News in brief | Nature Reviews Drug Discovery

The health-care reform legislation signed into law by President Barack Obama in March has varying implications for the drug industry.

The lowdown: After months of debate and negotiation, legislation on the most substantial changes to US health-care provision in decades was completed in March. Among the core reforms is the

provision of health-insurance coverage for the ∼32 million people who are currently uninsured in the United States. This expansion of the health-care market is anticipated by analysts to

provide a major boost to sales of branded pharmaceuticals, although the extent of the increase is unclear owing to the growing emphasis on the use of generics. In return, the pharmaceutical

industry will provide ∼US$90 billion in fees and discounts in pricing for Medicaid and Medicare, the US health-care insurance programmes for those with low incomes and those over the age of

65, respectively. For example, there will be a narrowing of the 'doughnut hole' within Medicare Part D prescription-drug coverage (a coverage gap that an insured person reaches once they

have passed a pre-stated cost threshold; above this threshold, they pay 100% of their prescription costs until they reach a higher threshold at which costs are shared with the insurer

again).

Pharmaceutical companies that have biologics capabilities and biotechnology companies are anticipated to benefit from the inclusion in the bill of 12 years of data exclusivity for the

developers of pioneer biologics before generic competitors can use such data in regulatory submissions. This is part of a newly established pathway for approval of follow-on products (also

known as biosimilars; Nature Rev. Drug Discov. 7, 479–488; 2008) and was considered a triumph for biologics manufacturers, as the US administration and the Generic Pharmaceutical Association

had sought substantially shorter periods of data exclusivity.

Small companies could benefit from the provision of a tax credit known as the Therapeutic Discovery Project Credit. It is limited to companies that have fewer than 250 employees and have

invested in projects in 2009–2010 that aim to prevent or treat disease (including preclinical and clinical research activities), develop molecular diagnostics to guide therapeutic decisions

or develop products that aid drug delivery or administration. $1 billion has been allocated for this tax credit over 2 years. Another provision in the bill established the Cures Acceleration

Network, a new competitive grant programme at the National Institutes of Health that aims to speed the translation of basic discoveries into treatments, through individual awards of up to

$15 million per year, with an annual budget of ∼$500 million.

The Critical Path Institute, The Global Alliance for TB drug development (TB Alliance) and the Bill and Melinda Gates Foundation have launched an initiative to accelerate the development of

combination therapies for the treatment of Mycobacterium tuberculosis (TB) infection.

The lowdown: On 18 March, the Critical Path to TB Regimens (CPTR) initiative was launched. Bringing together ten pharmaceutical companies — Anacor Pharmaceuticals, AstraZeneca, Bayer,

GlaxoSmithKline, Johnson & Johnson (J&J), Novartis, Otsuka, Pfizer, Sanofi–Aventis and Sequella — and scientists from the US FDA, the aim is reduce the time that it takes for combination

therapies to be approved. In parallel with the clinical development of promising regimens, the CPTR will address regulatory challenges that will “allow for the most efficient, accurate, and

robust evaluation and application of these new testing models.” They also plan to address issues related to the lack of clinical trial capacity and funding.

The current treatment for drug-susceptible TB is a four-drug regimen (isoniazid, rifampin, ethambutol and pyrazinamide) taken for 6 months or more, which the CPTR highlighted took ∼24 years

to develop. The CPTR thinks that, by testing promising regimens of investigational therapies early in their clinical development, they can reduce the overall development time to ∼6 years.

Another key aim is to develop regimens that will shorten the 6-month treatment time. This could increase patient compliance to a regimen, thereby reducing the risk of drug resistance

developing owing to inadequate control of the bacterial infection. According to the World Health Organization, in some areas of the world, one in four people with TB is infected with a

drug-resistant strain.

There are six new investigational drugs in clinical trials for the treatment of TB. Four are in Phase II: PA-824 (Chiron/TB Alliance), a nitroimidazole agent; TMC-207 (Tibotec, a subsidiary

of J&J/TB Alliance), a diarylquinoline agent; LL-3858 (Lupin), an unspecified agent; and OPC-67683 (Otsuka), a nitro-dihydroimidazo-oxazole-derived agent. Two are in Phase I: AZD-5847

(AstraZeneca/Quintiles), an oxazolidinone agent, and SQ-109 (Sequella), a second-generation ethambutol analogue. In addition, the TB Alliance is developing more than 20 preclinical projects

that it hopes will feed into future trials run by the CPTR.

Recent guidance from the FDA on the clinical evaluation of products for the treatment of irritable bowel syndrome (IBS) emphasizes that a suitable instrument for measuring clinical signs and

symptoms of IBS that are reported by the patient is not available.

The lowdown: In their draft guidance, which was published in March 2010, the FDA recommended that a multi-item patientreported outcomes (PRO) instrument should be developed that captures all

of the clinically important symptoms of IBS. The FDA acknowledged that such an instrument does not exist at present and recommended strategies for industry to follow when designing clinical

trials for therapies to treat IBS with constipation and IBS with diarrhoea until such an instrument becomes available. These strategies were established by the IBS scoping group (a working

group of the PRO Consortium), members of which are from the FDA, academia and a patient advocacy group known as The International Foundation for Functional Gastrointestinal Disorders.

The PRO Consortium was formed by the FDA and the Critical Path Institute for the purpose of developing, evaluating and qualifying PRO instruments for use in clinical trials, and has 23

pharmaceutical companies as members. To date, the consortium has focused on five disease areas: asthma, depression, cognitive disorders, IBS and oncology. The recent FDA guidance for IBS is

the first set of disease area-specific guidelines to have received input from this consortium. At the end of December 2009, the FDA published a general guidance for industry on the use of

PRO measures in medical product development to support labelling claims.

The US FDA hosted its first public meeting on 12 April to obtain comments on the Prescription Drug User Fee Act (PDUFA) before PDUFA IV expires in September 2012.

The lowdown: Discussions have begun between the FDA and stakeholders to consider how the PDUFA should be updated when it is scheduled for reauthorization in 2012. Highlights reported from

this first meeting include a request to improve the safety and promotion of prescription drugs and to have clearer drug labels that list risks and benefits of therapies. There is also a

fresh emphasis on meeting review timelines, which has been a problem in recent years partly owing to workload and new requirements from the FDA Amendments Act (FDAAA) 2007, such as the

requirement for Risk Evaluation and Mitigation Strategies. It has also been reported that the FDA and industry will negotiate new fees from June to January 2010, and a public review of the

proposal is planned for September to November 2011.

The PDUFA was first passed in 1992 to allow the FDA to obtain fees from drug makers to help expedite the review of new drug applications (NDAs) and biologic licence applications (BLAs). The

Act was introduced to address the problem of understaffing at the FDA, which had caused drug reviews to be a slow (typically taking up to 2 years) and unpredictable process. By allowing the

FDA to obtain fees from companies submitting regulatory applications, timelines were improved, the review process became more predictable and the FDA agreed to meet specific performance

goals.

With the reauthorization of PDUFA every 5 years, the legislation is amended, often leading to an increase in FDA responsibilities. For example, in PDUFA II, the FDA agreed to review 90% of

NDAs and BLAs within 10 months for standard reviews and within 6 months for priority reviews, a goal that it is still aiming to achieve today. Currently, PDUFA is within its fourth enactment

(authorized through the FDAAA 2007), which substantially increased the user fees to allow the FDA to increase staff and make considerable changes to modernize post-market drug safety

monitoring. A recent performance review by the FDA — with regard to meeting PDUFA IV goals — highlighted that the recent staff increases in the Center for Drug Evaluation and Research have

resulted in a decline in the average level of on-board review expertise and that certain PDUFA procedural goals were given lower priority in the first 12–18 months of PDUFA IV while new

FDAAA 2007 provisions were implemented.

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