A slightly different version of this article was originally published by TOPRA. This version has additional graphic figures.
Original TOPRA Publication:
D'Souza, R. (2016). Therapeutic product access and expedited review pathways in North America. Regulatory Rapporteur – Vol 13, Issue 2, February 2016, pages 15-19. Available at: http://www.topra.org/regulatory-rapporteur
Access to investigational drugs, biologics and medical devices can be sought outside of clinical trials to treat serious or lifethreatening diseases. When applying for market approval, these therapeutic products can receive an expedited review by regulatory agencies. The US FDA and Health Canada have different regulatory mechanisms that are highly sought after by manufacturers in a competitive industry.
In the US, to conduct a clinical trial, an investigational new drug (IND) submission or an investigational device exemption (IDE) must be submitted to the FDA. Patients with serious or immediately life-threatening diseases who have no comparable or satisfactory therapeutic alternatives on the market look to participate in clinical trials to receive promising investigational therapies. However, this is not always possible as current clinical trials may have study protocols with subject criteria that exclude such patients from participating. At times, there may not be ongoing clinical trials available for participation.
The FDA therefore created its “expanded access program” (EAP) so that patients with serious or immediately life-threatening diseases with no comparable or satisfactory therapeutic alternatives can access investigational therapeutic products outside of a clinical trial. Different expanded access categories exist (Figures 1 and 2), each with its own set of eligibility criteria. All eligibility criteria must be met for consideration under an expanded access pathway. In general, the criteria ensure that: (1) only patients with critical need and no alternative can access investigational products; (2) investigational products are sufficiently safe and effective for the intended use under expanded access; and (3) existing clinical trials and market application plans for investigational therapeutic products can proceed without disruption from the EAP. The FDA centres (Center for Drug Evaluation and Research (CDER) and Center for Biologics Evaluation and Research (CBER)) have allowed most of the expanded access INDs and protocols received between 2010 and 2014 to proceed (Figure 3, Appendix 1).
Figure 1: Expanded Access - Drugs, including Biologics
Figure 2: Expanded Access - Medical Devices
Figure 3: Expanded Access INDs & Protocols
Expedited Review Programs for Serious Conditions - Drugs & Biologics
Drugs, including biologics, intended to treat serious or lifethreatening conditions can receive an expedited FDA review. Factors that determine if a condition is serious can vary and include survival, day-to-day functioning, or the likelihood that the condition, if left untreated, will progress from a less severe condition to a more serious one. Four expedited review programmes exist: fast track designation (FTD), breakthrough therapy designation (BTD), accelerated approval pathway (AAP) and priority review designation. The FDA has approved many drugs via fast track1 and priority review2 designations as well as via the AAP.3
Fast Track Designation
The FTD can be applied to drugs intended to treat serious conditions and address an unmet medical need. Drugs that are considered for FTD include drugs that: (1) show superior effectiveness, an effect or improved effects on serious outcomes; (2) improve diagnosis ofa serious condition where early diagnosis produces an improved outcome; (3) do not produce side-effects of available therapies; (4) decrease a clinically significant toxicity of an available therapy that is common and causes treatment discontinuation; and (5) address ananticipated or emerging public health need.
Drug manufacturers must request FTD during drug development. This can be done with an IND but no later than a pre-new drug application (pre-NDA) or pre-biologic license application (pre-BLA) meeting. FDA review time is 60 days. Drugs that receive FTD can benefit from some or all of the FTD features, which include frequent meetings and written correspondence with the FDA, a rolling review whereby the FDA reviews sections of a new NDA or a BLA as they become ready. If relevant criteria are met, drugs that receive FTD may even become eligible for accelerated approval or priority review. Drugs that no longer meet the qualifying criteria for FTD listed above can have their designation rescinded.
Breakthrough Therapy Designation
Drugs intended to treat serious conditions and which have preliminary clinical evidence demonstrating substantial improvement, such as improved duration or magnitude of treatment effect, in one or more clinically significant endpoints over an available therapy are considered breakthrough therapies. Clinically significant endpoints can include:
- A significantly improved safety profile compared with availabletherapy (eg, less dose-limiting toxicity for an oncology agent),with evidence of similar efficacy
- An effect on a pharmacodynamic biomarker that fails criteriafor an acceptable surrogate endpoint, but strongly suggeststhe potential for a clinically meaningful effect on the underlying disease
- An effect on an established surrogate endpoint such as a alaboratory measurement, radiographic image, physical sign orother measure thought to predict clinical benefit, but is not itselfa measure of clinical benefit
- An effect on an intermediate clinical endpoint, such as aneffect on irreversible morbidity and mortality (IMM), consideredreasonably likely to predict a clinical benefit (ie, the accelerated approval standard).
Ideally, drug manufacturers can request BTD with the IND or as an IND amendment before the end of Phase II meeting or before the clinical trial for demonstration of efficacy. Like the FTD, the BTD has an FDA review time of 60 days. Another feature shared with the FTD is the rescinding of the BTD if a drug does not meet the above qualifying criteria. Drugs receiving BTD can be eligible for FTD features and will gain organisational commitment from the FDA including senior managers to provide intensive guidance on an efficient drug development programme that begins as early as Phase I. CDER and CBER have granted less than a third of all the BTD requests received, but at a high review performance rate (Figures 4 & 5, Appendix 2).
Figure 4: CDER & CBER Breakthrough Therapy Designations
Figure 5: FDA Review Performance of Breakthrough Therapy Designations
Accelerated Approval Pathway
A drug may be approved via the AAP if it meets all of the following criteria:
- Indicated for a serious medical condition
- Generally provides a meaningful advantage over available therapies
- Demonstrates (a) an effect on a surrogate endpoint that is reasonably likely to predict clinical benefit; or (b) an effect 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 (c) other clinical benefit (ie, an intermediate clinical endpoint).
Post-market controlled confirmatory trials are required for drug approval to verify that the drug’s effect on the surrogate endpoint or the intermediate clinical endpoint predicts a clinical benefit. The FDA and the sponsor must agree on study design and conduct.
Priority Review Designation
Drug manufacturers can request a priority review designation with their NDA, BLA or efficacy supplement. Priority review designation is assigned at the time of original filing but the FDA has a 60-day response timeframe. If designated, the marketing application review time is shortened to six months.
Different qualifying criteria exist for the priority review designation, including the need to demonstrate significant improvements when compared with standard applications. Examples of significant improvements include evidence of increased effectiveness in treatment, prevention, or diagnosis of condition; evidence of safety and effectiveness in a new subpopulation; elimination or substantial reduction of a treatment-limiting drug reaction; or documented enhancement of patient compliance that is expected to lead to an improvement in serious outcomes.
Special Access Program
In Canada, “special access programs” (SAPs) exist for drugs and medical devices. Practitioners can request access to drugs intended for serious or life-threatening conditions if evidence supports the intended use and marketed alternatives do not exist, have failed or are unsuitable. Similarly, practicing healthcare professionals can request access to custom-made and unlicensed medical devices for emergency use or when conventional devices have failed, areunsuitable or unavailable. Under the SAP, healthcare professionals and manufacturers bear responsibilities such as drug record-keeping and reporting with respect to adverse drug reactions and device problems. Manufacturers additionally control various conditions of sale such as price and conditions of use.
While not a mechanism for expedited regulatory review or a substitute for a clinical trial, the SAP can be used in cases of drug shortage, drug discontinuation, or to gather new or confirmatory safety and efficacy evidence when a clinical trial is inappropriate. SAP can also be used under certain conditions for access to a drug that has received a negative regulatory response.
Health Canada may consider a new drug submission (NDS) or supplemental new drug submission (SNDS) for priority review status if the drug meets eligibility criteria. Drugs considered must be intended for serious, life-threatening or severely debilitating diseases or conditions. Drugs with no marketed alternatives must demonstrate effective treatment, prevention or diagnosis. Alternatively, drugs for priority review must reveal a significant increase in efficacy and/or significant decrease in risk such that the overall benefit–risk profile is improved over existing therapies, preventatives or diagnostic agents. For instance, in its benefit–risk evaluation, Health Canada will consider a reduction in toxicity over the marketed drug, an improved serious outcome or a favourable effect on a serious symptom of the condition. At least two well-controlled clinical studies are generally required as substantial evidence for clinical effectiveness.
Health Canada expects that drugs granted priority review status will have submissions filed within 60 calendar days. The priority review status means drugs will have a shorter review timeframe of 180 calendar days. With initial processing and screening, this brings the total processing time to 215 calendar days.
Notice of Compliance with Conditions (NOC/c)
Drug therapies for the treatment, prevention or diagnosis of serious, life-threatening or severely debilitating diseases/conditions that either have no available alternative Canadian therapy or represent a significant improvement in the benefit–risk profile over existing products are eligible for “notice of compliance with conditions” (NOC/c) consideration by Health Canada. The NOC/c provides for earlier market approval but with conditions such as an agreement by the sponsor to: (a) undertake confirmatory trials to prove clinical benefit; (b) perform enhanced post-market surveillance and reporting for drug safety; and possibly (c) conform to restrictions with respect to advertising and drug distribution. New drugs (NDS, SNDS) and generic drugs (abbreviated new drug submission (ANDS), supplemental abbreviated new drug submission (SANDS)) can utilise the NOC/c policy. Generic drugs (ANDS) would probably not require confirmatory trials; though there can be exceptions, eg, a circumstance where the Canadian reference product (CRP) sponsor withdraws their drug from the market prior to completing and/or submitting the confirmatory trial(s).
NOC/c can be granted directly by Health Canada on review completion of any submission if there is substantial evidence of effectiveness. The sponsor can also request advanced consideration under the NOC/c at the pre-submission meeting. The sponsor must then submit the drug submission within 60 calendar days following notification of eligibility. NDS and SNDS under the NOC/c advance consideration policy can have a review period of 200 calendar days (+35 days receipt and screening) while an ANDS or SANDS thatreferences a CRP with NOC/c status will be subject to a review target of 180 days. Various drugs have been issued the NOC/c by Health Canada.4
The fact that very many drugs have already received approvals [expanded access (Appendix 1), BTD (Appendix 2), FTD,1 priority review designation,2 AAP,3 NOC/c4 ] are a testament that regulatory mechanisms for early or expedited market access are highly coveted in a competitive industry. For instance, recently, Merck KGaA and Pfizer received both BTD and FTD for avelumab, a drug in its investigational stage for a rare form of skin cancer, metastatic Merkel cell carcinoma (MCC).5 Bristol-Myers Squibb, Roche and AstraZeneca all have immunotherapies further in development than avelumab but, according to journalist Nick Paul Taylor in FierceBiotech, Merck KGaA and Pfizer hope to “leapfrog rivals” in this corner of the market.5 In another example, Daiichi Sankyo, with its patent losses for blood pressure drug Benicar and diabetes treatment Welchol, has coveted BTD for its Phase III cancer drug, pexidartinib.6
Thus, the various regulatory mechanisms for access and expedited review can prove strategic when incorporated into the marketing plans of drug and medical device manufacturers. Regulatory professionals play a key navigational role with their design and execution of custom, objective-based regulatory strategies.
Appendix 1: Expanded Access INDs & Protocols
Appendix 2: Breakthrough Therapy Designation Requests since Inception (Jul 09, 2012 Food and Drug Administration Safety and Innovation Act)
1. FDA. Fast Track Approvals [online], 2015. Available at: www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/NDAandBLAApprovalReports/ucm2007016.htm (accessed 3 November 2015).
2. FDA. Priority NDA & BLA Approvals [online], 2015. Available at: www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/NDAandBLAApprovalReports/ucm2007012.htm (accessed 3 November 2015).
3. FDA. CDER Drug and Biologic Accelerated and Restricted Distribution Approvals [online], 2015. Available at: www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/DrugandBiologicApprovalReports/NDAandBLAApprovalReports/UCM404466.pdf (accessed 20 November 2015).
4. Health Canada. Notice of Compliance with conditions (NOC/c) – Drug Products [online], 2015. Available at: www.hc-sc.gc.ca/dhp-mps/
prodpharma/notices-avis/conditions/index-eng.php (accessed 20 November 2015).
5. N Taylor. ‘Merck KGaA, Pfizer bag “breakthrough” status for PD-L1 immunotherapy’, FierceBiotech [online], 2015. Available at: www.
fiercebiotech.com/story/merck-kgaa-pfizer-bag-breakthrough-status-pdl1-immunotherapy/2015-11-18 (accessed 20 November 2015).
6. D Garde. ‘Daiichi Sankyo’s cancer drug wins the FDA’s coveted “breakthrough” tag’, FierceBiotech [online], 2015. Available at: www.
fiercebiotech.com/story/daiichi-sankyos-cancer-drug-wins-fdas-covetedbreakthrough-tag/2015-10-30 (accessed 20 November 2015).