suggestions and to build rules for when to deliver the suggestions in order to help individuals be more active. To do this the application records a variety of outcomes. In this case, the app collects the minute-by-minute step count from the participant’s activity-tracking wristband throughout the day, the participant’s overall level of physical activity, and the participant’s context at each of the 5 times per day (using GPS to determine the person’s location and the local weather). The resulting data is used by researchers to assess the effectiveness of the activity suggestions and to build rules for when and where to deliver the suggestions. In other MRTs, the randomization could apply to what type of intervention to provide, rather than whether or not to provide an intervention. The ultimate goal of Heartsteps is the development of a JITAI that will successfully encourage higher levels of physical activity. The study design of the MRT used in Heartsteps is shown below.

MRTs are an emergent innovation in behavioral science.

We are in the digital era and digital tools will become more used in interventions (especially the adaptive intervention) for lifestyle and behavior changes. However, we don't think that the 'micro-randomized trials' will be suitable for drug trials for registration purposes. 

• On this date, there are 16 registries in clinicaltrials.gov using micro-randomized trials. Not surprisely, all micro-randomized trials are in the behavioral science field.  
• Xu et al "Multi-Level Micro-Randomized Trial: Detecting the Proximal Effect of Messages on physical activity"
• “Micro-randomized Trials in Mobile Health” with Zhenke Wu, PhD
• Dr. Susan Murphy: Micro-randomized Trials for JITAI Development