Speeding Access to Therapies
FDA has taken steps towards making investigational drugs more widely available to severely ill patients as well as towards speeding the review and approval of NDAs and BLAs for these products. This lecture will cover access to investigational drugs outside of a clinical trial and speeding the review and approval of NDAs and BLAs.
FDA allows access to investigational drugs for patients with serious or immediately life-threatening diseases or conditions who lack other therapeutic options. It is not always possible for all patients who want access to investigational drugs to enroll in clinical trials. Patients may not meet eligibility criteria or may be geographically isolated from a study site. In these situations, FDA makes promising, but still investigational products available outside of a clinical trial to patients with serious and life-threatening illnesses. This investigational therapy is offered in a way that does not pose an unreasonable risk to the patient and retains valuable information about the effect of the drug. This is through treatment use or emergency use of the investigational drug.
Speeding the development and availability of drugs that treat serious diseases are in everyone’s interest, especially when the drugs are the first available treatment or have advantages over existing treatments. The FDA has developed approaches to making such drugs available as rapidly as possible. There are many mechanisms under which this can be done, but the mechanisms that we will discuss in this lecture include sub-part E, priority review, accelerated approval, and fast track. Please note that these mechanisms are not mutually exclusive.
First, let’s look at treatment use. During the clinical investigation of a drug, it may be appropriate to use the drug in the treatment of patients or a single patient not in the clinical trials through a treatment protocol or treatment IND. This allows promising new drugs to be made available to desperately ill patients as early in the drug development process as possible. Additional data on the drug safety and effectiveness is also obtained. A drug is ordinarily made available for treatment use during phase three or after all clinical trials have been completed. However, in some circumstances, a drug may be made available for treatment use during phase two.
Although treatment may be focused on an individual patient, a study protocol may be written to ensure that the treatment is administered appropriately and that patients are monitored for toxicity. It is important to note that a manufacturer of the investigational drug must first agree to provide the product. FDA cannot mandate that the requested products be supplied. Informed consent must be provided to the patient, an IRB must be in place, and IND safety reports must be submitted.
The second manner which we’re going to look at to expand the use of these therapies beyond an investigational trial, or a clinical trial that’s already in place, is through emergency use.
Emergency use is defined as a use of an investigational drug, in a life threatening situation, where no standard acceptable treatment is available, and in which there is not sufficient time to obtain IRB approval.
The emergency use provision in the SDA Regulations is an exemption from prior review, and approval by the IRB.
This exemption allows for one emergency use of an investigational drug without perspective IRB review.
Even for an emergency use, the investigator is required to obtain informed consent. However, informed consent can be weighed, as we discussed in the lecture, only informed consent to review. As we discussed in the lecture on informed consent. You may want to go back and review that lecture, because the exemptions for when informed consent need not be obtained, are discussed in that lecture, and I’m not going to repeat them here.
Emergency use of an investigational drug requires an IND. If the intended subject does not meet the criteria of an existing study protocol, or if an approved study protocol does not exist, the usual procedure is to contact the manufacturer and determine if the drug can be made available for emergency use under the company’s IND.
The need for an investigational drug may arise in an emergency situation, that does not allow time for a submission of an IND. In such a case, FDA, may authorize shipment of the drug in advance of an IND submission.
Now we’re going to move into some mechanisms that FDA has in place to expedite the review of NDAs and BLAs and speed approval of products to the market. Notice that these mechanisms do not speed the review of INDs. They are only for the marketing application phase of development.
And first we’re going to look at Sub-Part E regulation, and Sub-Part E is somewhat of a slang phrase that we use to describe this process, which is codified in Sub-Part E of Part 312 of Title 21 of the Code of Federal Regulations.
The agency’s procedures in Sub-Part E of the IND Regulations expedite the development, evaluation and marketing of therapies to treat individuals with life-threatening and severely debilitating illnesses. This part was put in place in 1988 in response to the AIDS crisis, and on this slide, I’ve given you the definitions of life-threatening and severely debilitating diseases or conditions, and these definitions apply to other expedited and expanded access programs.
This regulation reflects that the agency must make a medical risk benefit judgment in deciding whether to approve a drug product. While this decision making is taken for granted today, in 1988, when this regulation was first codified, this was novel thinking.
As part of this risk benefit analysis, the agency takes into consideration the severity of the disease, and the absence of satisfactory alternative therapy. Procedures reflect the recognition that physicians and patients are generally willing to accept greater risks or side effects from products that treat life-threatening and severely debilitating illnesses, than they would accept from products that threat less-serious diseases.
Under Sub-Part E, drug development is considered a continuum, from early pre-clinical and clinical studies, through submission of a marketing application. The regulations emphasize the critical nature of close and early communication between the agency and the sponsor, outlines procedures, such as pre IND and end of Phase One meetings as methods to improve the efficiency of pre-clinical and clinical development and focus on efforts by the agency and the sponsor to reach early agreement on the design of the major clinical efficacy studies that will be needed to support approval.
The thinking codified in Sub-Part E provided a foundation for laws, regulations and procedures outlining in the Prescription Drug User Fee Act and the FDA Modernization Acts that were put in place in the mid-1990s.
FDA’s accelerated approval procedures are available for drugs that have been studied to treat serious or life threatening illnesses, and that provide meaningful therapeutic benefit to patients over existing treatments. For example, the ability to treat patients unresponsive to, or intolerant of, available therapy. Under these procedures, FDA may approve drugs based on surrogate endpoints that reasonably predict that a drug provides clinical benefit. This clinical benefit is then confirmed through additional clinical studies that are completed after approval.
These studies must be adequate and well controlled, and are usually underway when approval is granted. In fact, if they aren’t underway, at least a protocol has to be put in place, and the agency has to provide input that that protocol is adequate. The approach under accelerated approval, also provides for removal of the drug from the market if further studies do not confirm the clinical benefit of the therapy.
Priority review facilitates the development and expedites the review of drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. Review classifications for NDAs and BLAs have been established to prioritize the review of these submissions. A priority designation is intended for drugs that have the potential for providing a significant improvement compared to marketed products in the treatment, diagnosis, or prevention of a disease, or a product that eliminates or substantially reduces a treatment limiting drug reaction, enhance patient willingness or ability to take the drug, or establish safety and effectiveness in a new subpopulation such as children.
When a BLA or NDA is filed with the agency, a review time period is assigned for the marketing application. A standard application for drugs which offer only minor improvement over existing therapies is given a 10 month review timeframe. A marketing application that is assigned priority review receive a six month timeframe. At the end of that timeframe, the FDA must issue an action letter, which is a letter that either contains deficiencies that need to be addressed prior to the drug being approved, or it is an approval letter. So if one is able to receive a priority review designation when the company submits the NDA or BLA, then one has the ability to gain an additional four months on the market with the product. If you’ve got a blockbuster product, that’s a lot of revenue that you’re generating during that four month period.
The fast track program is designed to facilitate the development and expedite the review of drugs that are intended to treat serious or life-threatening conditions and that demonstrate the potential to address unmet medical needs. An unmet medical need is defined as a medical need that is not addressed adequately by an existing therapy. Advantages include more frequent meetings and written correspondence with the agency and rolling review. A rolling review is when a company submits a BLA that is not complete. If a company under other circumstances submits a BLA that is not complete, meaning that sections in the BLA are missing, the sponsor or the applicant will receive a refuse-to-file letter, so the agency will not file that BLA or NDA. Now, there is a filing fee associated with NDA and BLA filings. It’s close to a million dollars today in 2018. If FDA refuses to file your application, they keep a piece of that, a chunk of that filing fee, so not only do you have to resubmit your application, but you also lose a lot of money.
Now, under fast track, you can submit sections of your NDA or BLA and not have FDA refuse to file the application. For example, when we do drug development, frequently the CMC section is the first to be completed for our marketing application, and usually the clinical section is the last to be completed, because one is waiting for the results and analysis of that Phase 3 study. Under fast track, when your CMC section is completed, you can submit that to the agency and have them begin your CMC review and get questions and deficiencies back to you prior to submitting your clinical section, prior to submitting your preclinical section. It does offer a great advantage timewise in that the agency is looking at sections of the application as they are complete, and you don’t have to wait for the entire application to be complete prior to filing.