Laurie Halloran

	Over the last several decades, contract research organizations (CROs) have become heavily involved in the conduct of clinical trials. Sponsor companies often saw the involvement of CROs as an opportunity to alleviate burdens on their internal teams and staffing, to reduce risk by not investing in full-time employees, and to gain targeted knowledge related to disease areas, trial designs, geographies, and clinical sites. In situations where CROs have acted as true operational and strategic partners with the sponsor, these benefits have usually been realized.

	However, the reality is more commonly that relationships between sponsors and CROs are not seamless, and outsourcing to a CRO ends up causing a different slew of complications for the sponsor. These can include duplication of effort, increased decision-making time, failure to identify important issues of trial design or execution, frustrations associated with the management of the high rates of turnover of study staff, and other administrative stressors like contracts and payments associated with any vendor.

	Because of this, some of the most “innovative” companies are rethinking their outsourcing models. They are bringing certain functions back in-house and reducing the amount of work out-sourced throughout all phases of clinical trials, from conception to completion.  

	Recently at an executive retreat we held a workshop and except for a couple of very large pharmaceutical companies who already conduct their clinical development programs completely in-house, attendees from every other size company were in agreement that if they could, they would shift away from outsourcing their work. The two biggest areas of focus during the discussion that followed pinpointing specific areas of dismay are monitoring and project management of the trials.

	In companies of all sizes, managing and overseeing outsourced projects involves dozens of both parallel and sequential activities with significant redundancy between the sponsor and the vendor. There are a million ways things can go wrong, and most sponsor PMs feel a sense of ownership that can never be matched by a vendor who has multiple projects of their own to manage.

	One client of ours is moving project management and monitoring in-house because they are spending millions of dollars each year to redo the work of their vendors. Their position in a niche market requires physicians with specific knowledge-something that project managers and monitors from CROs don’t have. Making this shift is a multi-year process, but cloud-based technologies will enable them to do this. They have estimated that, by taking the work in-house, they will save 10% in their development costs the first year, rising to 15% in year two onward.

	A second client with a large portfolio has made similar assessments regarding the value of a single, preferred provider. They are embarking on a four-month process to evaluate methods and improve results. Their development leaders have been sharing best practices with companies who wish to shift work in-house, and their consistent advice is to build in-house capabilities with technology and personnel to launch trials and focus any outsourced activities to extract the most value.

	While the industry is certainly experiencing a shift towards insourcing, it is unrealistic to think that every company can and will shift to in-house resources to run trials. The constraints on many companies will simply not allow for this. Whether it is due to their smaller size, stage of development or future business goals, many companies will continue to take on the challenges of working with the CRO over investing in a complete change of business model.

	There is much to be learned from the companies that have chosen to change their business model towards greater insourcing. Companies that choose not to expand insourcing should still critically examine their relationships with CROs and other vendors and invest in creating long-term strategic relationships built on trust, focusing on strong project management, open communication, and CRO employee retention. At least for the foreseeable future, CROs are here to stay. Their services are attractive, ideally providing near turn-key solutions to major clinical trials challenges, and their presence is strongly engrained in the industry. It will take more than a few innovative companies to change this.

President and CEO of Halloran Consulting Group

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An industry shift has led toward more insourcing and in-house resources to run trials.

Expected Changes to the Vendor Landscape in 2018

There are significant steps needed to prepare and ensure high likelihood of successful navigation through an FDA inspection. If the inspection results in an FDA Form 483, the pressure is on to escalate the findings to a high priority organization-wide process improvement program because there will be a re-inspection, and it is imperative to demonstrate that the findings in the earlier inspection have been resolved in order to get off the path of escalation to a Warning Letter.	 	Your Corrective and Preventive Action (CAPA) program is a critical tool in your response to an FDA Form 483 and can prevent a Warning Letter. Here are some tips for using CAPA in your response: 	 	

1.  Use your CAPA form and a cover letter instead of a memo.

	If you have an electronic system with an easy-to-follow output format, use a cover letter and copies of the forms instead of starting from scratch with a memo. This makes it easier to read and demonstrates a robust CAPA program.	 	

2.  Document the investigation that was conducted for each observation with a concisely stated root cause.

	Document how you determined the root cause. Look beyond the immediate scope of the FDA 483 to ensure that a similar problem cannot occur elsewhere in a different study.	 	

3.  Identify containment measures and corrections to address each specific observation noted by the FDA inspector.

	Identify if immediate containment is necessary and how you can correct the problem, then attempt to implement the containment and corrections during your FDA inspection. The new CAPA issued from this inspection should identify containment and corrections that have been or will be implemented.	 	

4.  Identify corrective actions planned and the date(s) you expect to complete implementation.

	Ensure your corrective actions are clear and brief; timelines are realistic (be sure you can achieve the target dates); and there is a responsible person and role for each action.	 	

5.  Include documentation of containment and corrective actions already completed when you submit your response to the FDA.

	Show the Agency that you are taking action. If you revised a SOP and scheduled a group training, then provide the FDA a copy of the revised procedure and a copy of the agenda for your planned training session. Remember to only commit to actions you are certain you will implement and do not forget to include target dates. 	 	

6.  Follow-up with a memo confirming that all the corrective actions are complete and include all related documentation, including any necessary training for new procedures or corrective actions.

	Follow-up before FDA does. If the verification of effectiveness is compelling and received in a timely fashion after the inspection, you may convince the compliance office to hold off on a planned Warning Letter.	 	These straightforward steps are critical to steering the organization to appropriately handling the organizational response to a 483. The organizational changes and improvements a 483 response requires should be expeditiously addressed, however, the pace of change combined with the pressure a regulatory timeline brings can result in staff turnover or morale issues that impact company performance. The responses to a regulatory inspection often define the relationship with the Agency for years to come, so external expertise may be required to supplement an internal team.	 	 	Laurie Halloran is the founder, president and CEO of Halloran Consulting Group

If an FDA investigation results in a Form 483 then it is important to prove that earlier issues have been resolved upon re-inspection. The following steps using your Corrective and Preventive Action (CAPA) program are crucial to appropriately handling and responding to an FDA Form 483 in helping avoid a Warning Letter.

Laurie Halloran

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Expected Changes to the Vendor Landscape in 2018

CAPA as a Tool to Prevent a Warning Letter