Pharma flexes legal muscle to push FDA into action

The approval process for new drugs in the US is tightly regulated by the Food and Drug Administration (FDA), which has the final say in whether or not a company may market a new drug. While the FDA desires to ensure availability of new innovative drugs as well as cost-effective generics to patients in need, they are also meant to protect the public from unnecessary risks of new drugs.

The FDA occasionally finds themselves at odds with drug companies, which sometimes progressing to even a lawsuit. Many of the disagreements between the pharma industry and the FDA surround generic drug approvals, whether they originate from generics companies seeking approval, or pharmaceutical originators attempting to block approval of a generic.

A recent example of a disagreement between a generics company and the FDA was the delay of Watson Pharmaceutical's marketing approval for their generic version of Actos (pioglitazone), a widely prescribed drug for diabetes. Prior to the expiration of the patent for Actos, four generic drug companies, including Watson, Ranbaxy, Mylan, and Teva Pharma, simultaneously filed abbreviated new drug application (ANDA) for the approval of their respective versions of Takeda Pharmaceutical's Actos.

Normally, the first filer of a generic drug is awarded a full six months of marketing exclusivity by the FDA before other generics can launch, thus keeping profits relatively high for the first filer(s). In this case, shared exclusivity was awarded to three-of-the-four filers. For reasons not fully disclosed, the FDA denied Watson a piece of the shared exclusivity period, a decision that cost Watson millions of dollars. Following unsuccessful efforts to resolve the dispute with the FDA, Watson filed a suit to challenge the decision. The case was finally decided in Watson's favor, allowing them to launch their generic Actos in October 2012. However, nearly half-of-the-six-month exclusivity period was lost.

On the other side of the issue, they are attempts made by big pharma to delay or block generic competition and, if successful, the investment of a few hundred thousand dollars tied up in a lawsuit is well worth the additional revenue gained, if there is success in extending the exclusivity of a branded franchise that is possibly worth millions of dollars each quarter.

In the billion dollar pain market, Endo Pharmaceuticals is fiercely defending their opiod painkiller market from generic competition, and has resorted to suing the FDA in order to delay generic competition. Endo's Opana ER, oxymorphone hydrochloride (HCl), patent expired in January 2013 and is facing generic competition from Impax Laboratories. Endo no longer markets the Impax non-tamper resistant formulation (TRF) of Opana ER after voluntarily withdrawing the product in place of their new crush resistant formulation (CRF) of Opana ER.

Endo's currently marketed CRF Opana ER has sustainable patent protection until 2029, while Impax has launched the previously marketed Opana non-TRF formulation in January 2013. This is the premise for Endo's legal action against the FDA. Endo had hoped to force a decision from the FDA (through a lawsuit) before the end of 2012, causing the FDA to block the Impax non-TRF Opana ER.

However, the FDA is constrained by its legal authority to stop generic entry of a product previously considered safe that must now be found unsafe upon introduction of a new "safer and less-abused" formulation. Endo was not able to invoke FDA action through their lawsuit, as the process to withdraw approval of a previously-approved generic is fraught with liability from the FDA's standpoint.

Another recent example is the case of AstraZeneca and their attempt to preserve their lucrative Seroquel franchise from generic erosion. Seroquel and Seroquel XR, an anti-psychotic drug prescribed to treat schizophrenia and bipolar disorder, is a multi-billion dollar drug that was responsible for approximately 18 percent of AstraZeneca's total prescription and over-the-counter revenue in 2011.

With patent expiry looming, AstraZeneca attempted to delay the inevitable launch of generic rivals by claiming that the drug's data exclusivity, which had not yet expired, protected the safety data that AstraZeneca had generated in clinical trials; therefore, a generic manufacturer could not rightfully include this side effect information on their label.

However, labels for generic drugs must include the same warnings and precautions as the branded product. AstraZeneca initially filed a citizens' petition requesting that the FDA not approve any generic that omits this safety data from their label. When the FDA denied the petition, AstraZeneca filed suit against the FDA. However, the suit was dismissed by the court and generic Seroquel was approved on schedule. However, AstraZeneca did manage to win a separate battle to protect Seroquel XR, the long-acting formulation, as the drug's patent was found valid and protected until 2017.

Overall, pharmaceutical companies and the FDA usually maintain a rather positive relationship, with newsworthy disputes occurring relatively rarely. While drug companies will naturally tend to disagree when the FDA rejects their marketing applications or request additional data before approving, the agency must act first to protect the public.

Likewise, drug developers do not wish to introduce a harmful product in the market, the result of which would only tarnish their reputation and lose the confidence of their customers. A recent case of a rejection turning out to be quite prescient was the initial rejection of Merck's marketing application for Tredaptive, a drug for treating low high-density lipoprotein (HDL) cholesterol. Although the drug was already approved in Europe and some other countries, the FDA wanted to know if Tredaptive not only raised HDL cholesterol (the "good" cholesterol), but also if it would actually help to prevent heart attacks, which is the ultimate purpose of treating dyslipidemia.

The only way to determine this is by conducting a cardiovascular outcomes trial in which tens of thousands of patients at high risk of a heart attack are followed until enough subjects experience a cardiovascular event to know if the drug had an effect or not. Upon completing such a trial, the investigators found that the drug not only had no effect on preventing heart attacks, but was also associated with increased safety risks. This news prompted Merck to pull the drug from other markets where it was approved since the benefit no longer outweighs the risk, and the European Medicines Agency (EMA) is now reconsidering their position.

From the pharma industry's perspective, dealing with the FDA is generally challenging, to say the least. The most successful companies will employ or contract executives with skill and experience in negotiating with the FDA throughout the approval process. The FDA encourages the industry to initiate communication early in the development process and maintain a relationship throughout to evade potentially avoidable pitfalls down the road.