How Epizyme Developed and Launched a CRO Diligence Program on a Global Scale
The hurdles and costs associated with bringing a drug through the development and approval process have skyrocketed. Over the past forty years, the average cost of running a preclinical program has jumped from hundreds of millions of dollars to billions of dollars.1 This financial commitment is burdensome for everyone in the pharmaceutical industry but can be crushing for a small company. To combat this issue, many small companies have partnered programs with larger pharmaceutical companies to offset research spend. In more recent years, transitioning some work to a Contract Research Organization has become another common way to ameliorate cost and add flexibility.
In addition to its advantages, outsourcing comes with its own set of challenges. Nearly ten years ago, Cetero was investigated by the FDA for suspicion of falsified working documents and study results.2 More recently, in 2012, a scientist from China’s WuXi PharmaTech sold grams of two Merck compounds on the black market.3 These types of situations are sufficiently frightening to make some companies steer clear of the outsourcing model. But with the right controls and processes, outsourcing can be safe and reliable. Both small and large companies are embracing contracted work in an effort to lower research spends and add flexibility to their operating models.
Epizyme, Inc., a small biopharmaceutical company located in Cambridge, MA has relied heavily on partnerships with CROs since its early days of operation. The initial push to use an outsourcing environment was centered on the need to grow a panel of enzyme assays within the histone methyltransferase target class. The decision to outsource was primarily driven by space and time constraints; the panel had to be brought online quickly and would have required adding internal headcount in limited lab space. A CRO could immediately add multiple skilled scientists to the project and these resources were more fungible than internal employees. This assay panel was then continuously cross screened against new chemical matter, also being delivered by a handful of CROs. New enzyme assays were developed and validated in house before being transferred to an outside resource. By continuing to validate new assays and test enzymes against our proprietary chemical matter, the company positioned itself for swift program starts to fuel the research pipeline.
The effort required to build and maintain successful relationships with outsourcing organizations has been significant. Over the years, as corporate goals and technologies have changed, the sometimes complex relationships with CROs adapted as well. The key to a successful relationship cannot be minimized to a signed work order and transferred protocol. Over time, Epizyme has developed a diligence process that is used for both potential and existing vendors in the preclinical space. This can be divided into three main areas of learning: pre-collaboration vetting, the site visit, and continuing follow up.
Pre-Collaboration Vetting
When approaching a new vendor for service, it is critical to ask any questions that may have an impact, positive or negative, on the work being done. Making assumptions can be the demise of a successful collaboration. Developing a set of questions from a few discipline groups that can be passed along to the CRO contact directly is encouraged and provides a written document that can be referenced by both parties. Of course, the questions that are asked will vary based on the type of work requested. For instance, a CRO that is only being utilized for chemical synthesis will not need to be screened for assay capabilities. However, that CRO will need to be screened for sample handling, data infrastructure, and information security. In fact, these three specific disciplines should be covered across all CROs. Ultimately, the quality of the end product, be it data, compounds or reagents, will be irrelevant if you can’t ensure that samples were handled correctly and your intellectual property is secure. A sample subset of questions pertaining to a number of different groups can be found in Table 1.
Table 1. Sample subset of diligence questions broken down by discipline to submit to CRO prior to initial site visit.
The Site Visit
Many companies, especially smaller ones, may not consider sending anyone to a vendor location halfway around the world for an onsite meeting, yet this can be a defining moment for how the collaboration will unfold. Using that written diligence form, the scientist can compare and contrast what was reported versus what the site actually looks like. Every company will have a different lab set up, different equipment, different capabilities, etc., and all of these need to be considered when engaging with a new vendor. For example, two chemistry vendors, CRO A and CRO B, are being considered for a project. Both vendors have impressive chemical expertise and adequate labs. However, the computers used for data processing of the compounds at CRO A are in a common space area versus the separate office space designated for scientists on one project at CRO B. This does not rule out CRO A as a vendor by any means, but when thinking about intellectual property, it does make CRO B slightly more appealing.
Visiting the site allows the scientist to meet the people that will be performing lab work as well as those that will be responsible for logistical functions like handling compounds and analytical QC. This will already establish a more positive relationship as the project progresses. Walking around the labs allows one to identify any potential red flags. For example, are compound structures written on fume hoods or are papers with proprietary information clearly visible? Are scientists adhering to the safety rules of the lab and, if not, does there seem to be any enforcement by management? Is the lab clean and are waste containers labeled appropriately? These are just a few specific examples of questions that may not be answered in an initial questionnaire, but are absolutely vital to ensuring data quality throughout the collaboration. More examples of site visit questions can be found in Table 2.
Table 2. Sample questions that can be answered by visual inspection during the site visit.
The length of the initial visit will depend highly on the flexibility of both companies. Hosting a visitor can be an interruption to the regular schedule of the vendor employees involved, so it is important to be mindful of what truly needs to be accomplished during the visit. For new vendors that will run assays, it is often mutually beneficial to transfer these assays in person and run a series a protocols side by side in the CRO lab to ensure data quality. Additional time will be required to complete the entire process from sample preparation through data analysis and notebook reporting. Full trust in the work that is being done by another set of hands is part of the commitment to the outsourcing model; there is no better way to build that trust than to work alongside the CRO scientists. To report those data internally, one needs to be just as confident in the procedures and handling as if it was done in house. Additionally, this can help one glean a typical day’s routine at the vendor site and build timeline expectations.
Continuing Follow-Up
After the pre-collaboration launch and successful site visit, the diligence efforts must maintained to ensure continued success. The follow-up diligence can be divided into immediate term and long term analyses. Regular teleconferences and e-mail exchanges can serve to ask and answer questions and resolve issues expediently. For assay work, if controls begin failing in experiments, knowing the lab and processes can be a big help. If a cell based experiment has failed, an evaluation of the tissue culture space and personnel has already occurred, so one may be able to rule out the possibility of contamination. This knowledge may be the difference between losing a couple of days of time versus a couple of weeks.
In the long term, it is advised to continue the diligence work, including on-site visits, on an annual basis. With consistent communication week by week, these visits can be shorter than the initial visit, but still very informative. Additional on-site visits allow one to see if anything at the vendor has changed in either positive or negative directions. For example, some labs may have been renovated or new equipment added since the last visit. Conversely, perhaps turnover in the employees that are being brought into the business meetings has occurred. An increase in employee turnover may indicate an issue on the business side of the company that would be important to address. As these vendors are handling your compounds, your materials, and your data, you must be allowed to ask these questions and obtain acceptable answers to ensure the work is still being done at the best place. Moreover, the effort put forth to have face to face conversations does not go unnoticed and can contribute to a better outsourcing experience.
Conclusions
Experience with outsourcing will vary at every company and not all experiences will have a positive outcome. Ultimately, a trusting relationship where data quality is high will come from a clearly communicated plan of action and by the reaction of both companies when something inevitably does go wrong. A relationship where you can openly troubleshoot the problem without the CRO being concerned that their contract will be cancelled will be vital. Similarly, it is virtually impossible to work with a vendor that hides problems or mistakes. By taking the opportunity to ask questions at the forefront, expectations for the quality of the laboratory and experimental data will be established before any materials are transferred. Following this, a site visit will provide verification of all the answers received ahead of time. Seeing the lab space and meeting the employees at the company can aid in resolving any issues down the line and make for a more collaborative relationship. Arguably, the most important part of creating a successful outsourcing model will be the commitment to follow up at the vendor, both through verbal and written communication on the short term, and periodic site visits in the long term. This method has proved invaluable to the advancement of the preclinical research pipeline at Epizyme and is a practice that will continue to evolve as the needs of projects expand. Not to be understated, the diligence program only works if all disciplines are committed to ensuring the data quality at the CROs. Support from management and cooperation among all the research groups internally is vital to the success of the diligence program. In the end, a successful outsourcing model is as much of an internal commitment of time and resources as it is an external one. By engaging with all parties, outsourcing has and will continue to aid drug discovery projects successfully at Epizyme and bring the company closer to the ultimate goal of helping patients in need.
References
- Pharmaceutical Research and Manufacturers of America (PHRMA). Biopharmaceutical Research and Development: The Process Behind New Medicines Brochure. Available at: http://www.phrma.org/sites/default/files/pdf/rd_brochure_022307.pdf. Accessed August 15, 2016.
- Food and Drug Administration (FDA). Certified Letter from Department of Health and Human Services. Available at: http://www.fda.gov/downloads/Drugs/.../UCM265594.pdf. Accessed August 8, 2016.
- Areddy JT, Jie Y, Weaver C. Scientist Convicted of Stealing Merck Drugs. The Wall Street Journal. http://www.wsj.com/articles/sb1000142405270230391820457744822151411088. Published June 5, 2012. Accessed August 8, 2016.
Elizabeth Admirand is a Principal Research Associate in Lead Discovery at Epizyme, Inc. where her primary responsibility is compound management. In that role, Ms. Admirand has implemented streamlined compound management protocols and processes including implementing disaster recovery sets, management of fragment libraries and the addition of clinical and preclinical sample management. Ms. Admirand was previously employed at Proteostasis Therapeutics.