COMBINATION – Regulatory Overlord The Regulatory Overlord Chronicles Mon, 31 Oct 2016 14:14:52 +0000 en-US hourly 1 The Chasmic Shift in Disruptive Business Climates Wed, 09 Dec 2009 21:16:55 +0000 The Chasmic Shift in Disruptive Business Climates

The Chasmic Shift in Disruptive Business Climates

It has been a few months since I have had an opportunity to write for pleasure. After completing my doctoral work on August 25th, working on a major global submission, and teaching 2 sections of Healthcare Marketing and Communications at West Virginia University, I needed some time off to focus on other initiatives. But, there is nothing like a break from the absence of grading 20 papers and discussion boards weekly to rekindle interest and chime in on the debates.

On Tuesday, September 15th, I was session leader (Combination Products in Asia – Regulatory Challenges and Successful Development and Approval Strategies) at the Regulatory Affairs Professional Society Annual Conference and it was noticeably smaller as compared with the Boston conferences of 2007 and 2008.  Yes companies reduced the numbers of attendee, but there were less companies overall. This year has seen victims of shrinking capital markets, disappointing FDA feedback and company decisions to forgo developmental targets and potential indications owing to funding priorities.

Traditionally, FDA approval of new drugs used to be based upon sponsors’ demonstration of safety and effectiveness via a Biologics License Application (BLA), New Drug Application (NDA), Premarket Notification (510k) or Premarket Application (PMA), and on the basis of information submitted in support of the marketing application. Based on bureaucratic learning, past FDA errors and resulting criticisms, FDA divisions have added clinical relevance and utility as benchmarks for approval and standard setting.

Gone are the days of business models where companies created entire business structures that revolved around one or two developmental compounds in clinical trials. The industry has moved from a history of exuberant excesses to lean manufacturing, better evidence for reimbursements and business practices for long term profitability.  Now we are in the era of “healthcare reform” where the current healthcare crisis has been characterized as a demonization of the insurance industry, similar to the “evil pharma” campaign that characterized the prescription drug debates.

Though the “reform friendly” medical products industry is distinguishable from other health care services because it provides tangible products, the industry remains vulnerable. Current indicators suggest that government and legislative policy has resulted in negative confidence of future growth. The Obama Administration’s ambitious foray into “health reform” amounts to a de facto restructuring of one-sixth of the ~$15 trillion US economy and ushers the question: How will this shape business models and more importantly, how will medical products and healthcare companies do business in a post-reform environment?

Following are a few obvious guidelines for evaluating the “post reform” healthcare paradigm.

Universal Coverage = More Governmental Control

Common sense dictates that universal coverage will lead to a fully funded government mandate and obligation. This will ultimately result in cost containment and thus limit access and choice.

More Healthcare Demand without Increasingly Supply = Higher Than Projected “True Economic Costs”

Economic fundamentals dictates that increasing demand for healthcare consumption by extending coverage to the uninsured without concomitant policies aimed an incentivising facility construction  or adding more physicians, will increase healthcare costs on an individual and governmental level. The unanswered question is which of the stakeholders (employers, industry, government, patients or providers) will end up covering the bill.

Reform = Different or Disproportionate Impacts on Primary and Specialty Medical Products

Expanding access to healthcare for the uninsured will increase demand for primary care medical products used to treat and prevent chronic conditions. This will have a disproportionate impact on the higher priced specialty medical products used to treat and manage diseases targeted to smaller patient groups and which are marked by higher co-pays and limited or no reimbursements.

Disconnected Expert Panels = Potential for Danger

Attempts to shield the government from the appearance of political involvement by relying on expert panels to decide on coverage and reimbursements can be open to “stakeholder pressure.” These elites who are not necessarily vested and politically insulated in an ivory tower can be a recipe for danger. Outside US, the experience with these types of panel suggest that they encourage companies to utilize patient groups and other strategies to influence coverage and access.

Piecemeal Approaches = Similar Outcomes

The theory of structuration as proffered by Anthony Giddens (1986) emphasizes “a differentiation between the concepts of ‘structure’ and ‘system’” (Giddens, 1986, p. 17). Giddens points out that “structure is a set of rules, systems ….comprise… human agents” and structuration “is….. the duality of structure” (Ibid., p. 25). In examining congress, the underlying construct is in seeking a balance or duality between the risks of nothing doing anything versus the risks of doing to much. Regardless of whether full reform is achieved or negotiated piecemeal stop gap measures, pressures will continue to have an effect on the structure and we are likely to revisit again in 10-20 years.


A fundamental tenet of healthcare economics is premised on the idea that we are all born with a stock of good health and our lifestyle choices and access to healthcare determines appreciation or depreciation. The fundamental question has been muddled and is simply whether we as Americans support a “floor” not a “ceiling” to cover those less fortunate.


Giddens, A. (1986). The Constitution of Society: Outline of the Theory of Structuration. University of California Press.

The Future of Convergent Technologies Wed, 06 May 2009 01:05:57 +0000 more »]]> BIOMEDevice Forum 2009

BIOMEDevice Forum 2009

(Report from BIOMEDevice 2009 Executive Forum)

I took time off to finalize my doctoral thesis draft and research bleeding edge companies presenting at BIOMEDevice 2009 held at Boston Convention Center on Tuesday April 21st through Wednesday, April 22, 2009. BIOMEDevice Forum is coined by the organizers Canon Communications LLC “Cancom”, as “New England’s premier executive-level conference focusing on convergence and cross-sector collaborations among companies in the biotechnology, medical device, IVD, and pharmaceutical industries.” The theme was convergence and going beyond the simple combination and complementary, to integration of disciplines for developing products that echo the era of translational medicine. Combination implies that products are developed as standalone components to be used jointly. Convergence really aims to blur the line between two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic). What makes convergence so exciting is that when it is applied to life sciences, the result is a cornucopia of advances in diagnosis, prevention, treatment and management of disease and medical conditions.

I participated in the Executive Forum and like previous years, the lists of invitees included CEOs, CFOs, R&D executives from mature and emerging life sciences firms, investors, industry analysts, academia and entrepreneurs with novel approaches and technologies for solving old problems and new technologies with unique applications.

The two-day event brings together key players involved in investing, partnering, licensing, and developing business opportunities in the rapidly growing market for innovative healthcare products. It was sponsored by R&D Directions (focuses on pharmaceutical companies’ R&D business strategies and decisions), IVD Technology (focuses on diagnostics technologies—including research, development, and manufacturing), Massachusetts Biotechnology Council and Massachusetts Medical Device Industry Council (MassMEDIC), whose president Thomas J. Sommer, I had a very pensive and enlightening discussion during lunch on day one.

My most memorable presentation was that of Imran Nasrullah, JD., Chief Business Officer, Massachusetts Biotechnology Council and a former Millennium Pharma colleague. Imran cleverly compared the 150th anniversary of Darwin’s evolutionary theory On the Origin of Species to the evolution of life science business models. If we look at life science business models of the past, we see companies building an entire company infrastructure to support a few investigational candidates without having a product on the market. The challenge to innovation can be best described in terms of selective policy pressures. Whether it is healthcare reform, FDA inefficiencies or patent reform, these all create a downward pressure on innovation which attenuates the pipeline for life saving medical products.

I sat next to Prof. Michael J. Cima, a Sumitomo Electric Industries Professor of Engineering and Faculty Director, Lemelson-MIT Program at lunch on day one. Dr. Cima commented that the real value lies in drugs used in procedures i.e those that allow procedures to be used in new settings. These can be in the form of enabling technologies or site or delivery or systemic delivery advances. Dr. Cima’s research has spawned a number of companies and two were represented Tengion (developing new human organs and tissues that are derived from a patient’s own cells. Speaker: Gary Sender, CFO) and MicroCHIPS (pioneering intelligent implanted devices designed to improve the health of millions of people with chronic conditions that require careful monitoring and precise therapy. Speaker: Maggie Pax, Vice President, Business Development).

The convergence of biology, chemistry, photonics, materials science, engineering, robotics, epidemiology and mechanics for translational medicine points the way forward. However, creating convergent products raises a spectrum of unique business, technical, and regulatory questions.  Developers must recognize, early in the process, when the product design assumes characteristics of a combination product, convergent product or virtual combination (product is packaged separately and the package inserts or instructions for use specifically mention the use of another product by brand name, requiring mutually conforming labeling). It may even change the Primary Mode of Action determination for deciding which FDA center will act as lead in reviewing the marketing application. The FDA received 333 original applications for combination products in FY 2007. A 42 percent increase from the 235 original applications for combination products in FY 2006. The number of intercenter consulting reviews increased to 390 for FY 2007 from 335 in FY 2006 representing a 16 percent increase in intercenter consults. Recent examples of approved combination products can be found at:

Historical Perspectives

2003-2007 Combination Products FDA Marketing Applications

2003-2007 Combination Products FDA Marketing Applications

Combination products have been in existence for many years.  By their nature, they raise unique challenges and have produced more than its share of controversy within the medical community.  The official history of combination products did not start until after 1990.  The Safe Medical Devices Act (SDMA), Section 503(g) was established at that time. Though worthy of explicit recognition in the Safe Medical Devices Act of 1990, combination products were still perceived as a theoretical regulatory problem. Combination products were seen as products of the future, whose potential was yet to be realized. As device and pharmaceutical industries continue to merge or partner to offer new products, it is revolutionizing the healthcare industry. Many pharmaceutical companies started partnering with medical device and biologic firms to formulate more “combination products,” and by the end of 2002 it was safe to say that the future was here. As we go beyond 2009, these products are a growing market with great potential.

Some estimates forecast that the combination products market could increase from approximately $6 billion in 2004 to nearly $10 billion by 2009 (“Regulations, Guidances in the Works for Rapidly Advancing Combination Products Sector”; Food and Drug Letter, Issue No. 717, February 11, 2005). Others estimate that combination drug delivery products alone are growing at an annual rate of 14 percent, an increase expected to add up to $38 billion in yearly sales by 2008 (“Drug-Device Makers Can Expect New Guidance”; AAMI News, February 2005). Furthermore, BCC Research Inc. estimates that the total global value of the drug-device combination products market will increase from $5.4 billion in 2004 to $11.5 billion in 2010 (“Drug-Device Combinations”, BCC Research, June 2005). Cardiovascular applications currently dominate, with 88% market share but expect to see those numbers decline as convergent products and platforms mature.

There are three (3) paramount issues that need to be addressed when a company is considering the development of convergent products.
1. Organizational Considerations (which I will not address)
2. Business Considerations
3. Regulatory Considerations

Regulatory Considerations

Regulatory Approaches to Combination Products

Regulatory Approaches to Combination Products

Regulatory Issues are always important since it is the only pathway by which a product can be marketed after it meets statutory requirements for approval and the adequate writing of directions for use (DFU) or package inserts (labels). Up until the time they are combined, drugs and biologics comply with cGMP (current Good Manufacturing Practices), devices comply with QSRs (Quality Systems Regulations) regulation but once the constituents come together and form the combination product:  BOTH SETS OF REGULATIONS ARE APPLICABLE.

The conventional wisdom at the FDA was that the primary mode of action was a determinant factor for the designating primary jurisdiction amongst the centers (CDER, CBER & CDRH). The FDA then promulgated 21 CFR Part 3 – Product Jurisdiction.  This regulation specified how the FDA was to determine which center was designated to have the primary jurisdiction for the premarket review and regulation of the combination product. By using these laws, regulations, and the Intercenter Agreements, a sponsor begins to determine the regulatory path for its product.

The challenges faced most often by sponsors are:

  • Absence of a pre-defined regulatory pathway to rely on for conformity
  • No specific submission process or marketing application
  • FDA regulations/practices differ for drugs, biologics and devices
  • Different cultures between CDER, CBER and CDRH
  • Companies are forced to work within the current statutory framework

Business Considerations

Business considerations for the development of convergent products are important. This is especially true when two parties are involved and the Intellectual property is not jointly owned or licensed.

The primary considerations to be analyzed are:

  • Who will fund the project?
  • Who owns the intellectual property?
  • Where will the product be developed, which facility?
  • What company’s sales force will sell the product?
  • Is there a mechanism in place for second-generation products to be produced?

Business actions can reduce the regulatory burden and it is incumbent on sponsors to look at ways to reduce regulatory burden.

These can be in the form of:

  • Adjusting the labeling claims, generalizing them as not to be tied to a single drug, biologic, or device.
  • Investigate whether or not there are other drugs, biologics or devices that are consistent with the labeled indication of the convergent product.
  • Adjust the packaging as to separate the drug, biologic and device components.
  • For post-marketing considerations, segmenting drug and device manufacturing may help to minimize some of the registration and GMP conflicts.

The Future – the big problem with the next big thing

Convergent products appear to be the wave of the future and technology will continue to advance for different combinations and continued development of nanotechnology and drug delivery systems. Pharmaceutical companies are also developing combination products and that will present its own set of challenges and inefficiencies.

Waves of promising new technologies come and go and entrepreneurs and media never seem to grow tired of oversimplification and buzzwords. In the past, venture capitalists swarmed and poured money into antisense, gene delivery, wound healing, rational design, genomics, proteomics, RNAi and now nanotechnology. If there is one thing we should have learned by now about medicine, it is that human biology does not quickly, predictably or inexpensively yield its secrets.

Real advances in medicine will continue to come from groups intensely focusing on a specific disease or drug delivery process, and bringing to bear every piece of ingenuity they can find—be it nano, micro or whatever. I can live with the idea and the words ‘convergent technologies’ so long as the objectives of the products that come from it are not oversimplified or concatenated in more buzzwords.

It is important for companies to:

  • Explore what precedents exist for the likely combination, i.e., find drug-device, biologic-device, drug-biologic and device-drug-biologic product examples.
  • Use the request for designation (RFD) and primary mode of action (PMOA) concepts to your advantage in bringing products to market more efficiently.
  • Understand how the cultural and philosophical differences between CDER, CBER and CDRH impact the FDA approval process.
  • Avoid pharmaceutical-nutraceutical and medical device-nutraceutical combinations.
  • Understand the manufacturing challenges of combination products, i.e., sterility, shelf-life, packaging, etc.
  • Learn from drug-eluting stents.
  • Understand the challenges of convergence.
  • Learn how companies communicate with drug, biotech and medical device – i.e. you don’t speak the same language.
The Policy Connection Mon, 23 Mar 2009 03:41:03 +0000 more »]]> The many facets of policy interactions....

The many facets of policy interactions….

In Foundations of the Law, Professor’s Bailey Kuklin and Jeffrey Stempel assert that “during its history, United States law has frequently resulted from commercial, geographic, social and political conflict” (1994:138). The regulation of medical products is no different; various perspectives apply to various constituents or stakeholders. Whether one is a patient, a medical practitioner, a developer of medical products “industry,” an academician, a legislator/regulator or a special interest entity, views are closely aligned by individual or collective interest, inherent philosophical beliefs, and conscious or unconscious ideologies and pedagogies.

The underlying construct for the regulation of food and drugs is in seeking a balance between prevention of harm vs. promotion of benefits and the public good. Finding the right balance shifts with political and societal changes over time. The political changes reflect the mandate of a party’s platform and have a direct bearing on what the overall “annual goals” would be. The societal changes can be political, economic, social, and technological or scientific/ technological advancements. What makes administrative law unique and has regulatory agencies in a conundrum is that they are ultimate responsible to everyone and have a perceived duty to be balanced. They are responsible to congress, the judiciary, legislators, the executive branch, industry, special interests and the public at large. Regulatory agencies are ultimately in a battle for legitimacy and this takes a toll on resources and indeed agency morale.

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