FDA procedures for new medical treatments

There's been some discussion among Network members about the drug approval process, as KRN23 is entering Phase 3 clinical trials, and you may be wondering just what is involved and how long it takes.

In extremely simplified form, the process in the United States (each country has different rules, but they're likely to be similar) involves negotiations between the applicant (in the case of KRN23, that would be Ultragenyx Pharmaceutical) and the Federal Drug Administration (FDA).

The first step (long since completed in the case of KRN23) is to do some initial laboratory testing (NOT on humans) to determine whether the product is likely to be toxic or not.

If the initial results are encouraging, the next step is to apply to the FDA for an Investigational New Drug exemption from the law that prohibits testing on humans by offering data that suggests it's reasonable to believe it's safe.

If the FDA believes that testing in humans is reasonably likely to be safe, then the applicant can proceed with the third step, which is to design the Phase 1 testing. Before each of the clinical trial phases, the applicant will be discussing the study design and protocol (exactly how the study will be carried out) with the FDA to increase the likelihood that the results will satisfy the FDA later in the process.

Once the study is designed and a protocal established, the applicant must obtain Institutional Review Board (IRB) approval. An IRB is an independent group of experts who review of the existing data to data to make a preliminary recommendation with respect to proceeding with testing on humans.

Phase 1 clinical trials are generally small (less than 100 patients), often healthy patients (not having the condition being tested) and are solely to determine toxicity. Approximately thirty percent of tested drugs fail at this point. KRN23 successfully completed this Phase several years ago.

If the Phase 1 testing suggests that the drug is reasonably safe, then Phase 2 can begin, again after discussing the study design and protocols with the FDA and another IRB review. This is a broader trial, both in terms of how many people are enrolled (although it's still a relatively small number) and in terms of what is being studied. In addition to safety, researchers are considering whether the drug actually works. Approximately sixty percent of tested drugs fail at this point. KRN23, however, had encouraging data at this phase, and is moving on to the next step.

Phase 3 clinical trials are the broadest and most complicated trials. Again, they're designed by the applicant, with feedback from the FDA. Significantly more patients are needed for these trials. KRN23 is currently in Phase 2B, with patients who previously volunteered in Phase 2. When Phase 3 begins later in 2015, it will be open to anyone meeting the eligibility requirements. On average, Phase 3 trials last from one to three years. Getting sufficient volunteers who are eligible for the study can be a challenge for rare diseases like XLH and can delay completion of the trials. Note that another thirty percent of tested drugs fail at this point. We're hopeful that won't be the case for KRN23, however!

Finally, upon satisfactory completion of the Phase 3 trials, the applicant files a New Drug Application with the FDA, with analysis of the data from the clinical trials and a draft of the label (the printed information you get when the prescription is filled), and the FDA undertakes its review. Only about fourteen percent of drugs fail to get approval at this stage.

There are two levels of priority for review, which determines the timeframe. The standard period is twelve months from filing the New Drug Application (after the Phase 3 trials) to a decision by the FDA. Note that a "decision" may consist of a request for more information, so it's not a guarantee that the matter will be resolved in that timeframe. There's also a priority review period that's slightly faster, at eight months, for treatments for conditions that have no alternative therapy. It's possible that KRN23 will qualify for that expedited review, since the existing treatments manage symptoms rather than getting to the root of the condition.

Once the FDA has reviewed the New Drug Application and made a final decision with respect to the right to market the drug and the exact wording of the label, the drug can be marketed. The FDA may require an additional set of clinical trials, however, called Phase 4. These are intended to resolve any remaining questions the FDA may have, and are common where there are issues relating to symptoms or clinical outcomes that may take ten or more years to get answers for. This testing, however, does not stop the marketing of the product, except in the event of serious unexpected side-effects being reported.