Accelerated Approval

Hi All,

Thought I would do a deep dive into the Accelerated Approval process which is currently being explored in the form of the type A meeting. I have left most of the wording to be explained straight out of the FDA Guidance as it gives the best explanation,but full Disclosure, yes I am biased and bullish towards Mesoblast succeeding.

There are three qualifying criteria to Accelerated approval.

1.A drug that treats a serious condition AND generally provides a meaningful advantage over available therapies

The accelerated approval regulations state that accelerated approval is available only for drugs that provide a meaningful therapeutic benefit over existing treatments.18The accelerated approval provisions of section 901 of FDASIA (amending section506 of the FD&C Act) require FDA to “. . .tak[e] into account . . . the availability or lack of alternative treatments.”

AND

2.Generally provides a meaningful advantage over available therapies

There are none.
AND

3. Demonstrates 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 (IMM) that is reasonably likely to predict an effect on IMM or another clinical benefit (i.e., an intermediate clinical endpoint)

The two types of endpoints that can be used as a basis for accelerated approval are: (1) a surrogate endpoint that is considered reasonably likely to predict clinical benefit and(2) a clinical endpoint that can be measured earlier than IMM that is reasonably likely to predict an effect on IMM or another clinical benefit (also see section VII.D.2.).

For purposes of this guidance, these categories of endpoints are referred to as surrogate endpoints and intermediate clinical endpoints, respectively. A clinical endpoint is a characteristic or variable that directly measures a therapeutic effect of a drug––an effect on how a patient feels (e.g., symptom relief), functions (e.g., improved mobility), or survives. A clinical benefit is a positive therapeutic effect that is clinically meaningful in the context of a given disease. The clinical benefit must be weighed against a treatment’s risks to determine whether there is an overall benefit for patients (i.e., a positive benefit-risk profile).

1.A surrogate endpoint is a marker, such as a laboratory measurement, radiographic image, physical sign, or other measure, that is thought to predict clinical benefit,but is not itself a measure of clinical benefit. Depending on the strength of the evidence supporting the ability of a marker to predict clinical benefit,the marker may be a surrogate endpoint that is known to predict clinical benefit (a validated surrogate endpoint that could be used for traditional approval), a surrogate endpoint that is reasonably likely to predict a drug intended clinical benefit (and that could therefore be used as a basis for accelerated approval), or a marker for which there is insufficient evidence to support reliance on the marker as either kind of surrogate endpoint (and that therefore cannot be used to support traditional or accelerated approval of a marketing application).

Examples of surrogate endpoints that FDA has used to support accelerated approval includethe following:

-Prolongedsuppression of HIV viral load in plasma has been shown to reduce the morbidityand mortality associated with HIV disease and has been the basis for ContainsNonbinding Recommendations 18 traditional approval. Shorter-term suppression ofviral load has been used in the past as a surrogate to support acceleratedapproval because it was considered reasonably likely to predict an effect onmorbidity or mortality. Data now demonstrate that short-term suppression ofviral load may support full approval, in some circumstances

2.Anintermediate clinical endpoint is a measurement of a therapeutic effect thatcan be measured earlier than an effect on IMM and is considered reasonablylikely to predict the drug’s effect on IMM or other clinical benefit. Animportant question is whether the demonstrated therapeutic effect alone wouldbe a basis for traditional approval. Approvals for products for seriousconditions based on clinical endpoints other than IMM will usually beconsidered under traditional approval procedures. Approvals based on suchclinical endpoints will be considered under the accelerated approval pathwayonly when it is essential to determine effects on IMM or other clinical benefitin order to confirm the predicted clinical benefit that led to approval.Although FDA has limited experience with accelerated approvals based onintermediate clinical endpoints, FDA believes intermediate clinical endpointsgenerally could be used to support accelerated approval in situations such as:

-Astudy demonstrates a relatively short-term clinical benefit in a chronicdisease setting in which assessing durability of the clinical benefit isessential for traditional approval, but the short-term benefit is consideredreasonably likely to predict long-term benefit.

As we know graft-versus-hostdisease is a serious condition with high mortality rates.There is currently no treatment for children under the age of 12 and Remestemcel-L metits primary objective; the Day-28 ORR was 69.1% (95% CI: 55.2, 80.9) in theFAS. The primary endpoint results in MSB-GVHD001 were statisticallysignificant, and the measured response was durable (median 54 days), and theresults were consistent across subpopulations and secondary efficacy endpoints.

An approval foraccelerated approval should be based on an effect on a surrogate endpoint or anintermediate clinical endpoint that is reasonably likely to predict a drug’sclinical benefit, although the FDA does say that an accelerated approval shouldordinarily be discussed throughout the development. I can’t see where this hasbeen discussed, but we cannot rule out that this has already been discussedwith the FDA prior to the CRL.

The acceleratedapproval provisions of FDASIA in section 506(c) of the FD&C Act providethat FDA may grant accelerated approval to:

. . . a productfor a serious or life-threatening disease or condition . . . upon a determinationthat the product has an effect on a surrogate endpoint that is reasonably likelyto predict clinical benefit, or on a clinical endpoint that can be measuredearlier than irreversible morbidity or mortality, that is reasonably likely topredict an effect on irreversible morbidity or mortality or other clinical benefit,taking into account the severity, rarity, or prevalence of the condition andthe availability or lack of alternative treatments.

For drugsgranted accelerated approval, post marketing confirmatory trials have beenrequired to verify and describe the anticipated effect on IMM or other clinicalbenefit (see sections VII.D.2. and VII.D.3.).16

FDA believesthe new provisions provide additional flexibility concerning the implicationsof available therapy on eligibility for accelerated approval (see sectionVII.A.2.). They also provide clarification concerning the use of clinicalendpoints (herein referred to as intermediate clinical endpoints) as a basisfor accelerated approval (see section VII.B.2.). In addition, the newprovisions make clear that FDA has the authority to consider pharmacologic orother evidence developed using biomarkers or other scientific methods or tools,in conjunction with other data, in determining whether an endpoint isreasonably likely to predict clinical benefit (see section VII.C.).17 By indicatingthat FDA should take into account, “. . . the severity, rarity, or prevalenceof the condition . . .” in considering whether to grant accelerated approval,FDASIA reinforces the Agency’s longstanding commitment to regulatoryflexibility regarding the evidence required to support product approval for thetreatment of serious or life-threatening diseases with limited therapeuticoptions.

The acceleratedapproval pathway has been used primarily in settings in which the disease the course is long and an extended period of time would be required to measure theintended clinical benefit of a drug. For example, accelerated approval has beenused extensively in the approval of drugs to treat a variety of cancers andhuman immunodeficiency virus (HIV) disease where an effect on tumor growth orviral load can be assessed rapidly, but demonstrating an effect on survival or morbiditygenerally requires lengthy and sometimes large trials because of the durationof the typical disease course. Accelerated approval is also potentially usefulin acute disease settings where the intended clinical benefit can bedemonstrated only in a very large study because the clinical event that wouldneed to be evaluated to demonstrate clinical benefit occurs rarely. For example,accelerated approval could be used for an acute condition where an effect on a surrogateendpoint could be shown in a small number of patients, but a much larger studywould be needed to show the effect on a clinical outcome, such as survival.

FDA encouragessponsors to communicate with the Agency early in development concerning the potentialeligibility of a drug for accelerated approval, proposed surrogate endpoints orintermediate clinical endpoints, clinical trial designs, and planning andconduct of confirmatory trials. A sponsor seeking accelerated approval may alsoneed to prepare for a more rapid pace for other aspects of the drug development(e.g., manufacturing (see section IX.A.), development of a necessary companiondiagnostic (see section IX.D.)).

Drugs grantedaccelerated approval must meet the same statutory standards for safety andeffectiveness as those granted traditional approval. For effectiveness, thestandard is substantial evidence based on adequate and well-controlled clinicalinvestigations. For safety, the standard is having sufficient information todetermine whether the drug is safe for use under conditions prescribed, recommended,or suggested in the proposed labeling. Under accelerated approval, FDA can relyon a particular kind of evidence, such as a drug’s effect on a surrogateendpoint, as a basis for approval. FDA carefully evaluates such evidence toensure that any remaining doubts about the relationship of the effect on thesurrogate to clinical benefit are resolved by additional post approval studiesor trials. An application for accelerated approval should also include evidencethat a proposed surrogate endpoint or an intermediate clinical endpoint isreasonably likely to predict the intended clinical benefit of a drug.

Determiningwhether an endpoint is reasonably likely to predict clinical benefit is amatter of judgment that will depend on the biological plausibility of therelationship between the disease, the endpoint, and the desired effect and theempirical evidence to support that relationship. The empirical evidence mayinclude “. . . epidemiological, pathophysiological, therapeutic, pharmacologic,or other evidence developed using biomarkers, for example, or other scientificmethods or tools.” Evidence of pharmacologic activity alone is not sufficient,however. Clinical data should be provided to support a conclusion that arelationship of an effect on the surrogate endpoint or intermediate clinicalendpoint to an effect on the clinical outcome is reasonably likely.

In making thejudgment as to whether a drug’s effect on a given endpoint is reasonably likelyto predict clinical benefit, FDA considers all relevant evidence and mayconsult external experts, as needed. This guidance provides an overview of someof the important factors to consider in identifying and assessing thepredictive potential of surrogate endpoints or intermediate clinical endpoints.This guidance does not, however, address the specific clinical evidence neededto support a conclusion that a particular surrogate endpoint or intermediateclinical endpoint is reasonably likely to predict clinical benefit or IMMbecause such evidence is case-specific and is not readily generalizable.

Conditions ofAccelerated Approval

1.PromotionalMaterials Unless otherwise informed by the Agency, an applicant must submit tothe Agency for consideration during the preapproval review period copies of allpromotional materials, including promotional labeling as well asadvertisements, intended for dissemination or publication within 120 daysfollowing marketing approval.29 After 120 days following marketing approval,unless otherwise informed by the Agency, the applicant must submit promotionalmaterials at least 30 days prior to the intended time of initial disseminationof the labeling or initial publication of the advertisement.

2.ConfirmatoryTrials For drugs granted accelerated approval, post marketing confirmatorytrials have been required to verify and describe the anticipated effect on IMMor other clinical benefit. These trials must be completed with due diligence.FDA has interpreted the due diligence requirement to mean that the post marketingtrial(s) intended to verify the clinical benefit must be conducted promptly tofacilitate determination, as soon as possible, of whether clinical benefit hasbeen verified. The protocol for a post marketing trial should be developed asearly as possible, and timelines for the trial should be specified; forexample, timelines for enrolment and trial completion should be stipulated.There should be agreement between FDA and the sponsor on the design and conductof the confirmatory trial(s). If it is clear during development that a productis intended to be approved under accelerated approval on the basis of asurrogate endpoint or an intermediate clinical endpoint, confirmatory trial(s)should be underway at the time the marketing application is submitted. If it isnot clear until shortly before or after submission of a marketing applicationthat a surrogate endpoint or an intermediate clinical endpoint will be theproposed basis for accelerated approval, there should be agreement on thedesign and conduct of such trial(s) before approval.

Generally,the confirmatory trial would evaluate a clinical endpoint that directlymeasures clinical benefit. For example, the confirmatory trial population wouldordinarily be the same disease population that was studied to supportaccelerated approval. In some cases, however, the commercial availability of adrug following accelerated approval may make it difficult to enroll patients inthe same disease population. In these cases, a confirmatory trial may beconducted in a different but related population that is capable of verifyingthe predicted clinical benefit. This is often the case in oncology, where afteraccelerated approval of a drug for late-stage disease is granted, theconfirmatory trial is conducted in an earlier stage of the same cancer.

Thereare also cases in which additional evaluation (longer duration) of the samesurrogate endpoint that was used to support accelerated approval (rather than aclinical endpoint) in the same population could be persuasive evidence ofclinical benefit. For example, in the case of HIV treatment, an effect on viralload of relatively short duration (24 weeks) was considered reasonably likelyto predict clinical benefit supporting accelerated approval. An effect oflonger (1 year) viral load suppression was more convincingly related to durableclinical benefit in the setting of lifelong therapy and thus was used to verifyclinical benefit for traditional approval.

Whenit is possible to use a later effect in a trial to verify the effect seenearlier in the same trial that supported accelerated approval, the sameclinical trial(s) can be used to support accelerated approval and verify anddescribe the clinical benefit. In this case, the protocol and the statisticalanalysis plan should clearly account for an analysis of the surrogate endpointdata to provide support for accelerated approval, with continuation of therandomized trial(s) to obtain data on the clinical endpoint that will be thebasis for verifying the clinical benefit. When the same trial is used tosupport accelerated approval and verify clinical benefit, the data to verifythe clinical benefit may be, in some cases, nearly complete by the time ofaccelerated approval.

There arecurrently 244 CDER Drug and Biologic Accelerated Approvals Based on a SurrogateEndpoint. -. The majority on this listserve to fill an unmet need for a severe disease in a vulnerable and limited patient population. We also satisfy this requirement

Sources:

https://www.fda.gov/files/drugs/published/Expedited-Programs-for-Serious-Conditions-Drugs-and-Biologics.pdf
https://www.fda.gov/media/140986/download
https://www.fda.gov/media/88907/download