Guidebook for Drug Regulatory Submissions by Sandy Weinberg
Formal Submission: permission to move forward with drug development project, with the promise of improvement and corporate profits. The submission represents the tightest of bottlenecks in the development process:
Most common types of submissions:
1. FDA Meeting Request
2. Orphan Drug Applications
3. Investigational New Drug Applications (INDs)
4. New Drug Applications (NDAs)
5. 505 (v) 2 NDAs
6. Abbreviated New Drug Applications (ANDAs)
7. Annual Reports
10 rules for regulatory submission:
(IND):The granting of permission to conduct clinical studies
(NDA): carries permission to market
Each major and minor regulatory step is characterized by a submission, a regulatory review, and a decision. When a decision is contrary to expectation, it may be followed by a revision, and in RARE cases an appeal.
Regulatory professionals inside the FDA are prepared to assist in the process with guidance documents, controlled conferences, and informal advice. Think of the submission process as a major exam but one for which you have the questions in advance, you can use your notes, and hopefully retake the exam on rare occasions.
10 summary rules to seek approvals
1. Seek guidance: Consult with the FDA. Webcasts, formal meeting, phone calls and build a relationship with the FDA. Some places may get hire a consulting firm to help but such strategiescarry risk. When your company makes a submission, it assumes full responsibility and liability for the content, regardless of who prepared it. If using a consulting firm just use them for guidance for the format, recommendations of working, the publishing and delivery services that may be onerous, and even an initial draft review. Make certain that your effort and submissions are team affairs and not just the director.
2. Focus on Format(in addition to content) 1st hurdle is format review as it varies from submission to submission. A CNS review may have different criteria or preferences than a metabolic team as INDs have a different requirement than orphan applications. The biggest difference beween FDA groups and submission types is in referencing preferances. Most applications and most teams require that actual copies of the reference be included in the submission. Some like numbered references to a bibliography and some like and editorial style (name or date) linked to it. Cover letters are required for submissions. These need simple items such as names of contacts, phone numbers or emails to reach them, company spokesperson ect… Any information left out can delay your application and affect your reputation and impression your working to build. Rember the content is principal, but the other is just to have a chance to get on the field.
3. Document everything. A major submission may take weeks – some take months to assemble. During that time the draft is reviewed rewritten and reviewed ect… What companies need to watch is when reviewing an item there is a natural tendancy to begin subconsciously thinking of statements as self obvious and hence needing documentary support. It is important to take nothing lightly and assume nothing is self obvious as it may make key issues weaker. To avoid these problems identify all claims and assumptions in the first draft and have an independent reviewer reexamine to make sure all important points are appropriately referenced. Most FDA submissions permit unpublished as well as published references. Supporting letters, studies not yet in print, copies of speeches and papers, and other unpublished references can be included. Web site and information can also be included. It is better to have to much than too little documentation. Every reference potentially adds to your credibility.
4. Self-regulate: The FDA considers the pharmaceutical industry to be self-regulated; FDA persons perceive their job as checking that you appropriately self regulated. That is why a technical process, even if appropriate and successful, is considered inadequate if lacking a validation and QA control review. The double check, self regulation step is always required. Counting on the FDA as your primary submission reviewer is as inappropriate as they want you to have done that work. This means your QA team should look for weaknesses before submission so it may be corrected and rereviewed prior to actual submission. Self regulation through an appropriate QA review allows companies to take control of the process and to assume appropriate responsibility.
5. Examine electronic submission options: Most FDA submissions can be made manually (paper) or electronically. Obviously, the electronic submission is more efficient especially when delivering large documents (INDs routinely run over 5,000 pages and NDAs may be even larger). However there are some additional considerations. Electronic submission standards are evolving and may not clearly be established for all FDA groups and divisions. For example the ESG (electronic submission gateway) is sometimes problematic. Some submissions are best done with paper with an accompanied hyperlinked CD-Rom disk, allowing reviewers to move between electronic and paper versions.
6. Schedule the submission: Not only does the submission take some lead time planning (perhaps as much as six months for development of an NDA-much less for other submisisons), but there are other considerations as well. An orphan –drug application and IND both receive responses in about 30 days. Submisisons should not be scheduled so that the responsed date will not fall within planned vacations or critical international travel. Most importantly though avoid submission bottlenecks, a clear schedule allows other team members-proofers, printers, collators, IT, QA, ect. To make certain they are prepared. If QA needs a three day period to reiview, count back a week ( their three days, and two more to correct any problems they find) from the planned duplication, assembly, and submission dates.
7. Designate Contacts: FDA submissions require a designated contact person, identified in the cover letter and in the submission itself. The contact person should identified by name and title, with telephone (office and cell) and email contact information provided. Also have aback up contact incase the 1 designated person can’t be reached due to illness or travel etc… Sometimes companies can set up a designated email which can be checked by any employee whom can pass the information on the the person needed. Point being it is critical not to miss a contact or message from FDA personnel because with their busy schedule it may be several days before they try to contact you again.
8. Keep the FDA informed: Once a file has been opened through a meeting request, inquiry, or submission, the project is assigned to an FDA contact. The designated individual can serve as a conduit to appropriate directors, committees, review boards, and divisions. Communication with the FDA contact can take a variety of forms; most will accept phone call and emails and will request formal, written communications when significant issues arise. Regardless of the format, keep your contact in the loop if shcedules or plans change. All contacts – even contact reports of telephone conversations will be appended t the file. Keep all questions clear and direct and avoic speculative questions. Use the contact to keep the FDA informed of all official issues, but nothing is “off the record”.
9. Make appeal and legal action as very last possible step: Regulatory decisions on submissions are communicated to applicants through a variety of channels, including verbal (telephone calls), emails, and formal letters. With careful self-regulation through a thorough QA review prior to submission, you should gain some control over the review prior to submission and you should gain some control over the process, avoiding unpleasant surprises. If the review result is not what was anticipated or expected, there are several levels of response that are possible. 1st, and generally most successful, is a conversation to pinpoint the problem, followed by a clarification (in some cases there is just a misunderstanding), submission amendment (more detail may be needed), or resubmission (if significant issues need to be addressed). These informal requests for reconsideration are often successful, particularly if approached in a cooperative framework. There are other avenues also if additional steps need to be taken such as: formal appeals process, the FDA Office of the Ombudsman has a dispute-resolution procedure, and finally it is possible to bring suit against the FDA in Federal Court of which these should be looked upon as last resorts.
10. Build a partnership: In an appropriately self regulated environment the working relationship between the FDA and a submitting organization should be one of cautious partnership, working together within a carefully designed legal and administrative framework to achieve common goals. Both parties share the same general objective: bring proven safe and effective drug products to a a public in need of the potential treatment, therapy, or preventative. Not-for-profit institutes have a natural affinity for such partnership arrangements since they avoid the natural skepticism that comes from a profit motivation. Even profit motivated companies can create a virtual relationship/partnership by communicating clearly to the FDA –in action as well as in words- a willingness to put public health and safety above short term revenue goals. In all interactions verbal, face-to-face, and in submission keep this principle primary, genuine concern for public health and safety as an underlying theme.
11. Summary: For all companies the submission process can be very traumatic. This is why if you have a good QA process that checks the submission against all FDA criteria through the use of an internal, self-regulating review process that applies the checklist criteria used by the FDA to submission process.
