Article | August 23, 2019

3 Strategies To Use When Selecting A CRO For A Gene Therapy Study

By Zamas Lam

CRO Selection 101 — How To Get Started

Hemophilia, congenital blindness, muscular dystrophy, cancer, neurodegenerative diseases, Parkinson's Disease, Huntington's Disease, influenza, HIV, hepatitis, heart disease, and diabetes all have one thing in common: During the past few decades, important medical advancements related to the treatment of these conditions have been made through gene therapy.

Now is an exciting time for gene therapy as the FDA has recently approved several gene therapies in the U.S. market, and many more treatments are in development. The growing demand for gene therapy has two main drivers. First is that there has been a mini-renaissance in nucleic acid drug delivery technologies that were conceived many years ago but have matured only recently. Examples are mRNA encapsulation and tagged siRNA targeting specific cellular receptors. Second is the increased pressure from patient advocacy groups to develop treatments for rare and orphan diseases. Rare and orphan diseases affect fewer than 200,000 people in the U.S. However, the growth of patient advocacy groups — fueled by social networking — over the past several years has increased the demand to obtain medications for these patients to treat their diseases.

Many biopharmaceutical companies have made significant investments in research and the clinical development of gene therapies. For those working to develop and bring new gene therapy treatments to market, it is critical to select the right contract research organization (CRO) to conduct these studies. Here are three helpful strategies to follow when selecting a CRO partner:

1. Do your due diligence when researching each CRO for your gene therapy study.

Study sponsors need CROs to share their knowledge and experience in order to drive the design of successful gene therapy studies. There are several insights a sponsor can glean from a simple discussion with a CRO to prepare for a gene therapy study. When screening CRO candidates it is important to inquire about:

  • Experience - Experience plays a key role when selecting a CRO. Asking about the number of gene therapeutic studies a CRO has performed is helpful. A CRO that has performed numerous studies in multiple modalities and indications successfully is more likely to be a good pick. Organizations should seek out CRO partners whose scientists understand the regulatory landscape and have proven expertise designing custom nucleic acid assays for drug modality as well as pharmacodynamic (PD) markers.
  • Technology - A CRO will need multiple platforms to support nucleic acid drug quantitation. Some CROs may have only one technology platform at their disposal. However, when it comes to gene therapy, multiple technologies are required: hybridization-ELISA, UPLC-HRMS (high-resolution mass spectrometer), UPLC-MS/MS, hybridization-LC-FLD, LC-UV, and quantitative PCR (polymerase chain reaction) are the most common methodologies being used.
  • Whether a CRO has more than one function – Look for a CRO that can understand the translational aspects of gene therapy, meaning it can apply scientific knowledge and past experience to the scope of the study, and determine whether the studies are needed and when these studies should be performed.  A CRO needs to offer multiple functions under one umbrella — for instance, drug metabolism and pharmacokinetics (DMPK), toxicology, bioanalysis, translational medicine, and others. It’s also essential the CRO have hands-on scientists who understand the chemistry, biology, and biomarker components, while also having a solid grasp on the inclusion and exclusion criteria for patient selection. Without this knowledge across multiple functions, a CRO will be hard pressed to successfully deliver a gene therapy study.

Keep in mind that before screening a CRO, it is necessary to think about the methodology that is appropriate for each study. For example, an mRNA will require a different approach than a small nucleic acid. Finding a knowledgeable CRO that can support your required methodology is key.

2. Look for CLIA experience.

The Centers for Medicare & Medicaid Services (CMS) regulates all laboratory testing performed on humans in the U.S. through the Clinical Laboratory Improvement Amendments (CLIA). In total, CLIA covers approximately 260,000 laboratory entities. So, why is CLIA important? In general terms, CLIA regulations establish quality standards for laboratory testing performed on specimens from humans — such as blood, body fluid, and tissue — for the purpose of diagnosis, prevention, or treatment of disease or assessment of health.

Having a CRO that understands, has developed validated GLP assays, has a track record for getting these assays CLIA-certified, has ran these CLIA assays successfully — specifically for patient selection — and has a dedicated CLIA director, is beneficial. Getting CLIA certification from all 50 states is complicated, and each assay must be certified individually.

3. Anticipate the challenges associated with gene therapy studies.

Like any other study, gene therapy studies present unique challenges. It’s imperative for CROs to be prepared for these challenges and ready to work with study sponsors to solve them. Three of the main challenges that often arise are off-target toxicity, delivery, and cost.

Off-target toxicity refers to the toxicity resulting from interaction of the drug with targets other than the intended target. For example, if the target organ is the liver and the therapy is transported to other organs — for example, to the thyroid — there may be adverse effects. Similar to off-target toxicity, simply delivering the gene therapy to the correct place within the body can be a challenge. Cost of goods is also a common obstacle to overcome. It’s very expensive to make siRNA and mRNA. In circumstances where there is off-target delivery or accumulation, for example, as the number of doses to test goes up, or quantity of experiments increases, so does the cost. At the very least, CROs need to be aware of the challenges that are common in gene therapy studies. Experienced CROs will anticipate challenges and be ready to offer and put solutions in place.


Gene therapies have the potential to dramatically change the lives of large groups of patients with common health issues — such as high cholesterol — and help smaller patient groups with extremely rare conditions. As biopharmaceutical companies continue to forge ahead on the exciting gene therapy frontier, they will be faced with important decisions when it comes to researching new drugs. Selecting the right CRO to partner with is one of those decisions. Therefore, it is necessary for companies to consider whether CRO candidates have the knowledge and experience, the agility to overcome obstacles, and the understanding of CLIA that is required to deliver a successful gene therapy study. Using these criteria to screen and select a CRO can improve your odds of successfully bringing a gene therapy drug to market.

About The Author:

Zamas Lam, Ph.D., serves as SVP and global head of preclinical development for QPS. Lam is one of the world’s few high-resolution mass spectrometrists by training and by trade, with a passion for biologics, mass spectrometry, and gene therapy. Within QPS, he is an integral part of the preclinical and bioanalysis team supporting a first in the industry — the world’s largest gene therapy trial with patients numbering more than 1 million. Lam is a regularly published thought leader, with his expert insights appearing in publications such as Bioanalysis Zone, Analytical Chemistry, and Carbohydrate Research.