Draft Guidance Calls for Lengthier Premarket Safety Databases for Rheumatoid Arthritis Treatments

| 30 May 2013 |  By 

The US Food and Drug Administration (FDA) has published a new draft guidance document regarding the development of pharmaceutical and biological products meant to treat rheumatoid arthritis, a painful and debilitating autoimmune disease that affects a patient's mobility.


Rheumatoid arthritis has been something of a minefield for FDA and industry in the last decade. In 2004, pharmaceutical giant Merck voluntarily withdrew its blockbuster drug Vioxx, a non-steroidal anti-inflammatory drug (NSAID) from the market after regulators found that the drug was associated with a massive uptick in the number of heart attacks suffered by patients. Studies estimated the drug had caused between 88,000 and 139,000 heart attacks.

The withdrawal was as big a black eye for FDA as Merck, and confidence in the regulator suffered greatly in the aftermath of the withdrawal as some experts said the drug should have been forced off the market years prior. Similar risks have been recently noted with NSAIDs in general, with a report in The Lancet on 30 May 2013 showing that the drugs are associated with a modest increase in heart attacks.

Several pharmaceutical therapies are approved or otherwise used to treat RA, such as methotrexate, sulfasalazine, leflunomide, tumor necrosis factor alpha blockers, COX-2 inhibitors and other monoclonal antibodies.

In November 2012, FDA approved a new drug intended to treat the condition, Pfizer's Xeljanz (tofacitinib), a biologic that carries a boxed warning regarding an increased risk of developing infections, cancer and lymphoma, and a Risk Evaluation and Mitigation Strategy (REMS) intended to educate patients and prescribers through the use of a Medication Guide.

The Guidance

In light of the variety of treatment options available, FDA's new draft guidance seems geared not toward building a development framework for the drugs, but rather clarifying the specific clinical development criteria that will help expedite development in general. FDA notes that a similar guidance was published in 1999, and that the new draft is a revision of that document.

At least six major revisions are present in the guidance, with some reflecting new agency expectations, and others reflecting new technological advancements like the emergence of drug-device combination products to treat or identify the disease. The six main revisions are:

  • Nominal dose(s) and dosing regimen(s) selection throughout the clinical development program are based on a benefit:risk assessment supported by data.
  • Expectations are set for establishing efficacy in RA based on signs and symptoms and physical function domains. FDA said it believes the ACR20 response criteria is appropriate for evaluating efficacy of a product.
  • Use of efficacy endpoints such as clinical remission and prevention of structural damage progression are now acceptable.
  • Due to the number of treatments available, the use of placebo controls should be limited in favor of active comparators.
  • Due to the number of safety risks present in RA treatments, FDA says it plans to request premarket safety databases of larger size and longer duration than recommended now by the International Conference on Harmonisation's E1A guideline for new molecular entities. This will "likely include" at least one year of controlled safety data.
  • Development of drug-device combination products, such as auto-injectors, should take into account the characteristics of both drug and device and how they act on one another.

To FDA, the overriding concern reflected in much of the draft guidance appears to be related to safety.

"Many drug products intended to treat RA have the potential to cause serious dose-related adverse reactions, such as opportunistic infections and malignancy, which may not be apparent in short-term clinical trials," FDA explained, alluding to some of the aforementioned risks found in Vioxx and other drugs such as Xeljanz. "Dose-ranging exploration should begin early in the development program and often should continue throughout definitive efficacy and safety study(ies)."

"Inclusion of more than one dose of investigational drug product [in a premarket safety database] can provide important dose-response information with regard to efficacy and safety," it added later in the guidance. "For safety issues of interest, sponsors should consider an independent adjudication process."

Comments on the draft guidance will be accepted through 31 July 2013.

Guidance for Industry: Rheumatoid Arthritis: Developing Drug Products for Treatment

Federal Register


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