FDA Breakthrough Designation and what it means for Pharma

Drugs in Phase I clinical trials may be finding themselves bumped straight up to market after a new "Breakthrough Therapy Designation" was introduced by the FDA as part of the 2012 FDA Safety and Innovation Act (FDASIA) on July 9 of 2012. 

Amidst criticisms that the development and regulatory process of the FDA is too lengthy (Phases I-III commonly take 8-9 years to complete, followed by 1-2 years of FDA paperwork), and that drugs targeting serious life-threatening conditions receive the same treatment as the less urgent "lifestyle medications", the FDA has begun to address the issues with new regulations which facilitate market entry for drugs addressing therapeutic niches of unmet and pressing need. Essentially four priority lanes for such drugs now exist: "Fast Track", "Accelerated Approval", "Priority Review" and now "Breakthrough Therapy Designation". In addition, some drugs qualify for "Flexible Clinical Development" programs whereby the FDA grants the developer flexibility in the traditional clinical trial design. This scenario is mostly intended for orphan indications and rare diseases.

A Fast Track designation was instated in 1992 and is intended to facilitate the development and expedite the review of drugs to treat serious conditions and fill an unmet medical need. Designation may be granted on the basis of preclinical data. A sponsor of a drug that receives fast track designation will typically have more frequent interactions with FDA during drug development. In addition, products that have been designated as fast track can submit portions of a marketing application before submitting the complete application, known as rolling review.

The Accelerated Approval program can be used for speeding the development and approval of promising therapies that treat a serious or life-threatening condition and provide meaningful therapeutic benefit over available therapies. Accelerated approval allows approval of a drug that 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 an effect on irreversible morbidity or mortality (IMM) that is reasonably likely to predict an effect on IMM or other clinical benefit. 

Thus, the accelerated approval pathway is most often useful in settings in which the disease course is long and an extended period of time is required to measure the intended clinical benefit of a drug, even if the effect on the surrogate or intermediate clinical endpoint occurs rapidly. Nevertheless, even after the drug enters the market, the sponsor may be required to conduct post-marketing trials to verify and describe the drug’s clinical benefit. If further trials fail to verify the predicted clinical benefit, the FDA may withdraw approval.

A drug that has received a breakthrough therapy designation or a fast track designation can be eligible for the accelerated approval pathway, if the relevant criteria are met. 

Priority Review: Under the Prescription Drug User Fee Act (PDUFA), FDA agreed to specific performance goals for completing the review and taking an action on an application according to a two-tiered system of review times: Standard Review and Priority Review. Priority review shortens the review goal date to 6 months from the standard review timeline of 10 months.

Although definitive guidelines on the Breakthrough Therapy Designation (BTD) are only expected by the end of 2013, in essence this program has all the qualities of a Fast Track designation with an added bonus: whilst a Fast Track designation is granted to drugs which target unmet medical need for serious conditions, a Breakthrough Therapy Designation can contend for saturated therapeutic niches as long as preliminary studies have demonstrated outstanding superiority in efficacy over existing drugs. According to the FDA,  BTD drugs are “drugs that are intended, alone or in combination with one or more other drugs, to treat a serious or life-threatening disease or condition and preliminary clinical evidence which indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.” BTD drugs benefit from more dedicated FDA attention, and particularly receive FDA support on the design and process of clinical trials. BTD is, thus, the most superior of all FDA priority lanes. 

Breakthrough drugs may qualify for market entry after as early as after extended Phase I clinical trials, but this does not get the developers off the hook in terms of R&D as Phase IV-equivalent trials (mass safety and efficacy monitoring of the drug-taking population) will have to be completed alongside sales. Other than that, BTD drugs on the market are not under any kind of restrictions on patient size or marketing conduct. Another initiative advocated by FDA's Director of the Center for Drug Evaluation and Research Janet Woodcock is a richer and more accessible network of hospitals and doctors which would facilitate market entry for BTD drugs, whose developers would otherwise need to build networks of suitable patient facilities and physicians from scratch. The FDA is likely to work on establishing this healthcare-wide network over the coming years. 

Therapeutic niches addressed by the Breakthrough Therapy Designation   

The FDA has not specified which disease areas are considered life-threatening or serious, and said it will consider all cases on an individual basis. Clearly, matters or urgency will be the defining factor in whether a disease is eligible for BTD attention. Diseases which have a high mortality rate, low patient survival rates even with available therapies, and patient cohorts with low treatment success percentages by current therapies will be ideal BTD candidates. In the current therapeutic landscape, cancers (particularly lung cancer & lymphomas), heart disease, Alzheimer's disease, diabetes and some infectious diseases are likely to be the primary targets of BTD applications. Many of the 7000 classified orphan diseases, such as cystic fibrosis and gaucher disease (those affecting less than 200,000 people in the US), are also eligible. 

Drugs which have already received Breakthrough Therapy Designation

Since the regulatory pathway's preliminary inception in July of 2012 the FDA has already received 18 BTD applications, 3 of which have so far been denied and 5 granted. For the most part, the 18 applications targeted cancer, but two of the granted breakthrough designations were for the treatment of cystic fibrosis, developed by Vertex Pharmaceuticals: the drug Kalydeco, approved for marketing on Jan 31, 2013, and the experimental molecule VX-809. The pair are now being studied as a combination therapy. 

The third BTD designation, which is in fact two separate BTDs for two targets, was granted to Janssen & Pharmacyclics' ibrutinib as monotherapy for two B-cell malignancies: in patients with relapsed or refractory mantle cell lymphoma (MCL) who have received prior therapy, and in patients with Waldenström’s macroglobulinemia. 

On March 15, 2013 a fourth BTD was granted to Novartis's LDK78, an investigational compound intended for patients with anaplastic lymphoma kinase-positive non–small cell lung cancer.

On April 10, 2013 a fifth FDA designation was granted to Pfizer's Palbociclib-PD-0332991-an oral and selective inhibitor of cyclin dependent kinases 4 and 6.

It is up to the companies to announce FDA decisions on their applications, thus it is unknown which applications were refused and which are pending. 

What the Breakthrough Therapy Designation means for Pharma and Biotech

The length of Phase I trials averages between 2 and 4 years, and a drug which is able to commence sales after so short a development time is essentially prolonging its revenue-generating life by nearly a third. The designation itself can be obtained from the FDA during or shortly after preclinical trials, and an announcement such as a BTD receipt can send a company stock soaring or, for small private biotechs, can make of break their fundraising success. 

This designation will be another incentive for small biotechs to go it alone, rather than co-develop with larger pharma, because the costs involved in clinical trials of BTD drugs will be substantially lower. According to FastCompany.com: 

• Average out-of-pocket cost of developing a new drug, from inception to approval: $494 million
• Average out-of-pocket clinical cost for each new drug: $153.2 million
• Average out-of-pocket cost for each phase of clinical trials:
• Phase I - $18.6 million 
• Phase II - $28.8 million 
• Phase III - $105.8 million

A breakthrough therapy designation can thus save a biotech on average $130+ million, cutting clinical trial costs by up to as much as a whopping 90%. This is also likely to increase the survival rate of drugs and technologies whose destiny is determined by lack of funds rather than their value. 

It is important to note that a Fast Track or a Breakthrough Therapy Designation is not implicative of an increased chance of approval. It simply means that a drug will be eligible for review much sooner--thus, even if it fails, the risk of investment in it is lower despite its probability of approval being unchanged.  It also does not imply that payers or governments will necessarily cover the costs of treatment, although it would be logical to assume that breakthrough drugs would also have somewhat of a market priority. This is particularly relevant in light of the "physician networks" for BTD drugs which the FDA is working on. 

Whether or not investing in a BTD drug pays off remains to be seen. Bioassociate will keep track of all breakthrough designation grants over the coming months, and also of their fundraising activity/stock price. Follow us for upcoming stats of BTD "profitability".