FDA issues warning letter to clinical investigator studying marketed drugs

FDA recently issued a warning letter to clinical investigator Betty Tuller, PhD, after she purportedly violated several requirements under 21 CFR Part 312 while working at Florida Atlantic University’s Center for Complex Systems and Brain Sciences.

According to the letter, a 2011 FDA Bioresearch Monitoring Program inspection found that Tuller conducted 5 clinical studies of a marketed drug that required compliance with FDA’s Investigational New Drug (IND) regulations—despite the product’s currently-approved status.  Among the violations outlined in the inspection report and warning letter, Tuller often failed to obtain informed consent from patients, failed to maintain adequate records, and failed to properly report to an IRB.

The warning letter clearly indicates to Tuller that “by not providing the subjects under your care with the information they were entitled to receive to assist them in making an informed decision about whether to participate in the studies, you compromised the rights, safety, and welfare of those subjects… [and] the IRB was unable to make an informed determination regarding the continued safety of the subjects enrolled in your investigations.”

The lesson here is that clinical studies of approved drugs involving new administration routes or dosage levels that increase the drug’s risks significantly must adhere to FDA’s IND regulations, requirements, and submission processes. That is, oftentimes, clinical research studies involving already approved drugs that are on the market not only need proper IRB oversight, but may also need to be conducted under an IND application.

For more information about properly planning, implementing, and managing clinical drug trials, click here to read Pearl IRB’s White Papers on the subject, or contact Pearl IRB today.

New FDA guidance on device approval considerations

FDA recently issued new final guidance for medical device manufacturers navigating the premarket approval (PMA) and de novo decision pathways.  The document, entitled Factors to Consider When Making Benefit-Risk Determinations in Medical Device Premarket Approval and De Novo Classifications was issued on March 28, 2012 and describes in detail how FDA will weigh the risks and benefits of a device during premarket review—both in the future and for devices currently under review.

Featured in the guidance is a worksheet designed to streamline the risk-benefit analysis of submissions by providing in advance several key features of the device’s potential to do both harm and good, including: the duration, type, and magnitude of risks and benefits; as well as risk likelihood, patient tolerance, reported value to patients, and available alternatives. According to the guidance introduction, “FDA believes that the uniform application of the factors listed in this guidance document will improve the predictability, consistency, and transparency of the premarket review process.”

For more information about the premarket process or for help with premarket device strategy, planning, and submissions, contact Pearl.

Forbes article explores biotech models from the VC perspective

Dr. Bruce Booth, Partner at Atlas Ventures, recently published an article on Forbes outlining the various models (or “worldviews”, as he calls them) of startup and early-stage biotechs, and how those models are perceived and evaluated for investments among the Venture Capital community.

Booth takes us from the more traditional, brick-and-mortar, product-generating platform companies (see Amgen); to the current trend of virtual, single-asset entities built for acquisition (see FerroKin). He outlines 3 critical success factors for each model; though different, the success factors all revolve around a theme of recruiting experienced core management and making effective use of resources and environment (in-house vs. outsourced development, early partnerships with big pharma, etc…).

The article is a great read for Pearl’s biotech clients—or anyone else developing and revising corporate strategy and fundraising campaigns in the biotechnology space.  To read the article, click here. Or contact Pearl for more information.

New models of biotech financing

It’s a brave new world when it comes to financing startup and early stage biotechs, and particularly for pharmaceutical development groups. No longer are there hundreds of pharma-focused VC firms able to independently fuel and sustain the growth of drug development programs.  These development paths are long-term and extremely risky investments that more often than not fail to generate sufficient returns to back startups.

Plus, it’s been tough for VCs all around since the economic crisis.  According to the National Venture Capital Association, the number of VC firms in the last decade has dropped from 1,022 down to just 462; and the biotech sector—with its extended timelines and lower probability of success—was arguably hit hardest by the shrinkage.

But with all that said, new models are emerging that give small and startup drug developers a chance to secure early capital and survive, and more importantly to share more effectively with investors and partners in both the risks and the rewards of the drug development process. And don’t worry—VCs haven’t dropped out of the race (total VC financing is up 34% from Q1 last year, according to BioWorld). Because after all, there are still enormous rewards to be earned; and often the focused effort of a small biotech is the most effective way to reach them.

A FierceBiotech report from VC heavy-hitter Burrill & Co. tracked $2.6B worth of the most recent biotech investing, which revealed several interesting players, partnerships, and trends. What stands out is the dramatically enhanced collaboration, co-investment, and partnership among various players as compared to years past. VCs, for example, are playing more nicely than ever before with governments, big pharma, academia, hospitals, trusts and foundations—and the result is a landscape of shared responsibility that enables biotechs to continue doing business.

Of course, this model won’t allow for the development of the next Amgen—with R&D, manufacturing, packaging, labeling, marketing, and just about everything else under one roof supported by bricks and mortar. But partnerships with major research foundations, governments, and big pharma—and the allocation of resources, responsibilities, and revenue that go along with them—may very well be the way of the future start-up and early-stage biotechs.

For more information, check out an Xconomy article by Luke Timmerman which does a good job identifying and explaining some of the newest trends and models in biotech financing. For regulatory, clinical, or product development support with your biotech, contact Pearl.

IOM report responds to Duke research, calls for greater “omics” oversight

In the wake of the recent commotion surrounding flawed research at Duke University on diagnostic tools based on molecular patterns (“omics” tests), an Institute of Medicine (IOM) panel has issued a report entitled Evolution of Translational Omics: Lessons Learned and the Path Forward calling for more conscientious oversight of such research and more stringent validation before it is applied in clinical trials.

In a controversy that dates back to a 2006 Nature Medicine publication by Duke researchers, headed by Dr. Anil Potti, Duke expects to retract 27 papers, has already cancelled three clinical trials, and is facing a lawsuit brought by patients of those trials.  IOM committee chair Dr. Gilbert Omenn, a computational biologist at the University of Michigan, said that the Duke scenario resulted from “a rush” to commercialize and license genomics-based tests in the clinic, adding that “there are a lot of lessons here that surely apply to other places.”.

The IOM report didn’t just find problems with Duke’s research and premature commercialization efforts; it also pointed to several problems that may be inherent to research that identifies patterns in large sets of molecules (e.g., DNA, RNA, proteins) such as omics-based testing, including “over-fitting” of data patterns due to relatively small patient sample populations, as well as the fact that the tests are so difficult to reproduce (which helps explain why so few have successfully reached the clinic). The report also specifically notes financial and institutional conflicts of interest that may have contributed to the oversight at Duke.

A recommended set of steps to more substantially validate omics tests is provided by the IOM report, which includes redundant tests from blinded samples across multiple institutions and a more proactive effort to share and review data among researchers.

For more details about the Duke case and the IOM report, see this Science article by Jocelyn Kaiser.  Or to read the full IOM report, click here.

BioPharm Int’l article presents recipe for CMO quality success

An article published this month by Susan J. Schniepp on BioPharm International illustrates the difficulty for contract manufacturing organizations (CMOs) in factoring in the quality priorities and needs of multiple clients into their own planning and operations.  The article attempts to identify a formula that could help define the quality relationship more clearly between CMOs and their clients, namely how to balance the quality commitments and regulatory obligations of both parties involved.

Schniepp identifies four basic variables (and no constants) that contribute to the landscape of the CMO quality relationship:

1) CMO’s needs,

2) compliance needs,

3) client’s needs, and

4) regulatory commitments.

Each of these four variables must be weighed and considered when drafting a quality agreement, and each must be clearly identified and thoroughly explained within the document.  According to Schniepp, “The Quality Agreement should be a living document that is reviewed and revised as often as needed to clarify the responsibilities of the client and the CMO as the product progresses through its lifecycle.”  In order to sustain a successful relationship, both the CMO and its clients must be very clear on the elements required for quality and compliance, and where those responsibilities fall in each case.  To read the full BioPharm article, click here.

At Pearl, we partner with our clients to assist them in building and managing the strongest quality compliance processes, including clearly defined vendor management systems and oversight, GMP audits, and more.  For a listing of our QA services, click here.  Or contact us at contact@pearlpathways.com to discuss your 3rd party supplier selection and management needs today.

Mayo v. Prometheus: reactions to Supreme Court’s decision to invalidate patents

Last week, the Supreme Court issued a unanimous decision on Mayo Collaborative Services v. Prometheus Laboratories, Inc., in which Mayo had challenged Prometheus’ patent claims covering diagnostic biomarker methods for personalized medicine, specifically as a companion diagnostic for autoimmune disease treatment with thiopurine drugs.  In a reversal of the Federal Circuit’s decision, the Court invalidated Prometheus’ patent claims on the grounds of “effectively claim[ing] underlying laws of nature”, stating that “laws of nature, natural phenomena, and abstract ideas are not patentable subject matter.”

The decision provoked strong reactions both supporting and opposing the ruling, represented by two starkly contrasting statements submitted to Patent Docs:

The American Medical Association (AMA) fervently supported the invalidation of Prometheus’ patent claims.  Dr. Robert Wah, AMA Board Chair, issued a statement maintaining that the ruling “prevented irreparable harm to patient care”, arguing that upholding “exclusive rights over the body’s natural responses to illness and medical treatment” would stand in the way of physicians’ unbiased collection and analysis of diagnostic data.  The AMA has garnered support from several other physician organizations and medical associations.

The Biotechnology Industry Organization (BIO) landed firmly on the other end of the spectrum, staunchly opposed to the Court’s decision.  In a short statement, BIO Deputy General Counsel for Intellectual Property Hans Sauer said, “We are surprised and disappointed in the Court’s decision…to strike down these patents for biomarker-based diagnostic methods.”  Sauer went on to explain that “it introduces new and confusing concepts into the traditional body of patent law, which…fail to appropriately recognize the importance of personalized medicine, and of the research and investment incentives needed to develop new individualized therapies for untreated diseases.”

BIO’s concern may stem from the fact that FDA requires parallel development testing and regulatory submission for companion diagnostics. What does this ruling mean for diagnostic companies and biopharma alike if they  aren’t able to protect intellectual property, secure royalty streams, etc?

With very little guidance accompanying the Supreme Court’s ruling, it is difficult to predict what the long-term impact will be on the field of companion diagnostics in the wake of this patent invalidation.  More reactions are expected, and the US Patent and Trademark Office (USPTO) has already distributed a short memorandum to patent examiners to help prepare for the implementation of changes in response to Mayo v. Prometheus.  To say the least, the discussion on subject matter eligibility, natural phenomena in patent claims, and companion diagnostics has not yet concluded.

To read the Court’s decision, click here.  To read the AMA amici curiae brief, click here.  To read the BIO amici curiae brief, click here.  For more on reactions to and impact of this ruling, check back with Pearl soon. Send us your comments!

Lilly and NCATS agree to drug screening partnership

Indianapolis-based pharmaceutical giant Eli Lilly signed a deal last week with the National Center for Advancing Translational Sciences (NCATS), providing for Lilly to screen over 3,800 currently approved and investigational new drugs for new potential therapeutic indications.  The medicines, which are part of NCATS’ extensive pharmaceutical collection, will be screened over the next 12-18 months.  Results will be posted online and publically accessible at the NCGC Pharmaceutical Collection website.

NCATS, having only been launched in January of this year, is the NIH’s youngest center.  With a mission to enhance efficiency in the drug development and approval process, NCATS acting director Thomas Insel said of the partnership with Lilly, “Working together, we can make drug development pipelines more productive.  The key is precompetitive collaboration to benefit all partners, ensuring broad access to the results.”

To read the press release from NIH and Lilly, click here.

Survey of FDA scientists reveals progress, problems with scientific integrity

The Union of Concerned Scientists (UCS) recently conducted a follow-up study to their 2006 survey regarding scientific integrity in the FDA in which FDA scientists pointed to several unsettling issues including the influences of political and special interests in scientific work being conducted.

Nearly 1,000 FDA scientists responded to the recent follow-up survey and although responses made it clear problems still persist,there has been a marked internal improvement in the scientific integrity of the Agency.  For example, among the 33 questions posed by the survey, one asked “Is the FDA acting effectively to protect public health?” to which 25% more scientists responded in the affirmative than in 2006.

The 2011 survey produced the following take-away points for FDA’s continued efforts toward integrity:

  • Leadership at FDA is stronger than it was 5 years ago
  • Communication and controversial publication are still discouraged
  • Science-based decision making is inefficient, complex, and slow
  • Political and industry influences persist, despite improvements

Across the boards, the outlook of 2011 responses is more positive than those from 2006. It is clear that FDA has taken strides to reduce external influences and enhance its support of scientists pursuing and discussing controversial or politically unpopular topics.  However, it is also evident that there is a great deal of room left for improvement:  55% of respondents feel FDA decisions are overly-influenced by political interests; and 40% feel the same about business interests.  Most concerning, over 1/3 of all respondents claimed to have firsthand experience of interference by one of these interests in their own work in the past year.

FDA Chief Scientist Dr. Jesse L. Goodman responded to the survey on his blog, saying, “While there may be differing views of what we can or cannot conclude from the science and data on which we rely, and while there are often multiple options that can be considered in developing a policy approach or making regulatory decision, FDA’s scientific decision-making on difficult issues must always be the product of an open and honest debate by the agency’s well-qualified employees. It is for these reasons that we stood up two new offices within the Office of the Chief Scientist whose missions explicitly include supporting Scientific Integrity (OSI) and Scientific and Professional Development (OSPD).”

To read more about UCS’ follow-up survey of FDA scientists and the responses that ensued, click here.

What’s coming for MDUFMA user fees?

An article published last week in MassDevice highlights the twists and turns (and resulting consensus) between FDA and medical device industry players in a series of February meetings targeting the medical device user fees program.

Among the meetings’ accomplishments, FDA and device industry leaders agreed to eliminate several exceptions from the Medical Device User Fee & Modernization Act; they developed a new fee structure to include adjustments for inflation; and they settled a discretionary fee waiver for tests developed in the lab.

After a tentative pledge to double medical device user fees from just under $300 million to just under $600 over the next 5 years, all eyes are on FDA to meet new performance goals and communicate more effectively with industry.  To read more about the meetings and their results and implications, read the full MassDevice story here.