Clinical Researcher—April 2022 (Volume 36, Issue 2)

SITES & SPONSORS

Paul Kim, PhD, MBA

 

In 1747, Dr. James Lind, a Royal Navy surgeon aboard the HMS Salisbury, noted high mortality rates among sailors suffering from scurvy—a condition caused by severe vitamin C deficiency that is often affiliated with seafarers due to the absence of fresh fruit on long voyages. In his mission to cure them, he divided 12 patients into groups of two and ordered each group to incorporate cyder, elixir vitriol, vinegar, seawater, fruit, or an electuary into their diet. By the end of what some consider history’s first clinical trial, Dr. Lind identified oranges and lemons as the optimal remedy for this disease. This research would go on to support the evolution of naval treatment of vitamin deficiency and contributed to the future structure of controlled clinical trials.{1}

Since the famous scurvy trial, clinical research—particularly the use of randomized controlled clinical trials—has become a cornerstone for how modern medicine advances. Today, we use clinical trials to improve how we prevent, detect, diagnose, and treat diseases with various phases testing for safety and efficacy. From concept to commercialization, standard drug development programs typically take more than a decade to reach consumers. However, the COVID-19 pandemic and the phenomenal success of the COVID-19 vaccines has shown a spotlight on the critical need and potential for rapid innovation and accelerated clinical trial processes in infectious diseases.

In recent years, phage therapy, which gained popularity in the early 1900s before losing traction due to the development of cheap and widely accessible antibiotics, has reemerged as having the potential to be a powerful solution to combat bacterial infections. In particular, treatment of antibiotic resistant strains of pathogens like E. coli, S. aureus, K. pneumoniae, A. baumannii, and P. aeruginosa, which cause the largest numbers of global deaths, are poised to benefit from this innovative approach.{2} As multiple groups advance into the clinic to deliver phage therapies to patients and combat the emerging pandemic of antibiotic resistance, it is more important than ever to understand the intricacies of the clinical and regulatory pathways for these life-saving medicines.

Design and Conduct of Bacteriophage Clinical Trials

The overall structure and administration of bacteriophage clinical development programs are similar to other drug development programs within a given indication. However, bacteriophages have unique nuances which must be accounted for in preparing preclinical and clinical development plans.

Perhaps the most prominent distinction is their pharmacokinetic (PK) characteristics—or how a drug is absorbed and transported inside and outside the body. Bacteriophages replicate within target bacterial cells, so the effective dose at the site of infection may be many times greater than the input dose, unlike most other drugs in which drug concentrations go down over time. This also creates other challenges such as optimizing delivery, accounting for predator/prey dynamics (which impact sample timing and quantification), specimen acquisition and stability, methods of quantification, and PK modeling.

For example, the gold standard for bacteriophage quantification is the plaque titer assay. This method involves skilled technical support and sometimes multiday processing before results can be interpreted. Because bacteriophages must remain viable through the process, care and consistency must be applied from collection, through shipment and storage, to final assay conduct. Methods for maintaining phages in good condition is also impacted by specimen type, which varies by indication.

The bacteriophage’s predatory relationship with bacteria, as well as its inherent desire to maintain a homeostasis with bacteria, must also be considered within the clinical program as the location, quantity, and lifestyle of these bacteria can directly influence resulting phage quantification. Fully understanding these dynamics requires sophisticated sampling and modeling techniques, many of which must be developed alongside the study, given that most PK modeling and reporting groups are unfamiliar with bacteriophage biology. Due to these complexities, few commercially available reference laboratories are capable of reliably performing plaque titer assays.

Two other major distinctions to note are:

• The specificity of this type of targeted therapy, in terms of how it spares the rest of the microbiome and theoretically prevents comorbidities like difficile infection.
• The unique mechanism of action, which is why everyone is so interested in developing phage therapies because they have potential to address antimicrobial resistance.{2}

Because of these considerations, early-phase investigations of bacteriophage products require special care for development of analytical methods and trial logistics to enable effective interpretation of the results.

Challenges of Selecting Human Subjects for Bacteriophage Trials

Bacterial pathogens causing a patient’s infection are typically identified via culture and susceptibility testing at a local or central laboratory, which can take several days. As a result, conventional modern medical practices typically start by empirically treating patients with broad spectrum antibiotics while waiting for the culture to identify the pathogen—a practice that contributes to the emergence of multidrug resistant bacteria. For a precision therapeutic such as bacteriophage, which targets a particular bacterial species, this conventional dynamic creates a challenge for identification and enrollment of the patient population most likely to benefit from the experimental therapeutic.

The most straightforward approach to counter these challenges is use of a bedside or other rapid diagnostic. However, there are still relatively few rapid clinical diagnostics available and even fewer that provide truly “rapid” results (e.g., less than two hours) that could be used to identify and enroll a patient with an acute infection into a clinical trial.

The next best option is to rely on a patient’s clinical symptoms and medical history. In urinary tract infections, for example, more than 80% of all infections are caused by E. coli. Likewise, most recurrent patients return with urinary tract infections caused by the same bacteria as the prior infection, meaning that patients’ medical histories can be used as an enrichment strategy when creating study eligibility criteria. Therefore, strategically selecting indications driven by pathogens with high prevalence and targeting patients through their medical histories and eligibility criteria can reach the populations most likely to benefit from participating in precision medicine clinical trials such as those conducted with phage therapies.

In less well-understood diseases such as those with chronic inflammatory indications (e.g., Crohn’s disease or ulcerative colitis), where bacteria seem to play a role in the underlying disease pathology, understanding the perturbations in the patient’s microbiome may help to identify specific subsets of patients where modifying their microbiome in a targeted way may improve their clinical outcome. In these cases, basic bacterial identification techniques are not enough to determine if patients could benefit from precision therapies; rather, patient identification would require advanced culture techniques to isolate individual strains and genetic deep sequencing technologies to sort through complex microbiome data. This is necessary not only to evaluate the relative levels of different types of bacteria, but also what molecules these bacteria are ultimately expressing.

In both cases described above, identification of patients who may benefit from a clinical trial involving bacteriophages requires a deep understanding of the disease, identification of the clinical sites and physicians seemingly best suited to enroll and manage these patients, and sophisticated laboratory logistics and testing programs.

Site and Principal Investigator Selection for Phage Clinical Trials

Identification of study sites with teams experienced in the target indication or patient population is critical for success of any clinical trial. Bacteriophage therapeutics being a new modality, especially in the United States, requires good sites, sponsors, and contract research organization (CRO) engagement to plan and execute these types of trials effectively.

Additionally, clinical sample testing labs as well as clinical sites and their staff must be trained in the handling of specimens, given that both the therapeutic target (bacteria) and therapeutic agent (bacteriophages) are living systems. Extra care must be taken to prevent cross contamination of samples and knowledge of the storage conditions required across multiple sample and assay types must be added to the clinical protocol. Collectively, this requires advanced site training from sponsors and partner CROs on the nuances of patient management and sample handling procedures, cleaning protocols, and coordinated sample logistics to ensure that samples provide accurate and reliable results.

Clinical Data and Institutional Review Board (IRB) Reviews

In general, bacteriophage therapeutics are considered intrinsically safe. Bacteriophages are ubiquitous in the environment—meaning that humans are constantly exposed to bacteriophages without any ill effects. Additionally, though not broadly used in the U.S. and other parts of the world, bacteriophages as a therapeutic modality have been safely used in Central and Eastern Europe for more than 100 years. Highlighting these points to IRBs—especially in regions where bacteriophages are not commonly employed—is an important first step to ensuring that these groups have the necessary information to accurately review proposals for new clinical programs designed to test phage therapies.

Bacteriophage programs are reviewed by IRBs just like any other therapeutic, meaning that nonclinical in vitro and in vivo testing, as well as information related to the drug properties and any prior clinical data, must be provided and summarized. In addition, the IRBs review elements of the clinical trial, including the protocol, informed consent form, and risk/benefit profile, just like for any clinical program.

Important Regulatory Considerations

Currently, there are no bacteriophage-specific U.S. Food and Drug Administration (FDA) regulations or guidance documents. The field at large is rapidly developing and becoming more sophisticated as more potential bacteriophage products approach and enter the clinic.

In 2017, the FDA held the Bacteriophage Therapy: Scientific and Regulatory Issues Public Workshop.{3} This workshop clearly defined bacteriophage therapies as biological drugs for which all clinical research must be conducted under Investigational New Drug (IND) regulations. Hence, for phage therapeutic products to be licensed for use in the U.S., safety and efficacy in the target population must be demonstrated, as well as key attributes of the drug must be defined, such as purity, potency, and consistency of manufacture.

With any clinical development program, the clinical trials must demonstrate statistically significant efficacy within a specific patient population. In this way, the steps involved in clinical development, and the pathways to regulatory approval for bacteriophage therapy, share some similarities with those for any other therapeutic product. However, the intrinsic safety of phages, their unique mechanism of action, and their ability to be genetically enhanced have opened up a window of opportunity to address a variety of infectious diseases as well as other diseases that have strong bacterial associations.

Despite the current lack of regulations which specifically encompass phage therapies, the FDA has been very supportive of testing phage in controlled clinical trials and the use of innovative study designs for this modality—including multistage and adaptive trial methodologies—to help to advance these important precision medicines.

As companies continue to progress phage therapies towards commercialization, clinical trial sponsors can play a key role in working with the FDA in the creation and evolution of bacteriophage-specific regulations and guidance documents. If these efforts go well, the future looks bright for the biopharmaceutical industry and global regulatory bodies to apply phage products to the increasing need for novel therapies that can potentially combat the “silent pandemic” of antibiotic resistance.

References

1. Evolution of Clinical Research: A History Before and Beyond James Lind (nih.gov)
2. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)02724-0/fulltext
3. https://www.fda.gov/vaccines-blood-biologics/workshops-meetings-conferences-biologics/bacteriophage-therapy-scientific-and-regulatory-issues-public-workshop-07092017-07102017

Paul Kim, PhD, MBA, is the Chief Development Officer at Locus Biosciences, a biopharmaceutical firm based in the Research Triangle Park region of North Carolina. He earlier held the position of Vice President of Program Management at Puma Biotechnology.