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Agnes Shanley is senior editor of Pharmaceutical Technology.
CRLs put the brakes on drug development and damage corporate reputation and stock prices. Upfront investment and better sponsor oversight are ways to prevent them.
Complete response letters (CRLs) have become a powerful way for FDA to push drug developers to improve their product and process understanding during early development phases. By pointing out failures discovered during FDA plant preapproval inspections (PAIs), whether issues involving current good manufacturing practice (cGMP) compliance or methods used to establish product safety or efficacy, CRLs stop the approval process until those problems are remediated. For companies that have received them, CRLs have resulted in significant loss of investor confidence and tumbling stock prices.
The purpose of a CRL, as its name implies, is to provide sponsors with the “big picture,” explains Christopher Smith, an independent consultant with the FDA Group. Before using them, FDA would handle everything in a piecemeal way, he says, and sponsors would get deficiency letters from the various disciplines within FDA (e.g., chemistry, clinical, bioequivalence, labeling, statistics, etc.) and might also be notified there was a “facility issue.”
During the process, it sometimes seemed to sponsors that FDA wasn’t communicating well internally. So FDA now uses a CRL to pull everything together and tell the sponsor where everything stands.
In January 2017, a number of commentators (1,2) called upon FDA’s commissioner Scott Gottlieb to make CRLs public, a policy option that he had invoked during his nomination hearings. As research (3) has found, companies that receive CRLs rarely publicize them, resulting in glaring disparity between what appears in company press releases about their new drug candidates and where they stand with FDA. Gottlieb proposed making CRLs available on a limited basis, restricting info to those CRLs whose lessons would offer the greatest potential impact to improve public health.
Whatever decision is ultimately made on releasing CRL information, 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 manufacturing, contract manufacturing, or contract research organizations’ (CDMO, CMO, or CRO) facilities (4).
In this article, two consultants who specialize in FDA compliance-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, communicate, and manage
PharmTech: In 2016, John Jenkins, retired director of the Office of New Drugs in FDA’s Center for Drug Evaluation and Research (CDER), drew attention to the growing prominence of cGMP issues in complete response letters, and the fact many of these problems 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 several things are happening here. First, the agency’s continued efforts to better link the application review process to the facility 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 inspections are PAIs, and sometimes 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, with the increase in outsourcing of the various activities involved--development, drug substance manufacturing, finished product manufacturing, primary and secondary packaging, labeling, quality control testing, stability 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 linking 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.
Avellanet (Cerullean Associates): Part of the answer sits in the decision-making that underlies the outsourcing 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 company 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 budget 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 quality 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 assessment, 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 bigger trials, and our manufacturer gets better and better at making this new product.’
Think about it. Firms hire folks to run clinical trials to kick off the trials far before they hire quality folks to do the manufacturing assessments. So inadvertently, they have set themselves up for failure because you can’t add in quality later on.
PharmTech: What are the most challenging aspects of CRO/CDMO oversight for any drug development project?
Avellanet (Cerullean Associates): There is very little staffing for supplier and supply chain oversight until after the initial CRO, CDMO, and CMO choices have been made. Again, many of these smaller firms are made up of scientists and financial backers, many of whom don’t realize that they should have dedicated supply chain and supplier oversight staffing.
After all, they may reason, when they were with their previous employers, they oversaw their lab suppliers. How much more difficult could this be?
Unfortunately, many of them never saw and were never involved in any of the back-office work that went into vetting and managing suppliers, from contractual terms and conditions to payables, to reviewing a supplier’s internal controls. More often than not, it’s a matter of not knowing what they don’t know.
Smith (The FDA Group): There are many challenges for the application sponsor in outsourcing these activities. A significant one is a certain lack of control and having to recognize that you are but one of many, sometimes hundreds, of clients that the service provider may have. Their systems, procedures, and priorities may not always be aligned with yours and must meet the needs of many masters.
Thus, even when a compliance issue is raised, a service provider must address it in light of the needs of many clients and, sometimes, commitments made to other clients in procedures, quality agreements, contracts, etc. The bottom line is that the entire supply chain has become much more complicated and addressing compliance issues in that chain have likewise become more complicated.
PharmTech: Where are sponsors falling short in their responsibility to oversee contract partners? What should they be doing differently to decrease risk and liability?
Smith (The FDA Group): Vendor management is not just about vetting the vendor to add to your approved vendor list, then having the quality assurance (QA) department conduct an audit of their facility or standard operating procedures (SOPs) every two or three years.
In the past several years, I’ve seen a much needed increase in the use of project managers on both sides, and this has helped to keep things on track and to address issues that arise more quickly and efficiently. Communication and transparency are key.
Sponsors who share information, keep vendors apprised of timelines and application status, and work with their suppliers, with the understanding they are but one of many customers, will fare much better than those who don’t.
The same concepts apply to vendors as well. While client confidentiality issues may hobble vendors somewhat, early and open communications regarding timelines, hiccups, unexpected problems, etc. can go a long way to decrease risk for all parties involved.
Avellanet (Cerullean Associates): I teach a number of workshops on practical data integrity, and one of the sections is on supplier oversight. I have a set of ‘Have you ever observed?’ type of interactive questions and exercises, one of which is the following True/False statement: We pick our suppliers based on their experience with our industry so we know they know what they’re doing.
Typically, at this point, everyone in the audience--to a person--chuckles and nods. Despite all the FDA and regulatory exhortations, FDA-483s, warning letters, CRLs, etc., firms continue to have this belief that, just because a CRO or a CDMO has been in business for years, they must know what they’re doing.
Warning letters often spell this out, with the recurring phrase ‘As a sponsor, you failed to oversee.’ A manufacturer chooses to work with a particular CMO or CRO, starts using them, and then, perhaps, runs into problems.
By the time the firm realizes that they picked the wrong partner, it’s too late, and they’re stuck in the middle of a seven-year contract or in the middle of a Phase II trial, etc. and now what you do you do?
Even for large companies, going back to senior management and saying, ‘Oh, we goofed, we need money and resources and time to start over with someone new …’ That’s not going to go over well.
And, let’s face it--many sponsors continue to believe that, if there is trouble during a clinical trial, that the CRO will be in the line of fire. It doesn’t work that way. FDA sees the sponsor and only the sponsor; the CRO is just a ‘department of your company that works at a different location.’
The CRO is really only accountable to the terms and conditions spelled out in your contract. So if you don’t understand the ins and outs of all that, you’re just setting yourself up for further disappointment and risk when things go wrong.
The real challenge is, once you’re in this predicament, what can you do? Assuming you cannot start over, what can be done to limit your risk and liability from today forward? That is all about doing increased oversight, increased testing on your end, etc.
So, as a simple example, instead of simply reviewing the clinical research associate’s trip reports, start doing more cooperative monitoring visits. Instead of waiting for the CMO to tell you about problems--or discovering them after the fact--put a temporary point person, a ‘person-in-the-plant’ to get you through the remaining batches to limit problems and issues.
Hire a third party to do a detailed assessment of the CMO--and give you a list of ‘here’s what you as the contract owner/sponsor should do’ recommendations. You already know that you have problems with the supplier.
You want a third party to give you insight and advice into what you should do--not what the supplier needs to fix, because the supplier may simply ignore it, and leave you holding the bag.
PharmTech: In general, what impact is the increase in CRLs having on drug development costs and timeframes, and the industry in general?
Avellanet (Cerullean Associates): I’m not sure that anyone has a firm grasp on this, because it really depends on the variables involved in the specific case.
What I see and hear around the United States and in Europe is that people are getting soured on using just one CRO to run their trials. My larger clients, for example, are shifting to a model in which they use multiple CROs on short-term contracts--almost a probationary type of contract for a small trial or arm of a trial--to limit their exposure and to be able to better evaluate which CRO works well with them.
Obviously, this is not really an option for smaller firms. In those cases, I’m pushing them to write short-term contracts with financial penalties for compliance failures.
It takes some thinking through and back-and-forth, so there are no cookie-cutter templates available, but everyone ends up happier because money is now tied directly to compliance and good quality data.
In the short-term, the increase in CRLs is going to drive up the cost of drug development as people adjust to the requirements. That said, the first firms out of the gates who ‘get it’--which can look at the example CRLs that FDA is going to release and incorporate lessons learned--is going to see its approval rates skyrocket.
It’s going to be interesting to watch over the next three to five years, and I’m pretty sure the financial analysts for the large investors are paying very close attention to which firms seem to ‘get it’ and which spend their money and time spinning wheels, repeating past mistakes, and struggling.
Startup firms seeking financing must be able to clearly answer how they will avoid the mistakes that caused CRLs in similar startup firms.
Smith (The FDA Group): I’ve certainly seen an increase in the industry’s attention to FDA inspectional findings and how they may apply the results to their own operations. But it’s a bit easier to stay abreast of 483 issues than it is to track deficiencies in CRLs, which are much less in the public domain.
No doubt that as firms learn what FDA expects, they’re doing a better job of meeting those expectations up-front.
The significant increase in FDA guidance that we’ve seen in recent months is very helpful. And I see more firms finally understanding the fact that FDA reviewers want more information in applications--not to cause pain, but to better understand how the process, the API, the formulation, [and] the finished product came together.
It’s not just about the finished product; it’s about months and years of research, culminating in the final application. This change had required investing more time and money up front, but I believe it’s bringing better quality products to market and assisting FDA in the application review process as well.
1. A. Feuerstein, “An Open Letter to Dr. Scott Gottlieb on FDA Transparency,” STATnews.com, January 27, 2018.
2. M. Nisen, “The FDA Should Shine More Light on Drug Rejections,” Bloomberg.com, January 18, 2018.
3. P. Lurie et al., “Comparison of Content of FDA Letters for Not Approving Applications for New Drugs and Associated Public Announcements From Sponsors’ Cross-Sectional Study,” BMJ 2015:350 h 2750 (2015).
4. A. Shanley, “Moving Toward Direct-to-Patient Models,” pharmtech.com, November 1, 2017.
Supplement: Partnerships in Outsourcing 2018
Pages: s18, s22Â–25
When referring to this article, please cite it as A. Shanley, “Avoiding Complete Response Letters," Pharmaceutical Technology Partnerships in Outsourcing 2018 Supplement (February 2018).