Safety And FDA’s Centennial: As The Agency Turns 100, “Adulterated Drugs” Is Taking On A Whole New Meaning

FDA could be forgiven for asking for a rewrite of 2005: the year saw the resignation of its commissioner, continued product withdrawals and criticisms that it was causing undue concern among patients about the safety of their drugs.

But instead of a fresh start, 2006 is shaping up to be a sequel to 2005. The agency again has an acting commissioner, and one of its first advisory committee meetings of the year may consider a product that has been pulled from the market 15 months after launch: Palatin/ Mallinckrodt's NeutroSpec .

While the December withdrawal of the appendicitis imaging agent has not had the ripple effect of Merck's removal of Vioxx , FDA will again be facing uncomfortable charges that a product representing only a limited clinical advance was approved without a complete vetting of its safety.

Following the Vioxx withdrawal, FDA focused on a series of initiatives designed to more clearly and rapidly present emerging safety issues to the public through a "Drug Watch" website. Faced with mounting industry criticism that un-contextualized information might cause unjustified concerns, the agency has now sent the concept back to the drawing board (¹ (Also see "“Drug Watch” Sent Back To The Drawing Board; FDA Turning To MedWatch?" - Pink Sheet, 12 Dec, 2005.), p. 3).

Agency leadership has been emphasizing the importance of considering a drug's efficacy when weighing post-marketing information.

From a management standpoint, the agency has made progress on its safety initiative with the recent hiring of a director of CDER's Office of Drug Safety. The drug center is also undertaking a reorganization designed to increase the administrative prominence of its safety functions (² (Also see "FDA’s Drug Center Reorganization Creates Second Safety Director Position" - Pink Sheet, 7 Nov, 2005.), p. 3).

Drug safety mechanisms are sure to be a major component in the debate on renewal of the user fee program, which needs to be reauthorized in 2007, although any congressional action on overhauling FDA's safety oversight will likely await studies from the Institute of Medicine and other government bodies.

Another key challenge facing FDA is its leadership, brought on by Lester Crawford's resignation after serving only two months as permanent commissioner.

The abruptness of Crawford's departure stunned observers, and an Inspector General investigation into the circumstances of his resignation is ongoing. But two of the primary areas of public speculation about the causes of Crawford's decision - the agency's Plan B response and charges of financial conflict of interest - can be seen as microcosms of the challenges facing FDA in 2006.

Barr's application for an OTC switch of its emergency contraceptive is on hold after the agency determined that it needed to issue rulemaking to regulate products that are sold both over-the-counter and Rx. The decision has drawn the ire of those who say that the agency is beholden to political interests, and led to the resignation of FDA Office of Women's Health Director Susan Wood (³ (Also see "Plan B Delay Draws Criticism From Congress, Academia, FDA Official" - Pink Sheet, 5 Sep, 2005.), p. 6).

Several veteran agency officials are understood to have told Crawford that they had lost confidence in his leadership after the Plan B decision was announced.

The allegations that Crawford had failed to disclose a potential financial conflict of interest are emblematic of another common charge made by some agency critics - that FDA has become too beholden to industry through the user fee funding that companies provide.

An identity crisis often accompanies milestone birthdays, and FDA seems to be suffering from a significant one as it prepares to celebrate the big 100 in 2006.

By naming long-time acting commissioner Crawford to the permanent post, the Bush Administration eschewed a dramatic gesture that would signal a new ethos for FDA, and few dynamic candidates have emerged in this round either. National Cancer Institute Director Andrew von Eschenbach immediately moved over on an acting basis after Crawford's departure, but HHS has indicated that he is not expected to take over the post permanently (⁴ (Also see "Von Eschenbach May Speed Changes In “Strategic Direction” At FDA – Galson" - Pink Sheet, 31 Oct, 2005.), p. 16).

The vacancy gives the administration a second chance for a re-imagining of the agency, and the attributes of the first FDA commissioner, Harvey Washington Wiley, could be instructive.

Academically minded but politically focused, Wiley, who headed the Department of Agriculture's Bureau of Chemistry, helped shepherd the 1906 Pure Food & Drugs Act into law, launching federal oversight of drug claims and paving the way for the modern pharmaceutical industry.

Wiley was a vigorous campaigner against quack cures, poor manufacturing standards and even hazardous imported drugs.

One hundred years later though, most public concerns about "adulterated" drugs appear to be not about products that are shoddily made, but those with hidden side effects.

If FDA does adopt broad new safety oversight functions, Vioxx could be seen as this century's sulfanilamide, the deadly elixir that led to the 1938 Food, Drug & Cosmetic Act and the first pre-market safety requirements.

As industry and FDA feel the pressure of lengthening approval times - the Critical Path initiative notwithstanding - some academics deem a refocusing of approval requirements toward the post-marketing arena as key to serving public health through access to new medicines (⁵ (Also see "Drugs Should Get Longer Patents In Exchange For More Safety Data – Wood" - Pink Sheet, 14 Nov, 2005.), p. 11).

The choice of a motivated outsider to take the helm could push the agency in such a direction.

Aside from the safety issue, generic biologics seems to be a topic ripe for FDA's attention in the year ahead. The debate is so embryonic that stakeholders cannot even agree on nomenclature, but discussions - and congressional action - could begin in earnest if FDA issues its "historical" white paper this year (⁶ (Also see "Follow-On Biologics Pathway Unlikely Without Confirmed FDA Commissioner" - Pink Sheet, 28 Nov, 2005.), p. 13).

The discussions may continue to focus mostly on science, but the underlying issue is money. There is the need to establish an approval pathway for follow-on biologics, but of equal or greater importance is policymakers' task of carving out a patent and exclusivity framework that satisfies both the innovators and generic stakeholders.

As FDA wrestles with issues of "sameness" for follow-on proteins, it could foreshadow the coming debate over cost-effectiveness of pharmaceuticals that may emerge if the Medicare Rx drug program's costs create serious congressional concerns.

Any new standards that are born from those discussions would probably fundamentally alter the nature of FDA approval - either in the way it was obtained, or in the market value of obtaining it.

A glimpse at one potential future is offered in an essay in the Jan. 12 New England Journal of Medicine by Vanderbilt University Medical School professors Wayne Ray and Michael Stein. The pair suggests expanding FDA's functions by creating a center for post-marketing studies and a center for drug information to complement a revamped center for new drug approvals.

The proposed post-marketing center would contract for independent studies of the relative effectiveness of products, and the drug information center would sponsor academic detailing to ensure proper use of drugs.

Ray and Stein argue that the expansion of FDA's post-marketing activities - and its funding through a tax on pharmaceutical sales rather than user fees - would be good for industry's bottom line because it would reduce the potential for product liability. With FDA holding considerable responsibility for what aspects of drugs are researched and how doctors and the public are informed of safety issues, drug companies could not be charged with failing to communicate risks, they suggest.

However, industry may be hesitant to embrace such an expanded post-marketing role for the agency.

No matter how one slices it, FDA is at a critical juncture as it celebrates its 100th year. At the agency's golden anniversary in 1956, Wiley was commemorated in a 3¢ postage stamp. Given the competing pressures currently on FDA, it would be a profound achievement if the new leadership eventually earns such public recognition.

- M. Nielsen Hobbs