Approvable Letter

An action letter must be issued within 180 days of the start of the review, unless an extension has been agreed with the applicant. If the submission is fully acceptable an Approval Letter is issued. However, if there are problems remaining, the applicant vdll receive a Not Approvable Letter (major problems), or an Approvable Letter (minor problems) in the case of an NDA and a Complete Response Letter in the case of a BLA. These not only summarise the deficiencies that exist but also either outline what steps need to be taken to address the issues or explain why the application carmot be approved. A negative action letter will usually trigger an end-of-review meeting between the FDA and the applicant. This allows the applicant and FDA to discuss and... 

Houn, F. (2003) FDA approval letter is available at the website, http // www.access.fda.gov/drugsatfolatda docs/appletter/2003/215491tr.pdf (accessed August 2010). 

Not Approvable Letter Application cannot be approved and deficiencies are detailed. 

Approvable Letter Deficiencies are minor and can be corrected or supplementary information has to be provided. Eventually the drug is approved. 

Approval Letter The drug is approved. An example of the approval news for Tykerb, a kinase inhibitor in combination with capecitabine for the treatment of advanced or metastatic cancer, is presented in Exhibit 8.3. 

On June 2, 2004, the PDA gave an approvable letter to market efaproxaril if the ongoing phase-three trial, called ENRICH (Enhancing Whole Brain Radiation Therapy in Patients with Breast Cancer and Hypoxic Brain Metastases), designed specifically for the use of efaproxaril to treat metastatic breast cancer to brain, is successful. The ENRICH phase three trial will seek to enroll approximately 360 patients at up to 50 cancer centers across North/South America and Europe. In the letter, the PDA stated, if the study shows effectiveness in this population (increased survival) using the prespecified analysis, and the study is otherwise satisfactory, we believe it would, together with the subset result in RT-009, support approval (http //biz.yahoo.eom/prnews/040602/law025 l.html). 

FDA Drug Approval Letter for Zyban, Company Glaxo Wellcome, Approval Date May 14, 1997, Retrieved April 7, 2004 from http //www.fda.gov/ cder/foi/nda/97/020711 zyban toc.htm... 

The FDA s Approval Letter to Geneva Pharma, for ANDA No. 74-315 (indicating dismissal date of suit related to 095 patent), posted at ... 

Docket Sheet for Abbott Labs. v. Geneva Pharma., Civil Action No. 96-1762 (N.D. Ill.)(indicating dismissal of Civil Action 96-1762 in May 1996) FDA s Approval Letter to Geneva Pharma, for ANDA No. 74-823 (indicating dismissal of Civil Action No. 96-1762 on 615 patent), posted at ... 

For every NDA, some clinical study is almost certain to remain in progress at the time when the NDA is submitted. Safety update reports are therefore required to be submitted to FDA by the applicant while the NDA is pending, and particularly following receipt of an approvable letter. Detailed systems and procedures are required to ensure that the data in the NDA and the safety updates are accurate and complete, and failure to meet these requirements is regarded by FDA as a serious deficiency. 

Until quite recently the actions of the FDA concerning an NDA were expressed in either, an approvable letter or a non-approval letter. In the case of a non-approval letter, the deficiencies were noted and were felt by the agency to require substantial action by the sponsor since a positive action by the agency in the present review cycle was not possible. Where the issues could be solved promptly by the sponsor, a non-approval letter was not necessarily a bad result because it officially clarified the remaining issues. 

An approvable letter usually stated some minor area of concern that needed to be resolved prior to final approval. The letter usually stated that if these concerns were resolved approval would be granted. 

In contrast, an approval letter meant that the submitted information justified approval. The only action usually requested for this t)q)e of letter was the submission of final printed labelling and advertising. In some cases, an approval letter could spell out other conditions for approval, such as post-approval studies, or restrictions on distribution or promotion. These conditions were generally discussed with the sponsor and agreed to prior to receipt of the letter. 

Efforts are underway to replace the nonapproval and approvable letters with a letter that lists all the deficiencies the sponsor will need to correct to obtain approval. If deficiencies are substantial the letter will read more like the old non-approval letter if the deficiencies are minor, the letter would read more like an approvable letter. To date, the use of such letters has been random at best, and it is still most common to receive one of the three action letters noted above. 

In four instances, the agency has invoked this rule at the time of approval of supplements for new indications for psychotropic drugs already approved for other psychiatric indications. It was noted in the approval letters for these supplements that, since the drugs in question would likely be used in children and/ or adolescents with the newly approved indications, the FDA required the sponsors of these products to conduct studies that would be pertinent to such use in the pediatric population. Since the products were ready for approval in adults, the FDA deferred the required pediatric studies to a future date. Alternatively, sponsors could make an argument for waiver of the requirement. The drug products and indications for which the FDA has required studies under the Pediatric Rule are as follows paroxetine for social anxiety disorder sertraline for post-traumatic stress disorder (PTSD) olanzapine for acute mania in bipolar disorder and fluoxetine in premenstrual dysphoric disorder (PMDD). 

Anti-thymocyte globulin (rabbit) [FDA used in approval letter]... 

The FDA has proved to be responsive to criticism, probably more so than many other federal agencies. To give one example, in 1989 it took roughly 33 months for a market approval letter to be issued from the date of request 10 years later this dropped to 13 months. Issues still remain, however. No new drug excipients had been approved in over 20 years because no manufacturer was willing to spend the money on the extensive toxicity testing required without commercial exclusivity or protection. 

In 1990, when FDA launched its preapproval inspections (PAI) program, the three-lot issue again arose. The PAI s chief architects (Richard Davis and Joseph Phillips, FDA Newark district directors) announced they would require evidence of three consecutive successful lots of commercial size prior to shipment of a new product across state lines as final evidence of process validation, even when the firm had already received its NDA approvable letter. 

Nearly every application has a required FDA transmittal form. Transmittal forms are primarily screening tools and are used to identify the information required and also provide administrative information for the application. Electronically generated forms may be used, provided the FDA approves the form prior to its initial use. A copy of FDA s approval letter should accompany the form the first time it is submitted. In some instances in which there are no transmittal forms, specific cover sheets or checklists are recommended. These are found within the guidance documents specific to the application type. 

Upon completion of the review, a written evaluation of the product is prepared in a review document and the comments of the various reviewers are reconciled and reviewed by the division director. The results of the decisions are communicated to the applicant in an approvable or not-approvable letter. In some cases, if the questions have been satisfactorily addressed during the review process, the agency may proceed directly to an approval letter. The scientific review divisions are independent from the district offices that conduct field facility inspections. The review division will wait for assurance that the preapproval inspections are completed satisfactorily prior to issuing... 

New drug product exclusivity Approvable letter to the applicant Not approvable letter to the applicant Submitting an abbreviated application for, or a 505(j)(2)(C) petition that relies on, a listed drug that is no longer marketed... 

Action letter An official communication from the FDA to an NDA sponsor that informs of a decision by the agency. An approval letter allows commercial marketing of the product. An approval letter lists minor issues to be resolved before approval can be given. A not approvable letter describes important deficiencies that preclude approval unless corrected. 

Safety update reports Reports that an NDA sponsor must submit to the FDA about new safety information that may affect the use for which the drug will be approved, or draft labeling statements about contraindications, warnings, precautions, and adverse reactions. Safety update reports are required 4 months after application is submitted, after the applicant receives an approval letter, and at other times upon FDA request. 

On December 24—a mere 6 days before the official approval letter was written for Zoloft—Leber (1991) responded to Temple s concerns about approving the drug. About the tougher standards in the European countries, Leber wrote ... 

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