By: Pankaj Mondal, DrugPatentWatch Staff Writer
When it comes to measuring the success of a new drug, the amount of time required to complete the entire approval process become a decisive factor. With the increasing need to accelerate the market launch and address the unmet needs of patients, major global health authorities are now speeding up the drug approval processes.
The FDA approves more drugs and does it faster compared to its European counterpart-the European Medicines Agency (EMA). According to an April analysis published in the New England Journal of Medicine, the FDA approved 170 new drugs between 2011 to 2015 compared to just 144 by the EMA.
Dr. David Kessler, who headed FDA in the 1990s, says that the US is the fastest in the world when it comes to drug approvals. He adds that if a person in the country gets sick, chances are he’ll get access to a new drug first. In 2008, just 40% of new drug applications were approved; however, there was an upsurge in these approvals, with the figure touching 60%, according to PriceWaterhouseCoopers. This is because the agency has been working very closely with drug manufacturers to facilitate the entire process and make it easy to get through without major hiccups.
Accelerating the availability of drugs that treat serious ailments is in the nation’s interest, particularly if the drug has advantages over existing treatments or if it’s the first available treatment. To have a meaningful discussion and understanding of the validation process and the necessary regulatory approval strategies for drugs that have been designated into different classes, companies should first understand each of these designations put forth by the FDA. Only then, will they be able to identify approaches and challenges when working to launch a fast track, breakthrough therapy or accelerated approval drug to the market.
The FDA has developed four successful and distinct approaches in making drugs accessible as swiftly as possible:
- Fast Track
Fast track is a process developed to further the development and speed the review of drugs to cater to an unmet medical requirement or treat a serious ailment. The objective is to make important new drugs accessible to the patient earlier.
Determining whether a condition is serious is based on how the drug will impact factors like day-to-day functioning, survival, or when the possibility for the condition to deteriorate if left untreated. Common examples include heart failure, Alzheimer’s, AIDS and cancer.
Any drug developed to prevent or treat a condition with no existential therapy is defined as an unmet need. A fast track drug must exhibit advantages over available therapies like:
- Diminishing a clinical significant toxicity of a common available therapy, which causes a cessation in the treatment
- Enhancing the diagnosis of a serious ailment where early diagnosis leads to a better outcome
- Preventing serious side effects of available therapies
- Displaying better effectiveness, greater effect on serious conditions
- Ability to address anticipated or emerging public health requirement
A drug upon receiving fast track approval is eligible for the following:
- Frequent interactions with FDA to deliberate on the development plan while ensuring collection of data to furnish drug approval requirements
- Rolling Review, indicating that the firm can submit completed sections of its NDA or Biologic License Application (BLA) prior to the entire application being reviewed, which saves a lot of time for the company.
- Eligibility for Priority Review and Accelerated Approval if important criteria are met
The request for Fast Track designation should be requested by the company and can be started anytime during the drug development process.
- Breakthrough Therapy
Breakthrough therapy is applicable when a drug is desinged to treat a serious ailment and preclinical evidence shows that it demonstrates greater improvement compared to available therapies on clinically significant endpoints. Clinically significant endpoint is an endpoint that measures the effect on symptoms representing serious outcomes of the disease or on irreversible morbidity or mortality (IMM).
Finding whether a drug is better than available therapies depends on the magnitude of the treatment effect, which includes duration of the effect and the significance of the observed clinical outcome.
A drug approved through breakthrough therapy stands eligible for the following:
- Comprehensive guidance by the FDA on a productive drug development program
- Organizational commitment from senior managers
- All features representing fast track designation
Breakthrough therapy designation should be requested by the pharmaceutical company. If a sponsor has not requested for this, FDA can ask the sponsor to submit a request if after analyzing the submitted information and data, the agency is of the opinion that the drug development program can meet the touchstones for breakthrough therapy designation and the remainder of the program can benefit from the designation.
The designation request should be sent to the FDA immediately after the end of phase 2 meetings. The agency does not anticipate the requests to be made after the submission of an original NDA or BLA or a supplement since the primary goal is to find evidence required to support approval in the most efficient manner. The drug company normally gets a response from the agency within sixty days after receiving the request.
- Accelerated Approval
Keeping in mind that it may take many years to actually know the efficacy of a new drug, the FDA established the Accelerated Approval regulations in 1992. These allow a drug for a serious ailment that fills an unmet medical requirement to gain approval based on a surrogate endpoint. In clinical trials, a surrogate endpoint is used for speedy approvals and includes a marker-a radiographic image, laboratory measurement, or physical sign that predicts clinical benefit, but is not a measure of clinical benefit.
A surrogate outcome is an intermediate outcome that is used instead of patient-centered outcomes. Since using patient-centered outcomes in randomized clinical trials (RCTs) takes longer and is larger, in certain disease conditions, surrogate outcomes are generally used as the fundamental outcomes in designing RCTs. This saves sample size, resources and time to show the efficacy of a particular treatment. According to the FDA, there are laboratory signs or findings that may not be a direct measure of how a patient survives, feels or functions, but are considered likely to predict benefit.
Using surrogate endpoints can save invaluable time in the approval process. Instead of waiting to find out whether a drug actually prolongs the longevity of a cancer patient, for example, the FDA can approve the drug based on evidence that it can shrink tumor since tumor shrinkage will likely foresee a real clinical benefit. An approval based on this evidence can occur imminently than waiting to know whether patients actually live longer. However, the pharma company is still entailed to conduct studies to validate that tumor shrinkage will result in patients living longer.
Approval of the drug may be withdrawn if trials fail to confirm the clinical benefit or demonstrate insufficient clinical benefit.
- Prescription Drug User Fee Act
The US passed the Prescription Drug User Fee Act (PDUFA) in 1992, which enables the FDA to collect fees from companies to quicken the drug approval process. According to the FDA, the main objective of the act is to make new drugs accessible faster than anywhere in the world. Ever since PDUFA was passed into law, over 1,000 drugs and biologics have hit the market.
The act implements two elements for gaining approval :Standard Review and Priority Review
The main objective of standard review is to get a drug approved within 10 months. Such a review is applicable to a drug that offers very little improvement compared to other available therapies in use. Priority review is reserved for drugs that provide treatment where none existed or offer significant advances in treatments. This is an expedited approval process where the FDA strives to get a drug through the approval process in six months. One major difficulty with priority review is that it approves an NDA before means are available to fathom the effectiveness of the drug-a crucial step that is usually required.
These FDA designations are developed to increase the availability of new drugs manufactured to treat serious conditions. Given that speed and dexterity has historically not been the FDA’s strong forte-commercialization of a drug has taken an average of 12 years, with the cost touching $25 billion-the ability for these designations to save both money and time are very attractive. That said, changes in both approaches and mindset are needed by drug regulators and innovators to ensure drug quality and validate processes within the faster-moving constructs.
Successful Approaches for Handling the Approval and Confirmation of Accelerated Approval Drugs
- Transparent and open communication with the FDA is imperative throughout the complete approval and after launch processes. The mindset of drug companies of their unwillingness to learn important things for apprehensions of revalidating based on the findings is obsolete in this augmented reality. Companies will have to continuously keep themselves updated about pre and post launch, and lots of modifications will have to be filed.
- The classic three runs-launch a commercial process with minimum experience and revise after approval-is not benchmark anymore. The degree of flexibility extended by regulators is determined for each specific product. Some important factors that are usually considered are complexity of manufacturing process, how serious the condition is and the associated medical requirements, riskiness of product characteristics, state of the innovator’s quality system and benefits of the innovator’s risk-based quality evaluation including Critical Quality Attributes (CQA).
- Manufacturers should acknowledge without any qualms where data is insufficient, prove that the missing data poses no threat to the safety of patients and create a blueprint for acquiring the missing data after it hits the market.
- Novel statistical approaches and models will have to be applied in various cases. Representative assays and samples for these models will have to be collected from sources-like use of comparability protocols and prior knowledge. Besides, determining the proper use of stability data from representative pilot scale lots will be necessary.
- Emphasize more on safe supply of first-rated product at launch and patient safety instead of process optimization. Furthermore, companies need to start with process characterization and critical product attributes work way ahead than a general pharmaceutical process. In most instances, considering broader quality product ranges for non-Critical Quality Attributes until the company acquires additional manufacturing experience post-approval works best.
The accelerated drug approval program by the FDA can help provide earlier drug access to patients with serious diseases where there is an unmet need. Gambling on new technology has given the US lifesaving innovations, such as the smallpox vaccine. Yet, not all risks are worthwhile considering that one third of new drugs approved by the FDA between 2001 to 2010 in its bid to make new drugs easily available were found to have serious implications. Consumers should therefore be concerned about the risks created by fast drug approvals while policy makers should be cautiously looking at long-term impact these approvals may have.