FDA Approval: From Mouse to Meds

By | 2017-01-13T20:42:46+00:00 January 2nd, 2014|
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Illustrations by Mark Weber

Illustrations by Mark Weber

A lot of us are anticipating a miracle drug that will allow us to shed our wheels to walk again, or at least live a pain-free life. Ongoing, there are drug or biologics being researched, tested and studied that may help us see these changes in our lifetime. We wondered how long it takes, after discovery, for a researched and tested drug to go through the approval system at the Food and Drug Administration to get that product from mouse to med.

Accelerated Paths
On July 9, 2012, the Food and Drug Administration, Safety and Innovation Act, was signed into law to strengthen Regulation 21 CFR 312, the expedited, new-drug approval system introduced in 1988. FDASIA now promotes innovation from drug companies; increases stakeholder involvement including end-user focus groups; and enhances the safety of the drug supply chain.

For a drug to get to the point of FDA application, it has gone through several phases of research and testing, taking an average 10 to 15 years to approval. Now, instead of the typical 10 to 12 months for FDA review and approval for serious or life-threatening conditions, the new accelerated system, offering FDA a more hands-on approach, allows approval within four to six months.

When a drug company applies for approval for a drug or biologic for a serious or life-threatening condition, they now can apply for Fast Track, Breakthrough or Accelerated Approval designation. During a recent webinar on drug development, sponsored by CureDuchenne, Dr. Robert Temple, deputy center director of Clinical Science and also acting director of the Office of Drug Evaluation and Research for the FDA, outlined the process:

After initial application, FDA has early consultations with the company to agree on the designation needed for approval so they don’t carry on studies that may not have a chance. All parties agree on needed studies and whether long-term data may be accepted after approval. Other meetings may include setting up treatment protocols and evaluation of risk and benefits of the drug. At this time, if the disease has no known treatment available, FDA may accept considerable toxicity that they may not otherwise.

Speeding up drug approval for serious conditions has opponents who cite possible side effects and/or complications that may not show up prior to approval.

“Bad neurological diseases need treatment,” said Temple during “On the Fast Track: The FDA and Drug Approvals,” which was part of the Washington D.C.-based, The Kojo Nnamdi Show. “When we’ve talked to people — that includes physicians and patients — they pretty much all agree that if you had something that worked when nothing else did for a serious or life-threatening disease, you would probably accept somewhat greater risk.”

Take the MS drug, Fingolimod, now marketed as Gilenya. “That got a priority review,” said Temple. “The first very effective oral drug that did so and it worked almost as well as a drug that people were quite worried about called Tysabri, which causes a rare neurologic disease.


[Fingolimod] got a priority review because it worked extremely well and that meant we gave it a six-month review,” Temple added. “That doesn’t mean we think that we decreased the level of review in any way. … we did it faster, we devoted more resources to it.”

Development, Review and Approval
If the drug is for a serious or life-threatening condition or it has more serious risks but less data, the following designations will help get the drug reviewed and approved faster, according to Temple and FDA.

Priority Review
The Prescription Drug User Fee Act of 1992 created a two-tiered system of review times — “standard review” and “priority review.”A priority review designation means FDA’s goal is to take action on an application within six months.

Overall attention and resources will be given to the evaluation of applications for drugs that show significant improvements in the safety or effectiveness of treatment, diagnosis, or prevention of serious conditions.

A serious condition refers to one with morbidity that has a major effect on day- to-day function and includes cumulative disability such as exacerbations in MS, progressive rheumatoid arthritis, progressive weakness and limitations in muscular dystrophy, to name a few.

Fast Track
Fast Track is a process designed to facilitate drug development and expedite the review of drugs to treat serious conditions to fill an unmet medical need. FT refers to getting in contact with the company that is developing the drug, helping them supply the most efficient possible studies and making it clear what the requirements are going to be, among other processes. It also will accept a “rolling review,” which means they’re allowed to submit their chemistry data before they submit clinical data.

mouse2The purpose of FT is to get new drugs to the person who needs it earlier. It addresses a broad range of serious conditions, based on if the drug will have an impact on survival or day-to-day functioning; or, if left untreated, the condition will progress from a less-severe condition to a more serious one.

The drug company must request FT designation, which can be initiated at any time during the drug development process.

Once the drug receives FT designation, communication begins between FDA and the drug company and is encouraged throughout the entire drug development and review process.

According to FDA.gov, any drug being developed to treat or prevent a condition with no current therapy is directed as an unmet need. If there are available therapies, an FT drug must show some advantage over available therapy, such as:

• Showing superior effectiveness or improved effect on serious outcomes
• Avoiding serious side effects of an available therapy
• Improving the diagnosis of a serious condition where early diagnosis results in an improved outcome
• Decreasing a clinically significant toxicity of an available therapy that is common and causes discontinuation of treatment
• Ability to address emerging or anticipated public health need

Breakthrough Therapy
Breakthrough therapy — also part of the drug development process — was added to the approval process via FDASIA. It is requested by the drug company, or FDA may suggest that the applicant consider BT if the data suggests that the drug program meets designation criteria.

BT helps speed up the development and review using preliminary clinical evidence that shows the drug may offer a substantial improvement over available therapies for people with serious or life-threatening conditions. Determining this is a judgment call.

Preliminary clinical evidence should show a clear advantage over available therapy and should suggest that the drug treats a serious or life-threatening condition that is not currently well treated.

mouse3“If a drug does something wonderful that’s never been done before, we will often accept the smaller safety database,” explained Temple during the webinar.

For BT designation, endpoints measure an effect on irreversible morbidity or mortality or on symptoms that represent serious consequences of the condition.

“Based on early evidence — animal, in vitro, or clinical for FT, early clinical evidence for BT,” explained Temple during the webinar. “Drugs will be designated as FT or BT if they are directed at serious conditions and provide benefit over available therapy. BT designation as well as FT, is primarily devoted to facilitating the development process.

“One element of the new BT designation specifically calls for involvement of senior FDA managers and experienced review staff for a cross collaborative, cross disciplinary effort [with the drug company],” added Temple. “I can tell you this is already having an effect.”

Temple added that FDA is also meeting with potential users of the drug much more than in the past.  For example, “We got a lot of help from people with MS who came to the advisory committee,” he said. “We’re very interested in consumer supported outcomes. Who knows better than the person using it how much it matters?”

Accelerated Approval
In 1992, FDA instituted accelerated approval regulations, knowing it may take an extended period of time to measure a drug’s intended clinical benefit.

AA refers to basing approval on a “surrogate endpoint” or “intermediate clinical endpoint,” which in a clinical trial can determine whether you may live longer, function better or have fewer symptoms that are not 100 percent predictive. Surrogate endpoints are markers that are thought to predict clinical benefit. An example of a surrogate endpoint is a measure like blood pressure, which may predict improved survival or fewer strokes.

Intermediate clinical endpoints measure the therapeutic effect that likely predicts the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality.

You can often get an answer on a surrogate endpoint long before the survival data come in. When that is used for approval it’s on condition that the real endpoint be studied in further studies afterward.

Advantages for using this system, according to Temple, include:

• Treatment where none existed.

• Effect on serious outcomes not provided by available drugs including available therapies that treat pain but not the bone damage or extreme limitations of motion such as with rheumatoid arthritis or CP.

• Better or added effects than provided by available therapies.

• Effects in people who cannot tolerate or do not respond to available therapies. For instance, the anti-psychotic drug, Clozapine, was approved despite considerable toxicity because it worked in people who didn’t respond to other therapies.

• Lack of toxicity another therapy has.

Using the approval system allows the FDA to be flexible in applying the standards. Studies needed for rare conditions are not going to have the 10,000 trials that may be available for cardiovascular outcome trials. Instead, they accept much smaller or historical controls, partly because the condition is better understood, and because they use flexibility while applying statutory standards.

Temple admits the new approval system is a mixed blessing, cautioning the risks of speeding new drugs to the public with less testing.

“I think it’s putting the money where the problem is,” Temple stated during the webinar. “Do we need that extra study, can they do some of the long-term toxicity studies after approval, are there ways to use adaptive designs to make the study more reasonable?

“Those are the things that can change a very long process into a shorter process and they need high-level input,” Temple stated. “To me, the new thing is, everybody’s watching and thinking hard on how to do this as efficiently as possible without losing what you need.”

Information for this article was gleaned from the webinar “Accelerated Approval Pathways” sponsored by CureDuchenne.org; “On The Fast Track: The FDA and Drug Approvals” from The Kojo Nnamdi Show broadcast; FDA.gov.