Should The FDA Require CV Outcome Studies For Diabetes Drugs Before Approval?

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As the waistline of Americans has increased, so has the incidence of Type 2 diabetes. Startling data from the Centers for Disease Control  shows that that prevalence of this disease, which is directly related to obesity, now exceeds 9% in the adult population. It was less than half that rate in 1996. Furthermore, there doesn’t seem to be an end in sight. As the incidence of Type 2 diabetes increases, so will its sequelae: kidney failure, amputations and, eventually, heart attacks and strokes, all caused by the high levels of blood sugar endured by these patients. The increased burden to the healthcare system as a result of Type 2 diabetes will be with us for years to come.

The biopharmaceutical industry has recognized the need for better treatments and, as the root causes of the disease has become better understood, it has discovered and developed new classes of drugs which are improvements in helping patients bring their blood sugar under control. In fact, the FDA approved 30 new drugs to treat diabetes from 2004 – 2013. The diabetes market, estimated to be over $35.6 billion in 2014, is dominated (55%) by various injectable insulins. The next biggest class of drugs in terms of sales are the DPP-IV inhibitors, such as Merck’s Januvia and AstraZeneca’s Onglyza which make up 25% of the market. These oral agents enhance the effectiveness of a natural hormone, GLP-1, thereby enhancing insulin secretion and reducing glucose production by the liver. Other newly approved drugs include GLP-1 agonists, such as AstraZeneca’s Byetta, and the latest oral agents SGLT-2 inhibitors exemplified by J&J’s Invokana.

All of these classes of drugs are linked by their ability to lower high blood sugar. However, their long-term effects are not well understood and this can be worrisome as these drugs will likely be taken by diabetics for the rest of their lives. This is not an idle concern. Long-term studies with GSK’s Avandia, a member of another class of anti-diabetic agents called glitazones, actually showed that its usage elevated the risk of heart attacks and strokes. This led the FDA to restrict the use of Avandia to special circumstances, essentially resulting in this drug only being prescribed rarely.

The FDA has not sat idly by. In 2008, they began requiring companies to carry out long-term cardiovascular outcome studies as part of post-approval commitments. The FDA does not require that the companies show that the new drug improves heart function, but rather that it does not significantly increase the risk of heart disease since it is accepted that a new drug, by virtue of its blood sugar lowering action, will reduce the risk of diabetic complications. Long-term cardiovascular outcome studies are not trivial to conduct. They typically involve studying anywhere from 5,000 to 15,000 patients over the course of 3 – 5 years at a cost of hundreds of millions of dollars. However, this is the best way to get a handle on the long-term safety and efficacy of these drugs.

This week, the FDA will hold an Advisory Committee meeting to review outcome studies with two DPP-IV inhibitors: AstraZeneca’s Onglyza and Takeda’s Nesina. Of particular interest will be the discussion around Onglyza and its outcomes trial known as SAVOR. This study showed that Onglyza did not increase ischemic events. However, the rate of hospitalizations for heart failure was increased and there may be a significant increase of all-cause mortality. How concerning are these effects? Is this a class effect or solely related to Onglyza? Should this drug and other DPP-IV inhibitors carry added warnings on their labels? These are the issues that the Advisory Committee will likely address.

There are a number of other such studies underway for marketed diabetes drugs. The results for Merck’s TECOS trial, a 14,000 patient cardiovascular study with Januvia will be reported at the American Diabetes Association in June. Furthermore, cardiovascular outcome studies now underway are not restricted to DPP-IV inhibitors nor to only oral agents. There are at least eight other trials ongoing which are exploring the long-term effects of GLP-1 agonists, SGLT-2 inhibitors and long acting insulin. All will provide important information on the value of each drug as well as drug classes to a diabetic’s overall health when taking these medications..

Independent of the results of this week’s Advisory Committee meeting, there are those already questioning the FDA’s stance on approving diabetes drugs based solely on blood sugar reduction. They espouse the view that there are already a lot of drugs on the market that lower blood sugar and that adding another, even one that acts by a totally new mechanism with great promise for reducing diabetic complications, should not be done without a full understanding of the long-term safety of the new entity. That will certainly resonate with many industry critics who feel that companies take the easiest road in order to get their drugs approved.

However, requiring companies to have cardiovascular outcome studies completed before FDA approval will have a chilling effect on future diabetes R&D. First of all, it will restrict the number of companies doing such research to only the biggest entities, as the cost for executing clinical trials will be probative for all but those with the largest R&D budgets. Second, as these outcome studies require 3 – 5 years, requiring their completion before approval will delay the availability of new, potential breakthrough diabetes drugs to patients in need. Also, the significant lengthening of the clinical program could result in a shorter patent exclusivity period which would also discourage investment.

The FDA is in a tough spot here. However, if it wants to encourage continued investment into diabetes R&D, it would be best not to require outcome study results as a precondition for drug approval. However, once a New Drug Application has been filed with the FDA, plans for the long-term cardiovascular study should be in place and patient recruitment underway in order to minimize the time between approval and trial completion.

Source: Forbes Health