On a panel titled “Activist FDA: Transformation Agent,” Prevision Policy founder and former Pink Sheet editorial head Cole Werble relayed the tale of Acadia Pharmaceuticals, a San Diego-based company with a stage three compound (pimavanserin) targeting Parkinson’s disease-related psychosis.

A month ago, Acadia met with FDA to discuss the proper design of a new phase III trial intended to confirm the results of a previous, 17-month study that met its primary endpoints. A confirmation trial was needed, Acadia presumed, since the first phase III trial of pimavanserin, conducted in 2009 at half the dose of the successful trial, had failed. Acadia had already begun to enroll patients in the confirmation trial – which represented an $18 million commitment – when it met with FDA in April to get the agency’s blessing.

To Acadia’s surprise, FDA responded that the additional confirmation trial wouldn’t be necessary, based on the pivotal phase III trial already on the books, combined with supportive data from other studies on pimavanserin. As a result, Acadia scrapped plans to do another trial, and began preparing its NDA posthaste. But the company wasn’t hasty enough, and investors dialing in to a call about the FDA meeting balked at the company’s projected filing date – near the end of 2014. Why not file immediately, they wanted to know? Acadia executives’ refrain in response, was, “these things take time.” FDA had reversed the waiting game, making Acadia itself responsible for the delay in review and commercialization of a new product.

This is just one example, of course; it isn’t likely that a big pharma looking to introduce another DPP4 into the market for type 2 diabetes, for example, would be told not to worry about additional trials studying cardiovascular or pancreatic side effects. But the fact remains that FDA approved 39 NDAs in 2012 – the most since 1997 – and the agency launched yet another expedited regulatory pathway – breakthrough therapies – at the beginning of 2013. The breakthrough therapies designation is likely to shorten the timeline from discovery to commercial approval – for those drugs receiving the designation – to between three and five years, according to IMS estimates.

Rachel Sherman, associate director of medical policy and director of the Office of Medical Policy, CDER, FDA

The timeline from discovery to approval could be as short as 26 months, said Rachel Sherman, FDA’s associate director of medical policy at the Center for Drug Evaluation and Research (CDER). Sherman said her office had received – to date – 39 requests for breakthrough therapy status, of which 12 have been granted and 14 denied, with 11 pending and two withdrawn. She said the breakthrough therapies program is already “an enormous success.”

Joseph Herring, CEO at Covance, noted that pharmaceutical companies are often difficult to work with, from his perspective as the head of a CRO. “[Investigators] want a perfect trial that can’t be enrolled.” He wondered about the interplay companies have with FDA regarding trial design discussions. In response, Sherman advised more communication. “If what we say doesn’t make sense, ask us. Argue with us. We’re receptive to it.”

How does a company know whether it’s sufficiently engaged with FDA? “If your lead clinical person is on a first name basis with the [respective] lead reviewer at FDA, you’re in good shape,” said Sherman. “If you’re not, you’re not.” Sherman cited the Clinical Trials Transformation Initiative as another program aimed at “identifying and promoting practices that will increase the quality and efficiency of clinical trials.”

“The point of all our programs is better evidence generation…we lack evidence,” said Sherman. “The most expensive drug is the one given to the wrong patient, or given incorrectly.”

On the subject of biosimilar approvals, Sherman said FDA hasn’t received a single application yet, adding that the phrase “follow-on biologics” is dead. The requirements for biosimilars, according to Sherman, are that a biosimilar be “highly similar” to the original product, with “no clinically meaningful differences.” Sherman said that does not mean “interchangeability,” though, suggesting that a biosimilar could not be substituted for a brand biologic at the pharmacy, without specific doctor’s orders.

Comparing the current activist FDA with the activism the agency demonstrated during the HIV epidemic, Werble said that in addition to the breakthrough therapies designation, FDA has also launched the GAIN ACT, and its anti-infective exclusivity provision; has opened up FDA meetings to rare disease outside consultants, who advise companies on efficient FDA regulatory navigation; and has implemented PDUFA 5’s “patient-focused drug development meetings,” which solicit patient opinions around specific diseases.

Speaking on the “agency-wide impact of management attention and staff commitment” mustered during the HIV crisis 20 years ago, Werble said the pendulum has once again swung back toward FDA activism. “That commitment [to HIV] was infectious 20 years ago, and it’s occurring again,” said Werble. He also noted that a solid one-third of all drug applications submitted to FDA now come from small companies, a rejection of the thesis that only big pharma is properly equipped to navigate FDA’s regulatory structure.

The Rutgers Business School Annual Healthcare Symposium, convened on April 30, was presided over by Mahmud Hassan, director of the Blanche and Irwin Lerner Center of the Study of Pharmaceutical Management Issues, at Rutgers. John Castellani, president and CEO of PhRMA, and Seyed Mortazavi, president of IMS Health US operations, also gave presentations.

While provinces in Canada select drugs for reimbursement, the PMPRB establishes the economic benchmark value of medicines once they enter the market. The NPDUIS serves to add an extra layer of analysis to help the Board keep up with trends in where the private sector is investing its development dollars. “The purpose is partly general information, partly to inform payers of what’s coming up. In a few years, these will be the drugs facing review for reimbursement. So for public payers, it can be used as a planning tool, “explains Bernard Lachapelle, President of The JBL Group.

The NPDUIS takes clear aim at novel high cost targets. 37 of the 135 drugs screened in its report are biologics. This compares with no biologics reported in the last installment, in 2011. Biologics, as well as drugs in therapeutic categories with high utilization rates(such as cardiovascular) and areas where cost of medicines are particularly high ( i.e. cancer) were carefully scrutinized in comparison with other medicines, as these are all drugs that can significantly affect drug plans and drive costs.

Of seven drugs mentioned since the last report that have been granted marketing rights by Health Canada, five of them have retained prices within guidelines set by the PMPRB; the drug Pirfenidone is subject to investigation; and one drug had yet to be sold as of March. All the compounds considered in the NPDUIS review are at the later stage Phase III in clinical trials. Other criteria set by the reviewers include drugs that can be used to treat life-threatening conditions, rare diseases and other areas of unmet need, or if they could potentially change clinical practice in a therapeutic area, such as medicines with novel mechanisms of action or new indications. Above all, the drugs must demonstrate one of the following: improved efficacy versus existing drugs, impacts on patient health such as increased life-expectancy or quality of life; new or redefined outcomes; or an improved safety profile.

But while PMPRB and NPDUIS have managed to aggregate these promising late-phase drugs and define how they can change therapeutic landscapes within Canada, Lachapelle points out the report renders no judgment around the cost concerns of the country’s provinces, which ultimately boil down to the question: “What are the long-term budgetary impacts of the introduction of those drugs? All the report talks about is efficacy and safety, so beyond the regulatory standpoint people are left to draw their own conclusions.” The new report suggests the federal government has the expertise to help render some basic conclusions about where the provinces might efficiently spend tax dollars on medicines provided to the public through subsidized benefit programs.  Whether the provinces are interested in applying this expertise – and thus institutionalizing a bigger federal oversight role in drug spending – remains to be seen.

PE: How is the disease community inspired by NORD industry working thus far? What have you accomplished?

NORD: Our collective partnership approach has been very successful and we look forward to more progress in the future. Among the achievements that we can cite to date: Connecting patients & patient organizations: We created a platform for online disease-specific communities. NORD and our European partner, EURORDIS, host these with disease-specific patient organizations in the U.S. and Europe. Posts can be translated into any of 5 languages. There are currently 36 communities interacting with each other. The platform is viewable at www.RareConnect.org.

Promoting global awareness and education through Rare Disease Day: EURORDIS launched Rare Disease Day in 2008 and sponsors this initiative globally. NORD is the national sponsor in the U.S. and we co-promote the day’s activities and related events with EURORDIS.

Position papers/white papers: We have co-authored position papers such as a recent one issued jointly by NORD, EURORDIS and CORD (the Canadian Organization for Rare Disorders) on basic requirements for patient registries, which are being used more extensively to help policy-makers track outcomes.

We have encouraged a more seamless working relationship between FDA and EMA in the area of rare diseases, which has a solid carryover effect in improving the medicines approval process to speed access to our patients.

Finally, we have invited companies that are members of NORD’s Corporate Council to join the EURORDIS Round Table of Companies and EURORDIS has encouraged its Round Table members to join NORD’s Corporate Council. This gives our advocacy with a private sector an integrated global approach.

PE: What challenges have NORD and EURORDIS found in their relations with biotech and pharmaceutical companies? What can be improved upon?

NORD: We face many of the same issues, and I believe that we can achieve more by collaborating and talking. We are always conscious that patient organizations need to maintain a position of independence in their advocacy positions. But companies and patient organizations on both sides of the Atlantic want to work together in appropriate ways. It’s just a matter of defining the terms of the relationships and maintaining appropriate transparency. We have to keep working on that.

PE: What do governments need to do in order to be more in sync with the collaboration going on between EURORDIS and NORD as well as other partnerships with international rare disease organizations?

NORD: Government agencies are focusing more attention on rare diseases and orphan products than ever before. This is because we are transitioning to an era of more personalized medicine, and toward a better understanding of the underlying basis of disease. We hear repeatedly from government agencies that we all have the same goal — to improve the lives and health of people with rare diseases – and we can accomplish more by working together. We want to build on these relationships and forge common understanding and goals.

PE: What sort of policy initiatives could help advance these partnerships? Does this come in the form of regulatory harmonization to ensure broader market access? Does it come in the form of giving patient groups more access to research initiatives taking place?

NORD: Certainly we encourage government agencies to talk with each other and share data and perspectives. The patient voice is very important. We have worked to help fashion at the US Food and Drug Administration (FDA) a program to create systems to strengthen the patient voice as a required interlocutor in the drug development and approval process, and we have made enormous strides. The US Congress last year endorsed that goal. We believe that the patient voice in the regulatory process is getting stronger and that it will continue well into the future.

PE: What can your two organizations do to speed up market access? For example, conducting international scale clinical trials?

NORD: We support any efforts to speed market approvals for new products and to assure patient access to them. Our contribution from the patient perspective is to identify and codify patient information that will lead to a better understanding of diseases and their natural histories, and to bring patients together more quickly so that clinical trial recruitment can be sped up. Most clinical trials these days are international in scope and of course we support more expansive trials when possible. Diseases do not have geographic boundaries.

PE: How has social media transformed the landscape of rare disease? What do you hope to accomplish in effectively wielding this new medium?

NORD: Social media is a tool that is just now being tapped. Both of our organizations encourage patients to use social media to communicate with each other and to share experiences and information. RareConnect is just one example of social media efforts. We hope to encourage more.

PE: Is there a concerted effort to expand this partnership beyond into a worldwide partnership/community? Or is that taking its time?

NORD: NORD just signed an agreement with the Japanese patient community to collaborate more formally. We will look for further opportunities to bring the international patient community together. Rare Disease Day, always the last day in February, at which time we celebrate the progress made by the rare disease community, has become an international event.

PE: As work on rare diseases moves forward, does NORD see the definition of rare diseases changing or shifting to accommodate currently excluded patient constituencies?

NORD: We are not aware of anyone in the rare disease community who believes their disease is being excluding from our work. We do wish to make the definition of rare disease as inclusive and wide-ranging as possible. All of our activities strive for that objective.

To learn more about NORD and its initiatives, visit their website: http://www.rarediseases.org/

Companion diagnostics are an application of personalized medicine that tests patients to identify a population likely respond to a drug.  The CSDD R&D Management Report points out that companion diagnostics continue to score points with developers because when co-developed with a drug, they increase the drug’s chances of approval. In certain cases, such as with ChemGenEx Pharmaceuticals, the FDA actually rejected approval of one of its drugs in 2011 for a specific type of leukemia, because it was not paired with a diagnostic.

But getting the diagnostic paired through the end of the approval phase is difficult. An increasing concern from drug companies is having to subsidize the entire burden of funding the development of a companion test.  Pharma is well aware of the need to convince other companies and venture capitalists to invest in companion diagnostics, as the businesses that develop them typically report low profit margins.

Timing is also key. The Tufts report emphasizes that collaborations between drug companies and companion diagnostics developers need to take into account the basic discrepancies in their business models. This is true not only within the context of effectively co-developing these products, but in maintaining harmony and pace between both entities to ensure the drug and diagnostics components are ready at the same time for review and approval  before the regulatory bodies.

All of this does little to ease the anxiety of health insurers and thereby the uncertainty regarding reimbursement for such medicines. The Tufts CSDD survey points to a growing number of partnerships and consortia between drug companies and academia as one way for the industry to move forward in general, and this can be of importance specifically when considering companion diagnostics’ growing role in establishing the efficacy of medicines.

Regulatory bodies will undoubtedly continue to evolve in their stance on the issue, with the FDA blazing a trail that denotes a level of trust that will ultimately guide other markets in actions to promote co-development and approval of companion diagnostics of their own.  The uncertainty identified by Tufts is unlikely to ease for some time.

Signed into law by President Ronald Reagan on January 4^th, 1983, the ODA gave orphan status to drugs for diseases affecting less than 200,000 American citizens. The law granted seven-year patent exclusivity, tax credits equivalent to one half of the development cost (later modified to a fifteen-year carry-forward provision and a three-year carry-back that can be applied in any profitable year), direct grants, FDA fast-track approvals, and expanded access to patients under the Agency’s Investigational New Drug Program. The law was also later amended to waive FDA user fees established under PDUFA.

Prior to passage of the ODA, only 38 drugs had been approved for rare diseases. Since then, 420 orphan drugs have been approved to treat 2,730 orphan designations. Nine percent of the drugs approved for orphan diseases have subsequently gained blockbuster status, including top-selling drugs such as Abilify, Provigil, and Cialis.

While the act failed to immediately entice big pharma into the orphan space, “the real explosion started about four years ago, and the pace seems to be accelerating,” says Mary Dunkle, VP of Communications for the National Organization for Rare Disorders, or NORD. Of utmost importance to the industry, as time has proved is the seven-year exclusivity provision granted to orphan drugs.

Applications for orphan drugs have indeed shot up in the past few years. Jim Ajer, Senior Vice President and Chief Commercial Officer at BioMarin Pharmaceutical Inc., notes that “The industry has gotten better at not only developing drugs for orphan disorders but also commercializing and making them available to treat patients.” Ajer expects this upward trend to continue, citing one third of FDA approvals in 2012 were for orphan designations, including Kalydeco for cystic fibrosis, Elelyso for Gaucher’s disease, Bosulif for chronic myelogenous leukemia, and Signifor for Cushing’s disease.

Since the ODA, the FDA Safety and Innovation Act (FDASIA) has been hailed as another score for orphan drugs. Signed in July 2012 by President Obama, FDASIA expanded the accelerated approval pathway and increased FDA’s communication with rare disease medical experts as well as giving patients a real seat at the registration table. “This gives patients the opportunity to have direct, on the spot input on things like risk benefit, which people with rare diseases see in a very different way than people with more common diseases and more available treatment pathways,” Dunkle adds.

In 2013, NORD will be working to ensure that FDASIA is implemented on schedule particularly in light of possible sequestration challenges and related budgetary uncertainties. NORD also plans to focus on medical foods (specifically, authorizing patient reimbursement for these, currently withheld for many rare disease patients), implementation of the insurance reforms in the Affordable Care Act, and reauthorization of the Newborn Screening Act.

Going forward, Ajer suggests, “It’s worth considering policy discussions to see if there are additional provisions that should be applied for drugs that treat ultra-orphan disorders.” As drug companies go after smaller patient populations to develop new drugs for this category (which BioMarin defines as 1-3,000 people worldwide), legislation to push incentives further down the development chain against most complex and smallest base diseases, is the next step.