PharmExec Blog

No More Approvable Letters: An Expert's Take

In response to last week’s blog about FDA’s announcement that, in future reviews of NDAs, it will ditch approvable and nonapprovable letters for “neutral” complete-review letters, Russ Somma sent an interesting and informative take on the likely effect of the new system on the industry. Somma is president of SommaTech, a pharmaceutical development technology consulting company in Somerset, NJ. He has an impressive track record of over 21 successful NDAs and more than 50 product and product assessments in only three years. He writes:

The FDA’s “complete response” letter to New Drug Applications (NDAs) will be a challenge for both sponsor companies and market watchers. While the letter is already business as usual in the biologic and vaccine areas, the decision by the Center for Drug Evaluation and Review (CDER) to use it starting August 11 for the “small molecule” players—supposedly for the sake of consistency—will create more confusion, or at least debate, for the industry.

This means that the outcome of a submission review will not be as transparent to the casual observer. Since the complete response letter has no “label”—as do the “approvable” and “nonapprovable” options it is replacing—the question as to its status, and subsequent market potential, will be cloaked. As a result, market watchers will not be in a position to prognosticate on the likelihood of an NDA’s approval and the drugmaker’s value.

This confusion will no doubt have a negative effect on startup companies sharing risk with a venture-capital business partner. In the case of large-caps, the letter’s trickledown on stock value will not play well in a market increasingly disenchanted with the earning potential of the pharma sector in portfolio planning.

But it is not only the industry watchers who will be working in the dark. This “unlabeled” letter will be a source of further confusion for the sponsor company, which will undoubtedly engage in an internal debate as to the “worth” of a major undertaking to resubmit a response since the outcome will have an unknown payback. Under the old system, when the end result was better defined, there was likely more motivation to make the investment to meet the additional CDER requirements. Whether the new system will result in fewer resubmissions—and fewer new drugs—is a question with potentially serious implications for patient health.

Should a decision to respond be taken, the firm is faced with assembling the data and the rationale for its interpretation—all of which is a familiar enough drill. The nature and scope will be unique for every product and for every complete response letter.

According to the final rule, a resubmitted NDA will be classified as either Class 1, which starts a six-month review clock, or Class 2, which starts a two-month review cycle. So in reality, the final outcome for a company’s original prior-approval submission may be delayed up to 12 months if given a Class 1 status since conventional wisdom would be to expect another round of questions from the reviewers.

The obvious sponsor strategy to address the new drug review process is to make the original NDA submission as solid as possible. FDA has made it quite clear that it expects more science-based and knowledge-rich dossiers. This involves assuring that the critical-quality attributes of the product as well as the critical-process parameters are defined well enough to guarantee safety and efficacy for the patient.

The current industry trend toward Quality by Design (QbD) makes this quite apparent. QbD is a systematic approach to attaining desirable quality through careful evaluation of all attributes of a drug from early development through the entire product lifecycle. Its goal is to assure the product’s identity, purity, quality and potency. QbD dictates that the information compiled during the studies should be used to determine the formulation- and process-critical parameters as well as supportive elements—including assembling a submission that is solid and science based.

FDA has opened the door to QbD in hopes of moving toward what Janet Woodcock, M.D., director of CDER, describes as “a maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high-quality drug products without extensive regulatory oversight.”

In the end the response letter is an action taken by FDA to address deficiencies for the safety of the patient. In a proactive sense, that is also what QbD is all about. It avoids FDA having to ask questions that should have been addressed in the development process and documented in the filing.

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One Comment

  1. Posted July 17, 2008 at 3:33 pm | Permalink

    I personally struggle to see how they will implement this so quickly without so much as a hiccup. By the end of August, we will see how the first litmus test turns out. Here’s hoping it flows smoothly for the company, the drug and the investor community so closely following such news.

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