Cathy L. Burgess, Esq., Crowell & Moring, LLP
For Life Science Companies
Preparing a response to a Form FDA 483 can be a time-consuming and stressful process. It diverts resources from other activities and, if not managed properly, the process can be overwhelming. If a 483 response is well written, factually correct and complete, it will establish that the firm has taken or is in the process of taking appropriate corrective and preventive action. This can allay FDA concerns about the firm's compliance, and reflect positively on the organization. If the response is poorly written, contains errors or omits critical information, it can trigger additional inspections or a Warning Letter. If the firm submits inadequate responses to a Warning Letter, the firm is at risk for seizures, suspension of product approvals, injunctive action or possibly criminal prosecution. While this article is focused on 483 responses, the recommendations apply equally to Warning Letters.
Firms that adopt a "check the box" or "fill in the blank" approach to 483 responses do so at their own peril.
Some firms use template responses, directing staff to use boilerplate language to respond to certain types of observations. This is a mistake. Firms that adopt a "check the box" or "fill in the blank" approach to 483 responses do so at their own peril. Crafting an acceptable response requires thoughtful analysis and precision. Following the three rules below will make this exercise more efficient and productive.
Rule 1. Have a plan. The response is an opportunity to communicate to the agency that you understand your compliance obligations. It is also an opportunity to demonstrate that you have corrected, or will correct, any deficiencies identified in the response and ensure that the problems do not recur. Most importantly, the response needs to demonstrate that your firm is operating in a state of control.
- Understand each observation. Section 5.2.3 of FDA's Investigations Operations Manual (IOM) requires that investigators make "every reasonable effort" to discuss observations as they occur or on a daily basis "to minimize surprises, errors and misunderstandings when the 483 is issued." The IOM also informs investigators that firm management may ask questions about observations, request clarification and inform the investigators about corrections that have been made or will be made during the inspection. During the inspection exit interview, you should take the opportunity to ask additional questions if an observation is not clear. If you believe that there are factual mistakes or that an observation is based on a misunderstanding, you should bring this to the inspection team's attention. You should not squander this opportunity by arguing about the observation. In medical device inspections, the firm has the opportunity to annotate the FDA-483 during the exit interview, to document corrections have already been made, are underway, or will be made. The firm is also allowed to annotate the FDA-483 to document the firm's disagreement with an observation.
- Form a team. Once you have read and understood the basis for each observation, you should form the response team. Depending on the number of observations and the types of deficiencies identified, the team could consist of 1-2 individuals or a much larger group. You should designate team members for the following roles.
- Subject matter experts. Subject matter experts (SMEs) provide technical expertise and should be knowledgeable about the particular issue identified in the observation. Subject matter experts typically are involved in development of corrective and preventive actions (CAPAs), or at least have the ability to explain and evaluate CAPAs. Subject matter experts can provide background and context regarding an observation, and should be involved throughout the drafting process to ensure that the response remains consistent with the facts.
- The writer. Don't assume that your Vice President of Regulatory Affairs or your Chief Scientist is necessarily the best writer in the organization. The writer should be someone who can communicate clearly and effectively. Subject matter experts should provide information to the writer, who will be responsible for the final written product.
- The clerk. Someone should be responsible for obtaining documents for review and possible submission as part of the response. (During the inspection, FDA requests copies of documents for its inspection file. The firm's inspection management SOP should require the inspection management team to make a second copy for the firm's inspection file. Subject matter experts should review the inspection file in preparing the response. They should not be allowed to remove documents from the inspection file.)
Rule 2. Address FDA's concerns.
- Determine the scope of the problem. Does the observation identify a problem that is isolated or systemic? Is the problem limited to a certain lot? Does the problem extend to other lots of the same product or to other products? Is the problem contained within a particular department or does it extend to other departments? Is the problem contained within a particular facility or does it extend to other facilities?
- Conduct a thorough investigation and take appropriate corrective action. Far too often, firms respond to 483s by simply defending their actions or relating the history of a problem. You should thoroughly investigate FDA's concerns and describe your investigation, investigation results and corrective actions in your response.
- Submit a well-written and precise response. Do not submit a response that is impossible to understand or omits pertinent information. Responses should be factual, complete and easy to read. They should include reasonable timelines, address issues item-by-item and demonstrate an understanding of regulatory requirements. A sloppy or defensive response will not be well received. In addition, you should provide supporting documentation as part of the response. Note also, that you should not make blanket admissions. There is a difference between acknowledging a mistake and agreeing with a 483 observation. Such an admission could be used against the firm in an FDA enforcement action, or a product liability or securities lawsuit brought by a private plaintiff.
Rule 3. Keep your promises. A common mistake is a firm's promise during the inspection's exit interview to submit a response as quickly as possible. While it is appropriate to respond in an efficient and timely manner, a lengthy 483 or one involving complicated issues could require more investigation than anticipated. In such cases, rushing to meet an arbitrary deadline could result in submission of a substandard response. If it becomes apparent that it will not be possible to meet your deadline, you should contact the agency and request permission to submit an interim response. You should assure the agency that submission of the final response remains a high priority, and submit the final document as soon as it is practicable to do so.
A firm should set timetables for CAPAs that demonstrate an appropriate sense of urgency. Commitments should be realistic, and firms must meet their commitments. Failure to keep your 483 promises will result in repeat observations (often the basis for a Warning Letter or other enforcement action). Failure to meet commitments in a Warning Letter response without keeping FDA apprised of the reasons for delay will most likely result in enforcement action.
Responding to a 483 can be a stressful process. Proper management of the response, thoughtful analysis and precision will make the process far less stressful. A bad 483 response is one that is incomplete, factually incorrect, poorly written and defensive. A bad response will ensure additional regulatory scrutiny. A good 483 response communicates an understanding of regulatory requirements and that the firm is operating in a state of control.
Cathy L. Burgess, Counsel, advises clients on compliance programs, adequacy of SOPs, investigation reports, inspection management, responding to Form FDA 483s and Warning Letters and recalls. She also conducts internal investigations and special audits related to FDA compliance. Cathy's practice includes regulatory advice concerning complex corporate transactions, clinical trials and matters related to blood establishments. Cathy also provides advice on legislative matters affecting FDA regulated entities. She assists in development of legislative strategies, assists clients with testimony, prepares staff for interviews with committee staff and provides advice on pending legislation. She has prepared testimony regarding patent extension under the Hatch-Waxman Act, and prepared position papers on drug pricing for President Clinton's transition team. Prior to joining the firm, Cathy was associate general counsel for the American Red Cross, where she served as regulatory counsel for the organization. In 1992, Cathy was the number two person on the defense team in United States v. Barr Laboratories, Inc., the leading case on current good manufacturing practices for pharmaceutical companies.
"What to Expect During an FDA User Facility Inspection," http://www.fda.gov/cdrh/fusenews/fuse24.pdf
"What a Form 483 Really Means." Goebel, Paul; Whalen, Matthew; Khin-Maung-Gyi, Felix. Applied Clinical Trials Online. Accessed 3/20/09. http://appliedclinicaltrialsonline.findpharma.com/appliedclinicaltrials/article/articleDetail.jsp?id=92055