BioPharm

8 BioPharm International eBook March 2018 www.biopharminternational.com Outsourcing Resources Complete Response Letters In January 2017, a number of commentators (1,2) called upon FDA's commissioner Scott Gottlieb to make CR Ls public, a polic y option that he had invoked dur- ing his nomination hearings. As research (3) has found, companies that receive CRLs rarely publicize them, resulting in glaring dispar- ity between what appears in com- pany press releases about their new drug candidates and where they stand with FDA. Gottlieb proposed making CRLs available on a lim- ited basis, restricting info to those CRLs whose lessons would offer the greatest potential impact to improve public health. OUTSOURCING AND RECENT CASES Whatever decision is ultimately made on releasing CRL informa- tion, avoiding CRLs is a crucial goal for drug manufacturers and their contract services partners. In 2016, FDA issued 14 CRLs for new drugs, more than one third of which involved cGMP issues at contract development and manu- facturing, contract manufacturing, or contract research organizations' (CDMO, CMO, or CRO) facilities (4). In this article, two consultants who spec ia lize in FDA compli- ance—Christopher Smith, a former FDA staffer, and John Avellanet, principal of Cerullean Associates— share their observations on issues that often lead to CRLs, and how sponsors and contract partners can work together to avoid them. In the end, however, the onus is on the sponsor to oversee, communi- cate, and manage. COLLABORATION AND OVERSIGHT BioPharm: In 2016, John Jenkins, retired director of the Office of New Dr ugs in FDA's Center for Dr ug Eva luat ion a nd Resea rch (CDE R), d rew at tent ion to t he g row i ng prom i nence of c GM P issues in complete response letters, and the fact many of these prob- lems involved contract research, development, and manufacturing partners. Apart from the general increase in outsourcing, why have the number of CRLs increased, and why are so many of these related to manufacturing and outsourced manufacturing? Smith (The FDA Group): I think s e ve r a l t h i ng s a r e h ap p e n i ng here. First, the agency's continued efforts to better link the applica- tion review process to the facil- ity inspection process means that more inspections are occurring that have something to do with an application. In years past, a registered firm may have gotten a general GMP inspection. Today, more inspec- t ions a re PA Is, a nd somet imes inspections cover several different applications in which the facility is named. If significant compliance issues are noted, this can trigger CRLs to a number of applications. Second, w ith the increase in outsourcing of the various activi- ties involved—development, drug substance manufacturing, finished product manufacturing, primary and secondary packaging, label- ing, quality control testing, stabil- ity storage, distribution, etc.—and the requirement that any and all of the service provider facilities be named in the applications, it is not surprising that an increase in CRLs would be seen. Finally, I think the agency's link- ing of facilities inspections to the application process is being used as a both a carrot and stick incentive to drive better GMP compliance across the board. Ave llanet (Cerullean Associates): Part of the answer sits in the deci- sion-making that underlies the out- sourcing of the clinical trial. Some of the firms are small companies whose staffers have no experience with manufacturing. As a result, they often make choices on where to manufacture the investigative drug that do not involve quality assessments. Instead, decisions may be based on such factors as pricing or location. Often, a choice is made because 'the previous company I worked for used them' (without realizing that the previous com- pany wound up having a 'person- in-the-plant' just to manage quality, compliance, and other issues). Sometimes the decision is made with short-term thinking, as in 'Let's just use this CMO for this first trial, but then we'll switch later and do a more comprehensive vetting for our other trials.' Often that 'better/more comprehensive vetting' never comes. It's very easy to say, 'We'll bud- get the money and time for this in the future' in a meeting that's focused on getting started, but much more difficult when it's time to actually budget the money and the time. Remember that many firms with investigative drugs simply do not understand the true implications of early choices: if I intentionally choose a 'temporary' CMO, I don't pay enough attention to their qual- ity and their data integrity up front, so I don't realize that the data that I'm seeing from them may be of poor quality. In other words, I've unwittingly set myself up to make decisions based on data that may not be reliable. Many of these companies don't have the money or the time any longer to go back to do the assess- ment, so they just go forward. I wouldn't say that they go forward with an 'I hope this doesn't come to light' attitude, but more of an 'I hope this won't have much of an impact as we go to bigger and big- ger trials, and our manufacturer

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