Drug design

Drug design, sometimes referred to as rational drug design or more simply rational design, is the inventive process of finding new medications based on the knowledge of a biological target.^[1] The drug is most commonly an organic small molecule that activates or inhibits the function of a biomolecule such as a protein, which in turn results in a therapeutic benefit to the patient. In the most basic sense, drug design involves the design of small molecules that are complementary in shape and charge to the biomolecular target with which they interact and therefore will bind to it. Drug design frequently but not necessarily relies on computer modeling techniques.^[2] This type of modeling is often referred to as computer-aided drug design. Finally, drug design that relies on the knowledge of the three-dimensional structure of the biomolecular target is known as structure-based drug design.
The phrase "drug design" is to some extent a misnomer. What is really meant by drug design is ligand design (i.e., design of a small molecule that will bind tightly to its target).^[3] Although modeling techniques for prediction of binding affinity are reasonably successful, there are many other properties, such as bioavailability, metabolic half-life, lack of side effects, etc., that first must be optimized before a ligand can become a safe and efficacious drug. These other characteristics are often difficult to optimize using rational drug design techniques.

Background

Typically a drug target is a key molecule involved in a particular metabolic or signaling pathway that is specific to a disease condition or pathology or to the infectivity or survival of a microbial pathogen. Some approaches attempt to inhibit the functioning of the pathway in the diseased state by causing a key molecule to stop functioning. Drugs may be designed that bind to the active region and inhibit this key molecule. Another approach may be to enhance the normal pathway by promoting specific molecules in the normal pathways that may have been affected in the diseased state. In addition, these drugs should also be designed so as not to affect any other important "off-target" molecules or antitargets that may be similar in appearance to the target molecule, since drug interactions with off-target molecules may lead to undesirable side effects. Sequence homology is often used to identify such risks.
Most commonly, drugs are organic small molecules produced through chemical synthesis, but biopolymer-based drugs (also known as biologics) produced through biological processes are becoming increasingly more common. In addition, mRNA-based gene silencing technologies may have therapeutic applications.

Types

Flow charts of two strategies of structure-based drug design

There are two major types of drug design. The first is referred to as ligand-based drug design and the second, structure-based drug design.

Ligand-based

Ligand-based drug design (or indirect drug design) relies on knowledge of other molecules that bind to the biological target of interest. These other molecules may be used to derive a pharmacophore model that defines the minimum necessary structural characteristics a molecule must possess in order to bind to the target.^[4] In other words, a model of the biological target may be built based on the knowledge of what binds to it, and this model in turn may be used to design new molecular entities that interact with the target. Alternatively, a quantitative structure-activity relationship (QSAR), in which a correlation between calculated properties of molecules and their experimentally determined biological activity, may be derived. These QSAR relationships in turn may be used to predict the activity of new analogs.

Structure-based

Structure-based drug design (or direct drug design) relies on knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography or NMR spectroscopy.^[5] If an experimental structure of a target is not available, it may be possible to create a homology model of the target based on the experimental structure of a related protein. Using the structure of the biological target, candidate drugs that are predicted to bind with high affinity and selectivity to the target may be designed using interactive graphics and the intuition of a medicinal chemist. Alternatively various automated computational procedures may be used to suggest new drug candidates.
As experimental methods such as X-ray crystallography and NMR develop, the amount of information concerning 3D structures of biomolecular targets has increased dramatically. In parallel, information about the structural dynamics and electronic properties about ligands has also increased. This has encouraged the rapid development of the structure-based drug design. Current methods for structure-based drug design can be divided roughly into two categories. The first category is about “finding” ligands for a given receptor, which is usually referred as database searching. In this case, a large number of potential ligand molecules are screened to find those fitting the binding pocket of the receptor. This method is usually referred as ligand-based drug design. The key advantage of database searching is that it saves synthetic effort to obtain new lead compounds. Another category of structure-based drug design methods is about “building” ligands, which is usually referred as receptor-based drug design. In this case, ligand molecules are built up within the constraints of the binding pocket by assembling small pieces in a stepwise manner. These pieces can be either individual atoms or molecular fragments. The key advantage of such a method is that novel structures, not contained in any database, can be suggested.^[6][7][8]

Active site identification

Active site identification is the first step in this program. It analyzes the protein to find the binding pocket, derives key interaction sites within the binding pocket, and then prepares the necessary data for Ligand fragment link. The basic inputs for this step are the 3D structure of the protein and a pre-docked ligand in PDB format, as well as their atomic properties. Both ligand and protein atoms need to be classified and their atomic properties should be defined, basically, into four atomic types:

• hydrophobic atom: All carbons in hydrocarbon chains or in aromatic groups.
• H-bond donor: Oxygen and nitrogen atoms bonded to hydrogen atom(s).
• H-bond acceptor: Oxygen and sp² or sp hybridized nitrogen atoms with lone electron pair(s).
• Polar atom: Oxygen and nitrogen atoms that are neither H-bond donor nor H-bond acceptor, sulfur, phosphorus, halogen, metal, and carbon atoms bonded to hetero-atom(s).

The space inside the ligand binding region would be studied with virtual probe atoms of the four types above so the chemical environment of all spots in the ligand binding region can be known. Hence we are clear what kind of chemical fragments can be put into their corresponding spots in the ligand binding region of the receptor.

Ligand fragment link

Flow chart for structure-based drug design

When we want to plant “seeds” into different regions defined by the previous section, we need a fragments database to choose fragments from. The term “fragment” is used here to describe the building blocks used in the construction process. The rationale of this algorithm lies in the fact that organic structures can be decomposed into basic chemical fragments. Although the diversity of organic structures is infinite, the number of basic fragments is rather limited.
Before the first fragment, i.e. the seed, is put into the binding pocket, and other fragments can be added one by one, it is useful to identify potential problems. First, the possibility for the fragment combinations is huge. A small perturbation of the previous fragment conformation would cause great difference in the following construction process. At the same time, in order to find the lowest binding energy on the Potential energy surface (PES) between planted fragments and receptor pocket, the scoring function calculation would be done for every step of conformation change of the fragments derived from every type of possible fragments combination. Since this requires a large amount of computation, using different tricks may use less computing power and let the program work more efficiently. When a ligand is inserted into the pocket site of a receptor, groups on the ligand that bind tightly with the receptor should have the highest priority in finding their lowest-energy conformation. This allows us to put several seeds into the program at the same time and optimize the conformation of those seeds that form significant interactions with the receptor, and then connect those seeds into a continuous ligand in a manner that make the rest of the ligand have the lowest energy. The pre-placed seeds ensure high binding affinity and their optimal conformation determines the manner in which the ligand will be built, thus determining the overall structure of the final ligand. This strategy efficiently reduces the calculation burden for fragment construction. On the other hand, it reduces the possibility of the combination of fragments, which reduces the number of possible ligands that can be derived from the program. The two strategies above are widely used in most structure-based drug design programs. They are described as “Grow” and “Link”. The two strategies are always combined in order to make the construction result more reliable.^[6][7][9]

Scoring method

Main article: Scoring functions for docking

Structure-based drug design attempts to use the structure of proteins as a basis for designing new ligands by applying accepted principles of molecular recognition. The basic assumption underlying structure-based drug design is that a good ligand molecule should bind tightly to its target. Thus, one of the most important principles for designing or obtaining potential new ligands is to predict the binding affinity of a certain ligand to its target and use it as a criterion for selection.
One early method was developed by Böhm^[10] to develop a general-purposed empirical scoring function in order to describe the binding energy. The following “Master Equation” was derived:

where:

• desolvation – enthalpic penalty for removing the ligand from solvent
• motion – entropic penalty for reducing the degrees of freedom when a ligand binds to its receptor
• configuration – conformational strain energy required to put the ligand in its "active" conformation
• interaction – enthalpic gain for "resolvating" the ligand with its receptor

The basic idea is that the overall binding free energy can be decomposed into independent components that are known to be important for the binding process. Each component reflects a certain kind of free energy alteration during the binding process between a ligand and its target receptor. The Master Equation is the linear combination of these components. According to Gibbs free energy equation, the relation between dissociation equilibrium constant, K_d, and the components of free energy was built.
Various computational methods are used to estimate each of the components of the master equation. For example, the change in polar surface area upon ligand binding can be used to estimate the desolvation energy. The number of rotatable bonds frozen upon ligand binding is proportional to the motion term. The configurational or strain energy can be estimated using molecular mechanics calculations. Finally the interaction energy can be estimated using methods such as the change in non polar surface, statistically derived potentials of mean force, the number of hydrogen bonds formed, etc. In practice, the components of the master equation are fit to experimental data using multiple linear regression. This can be done with a diverse training set including many types of ligands and receptors to produce a less accurate but more general "global" model or a more restricted set of ligands and receptors to produce a more accurate but less general "local" model.^[11][12][13]

Rational drug discovery

In contrast to traditional methods of drug discovery, which rely on trial-and-error testing of chemical substances on cultured cells or animals, and matching the apparent effects to treatments, rational drug design begins with a hypothesis that modulation of a specific biological target may have therapeutic value. In order for a biomolecule to be selected as a drug target, two essential pieces of information are required. The first is evidence that modulation of the target will have therapeutic value. This knowledge may come from, for example, disease linkage studies that show an association between mutations in the biological target and certain disease states. The second is that the target is "drugable". This means that it is capable of binding to a small molecule and that its activity can be modulated by the small molecule.
Once a suitable target has been identified, the target is normally cloned and expressed. The expressed target is then used to establish a screening assay. In addition, the three-dimensional structure of the target may be determined.
The search for small molecules that bind to the target is begun by screening libraries of potential drug compounds. This may be done by using the screening assay (a "wet screen"). In addition, if the structure of the target is available, a virtual screen may be performed of candidate drugs. Ideally the candidate drug compounds should be "drug-like", that is they should possess properties that are predicted to lead to oral bioavailability, adequate chemical and metabolic stability, and minimal toxic effects. Several methods are available to estimate druglikeness such as Lipinski's Rule of Five and a range of scoring methods such as Lipophilic efficiency. Several methods for predicting drug metabolism have been proposed in the scientific literature, and a recent example is SPORCalc.^[14] Due to the complexity of the drug design process, two terms of interest are still serendipity and bounded rationality. Those challenges are caused by the large chemical space describing potential new drugs without side-effects.

Computer-aided drug design

Computer-aided drug design uses computational chemistry to discover, enhance, or study drugs and related biologically active molecules. The most fundamental goal is to predict whether a given molecule will bind to a target and if so how strongly. Molecular mechanics or molecular dynamics are most often used to predict the conformation of the small molecule and to model conformational changes in the biological target that may occur when the small molecule binds to it. Semi-empirical, ab initio quantum chemistry methods, or density functional theory are often used to provide optimized parameters for the molecular mechanics calculations and also provide an estimate of the electronic properties (electrostatic potential, polarizability, etc.) of the drug candidate that will influence binding affinity.
Molecular mechanics methods may also be used to provide semi-quantitative prediction of the binding affinity. Also, knowledge-based scoring function may be used to provide binding affinity estimates. These methods use linear regression, machine learning, neural nets or other statistical techniques to derive predictive binding affinity equations by fitting experimental affinities to computationally derived interaction energies between the small molecule and the target.^[15][16]
Ideally the computational method should be able to predict affinity before a compound is synthesized and hence in theory only one compound needs to be synthesized. The reality however is that present computational methods are imperfect and provide at best only qualitatively accurate estimates of affinity. Therefore in practice it still takes several iterations of design, synthesis, and testing before an optimal molecule is discovered. On the other hand, computational methods have accelerated discovery by reducing the number of iterations required and in addition have often provided more novel small molecule structures.
Drug design with the help of computers may be used at any of the following stages of drug discovery:

1. hit identification using virtual screening (structure- or ligand-based design)
2. hit-to-lead optimization of affinity and selectivity (structure-based design, QSAR, etc.)
3. lead optimization optimization of other pharmaceutical properties while maintaining affinity

Flowchart of a Usual Clustering Analysis for Structure-Based Drug Design

In order to overcome the insufficient prediction of binding affinity calculated by recent scoring functions, the protein-ligand interaction and compound 3D structure information are used to analysis. For structure-based drug design, several post-screening analysis focusing on protein-ligand interaction has been developed for improving enrichment and effectively mining potential candidates:

• Consensus scoring^[17][18]
  • Selecting candidates by voting of multiple scoring functions
  • May lose the relationship between protein-ligand structural information and scoring criterion
• Geometric analysis
  • Comparing protein-ligand interactions by visually inspecting individual structures
  • Becoming intractable when the number of complexes to be analyzed increasing
• Cluster analysis^[19][20]
  • Represent and cluster candidates according to protein-ligand 3D information
  • Needs meaningful representation of protein-ligand interactions.

Examples

A particular example of rational drug design involves the use of three-dimensional information about biomolecules obtained from such techniques as X-ray crystallography and NMR spectroscopy. Computer-aided drug design in particular becomes much more tractable when there is a high-resolution structure of a target protein bound to a potent ligand. This approach to drug discovery is sometimes referred to as structure-based drug design. The first unequivocal example of the application of structure-based drug design leading to an approved drug is the carbonic anhydrase inhibitor dorzolamide, which was approved in 1995.^[21][22]
Another important case study in rational drug design is imatinib, a tyrosine kinase inhibitor designed specifically for the bcr-abl fusion protein that is characteristic for Philadelphia chromosome-positive leukemias (chronic myelogenous leukemia and occasionally acute lymphocytic leukemia). Imatinib is substantially different from previous drugs for cancer, as most agents of chemotherapy simply target rapidly dividing cells, not differentiating between cancer cells and other tissues.
Additional examples include:

• Many of the atypical antipsychotics
• Cimetidine, the prototypical H₂-receptor antagonist from which the later members of the class were developed
• Selective COX-2 inhibitor NSAIDs
• Dorzolamide, a carbonic anhydrase inhibitor used to treat glaucoma
• Enfuvirtide, a peptide HIV entry inhibitor
• Nonbenzodiazepines like zolpidem and zopiclone
• Probenecid
• SSRIs (selective serotonin reuptake inhibitors), a class of antidepressants
• Zanamivir, an antiviral drug
• Isentress, HIV Integrase inhibitor^[23]

Case studies

• 5-HT3 antagonists
• Acetylcholine receptor agonists
• Angiotensin receptor blockers
• Bcr-Abl tyrosine kinase inhibitors
• Cannabinoid receptor antagonists
• CCR5 receptor antagonists
• Cyclooxygenase 2 inhibitors
• Dipeptidyl peptidase-4 inhibitors
• HIV protease inhibitors
• NK1 receptor antagonists
• Non-nucleoside reverse transcriptase inhibitors
• Proton pump inibitors
• Triptans
• TRPV1 antagonists
• Renin inhibitors
• c-Met inhibitors

BIOSIMILARS

Biosimilars also known as follow-on biologics are biologic medical products whose active drug substance is made by a living organism or derived from a living organism by means of recombinant DNA or controlled gene expression methods.
Biosimilars or follow-on biologics are terms used to describe officially approved subsequent versions of innovator biopharmaceutical products made by a different sponsor following patent and exclusivity expiry on the innovator product.Biosimilars are also referred to as subsequent entry biologics (SEBs) in Canada.Reference to the innovator product is an integral component of the approval.
Unlike the more common small-molecule drugs, biologics generally exhibit high molecular complexity, and may be quite sensitive to changes in manufacturing processes. Follow-on manufacturers do not have access to the originator's molecular clone and original cell bank, nor to the exact fermentation and purification process, nor to the active drug substance. They do have access to the commercialized innovator product. Differences in impurities and/or breakdown products can have serious health implications. This has created a concern that copies of biologics might perform differently than the original branded version of the product. Consequently only a few subsequent versions of biologics have been authorized in the US through the simplified procedures allowed for small molecule generics, namely Menotropins (January 1997) and Enoxaparin (July 2010), and a further eight biologics through the 505(b)(2) pathway.

Approval processes

The European regulatory authorities led with a specially adapted approval procedure to authorize subsequent versions of previously approved biologics, termed "similar biological medicinal products" - often called biosimilars for short. This procedure is based on a thorough demonstration of "comparability" of the "similar" product to an existing approved product.In the US the Food and Drug Administration (FDA) held that new legislation was required to enable them to approve biosimilars to those biologics originally approved through the PHS Act pathway. Additional Congressional hearings have been held,. On March 17, 2009, the Pathway for Biosimilars Act was introduced in the House. See the Library of Congress website and search H.R. 1548 in 111th Congress Session. Since 2004 the FDA has held a series of public meetings on biosimilars.
The FDA gained the authority to approve biosimilars (including interchangeables that are substitutable with their reference product) as part of the Patient Protection and Affordable Care Act signed by President Obama on March 23, 2010 - none have yet been approved. The FDA has previously approved biologic products using comparability, for example, Omnitrope in May 2006, but this like Enoxaparin was also to a reference product, Genotropin, originally approved as a biologic drug under the FD&C Act ) .

Background

Cloning of human genetic material and development of in vitro biological production systems has allowed the production of virtually any recombinant DNA based biological substance for eventual development of a drug. Monoclonal antibody technology combined with recombinant DNA technology has paved the way for tailor-made and targeted medicines. Gene- and cell-based therapies are emerging as new approaches.
Recombinant therapeutic proteins are of a complex nature (composed of a long chain of amino acids, modified amino acids, derivatized by sugar moieties, folded by complex mechanisms). These proteins are made in living cells (bacteria, yeast, animal or human cell lines). The ultimate characteristics of a drug containing a recombinant therapeutic protein are to a large part determined by the process through which they are produced: choice of the cell type, development of the genetically modified cell for production, production process, purification process, formulation of the therapeutic protein into a drug.
After the expiry of the patent of approved recombinant drugs (e.g. insulin, human growth hormone, interferons, erythropoietin, and more) any other biotech company can "copy" and market these biologics (thus called biosimilars).
However, because no two cell lines, developed independently, can be considered identical, biotech medicines cannot be fully copied. The European Medicines Agency, EMEA, has recognized this fact, which has resulted in the establishment of the term "biosimilar" in recognition that, whilst biosimilar products are similar to the original product, they are not exactly the same. Small distinctions in the cell line, in the manufacturing process or in the surrounding environment can make a major difference in side effects observed during treatment, i.e. two similar biologics can trigger very different immunogenic response. Therefore, and unlike chemical pharmaceuticals, substitution between biologics, including biosimilars, can have clinical consequences and does create putative health concerns.
Biosimilars are subject to an approval process which requires substantial additional data to that required for chemical generics, although not as comprehensive as for the original biotech medicine. However, the safe application of biologics is also dependent on an informed and appropriate use by healthcare professionals and patients. Introduction of biosimilars also requires a specifically designed pharmacovigilance plan. It is difficult and costly to recreate biologics because the complex proteins are derived from living organisms that are genetically modified. In contrast, small molecule drugs made up of a chemically based compound can be easily replicated and are considerably less expensive to reproduce. In order to be released to the public, biosimilars must be shown to be as close to identical to the parent biological product based on data compiled through clinical, animal and analytical studies. The results must demonstrate that they produce the same clinical results and are interchangeable with the referenced FDA licensed biological product already on the market. As of December 2009, ambiguities concerning naming, regional differences in prescribing practices, and regional differences in legally-defined rules with respect to substitution are important points that still need to be resolved to ensure a safe use of biosimilars.

United States of America

BPCI Act

The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) was originally sponsored and introduced on June 26, 2007 by Senator Edward Kennedy (D-MA). It was formally passed under the Patient Protection and Affordable Care Act (PPAC Act), signed into law by President Barack Obama on March 23, 2010. The BPCI Act was an amendment to the Public Health Service Act (PHS Act) to create an abbreviated approval pathway for biological products that are demonstrated to be highly similar (biosimilar) to a Food and Drug Administration (FDA) approved biological product. The BPCI Act is similar, conceptually, to the Drug Price Competition and Patent Term Restoration Act of 1984 (also referred to as the "Hatch-Waxman Act") which created biological drug approval through the Federal Food, Drug, and Cosmetic Act (FFD&C Act). The BPCI Act aligns with the FDA's longstanding policy of permitting appropriate reliance on what is already known about a drug, thereby saving time and resources and avoiding unnecessary duplication of human or animal testing.

Data exclusivity

Data exclusivity is an important piece of the amendment in the Patient Protection and Affordable Care Act for biosimilars. It is the period of time between FDA approval and an abbreviated filing for a biosimilar on the original producer's data. Data exclusivity is designed to preserve innovation and recognize the long, costly, and risky process involved while the innovator waits to gain FDA approval. The time allowed for data exclusivity is critical for the future of biologics. A number of provisions for data exclusivity in recent legislative proposals ranged up to 14 years, however, the passing of the PPAC Act guarantees a 12 year time period from the time of FDA approval. This is supposed to compensate for perceived shortcomings in patent protection for biologics. Data exclusivity extends from the date of product approval, and this protection period runs concurrently with any remaining patent term protection for the biologic. That is to say, data exclusivity provides additional protection to the innovator when the remaining patent length is shorter than the data exclusivity period at the time of approval (which can occur due to lengthy pre-clinical and clinical research required to obtain FDA approval), or to the extent that the patent term is circumvented by a biosimilar prior to its expiry.

Market implications

The 2012–2019 patent cliff.^[13] Period of market exclusivity up to date of patent expiration for the Top 10 selling biologics for 2011. *Enbrel has been granted approval in 2011 for a patent filed in 1995, extending its patent life further 17 years.

The legal requirements of approval pathways, together with the costly manufacturing processes, escalates the developing costs for biosimilars that could be between 75–250 million USD per molecule. This market entry barrier affects not only the companies willing to produce them but could also delays availability of inexpensive alternatives for public healthcare institutions that subsidize treatment for their patients. Even-though the biosimilars market is rising, the price drop for biological drugs at risk of patent expiration will not be as great as for other generic drugs; in fact it has been estimated that the price for biosimilar products will be 65%-85% of their originators. Biosimilars are drawing market's attention since there is an upcoming patent cliff, which will put nearly 36% of the 140bn USD market for biologic drugs at risk (as for 2011), this considering only the top 10 selling products

orphan disease

A rare disease, also referred to as an orphan disease, is any disease that affects a small percentage of the population.
Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear. Many rare diseases appear early in life, and about 30 percent of children with rare diseases will die before reaching their fifth birthday.^[1] With a single diagnosed patient only, ribose-5-phosphate isomerase deficiency is presently considered the rarest genetic disease.
No single cutoff number has been agreed upon for which a disease is considered rare. A disease may be considered rare in one part of the world, or in a particular group of people, but still be common in another.

Definition

There is no single, widely accepted definition for rare diseases. Some definitions rely solely on the number of people living with a disease, and other definitions include other factors, such as the existence of adequate treatments or the severity of the disease.
In the United States, the Rare Diseases Act of 2002 defines rare disease strictly according to prevalence, specifically "any disease or condition that affects less than 200,000 persons in the United States,"^[2] or about 1 in 1,500 people. This definition is essentially like that of the Orphan Drug Act of 1983, a federal law that was written to encourage research into rare diseases and possible cures.
In Japan, the legal definition of a rare disease is one that affects fewer than 50,000 patients in Japan, or about 1 in 2,500 people.^[3]
However, the European Commission on Public Health defines rare diseases as "life-threatening or chronically debilitating diseases which are of such low prevalence that special combined efforts are needed to address them."^[4] The term low prevalence is later defined as generally meaning fewer than 1 in 2,000 people. Diseases that are statistically rare, but not also life-threatening, chronically debilitating, or inadequately treated, are excluded from their definition.
The definitions used in the medical literature and by national health plans are similarly divided, with definitions ranging from 1/1,000 to 1/200,000.^[3]

Relationship to orphan diseases

Because of definitions that include reference to treatment availability, a lack of resources, and severity of the disease, some people^[who?] prefer the term orphan disease and use it as a synonym for rare disease.^[3] The orphan drug movement began in the United States.^[3]
Others distinguish between the two terms. For example, the European Organization for Rare Diseases (EURORDIS) lumps both rare diseases and neglected diseases into a larger category of orphan diseases.^[5]
The United States' Orphan Drug Act includes both rare diseases and any non-rare diseases "for which there is no reasonable expectation that the cost of developing and making available in the United States a drug for such disease or condition will [be] recovered from sales in the United States of such drug" as orphan diseases.^[6]

Prevalence

Prevalence (number of people living with a disease at a given moment), rather than incidence (number of new diagnoses in a given year), is used to describe the impact of rare diseases. The Global Genes Project estimates there are some 350 million people worldwide currently affected with a rare disease.
The European Organization for Rare Diseases (EURORDIS) estimates that as many as 5,000 to 7,000 distinct rare diseases exist, and as much as 6% to 8% of the population of the European Union is affected by one.^[5]
Rare diseases can vary in prevalence between populations, so a disease that is rare in some populations may be common in others. This is especially true of genetic diseases and infectious diseases. An example is cystic fibrosis, a genetic disease: it is rare in most parts of Asia but relatively common in Europe and in populations of European descent. In smaller communities, the founder effect can result in a disease that is very rare worldwide being prevalent within the smaller community. Many infectious diseases are prevalent in a given geographic area but rare everywhere else. Other diseases, such as many rare forms of cancer, have no apparent pattern of distribution but are simply rare. The classification of other conditions depends in part on the population being studied: All forms of cancer in children are generally considered rare, because so few children develop cancer, but the same cancer in adults may be more common.
About 40 rare diseases have a far higher prevalence in Finland; these are known collectively as the Finnish disease heritage.

Characteristics

Rare diseases usually are genetic,^[7] hence chronic. EURORDIS estimates that at least 80% of them have identified genetic origins.^[8] Other rare diseases are the result of infections and allergies or due to degenerative and proliferative causes.
Classification of a disease's rarity also depends on the population being studied. Every form of cancer is rare among children,^[9] but some forms are common among adults.
Symptoms of some rare diseases may appear at birth or in childhood, whereas others only appear once adulthood is reached.
Research publications emphasize rare diseases that are chronic or incurable, although many short-term medical conditions are also rare diseases.^[10]

Public research

The NIH's Office of Rare Diseases Research (ORDR) was established by H.R. 4013/Public Law 107-280 in 2002.^[11] H.R. 4014, signed the same day, refers to the "Rare Diseases Orphan Product Development Act".^[12] Similar initiatives have been proposed in Europe.^[13]

Public awareness

The first Rare Disease Day was held in Europe and Canada in February 2008 to raise awareness for rare diseases.^[14][15] It is intended to be observed on the last day of February every year.^[16]

Support

The National Organization for Rare Disorders was established in 1983 by individuals and families with rare diseases.^[17][18]
Genetic Alliance, established in 1986, lists information and support groups for approximately 1200 rare diseases.^[19]
The Global Genes Project is one of the leading rare and genetic disease patient advocacy organizations in the world. The non-profit organization is led by Team R.A.R.E. (R.A.R.E stands for Rare disease, Advocacy, Research and Education).^[20] Global Genes promotes the needs of the rare and genetic disease community under a unifying symbol of hope – the Blue Denim Genes Ribbon™.^[21] What began as a grassroots movement in 2009 with a few rare disease parent advocates and foundations has grown to over 500 global organizations. Global Genes uses a simple concept of "genes and jeans" to broadly promote the needs of the rare and genetic disease community. The organization has launched a number of innovative rare and genetic disease awareness campaigns including, Hope, It's In Our Genes™,^[22] Wear That You Care™,^[23] 7,000 Bracelets for Hope™^[24] to represent the 7,000 different rare diseases and Unite 1 Million For RARE™ disease.
The Canadian Organization for Rare Disorders (CORD) is the national network of organizations who represent people affected by rare disorders within Canada. CORD's intention is to provide a strong common voice advocating for a healthcare system and health policy for those with rare disorders.^[25]
Patients with rare diseases in Greece are represented by the Greek Alliance of Rare Diseases.

Orphan drug

An orphan drug is a pharmaceutical agent that has been developed specifically to treat a rare medical condition, the condition itself being referred to as an orphan disease. In the US and EU it is easier to gain marketing approval for an orphan drug, and there may be other financial incentives, such as extended exclusivity periods, all intended to encourage the development of drugs which might otherwise lack a sufficient profit motive. The assignment of orphan status to a disease and to any drugs developed to treat it is a matter of public policy in many countries, and has resulted in medical breakthroughs that may not have otherwise been achieved due to the economics of drug research and development.

Orphan drug legislation

Orphan drugs generally follow the same regulatory development path as any other pharmaceutical product, in which testing focuses on pharmacokinetics and pharmacodynamics, dosing, stability, safety and efficacy. However, some statistical burdens are lessened in an effort to maintain development momentum. For example, orphan drug regulations generally acknowledge the fact that it may not be possible to test 1,000 patients in a phase III clinical trial, as fewer than that number may be afflicted with the disease in question.
Since the market for any drug with such a limited application scope would, by definition, be small and thus largely unprofitable, government intervention is often required to motivate a manufacturer to address the need for an orphan drug. Critics of free market enterprise often cite this as a failure of free market economic systems.
The intervention by government on behalf of orphan drug development can take a variety of forms:

• Tax incentives.
• Enhanced patent protection and marketing rights.
• Clinical research financial subsidization.
• Creating a government-run enterprise to engage in research and development (see Crown corporation).

United States

Orphan Drug Act

Main article: Orphan Drug Act

The Orphan Drug Act (ODA) of January 1983, passed in the United States, with lobbying from the National Organization for Rare Disorders and many other organizations,^[1] is meant to encourage pharmaceutical companies to develop drugs for diseases that have a small market. Under the law, companies that develop such a drug (a drug for a disorder affecting fewer than 200,000 people in the United States) may sell it without competition for seven years,^[2] and may get clinical trial tax incentives.^[2]
Orphan drug designation means that the sponsor qualifies for certain benefits, such as reduced taxes, from the federal government. It does not mean the drug is safe and effective and legal to manufacture and market in the United States.

Rare Diseases Act

Main article: Rare Diseases Act of 2002

In 2002 the Rare Diseases Act was signed into law. This legislation amended the Public Health Service Act to establish the Office of Rare Diseases. It also increased funding for the development of treatments for patients with rare diseases.^[3]

European Union

The European Union (EU) has enacted similar legislation, Regulation(EC) No 141/2000, in which pharmaceuticals developed to treat rare diseases are referred to as "orphan medicinal products." The EU's definition of an orphan condition is broader than that of the USA, in that it also covers some tropical diseases that are primarily found in developing nations.^[4] Orphan drug status granted by the European Commission gives marketing exclusivity in the EU for 10 years after approval.^[5] The EU's legislation is administered by the Committee on Orphan Medicinal Products of the European Medicines Agency (EMA).

Regulatory harmonization

In an effort to reduce the burden on manufacturers applying for orphan drug status, the FDA and EMA agreed in late 2007 to utilize a common application process for both agencies. However, the two agencies will continue to maintain separate approval processes.^[6]

Other countries

In addition to the United States and the European Union, legislation has been implemented by Japan, Singapore, and Australia that offers subsidies and other incentives to encourage the development of drugs that treat orphan diseases.^[7]

Effectiveness

Under the ODA and EU legislation, many orphan drugs have been developed, including drugs to treat glioma, multiple myeloma, cystic fibrosis, phenylketonuria, snake venom poisoning, and idiopathic thrombocytopenic purpura.
The ODA is nearly universally acknowledged to be a success.^[8] Before Congress enacted the ODA in 1983 only 38 drugs were approved in the USA specifically to treat orphan diseases.^[9] In the USA, from January 1983 to June 2004, a total of 1,129 different orphan drug designations have been granted by the Office of Orphan Products Development (OOPD) and 249 orphan drugs have received marketing authorization. In contrast, the decade prior to 1983 saw fewer than ten such products come to market. From the passage of the ODA in 1983 until May 2010, the FDA approved 353 orphan drugs and granted orphan designations to 2,116 compounds. As of 2010, 200 of the roughly 7,000 officially designated orphan diseases have become treatable.^[8] Some critics have questioned whether orphan drug legislation was the real cause of this increase (claiming that many of the new drugs were for disorders that were already being researched anyway, and would have had drugs developed regardless of the legislation), and whether the ODA has really stimulated the production of truly non-profitable drugs; the act also received some criticism for allowing some pharmaceutical companies to make a large profit off of drugs that have a small market but still sell for a high price.^[2]
Although the European Medicines Agency grants market access its 27 member states, in practice, medicines only reach the market when each member state decides that its national health system will reimburse for the drug. For example, 35 orphan drugs reached the market in Belgium, 44 in the Netherlands, and 28 in Sweden in 2008. 35 such drugs reached the market in France and 23 in Italy in 2007.^[10]

Orphan diseases

Main article: Orphan diseases

A rare disease, also referred to as an "orphan disease," is any disease that affects a small percentage of the population. Most rare diseases are genetic, and thus are present throughout the person's entire life, even if symptoms do not immediately appear. Many rare diseases appear early in life, and about 30 percent of children with rare diseases will die before reaching their fifth birthday.^[11] With a single diagnosed patient only, ribose-5-phosphate isomerase deficiency is presently considered the rarest genetic disease. No single cutoff number has been agreed upon for which a disease is considered rare. A disease may be considered rare in one part of the world, or in a particular group of people, but still be common in another.
Research has found that as many as one-in-ten Americans suffers from rare disease.^[12] Over 55 million people are estimated to suffer from a rare disease in Europe and in the US. Global estimates are between 5000 to 7000 rare diseases. New rare diseases are discovered every week and many have no treatments available. Currently, 350 orphan drugs have been approved for sale in the US.^[13]

Cystic fibrosis

Main article: Cystic fibrosis

In the 1980s, cystic fibrosis patients rarely lived beyond their early teens. However, drugs like Pulmozyme and Tobramycin, both developed with aid from the ODA, revolutionized treatment for cystic fibrosis patients by significantly improving their quality of life and extending their life expectancies. Now, cystic fibrosis patients often survive into their thirties and some into their fifties.^[3]

Homozygous familial hypercholesterolemia

Main article: Homozygous familial hypercholesterolemia

The 1985 Nobel Prize for medicine went to two researchers for their work related to homozygous familial hypercholesterolemia, an orphan disease that causes large and rapid increases in cholesterol levels. Their research led to the development of statin drugs that are commonly used to treat high cholesterol.^[7]

Wilson's Disease

Main article: Wilson's Disease

Penicillamine was developed to treat Wilson's Disease, a rare hereditary disease that can lead to a fatal accumulation of copper in the body. This drug was later found to be effective in treating arthritis.^[7]

Activism

Numerous advocacy groups such as the National Organization for Rare Disorders, Global Genes Project, Children's Rare Disease Network, Abetalipoproteinemia Collaboration Foundation, Zellweger Baby Support Network, and the Friedreich's Ataxia Research Alliance have been founded in order to advocate on behalf of patients suffering from rare diseases with a particular emphasis on diseases that afflict children.^[8]

Industry involvement

Key orphan drug developers including Synageva BioPharma Corp., Swedish Orphan Biovitrum, Shire plc, GlaxoSmithKline, Pfizer, Novartis, Genzyme, Lundbeck, Prosensa and BioMarin are leading the way in this growing industry. These pharmaceutical companies work together with national bodies such as the U.S.'s National Organization for Rare Disorders (NORD) and the European Organization for Rare Diseases (EURORDIS) to advance this field.

Research centers

Center for Orphan Drug Research

The Center for Orphan Drug Research at the University of Minnesota College of Pharmacy provides help to small companies with insufficient in-house expertise and resources in the areas of drug synthesis, formulation, pharmacometrics, and bio-analysis.^[14]

Keck Graduate Institute Center for Rare Disease Therapies

The Keck Graduate Institute Center for Rare Disease Therapies (CRDT) in Claremont, California supports projects to revive potential orphan drugs whose development has stalled by identifying barriers to commercialization such as problems with formulation and bio-processing.[

Supplementary protection certificate

In European Union member countries, a supplementary protection certificate (SPC) is a unique (sui generis) intellectual property (IP) right that extends the duration of the exclusive right. It enters into force after expiry of a patent upon which it is based. This type of right is available for various regulated, biologically active agents, namely human or veterinary medicaments and plant protection products (e.g. insecticides, and herbicides). Supplementary protection certificates were introduced to encourage innovation by compensating for the long time needed to obtain regulatory approval of these products (i.e. authorisation to put these products on the market).^[1]
A supplementary protection certificate comes into force only after the corresponding general patent expires. It normally has a maximum lifetime of 5 years. The duration of the SPC can, however, be extended to 5.5 years when the SPC relates to a human medicinal product for which data from clinical trials conducted in accordance with an agreed Paediatric Investigation Plan (PIP) have been submitted (as set out in Article 36 of Regulation (EC) No 1901/2006^[2]).
The total combined duration of market exclusivity of a general patent and SPC cannot normally exceed 15 years. However, the reward of a 6-month SPC extension for the submission of data from an agreed PIP can extend this combined duration to 15.5 years.
SPCs extend the monopoly period for a "product" (active ingredient or a combination of active ingredients) that is protected by a patent. For many SPC applications, there is no controversy about the definition of the "product" or whether it is protected by the patent upon which the SPC application was based. However, there are other SPC applications (particularly for medicinal products containing multiple active ingredients) where there may not be clear answers to questions such as what is a permissible definition of a "product", and what test should be applied for determining whether a patent protects that "product".
Supplementary protection certificates in the European Union are based primarily upon two regulations. Although all countries in the EU are required to provide supplementary protection certificates, no unified cross-recognition exist. Applications must be filed and approved on a country-by-country basis

Scope of the law

ECJ cases C-195/09 and C-427/09 effectively ruled that SPCs for medicaments (human or veterinary) are only available for those "products" that:
(a) are protected by a patent;
(b) have been subject to an administrative authorisation procedure; and
(c) have not been placed on the market anywhere in the EEA as a medicinal product prior to being subject to safety and efficacy testing and a regulatory review.
Until recently, decisions C-195/09 and C-427/09 could have been interpreted as ruling out the possibility of SPC protection for all "products" previously included in medicinal products that were marketed prior to the date(s) of the Marketing Authorisation(s) (MA(s)) specified in the SPC application. This is because the ECJ's rulings in C-195/09 and C-427/09 were based in part upon a desire to ensure that national patent offices are not required to assess whether an earlier MA was compliant with the standards for testing of safety and efficacy that were introduced in the 1970s (meaning that all prior MAs, whether or not compliant with those standards, should be treated equally under the SPC legislation).
However, the decision in Neurim Pharmaceuticals (C-130/11) has cast doubt upon this interpretation. In C-130/11, the ECJ held that an SPC can be granted regardless of the prior marketing of earlier (veterinary) medicinal products containing the "product" in question. Thus, cases C-195/09 and C-427/09 (which, in common with C-130/11, related to SPC applications based upon newly patented uses for old "products") could perhaps now be viewed as being of relevance only to those "products" that were marketed before being subject to a regulatory review. However, this might necessitate patent offices making a determination of whether prior MAs are compliant with current standards (i.e. whether the "product" had been subject to safety and efficacy testing prior to being granted an MA). As this is precisely the kind of determination that the ECJ had previously been keen for patent offices to avoid, further references to the ECJ may be necessary to clarify precisely which "products" fall within the scope of the SPC legislation and which do not.
With respect to (a) above, the question of how to determine whether a "product" is protected by a patent is the subject of ongoing controversy. Cases such as C-322/10 and C-422/10 have indicated that the "product" needs to be "specified [or identified] in the wording of the claims". However, the precise meaning of this test is yet to be clarified.
Further, although the SPC legislation mentions only Directives 2001/83/EC and 2001/82/EC as the "administrative authorisation procedure" for human or veterinary medicaments, SPCs are known to have been granted when MAs have not been obtained via those procedures (but instead via procedures that involve a similar level of safety and efficacy testing)[1].

Determination of term

The term of an SPC depends on the date of issuance of the first MA within the EEA and can be determined by the equation:

                 Term = date of 1st MA in the EEA − date of filing of corresponding patent − 5 years

Under normal circumstances, this means the following.

• No SPC term is available if less than 5 years have elapsed between the date of filing of the corresponding patent and the date of issuance of the first MA in the EEA.
• If the first MA is issued more than five years but less than ten years after the filing date of the corresponding patent, an SPC is granted for a term corresponding to the period elapsed between the five-year point and the MA issuance date.
• If the first MA is issued more than ten years after the filing date of the corresponding patent, an SPC is granted for a five-year term.

There have been very few cases where there was any controversy over the precise date of the 1st MA in the EEA. The Hässle AB case (ECJ case C-127/00^[3]) was one of that small number. In that case, the ECJ ruled that the decisive date for SPC purposes is the date of an authorisation from a regulatory body tasked with assessing safety and efficacy, and not the date of a subsequent authorisation that may be required under national pricing or reimbursement provisions.
So-called "centralised" (European Medicines Agency / European Commission) MAs were introduced by Regulation 2309/93^[4] and became available in January 1995 (i.e. some 2 years after the introduction of the original SPC legislation for medicinal products). The introduction of these authorisations added a new layer of complexity to the issue of determination of the date of a MA. This is because there are two dates associated with "centralised" authorisations, namely: (1) the date of the European Commission's decision to issue an authorisation; and (2) the date of notification of that decision to the MA applicant. Date (2) is usually a few days (e.g. 2 to 4 days) later than date (1). Although the standard practice of many national patent offices seems to be to calculate SPC term based upon date (1), an October 2011 article in Scrip Regulatory Affairs by Mike Snodin^[5] argues that this standard practice is incorrect and that date (2) should be used instead (with the result that some products may be entitled to a slightly longer SPC term than previously thought). Paramount amongst the reasons for preferring date (2) to date (1) is that a "centralised" authorisation does not become effective until it is notified to the MA applicant.
It is still too early to tell whether these arguments will prompt any of the above-mentioned national patent offices to change their standard practice. However, inspection of Belgian SPC certificates for products authorised via the "centralised" procedure reveals that at least the patent office in Belgium already appears to base calculations of SPC term upon date (2). For this reason, it seems that there are divergent practices across different territories within Europe with regard to the selection of a date for a "centralised" MA. If the issue were ever to be debated in a national court, this fact that there are divergent practices across different territories could provide basis for such a court to seek an authoratitive ruling from the ECJ in relation to which of dates (1) and (2) should be used for SPCs. This is because, as European Commission legislation, the Regulations governing SPCs should be interpreted consistently across all member states of the EU.
A MA in Switzerland was also considered as being a first MA for the calculation of the SPC duration, even though Switzerland is not part of the European Economic Area (EEA). This is because such a MA was automatically effective in Liechtenstein, which is a member of the EEA (since 1 May 1995). This was decided by the European Court of Justice (ECJ) in joined cases Novartis et al. v. Comptroller-General and Ministère de l'Economie v. Millennium Pharmaceuticals.^[6][7] However, as answer to the decision of the ECJ the contract between Switzerland and Liechtenstein was amended. Since 1 July 2005 the automatic effect of a Swiss MA in Liechtenstein is abolished. The recognition is now delayed by a time period, which is normally 12 months.

Paediatric extension

Article 36 of Regulation 1901/2006 provides for a 6-month extension to SPC term. The extension is available only under certain conditions, the most notable being the requirement for the submission of a new MA application containing data from all trials conducted in accordance with an agreed Paediatric Investigation Plan (PIP).
Consequences of the 6-month SPC extension include:

• the maximum term of an SPC can now be up to 5.5 years; and
• the maximum duration of market exclusivity (patent + SPC) can now be up to at least 15.5 years.

An extension of an SPC can only be awarded if there is an SPC to extend. As an unextended SPC only has a positive term if more than 5 years have elapsed between patent filing and MA issuance, this leads to the following two questions.
(1) Is an SPC available if less than 5 years and 1 day have elapsed between filing of the corresponding patent and issuance of the first MA in the EEA?
(2) If the answer to (1) is yes, what term should be awarded to the (unextended) SPC?
A July 2007 paper by Snodin and Miles,^[8] put forward three possible answers to this combination of two questions.
If the answer to question (1) is no, then it is not relevant to consider question (2). This corresponds to "Model B" of the 2007 Snodin and Miles paper, and produces a curious situation where longer marketing exclusivity can be obtained if the issuance of the first MA in the EEA is delayed (to at least 5 years and 1-day from filing of the corresponding patent).
If the answer to question (1) is yes, then question (2) becomes relevant. This question can be answered in two ways, corresponding to either "Model A" or "Model C" of the 2007 Snodin and Miles paper.
Model A assumes that SPC term can validly be either zero or negative if 5 years or less have elapsed from filing of the corresponding patent to issuance of the first MA in the EEA. In this event, a positive (and non-zero) SPC term is obtained (after extension) if the time from patent filing to MA issuance is more than 4.5 years.
Model C assumes that all term calculations that provide a negative answer are 'rounded up' to zero. This has the consequence of providing a minimum of 6 months of SPC term, irrespective of how little time has elapsed from patent filing to MA issuance.
Subsequent to the publication of the Snodin and Miles article, Merck & Co. filed SPC applications for the product sitagliptin. For example, from mid-August to mid-September 2007, Merck & Co. filed SPC applications in various countries, including the UK,^[9] Ireland,^[10] the Netherlands^[11] and Italy.^[12] These SPC applications provided an early opportunity for Models A to C to be tested in practice. Curiously, the patent offices of various EU member states did not reach any consensus on which model is correct. For example, the Netherlands^[13] and the UK^[14] favoured Model A, Germany,^[15] Portugal and Slovenia favoured Model B and Greece^[16] favoured Model C.
In connection with an appeal against refusal of the SPC application in Germany, and in view of the different stances taken by different national patent offices, the German Federal Court of Justice (Bundesgerichtshof) sought clarification of the law from the Court of Justice of the EU (in case C-125/10).
The decision of the Court of Justice, delivered on 8 December 2011,^[17] essentially agreed with Model A of the 2007 Snodin and Miles paper. Thus, useful (extended) supplementary protection can now be obtained so long as at least 4 years, 6 months and one day has elapsed from the date of patent filing to the date of the first MA for the product in the EEA.

Scope

According to Article 4 of Council Regulation (EEC) No 1768/92, the scope of an SPC extends "only to the product covered by the authorization to place the corresponding medicinal product on the market and for any use of the product as a medicinal product that has been authorized before the expiry of the certificate".
The European Court of Justice has decided, however, that the scope of an SPC is sometimes capable of encompassing more than just the single form of the active ingredient that is included in the medicinal product authorised for sale. Thus, in case C-392/97,^[18] the European Court of Justice held that: "where an active ingredient in the form of a salt is referred to in the marketing authorisation concerned and is protected by a basic patent in force, the certificate is capable of covering the active ingredient as such and also its various derived forms such as salts and esters, as medicinal products, in so far as they are covered by the protection of the basic patent".

Legal basis

Supplementary protection certificates in the European Union were based primarily upon two regulations:

• Council Regulation (EEC) No 1768/92 of 18 June 1992 concerning the creation of a supplementary protection certificate for medicinal products^[19] which entered into force on 2 January 1993. This has been cancelled by the below specified recodified regulation no. 469/2009 with effect from May 2009
• Regulation (EC) No 1610/96 of the European Parliament and of the Council of 23 July 1996 concerning the creation of a supplementary protection certificate for plant protection products^[20] which entered into force on 8 February 1997

The above Regulations have now been codified under the following regulation:

• Regulation (EC) No 469/2009 of the European Parliament and of the Council of 6 May 2009 concerning the supplementary protection certificate for medicinal products (Codified version)^[21]

Supplementary protection certificates may come into life at the expiry of a national or European patent. However, the European Patent Convention (EPC) needed to be modified to allow such "extension" of the term of European patent. Article 63 of the EPC was modified on 17 December 1991 to specify to, although European patents have a term of 20 years as from the date of filing of the application (Art. 63(1)),

" nothing (...) shall limit the right of a Contracting State to extend the term of a European patent, or to grant corresponding protection which follows immediately on expiry of the term of the patent, under the same conditions as those applying to national patents: (...)

(b) if the subject-matter of the European patent is a product or a process of manufacturing a product or a use of a product which has to undergo an administrative authorisation procedure required by law before it can be put on the market in that State. " ^[22]

This constituted the first revision of the European Patent Convention since its signature in 1973.
The paediatric extension is based primarily upon:

• Regulation 1901/2006 of 12 December 2006 on medicinal products for paediatric use and amending Regulation 1768/92, Directive 2001/20/EC, Directive 2001/83/EC and Regulation (EC) No 726/2004 ^[23]
• Regulation 1902/2006 of 20 December 2006 amending Regulation 1901/2006 on medicinal products for paediatric use^[24]

Statistics

According to research, more than 8,000 SPCs for medicinal and plant protection products have been filed in Europe between 1991 and 2003.^[25]