Deloitte has released a study, Avoiding no man’s land: Potential unintended consequences of follow-on biologics, that explores the debate on creating a regulatory pathway for the approval of follow-on biologics (FOBs, the biotech equivalent of generic pharmaceuticals). The study also outlines unintended effects of the Hatch-Waxman Act of 1984 and compares it with current proposed legislation.

The study notes that basic differences between the pharma industry in 1984 and the biotech industry in 2009 make it difficult to apply Hatch-Waxman as a model for FOBs legislation. According to the study, after 1984, patents protected innovators’ intellectual property and the data exclusivity period rarely came into effect.

At the heart of this debate
is one key issue: How
similar are the two
underlying industries?

In 1984, when the Hatch-Waxman generic drug legislation was enacted, the pharma industry was stable and mature.  Today the biotech industry is relatively young and complex and is highly reliant on risk capital. With follow-on biologics, Congress may need to consider a different set of rules to balance cost savings, patient safety, and economic incentives for future innovation.

Still, the essential debate has two main issues — patient safety and industry economics:

Patient Safety: What will constitute threshold “biosimilarity”? Specifically, what type and length of clinical trials will be required to establish that a new FOB is sufficiently similar to a currently approved and marketed “branded” biological drug, and thus permit the FOB a relatively quick path to market? Under what circumstances would a new FOB be considered “interchangeable” with a currently approved drug?

Industry Economics: How can new regulations most appropriately encourage competition while also maintaining sufficient economic incentives to foster scientific innovation? Specifically, what should be the appropriate period of time granted to a branded biological drug for protection of its underlying intellectual property prior to the approval and entry of an FOB?

Unintended Consequences

The  study outlines three of these unintended effects, and explores how this experience should be considered in current legislation:

  • “Make Hay” effect: Once a drug is introduced to the market, an innovator has a short time to recoup its development costs — upwards of $1 billion over 12 years — before a competitor enters the market. Faced with patent protection of limited duration, innovator companies must maximize their revenues in the short period before generics are introduced. To do this, they generally raise prices and invest more in marketing the drug, tactics that run counter to Hatch-Waxman, the intent of which was to lower prices.
  • “Blockbuster” effect: Facing increased drug development costs and a limited period of time before generics can compete, innovators typically focus only on those drugs that promise huge returns on investment. To recoup the amount of time and money an innovator spends on a new drug, experts have shown that to break even, a drug would have to achieve annual revenue of roughly $150 million, which is impossible unless a drug targets a large population, or charges a high price per treatment. This blockbuster effect has led pharma companies generally to focus development efforts on only the largest potential indications.
  • “No Man’s Land” effect: As soon as a company receives a patent for a compound, the clock for commercialization begins ticking. Each year a patented drug spends in development is another year of lost revenue. If enough time elapses, there comes a point where the compound will never be able to earn sufficient return on investment. This could lead to promising compounds being dropped from development, including those for critical diseases like cancer, Parkinson’s, Alzheimer’s and others, because there is no way to fund the research once the compound has crossed into this “no man’s land.” Deloitte estimates this can occur within as little as one year of achieving a patent.

According to the study, the most serious of these unintended consequences may be the ‘no man’s land effect,’ which could substantially reduce the biotech industry’s ability to continue to develop innovative treatments for our most pressing diseases and medical conditions.

The blockbuster effect runs exactly
counter to the direction and
promise of the science of biotech.

According to the study, the economics of drug development essentially forces innovators to focus on drugs with the largest possible market potential – in this way, again, what was true for pharma innovators will be true for biotech innovators. But, this effect runs  counter to the promise of biotech, which has the potential to create  highly targeted therapies. In order for personalized medicine to become a reality, drug innovators will need a regulatory environment that allows a return on their investments in research and development.

Because of the structural differences between the pharmaceutical industry of 1984 and today’s biotech industry, Congress will need to act with care as it looks to create a regulatory path for FOBs.

Get the entire paper here.

To see if patenting DNA still has a place, see the Non-obviousness of DNA at Patent Docs.

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    Beginning in the late 1970s, biopharmaceuticals began initially to be researched conceptually for their therapeutic potential. This research continues today with great enthusiasm.
    Known also as Red Biotechnology, it is believed that the first biologic therapy ever was a type of synthetic insulin called Humulin, which was from Genetech in 1982. This new insulin that utilized what is called rDNA technology was also is used to produce human growth hormones, it is believed.
    Later, the rights were sold to Eli Lilly for this insulin product. Yet Genetech was likely the catalyst and apex of biologic growth that exists now to a large degree. And such companies are truly research-driven compared with some other pharmaceutical companies.
    Today, biologic companies are numerous- and are believed to employ around 1000 scientists who express their vocational drive to research potential biologics. And Genentech, again which is the company who was at the advent of biologics, continues to be an independent company, although Roche owns a large portion of this company.
    Biologics are in essence distant relatives of the common synthetic, carbon-based pharmaceuticals that most are familiar with who are involved in treating patients. This distant relative has experienced a lack of innovation and creation of truly unique products in recent years utilizing this common method that has been utilized for several decades.
    In fact, presently large pharmaceutical companies are acquiring biopharmaceutical companies that usually are comparatively very small start-up companies. These large pharmaceutical corporations do this because, along with other reasons, biologics are in fact monopolies due to the undeveloped protocols for biosimiliars. Biosimiliars are the generic forms of typical branded pharmaceutical drugs.
    In addition, biopharmaceutical companies have historically experienced accelerated growth that has proven to be quite lucrative for them recently. Presently, this biologic industry is about an 80 billion or so dollar per year franchise- with roughly 15 percent growth each year with this particular market, it is believed. It has been reported that are about 250 biologics on the market presently, with more to come.
    How do these drugs differ from typical drugs that have been made before this advent of biopharmaceuticals? Unlike the small molecule, synthetic, carbon based pharmaceuticals of yesterday, biopharmaceuticals essentially are larger and very complex modified proteins derived from living biological materials, such as antibodies, hormones, or enzymes.
    One method of these creations is that a transformed host cell is developed to synthesize this protein that is altered and then inserted into a selected cell line. The master cell banks, like fingerprints, are each unique and cannot be accurately duplicated, which is why there are no generic biopharmaceuticals as of yet, as there is no known process to create them.
    So the altered molecules are then cultured to produce the desired protein for the eventual biopharmaceutical product. These proteins are very complex and are manufactured from living organisms and material chosen for whatever biopharmaceutical that may be desired to be created. It is difficult to identify the clinically active component of biopharmaceutical drugs.
    The goal of this molecular design created by others is to modify those physiological systems that are dysfunctional in order to restore the health of others.
    Clearly, manufacturing biopharmaceuticals clearly is a different and innovative process, and a small manufacturing change could and has raised safety issues of a particular biopharmaceutical in the developing process, as altering the immune system of a potential user of a biologic therapy is risky. Also, it takes about 5 years to manufacture a biopharmaceutical.
    And each class has a different method of production and alteration of life forms to create what the company intends to develop. Yet overall, their development methods are rather effective, and cost over a billion dollars to bring to market.
    Greater than 10 percent of biologic therapies have black box warnings now with their prescribing information because of unexpected consequences by those who have had such therapys . Yet as time progresses, biologics are becoming safer as more is learned about this technology.
    Over 20 biopharmaceutical drugs were approved in 2005, it has been reported, and their growth has tripled compared with what the large pharmaceuticals experienced then. Presently, over 20 biopharmaceutical products are blockbusters by definition, according to others. They are overall very effective treatments for what are viewed as very difficult diseases to manage and treat.
    This is due to the fact that some biologics target specific etiologies of these diseases, while limiting side effects because of the specific way in which such products work. Yet of the nearly 400 biopharmaceutical companies that are publicly traded, about a third are more or less going broke, it has been reported presently.
    There is risk for such companies because of the technology being so new, perhaps. Yet overall, this biologic industry employs about a quarter of a million people in the United States, it is believed.
    There are about a dozen different classes or mechanisms of action of biopharmaceuticals that have about a half of dozen different types of uses today. Label alterations for additional disease states occur often as well due to the progressive and novel effectiveness of biopharmaceuticals. Some of these drugs are catalysts for apoptosis of tumor cells.
    Some biologics are catalysts for angiogenesis to occur to block blood supply to the tumors of cancer patients. Then some biopharmaceuticals have multiple modes of action that benefit certain patient types and their diseases greatly, as with most biopharmaceutical products, the safety and efficacy is evident and reinforced with clinical data and eventual experience with the biopharmaceutical that is chosen to be utilized.
    The clinical trial protocol is somewhat different with pending biologics in comparison with what have been traditional medications. This is likely due to biologics being such a new development in the world of medicine.
    The country of Belgium provides the most biotech products to the biopharmaceutical companies in the United States, and the U.S. leads the world in regards to biopharmaceutical product creation- with more than 70 percent of both revenues and research and development expenditures in this country. Canada is ranked number two in this area, others have said.
    And with the government health care programs, who are the largest U.S. payers for pharmaceuticals, Medicare pays 80 percent of the cost of biopharmaceuticals, as many are administered in the doctor’s office, and Medicare part B covers the cost in large part for biologics.
    There are, however, some concerning issues with biologics, such as suspected overuse or inappropriate utilization of these therapies. Companies who make and market biologics are not exempt from federal prescription regulation that exists presently. Amgen, who makes an anemia biologic called Neupogen, recently had to pay a settlement as well as JNJ, who makes an identical drug called Procrit due to their marketing activities related with such issues.
    The settlements were due to the rebates and incentives both companies were giving to the users of their products, which were very lucrative benefits, and this resulted in some cases intentional overdosing their patients with these biologics at unreasonable and unnecessary levels, it has been reported. The doctors targeted with these biologics by the makers of these agents are nephrologists and oncologists, as anemia is often seen in their practices for various reasons.
    One controversy involving biologics is that, while they overall are efficacious and safe, the typical cost of biopharmaceuticals is rather unbelievable, as this cost may approach tens of thousands of dollars per month for some of these biologics. Furthermore, with cancer drugs, they are used together with chemotherapy for their treatment regimens in many treatment centers, so the quality of life comes into question if one considers the devastating side effects of chemo treatment.
    One criticism of biopharmaceuticals is that, with cancer patients in particular, they normally provide an extension of their life of only a few months. So there is a debate as to whether the value of biologics justifies their cost.
    Several years ago, I heard a presentation from Roy Vagelos, former CEO of Merck Pharmaceuticals, and heard him as he spoke to others at Washington University in St. Louis about his views on both the pharmaceutical and biologic industries.
    And during his presentation, he stated something similar regarding the cost of biopharmaceuticals and asked as well about the value of biologics.
    Also, with many biologics, such as those approved to treat cancer, between 70and 80 percent of these biologics are believed to be prescribed off-label, so it will be interesting on how these drugs will be used in such disease states now and in the future, and how they will be regulated as well.
    So the future looks good for this industry, as biologics have tremendous marketing power along with superior therapeutic value with many of them. Yet perhaps they need to improve their unreasonable cost structure with the biologics their developers make and promote. In addition, perhaps a more aggressive approach to bringing to market biosimiliars would enhance the image of this new industry.
    Regardless of the challenges and flaws that exist with biopharmaceuticals and their makers, I’m pleased to see the results and realization of true innovation in medicine that has numerous possibilities for enhancing the treatment of devastating disease states.
    “The progressive development of man is vitally dependent on invention.” — N. Tesla
    Dan Abshear (what has been written is based upon information and belief)