Guidance for industry Expedited Programs for Serious Conditions – Drugs and Biologics (May 2014)
The FDA has several programs which are intended to facilitate and expedite development and review of new drugs to address unmet medical need in the treatment of a serious or life-threatening condition: fast track designation, breakthrough therapy designation, accelrated approval and priority review designation. The programs are inteded to help ensure that therapies for serious conditions are approved and available to patients as soon as it can be concluded that the therapies’ benefits justify their risks.
The statuory and regulatory eligibility cirteria for expedited programs require that a drug be intended to treat a serious condition. This could include for example a diagnostic product inteded to improve diagnosis or detection of a serious condition in a way that would lead to improved outcomes, a product intended to mitigate or prevent a serious treatment-related side effect or to avoid or diminish a seirous adverse event associated with available therapy for a seirous condition (e.g., product that is less cardiotoxic than available cancer therapy) or a product intended to prevent a serious condition.
Serious disease or condition: is defined as a disease or condition assocaited with morbidity that has substantial impact on day-to-day functioning. Short-lived and self-limiting morbidity will usually not be sufficient, but the morbidity need not be irreversible if it is persistent or recurrent.
Fast Track:
Section 506(b) of the FD&C Act provides for the designation of a drug as a fast track product if it is entended, whether alone or in combination with one or more other drugs, for the treatment of a seirous or liefe-threatening disease or condition, and it demonstrates the potential to address unmet medical needs for such a disease or condition.
Fast track is a process designed to facilitate the development, and expedite the review of drugs to treat serious coditions and fill an unmet medical need. Determining wehther a condition is serious generally is based on whether the drug will ahve an impact on such factors as survival, day-to-day functioning, or the likelihood that the codition, if left untreated, will progress form a less severe condition to a more serious one. AIDS, Alheimer’s, heart failrue and cancer are obvious examples of serious conditios.
Filling an unmet medical need is defined as providing a therapy where none exists or providing a therpay which may be potentially better than available therapy.
Fast track designation must be requested by the drug company. A request for the designation may be made at the same time, or any time after, the applicaton submission for the investigation (study) of the drug under section 505(i) or section 351(a)(3) of the Public Health Service Act. FDA will review the request and make a deciion with 60 days based on whether the drug fills an unmet medical need to a serious condition. Once a drug recives Fast Track designation, early and frequent communication between the fDA and a drug company is encouraged throughout the entire drug development and review process.
Fast track request should be submitted with an IND or after, ideally, no later than the pre-BLA or pre-NDA meeting.
Breakthrough Therapy:
Section 506(a) of the FD&C Act provides for designation of a drug as a breakthrough therapy if the drug is intended, alone or in combination with 1 or more other drugs, to treat a seirous or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on 1 or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.
Unlike the information that could support fast track designation, which could include therectical rationale, mechanistic rationale (based on nonclinical data) or evidence of nonclinical activity, breakthrough therapy designation requires preliminary clinical evidence of a treatment effect that may represent substantial improvement over available therapies for the treatment of a serious condition.
Qualifying criteria is a drug that is intended to treat a serious condition and preliminary clincial evidence indciates that hte drug may demonstrate substantial improvement on a clinically significant endpoin(s) over available therapies.
A request for breakthrough therapy should be usbmitted with an IND or after, ideally, no later than the end of phase 2 meeting.
Accelerated Approval:
The accelerated approval provisions of FDASIA in section 506(c) of the FD&C provide that FDA may grant accelerated approval to a product for a serious or life-threatening disease or condition upon determination that the product has an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit, or on a clinical endpoint that can be measured earlier than irreversible morbidity or mortality, that is reasonalby likely to predict an effect on irreversible morbidity or mortality or other clinical benefit, taking into account the severity, rarity, or prevalence of the condition and the availability or lack of alternative treatments.
Surrogate endpoints are often thought to be a easmure for example the underlying cause of the diase (e.g., elvated uric acid and gout, elevated blood pressure, low thryoxine levels and hypothyroidism, high ammonia levels), an effect that predicts the ultimate outcome (e.e., tumor shrinkage oculd be expected to delay symptomatic progression and improve survival, diuresis could be expected to improve symptoms of ehart failure, effects on serum creatinine or glomerular filtration rate (if not transient or reversible) are accepted surrogates for predicitng effects on chronic renal disease and delaying the occurenc eof end-stage renal disease) and the state of the pathophysiologic pathway leading to the clinical outcome (e.g., low levels of the biomarker that increase with replacement of a missing enzyme or clotting factor)
Accelerated Approval. (FDA may approve drugs for serious or life-threatening diseases or conditions where there is an unmet medical need and the drug is shown to have an effect on a surrogate endpoint that is reasonably likely to predict a clinical benefit to patients (improving how patients feel or function, or whether they survive longer).
In 2012, Congress passed the Food and Drug Adminsitration Safety Innovations ACT (FDASIA). Section 901 of FDASIA amends the Federal Food, Drug, and Cosmetic Act to allow the FDA to base accelerated approval for drugs for serious conditions that fill an unmet medical need on whether the drug has an effect on a surrogate or an intermediate clinical endpoint. A surrogate endpoint used for accelerated approval is a marker -a laboratroy measurement, radiographic image, physical sign or other measure that is thought to predict clincial benefit, but is not itself a measure of clinical benefit. Likewise, an intermediate clinical endpoint is a measure of a therpaeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality (IMM).
The FDA bases its decision on whether to accept the propsoed surrogate or intermedate clincial endpoint on the scientific support for that enpoint. Studies that demonstrate a drug’s effect on a surrogate or intermediate clincial endpoint msut be adequate and well control as required by the FD&*C Act.
Using surrogate or intermediate clincial endpoints can save valuable time in the drug approval process. Instead of haivng to wait to elarn if a drug actually extends survival for cnacer pateints, for exaple, the FDA may approve a drug based on evidence that the drug shrinks tumors, becasue tumor shrinkage is considered reasonably likely to predict a real clinical benefit.
A sponsor should ordinarily discuss the possibility of accelerated approval with the review devision during development, supporting for exaple, the use of the planned endpoint as a basis for approval and discussing the confirmatory trials, which should usually be already underway at the time of approval.
Priority review Designation:
Qualifying criteria includes an application for a drug that treats a serious condition and if approved, would provide a significant improvement in safety or effectiveness or any supplement that proposes a leabeling change pursuant to a report on a pdeiatric study under 505A or an applicaiton for a drug that has been designated as a qualified infectious disease product or any application or supplement for a drug submitted with a priority review voucher.
Real-Time Oncology Review (RTOR):
510(k) premarket notification pathway:
A 510(k) notification is a premarket submission made to the FDA to demonstrate that a new device is substantially equivalent to a legally marketed predicate device.
For example, the FDA found that the Lumipulse G pTau217/beta-Amyloid 1-42 plasma ratio is substantially equivalent to the Lumipulse G beta-amyloid ration (1-42/1-4), which is the previously authorized test that uses CSF samples.
Breakthrough Device Designation:
Breakthrough Devices Program: The Breakthrough Devices Program is comprised of two phases; (1) the designation request phage where an interested sponsor of a device request the FDA grant that device Breakthrough device designation (based on critieria such as more effective treatment or diagnosis of life-threatening or irreversibly debiliating human disease or conditions)and (2) actions to expedite development of the device and the prioritized review of subsequent regulatory submissions.
Commissioner’s National Priority Voucher (CNPV) program:
The U.S. Food and Drug Administration has a Commissioner’s National Priority Voucher (CNPV) program to enhance the health interests of Americans. The new voucher may be redeemed by drug developers to participate in a novel priority program by the FDA that shortens its review time from approximately 10-12 months to 1-2 months following a sponsor’s final drug application submission.
Singe Patient Expanded Access IND:
A single-patient expanded access IND (often called a single-patient IND or compassionate use IND) is an FDA mechanism that allows one individual patient to receive an investigational drug or biologic outside of a clinical trial when no comparable or satisfactory approved therapy is available.
Umbrella Trials:
An umbrella trial is a type of clinical trial that evaluates ultiple targeted therapies within a single disease, which is divided into subgroups based on specific biomarkers or other defining characteristics. Unlike traditional trials that test one drug for one condition, umbrella trials assess several therapies simultaneously within the same disease fraemwork, assigning patients to different sub studies or “strata” according to theri biomarker profiles. Operating under a unified master protocol, a feature shared with basket trials, this approach increases efficiency by streamlining infrastructure and enabling precision medicine strategies tailored to individual molecualr or genetic features. Many umbrella trials are also adaptive, allowing researhers to modify the design in response to emerging data, thereby maintaining scientific rigor while accelerating the path to effective, personalized treatments.
An example would be starting with phenylketonuria (PKU), a classic metabolic live disorder caused by mutations in the PAH (phenylalanine hydroxylase gene) gene. With PKU, the subgroups are the patients who have different variants. The master clinical protocl should go into the first IND for the first gene of interest. Then as patients are enrolled for the second gene, a second IND is filed but the first IND is cross referenced. The only thing in the new IND are things specific to the variant version of the drug.
This umbrella system is perfect with respect to CRRISP gene editing. Each new editing system –base, prime, or nuclease can form its own regulatory backbone. A design system is created where only one small genetic component, the guide RNA (gRNA) changes for each patient while the rest –the lipid nanoparticle (LNP) delivery vehicle and the editor mRNA stays constant.
Real-Time Oncology Review (RTOR):
See RTOR (Guidance for Industry)
In a typical FDA drug review process, efficacy and safety data are submitted at the same time as other elements of a drug applicaiton (e.g., adminsitrative information, summary documents, clinical study reports, manufacturing informaiton, nonclinical study reports, etc) for a complete application. However, the prcess of assembling a drug applicaiton for submission typically takes at least several months.
The FDA Oncology Center of Excellence (OCE), in collaboration with the Office of Oncologic Diseases (OOD) started RTOR in February 2018 to facilitate earlier submission of top-line results (i.e., efficacy and safety resutls from clinical studies before the study report is completed) to support an earlier start to the FDA application review.
To be considered for RTOR, submission shoudl demonstrate 1) clinical evidence from adequate and well controlled investigations which indicate that the drug may demonstrate substantial improvement on a clinically relevant endpoint over available therapies, 2) easily interpreted clinical trails endpoints (e.g., overall survival, response rates) as determeined by the review division and OCE and 3) no aspect of the submission is likely to require a longer review time (e.g., requirement fro new REMS, advisory committee, etc). RTOR involved ealry engagement with the applicnt to discuss the submission timelines for RTOR components and the full appliction submission. At the time top-line results of a pivotal tria(s) are available and the database has been locked, an applicant may apply for review under RTOR by submitting a request to the Investigations New Drug Application (IND). If the application is not accepted into RTOR the applicant should follow routin applicaiton submission procedures.