Problems at FDA prompting slowdowns in development - should patients accept this?

The New Year is always a good time for a call to action, and the diabetes community certainly has a long bill of particulars that should be addressed: better access to care, greater reimbursement for doctors and educators, larger investments in prevention, a reduction in complications, an improvement in lifestyles, greater subsidy for healthy food (i.e. vegetables and fruits), and the list goes on.

If an outcry is needed, let’s make an outcry, and we’ll start with the Food and Drug Administration (FDA)!

 The FDA, an agency responsible for $1 trillion worth of products in the US economy, had an extremely difficult year in 2008 concerning its regulation of diabetes drugs and technology.  In particular, the FDA and the Division of Metabolism and Endocrinology Products (which oversees diabetes therapies) has been under intense scrutiny from Congress and attendant media. 

To top this all off, the FDA has been underfunded, understaffed, second-guessed, and pressured from several sides. Predictably, they have responded by retreating into a stance of extreme caution and attention to safety regardless of future cost, development and innovation. What is missing and what should matter most is patient benefit.

It is time to bring patient needs for effective new medicines back into the spotlight. We believe that the new rules the FDA has established will impair research and innovation into diabetes medications and devices. We advocate for safety, but the pendulum has swung too far, and the people who have the most to lose are the patients. Patients, we need to make our needs known!

The FDA’s most recent move causes us particular concern. The FDA has sent a letter to companies developing new diabetes drugs requiring a cardiovascular meta-analysis study based on phase 2 and phase 3 data to ensure that there is no cardiovascular signal. The new requirements are based on recommendations from an FDA Endocrinologic and Metabolic Drugs Advisory Committee meeting July 1-2, 2008. The argument, which was presented most avidly to the panel by Dr. Steven Nissen, goes as follows: “We already have diabetes drugs that lower blood sugar. Two thirds of people with type 2 diabetes die from cardiovascular disease. Therefore, we should require new diabetes drugs to prove that they do not increase the risk of cardiovascular disease.”

We disagree with the premise. diaTribe was at the meeting and noticed that only two individuals voted against the move: the sole FDA patient representative (Rebecca Killion is one incredible patient advocate) along with a leading smart-as-a-whip pediatrician from Emory, Dr. Eric Felner. Everyone else voted for it although some said the language was confusing and that they did not really understand what they were voting on. We thought the patient representative had it right – she said she did not want innovation slowed. Quite simply, we do not have sufficient diabetes drugs.

While clearly nobody wants diabetes drugs to be approved that increase cardiovascular risk, we think that the requirements outlined by the FDA will chill the development of new diabetes drugs and do very little for patient safety. The worry is that it will increase costs for phase 2 and phase 3 trials based on the number of cardiovascular events needed to prove to the FDA that there is no worrying signal. As Dr. Thomas Fleming stated, “In diabetes, there may be a baseline cardiovascular event rate of 20/1000 patient-years. If a study drug increased cardiovascular risk to 25, this difference of 20 vs 25 event rates per thousand person years would require a trial including an enormous 40,000 patient years to show that the drug increased cardiovascular risk.” We believe this move by the FDA may stymie a whole new generation of diabetes drugs that do not have the necessary funding.

Ironically, by slowing the development of new drugs, this plan will encourage the use of older drugs such as sulfonylureas, which are the only drug class that has been shown to increase cardiovascular risk (University Group Diabetes Program).

Not only will the FDA requirement delay availability of new therapies for patients, but we believe the requirements will have a strong chilling effect on development of new drugs altogether, limiting treatment options. Small companies dedicated to diabetes therapy may be unable to gather the large resources needed, and in the current financial climate, many will fold. Large companies may be unwilling to take on the additional cost, time, and risk and move out of diabetes treatments, as we are now seeing with companies moving away from obesity treatments. If the new requirements had been in place, we probably would not have Byetta and Januvia available today.

All in all, patients lose. With a growing diabetes epidemic and under 50% of patients meeting treatment goals, it is clear that the current treatments are not enough. Many of the drugs available now have safety and tolerability issues, and we lose hope of replacing these with better alternatives. Diabetes is a chronic progressive disease which currently is managed, not cured. Breakthrough therapies that could slow, stop, or cure this disease come from innovation.  We need to accelerate, not brake, innovation.

Here are a couple of recent examples of promising new therapies which are NOT available to US patients at present:

·       A pump with a low blood glucose sensor is being developed in the UK. It automatically turns off insulin delivery when blood sugar levels get dangerously low. It will be submitted to the EU regulatory body and people in the UK will likely be able to get this pump sometime next year. Why is this pump not being developed in the US? No one will say officially, but we constantly hear that Washington is so risk-averse that it probably wouldn’t approve it or would hold it up a long time.

·       Symlin is a drug that has been used successfully to reduce glycemic variability (in particular, high blood-glucose levels after meals – a tricky time for many of us). It is approved for those that use mealtime insulin – type 1 and type 2 patients. A clinical trial involved type 2 patients who used basal insulin only with Symlin at mealtimes. This could be a good option (even the FDA patient advocate has publicly stated she uses this drug), but the FDA struck it down without a reason. The data from the trial has been published in Diabetes Care showing no safety issues. The FDA won’t return phone calls asking why Symlin hasn’t been approved for this use.

diaTribe is working with DiabetesMine and TuDiabetes in putting together a petition asking for recognition of patient need for better diabetes drugs and an approval process that balances this need with risk. We hope patients join with us to have our voices heard by the FDA.

Comments

[Lahle Wolfe]

In the past, the FDA has had to backtrack and withdraw approved drugs or include additional patient warnings of diabetes and other treatment drugs as more problems became known. I was always glad for that protection when unforeseen side effects become known. But of late, the FDA has totally thrown patient concerns and needs out the window. For example, they took away my albuterol inhaler because it "polluted" the air. Forget that it saves lives and was relatively safe - and cheap in generic form. Now patients with asthma can now only purchase one non-generic inferior product that is known to be less effective, has caused deaths - actually making asthma attacks worse - and the FDA knew this when it made its chances, and is far more expensive. We have no choices now when it comes to fast-acting inhalers - we only get the one product now and risk our lives and pay triple the cost because insurance does not have to pay for brand name drugs even when there are no generic options.

Now I have to worry about not getting the best drugs for my diabetes, too? Come on FDA, your job is not to play God. Yout agency is riddled with hypocrisy as you have now ordered pharmaceutical companies to cough up the patent formulas for insulin so others can make it generic which will force consumers to pay full price for currently insured insulins or change to another product? Insulin is a far more complicated drug and yet you will require no studies on generic insulin to ensure safety but will excessively regulate oral meds?

If you were a business, you'd be bankrupt, out of business, and probably criminally liable. It is kind of scary when consumers are now screaming that they trust pharmaceutical companies more than the agency that is supposed to protect us.

[Dr. Val]

Great post, Kelly. I'll be doing a podcast interview with Amy T on December 24th to get the word out about the petition. The FDA risk aversion spans all diseases (I've been writing about what it does to cancer patients, for example). We need to find a balance between risk/benefit. It's the provider's job to explain each drug's risk/benefit analysis to patients, and then let them choose.

Unfortunately, patient choice is being undermined by absolute risk aversion - consider the case of Wyeth vs. Levine. A rare but known risk of phenergan (if erroneously injected into an artery) is tissue necrosis. This drug has been successfully and effectively administered over 200 million times in the US - but in 20 cases, a provider messed up and injected the drug into an artery, causing grave damage. Now one of those cases (literally 1 in 20 million) is suing Wyeth (with lay jury support). What will companies like Wyeth do about this in the future? Maybe they'll stop making good drugs available... Never mind that for every one injury 20 million patients were helped...

We have to educate patients about this kind of thing - and help them to understand that zero risk is not possible. Requiring the FDA to demonstrate a near zero risk profile for new medications before they're approved is going too far. :)

Preaching to the choir...

Val

[Scott K. Johnson]

BTW - I think Scott S. would make an incredible part of your team... you all should explore the opportunites!

[Scott K. Johnson]

Great post Kelly!

[Scott]

Back in March 2008, I responded to the FDA's "Draft Guidance for Industry on Diabetes Mellitus: Developing Drugs and Therapeutic Biologics for Treatment and Prevention" and said exactly the same thing. While it's nice to have others joining me in reaching this conclusion, it would have been nicer to have you join me back then!