Are You ASKING For An FDA Warning Letter?

By Ed Miseta, Chief Editor, Clinical Leader

Alan Minsk, partner and leader of the Food and Drug Practice, Arnall Golden Gregory LLP

Quality agreements, the contracts signed between drug sponsors and contractors, continue to be an object of interest for the FDA. The agreements are intended to define and explain the roles and responsibilities of parties involved in the making and handling of drugs and drug products. By stating who is responsible for what, they not only ensure regulatory compliance, but define responsibilities in the event of an adverse outcome. With the number of FDA 483s (Notice of Inspectional Observations) and warning letters on the rise, it is more important than ever for companies to not only have a quality agreement in place, but to make sure both sides adhere to its provisions.

“It’s not mandatory for firms to have a quality agreement in place,” says attorney Alan Minsk, partner and leader of the Food and Drug Practice for law firm Arnall Golden Gregory LLP. “There are provisions in FDA’s regulations that say there should be certain things written down, but that does not mean you are legally required to have a quality agreement per se. Not having one doesn’t necessarily mean you will get an enforcement letter. In fact, it’s possible you have the significant provisions of the contract agreement noted on other documents. However, I believe if you don’t have one, it could be a potential red flag for the FDA.”

Minsk tells his clients to expect FDA investigators to ask for the agreement. He believes if a firm has one, it demonstrates that some thought was put into the quality process, and each of the participants are aware of who is doing what. It also demonstrates to the FDA that you didn’t just have a phone conversation about responsibilities, or shake hands on an oral agreement on a golf course or over drinks.

“Not having a quality agreement does not guarantee you will get a warning letter,” says Minsk. “But firms need to be aware that having the agreement also does not guarantee that you will not get one. You could have an agreement in place but did not prepare it correctly or were not following it.”

The Number Of Warning Letters Spikes

There has been a clear increase in the number of warning letter issued by the FDA. During the years 2005 to 2009, the FDA averaged 487 per year. In 2011, it issued over 1,700. While many in the industry have speculated on the reasons for the increase, Minsk said it could be due to increased funding or a change in FDA policy which no longer requires all letters to go through the office of the chief counsel. But Minsk believes it primarily has to do with the FDA taking a closer look at the sponsor/contractor relationship, and ensuring quality production starts at the earliest stages. He believes the FDA is saying it is ok for pharma firms to outsource, but at the end of the day they are still responsible for their product. “For example, many pharma firms are procuring active pharmaceutical ingredients from regions of the world that are not as heavily regulated as the U.S.,” he states. “If a problem arises with any of those ingredients, you can’t simply say it’s their fault and you had an agreement in place stating they would comply with all FDA requirements. The FDA will ask how did you know they were complying. Did you have an agreement in place? Were you monitoring them? Did you audit them? Did you ask them for documentation of what they were doing? That is what the FDA is concerned about. Having a contract is not good enough. If it is your drug application, you are ultimately responsible.”

Listening to Minsk describe them, quality agreements resemble prenuptual agreements for the contract business. No one really thinks about the agreement when everything is going well. It only comes into play when an issue suddenly arises. He tells clients that when a problem does come up, you don’t want to be looking at each other and wondering, “What do we do now?” Firms need to anticipate what could go wrong and worst case scenarios, and use the quality agreement to stipulate what the remedy will be if the unexpected does occur.

Minimize Warning Letter

When consulting with clients, Minsk points to three quality issues that firms must ALWAYS be aware of, well before an FDA inspector comes through the door. He believes all are essential to avoid dealing with a warning letter.

1. Have a quality agreement. As stated earlier, this is the best way to show investigators that you are monitoring your contract firms and anticipating issues that may arise. Make sure the agreement specifically spells out the responsibilities of both the drug sponsor and the CMO or CRO. 

2. Responsibility for product quality is always with the drug sponsor. Do not draw up an agreement, assign responsibilities to your partners, and then forget about it. The FDA will want to know what you are doing to monitor your CMOs and CROs to ensure they are abiding by regulations.

3. Virtual companies pose unique challenges. Minsk defines a virtual company as one that has employees, but most of the staff working on the product are third-parties and are not located at the corporate headquarters. In these firms, all clinical and manufacturing work may be outsourced. Minsk notes that these firms will often tell the FDA they’re small and can’t be responsible for everything. The FDA is fine with that type of business model, but it continues to stress that even these firms have to be responsible for what their partners are doing.

Minsk reminds clients that quality agreements are contracts, and contracts are legal documents that should always have the input of legal counsel, whether in house or external. In addition, quality-related personnel should get involved early in the process, as they are most responsible for ensuring regulatory compliance.

You can contact Minsk through his website. For more information you can also go to www.expertbriefings.com.