Chapter Nine
How Are New Drugs Regulated?
The biotechnology and pharmaceutical industries are the most highly regulated global industry. Why is this so? Formal regulation was needed to stop inappropriate labeling and extravagant claims about medicines that were downright lies.
Drug development regulation is overseen by the three main agencies, the Food and Drug Administration (FDA) in the U.S., the European Medicines Agency (EMA) in Europe and the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan. Regulation of drug development started relatively recently.
Some argue that the regulations have become too burdensome, but a glaring example of the disaster that can happen when there is insufficient regulatory oversight is the outbreak of meningitis in October 2012.
A compounding pharmacy in Massachusetts made up steroid injections without seemingly obeying the usual sterility rules. The basic ingredient was contaminated with a fungus that was neither detected nor eliminated in the process of filling the vials for distribution. By the end of November 2012, 541 cases of meningitis had been confirmed in patients who had received a steroid injection into their spine. Fluid circulates in the meningeal space up and down the spine and around the brain, and the fungus was introduced into this fluid during the procedure. By the time the outbreak was recognized, the contaminated vials had already been distributed to 19 states. By early December 2012, the Center for Disease Control in Atlanta, Georgia, reported that 36 patients had already died.
The FDA was not given the close cooperation to contain, investigate and recall the faulty material that the pharmaceutical industry would have been expected to provide. Attorneys are lining up to sue the hapless manufacturer, the New England Compounding Center, and both civil and criminal charges are likely. This incident will prompt a review and tightening of the rules for compounding to protect the public from this happening again. More FDA inspection and oversight for compounding pharmacies has been called for before. Those who fought against such oversight will now have to reconsider.
Regulations governing the development and manufacture of new drugs have gradually become far more complex and daunting over the years. So to harmonize the drug development requirements across the three main regulatory authorities, the International Conference on Harmonization (ICH), has been established to avoid unnecessary studies being conducted in animals or humans.
Will these substantial requirements be interpreted with more flexibility for the development of oligomers targeting rare diseases? That remains to be determined. The authorities are aware that the current regulations will not permit development without some flexibility, especially for rare diseases. Ongoing discussion between scientists from academia and industry with those from the regulatory authorities has been encouraged and is mediated through a think-tank, the Oligonucleotide Safety Working Group (OSWG). Even now, the OSWG is developing consensus guidelines on various technical aspects of drug development as it applies to the new gene-patches, although such guides are not official FDA, EMA, or PMDA guidance.
The first guidance written by this think-tank with external, academic expert, and informal FDA input was published in August 2012. This guide was written to help companies and regulators understand the issues concerning the safety assessment for inhaled oligomers.
Many governments and administrations have passed orphan drug regulations in an effort to encourage development of drugs for rare diseases, with substantial success. More needs to be done; however, as the costs for drug development climb and new drug approvals decline. Against this uphill battle, several oligomer companies are now in clinical programs, studying their molecular “Band-Aids” in patients with encouraging early results.
In the next few years several of these programs are likely to lead to the final hurdle, the New Drug Application in the U.S. The FDA will review the extensive dossiers these companies have been obliged to compile. Once approved, these first few gene patch therapies will reach the marketplace.
Before explaining the drug development process in more detail, here’s a quick recap of the three main agencies:
History of the U.S. FDA
The Food and Drug Administration (FDA) is an agency of the U.S. Department of Health and Human Services. It regulates anything that interacts with your body (or that of your pet’s), whether you swallow it, smoke or inhale it, wear it on your skin, have it implanted inside you, or are exposed to its radiation.
The FDA is in charge of making sure that one trillion dollars worth of goods, including $275 billion in drugs, are safe for consumers.
The origin of the FDA goes back to 1883, when Harvey Washington Wiley was appointed chief chemist at the Department of Agriculture’s (USDA) Division of Chemistry. He led a program of research looking into the adulteration and misbranding of food and drugs on the American market.
The USDA Division (later Bureau) of Chemistry published a ten-part series entitled “Foods and Food Adulterants” over a five-year period up to 1902. It had no power to prohibit or punish the companies responsible for the adulteration or misbranding. Wiley, however, used these findings to lobby the government. He, and others, argued that there should be uniform standards for food and drugs set by federal law. The nation’s physicians, pharmacists and state regulators supported Wiley.
The public was also sympathetic following the publication of articles by Upton Sinclair and others outlining the hazards of leaving medicines unregulated. In 1906, President Theodore Roosevelt signed the Food and Drug Act into law.
This act made it illegal to transport adulterated drugs across state lines if their strength, quality or purity was not clear. The active ingredient of any medicine needed to be listed in the United States Pharmacopoeia or the National Formulary and the label on the container had to be clear. Misbranding of drugs was also declared illegal. Policing this new legislation, and examining the strength, quality and purity of drugs became the responsibility of Wiley’s USDA Bureau of Chemistry.
In 1927, the Bureau of Chemistry’s regulatory powers were reorganized under a new USDA body, the Food, Drug, and Insecticide organization. Then in 1930, the organization’s title was changed to the Food and Drug Administration (FDA), as it remains to this day.
In the twenties, public concern was increasing about some of the drugs that were allowed under the 1906 act. The regulators and emerging consumer organizations also expressed concerns. Even the media caught on to the prevailing mood and added to the clamor for stronger regulation. A list of harmful products that had been ruled permissible under the 1906 law was published, including radioactive drinks, cosmetics that caused blindness and fraudulent claims made by drugs for diabetes and tuberculosis.
For five years, Congress procrastinated and effectively blocked any modification to the 1906 act until a tragic scandal rocked the nation in 1937. The Elixir Sulfanilamide tragedy killed over one hundred people. The drug sulfanilamide was dissolved in diethylene glycol, a toxic solvent, instead of ethanol, to form an elixir which it was claimed to be. However an elixir was defined as a medication dissolved in ethanol. The fraudulent use of the title elixir allowed the FDA to claim that the product was mislabeled and seize it. This tragedy finally forced Congress to see sense and rapidly pass a new act.
In 1938, President Franklin D. Roosevelt signed the new Food, Drug, and Cosmetic Act (FD&C Act) into law. The new act required a pre-market review of the safety of all new drugs by the FDA, significantly increasing their power to approve or veto a new drug being marketed. Companies could be punished under the new act for making false therapeutic claims in their drug’s labeling. Particularly important was the fact that companies could be punished whether or not the company had been intentionally fraudulent. The new act authorized the FDA to inspect factories and, brought cosmetics and therapeutic devices under federal regulatory authority. It also set a new series of regulated standards for food. The 1938 FD&C Act remains the central foundation of today’s FDA regulatory oversight.
Soon after passage of the 1938 Act, the FDA began to designate certain drugs as safe for use only under the supervision of a medical professional. Prescription-only drugs became a designation in the 1951 Durham-Humphrey Amendment. Over the next quarter century, the FDA reviewed 13,000 new drug applications (NDAs), although much of it’s attention was focused on amphetamine and barbiturate abuse.
In 1959, further congressional hearings into concerns about pharmaceutical industry practices were held. Many thought that some promoted drugs were too expensive and had dubious claims of benefit. But as with the earlier calls for stricter regulation, any new legislation expanding the FDA’s powers was strongly opposed by vested interests.
Once again it took a tragedy to force politicians to act.
Although thalidomide had been blocked by the FDA from release in the U.S., it was marketed in Europe with tragic results. I can remember when English babies were born with deformed limbs after their mothers took thalidomide, which was marketed for treatment of “morning sickness” in early pregnancy. Routine ultrasound scanning had not then been established and thus the deformities were not detected until the first babies were born. Thalidomide was estimated to have affected up to 20,000 babies before it was withdrawn in 1961.
The thalidomide tragedy in Europe led to the passage of important legislation in the U.S. In 1962, a watershed moment in FDA history took place. An amendment to the FD&C act was passed. Substantial evidence of efficacy for any claim put forward was now required as part of any new drug application.
This was in addition to the existing requirement for pre-marketing demonstration of safety.
Substantial evidence of safety in animals is needed before the FDA will allow even very small single doses of a drug to be given to humans. A large body of preliminary toxicological data is therefore common as part of the investigational new drug (IND) application that the FDA reviews before any clinical study in humans can begin.
The 1962 Amendment marked the start of the FDA approval process as we now know it today. It also required that drugs approved between 1938 and 1962 be reviewed by the FDA for evidence of efficacy. When that efficacy was not satisfactorily demonstrated, the offending drug was withdrawn from the market.
The amendment also restricted advertising to FDA-approved indications, and expanded FDA powers to inspect drug manufacturing facilities.
Due to these requirements, it took longer to develop a drug, which shortened the time a drug could be sold before its patent expired. Once a drug is out of patent, anyone can manufacture and sell a generic version of the same drug, without performing any additional research. Thus generic manufacturers do not have to work for a decade developing a huge dossier of data, nor spend the money required to do so. With no development costs, they can charge for just the cost of manufacturing and their profit. That’s why generic drugs cost so much less than brand-name drugs. To try and match these generic drug prices, the original brand’s price often tumbles when its patent expires, so it becomes far less profitable.
To compensate for this, the Hatch-Waxman Act of 1984 was passed. This bill extended the amount of time a drug manufacturer could hold a patent on a drug before the generic manufacturers could enter the market.
In the 1980s, the AIDS epidemic struck. New drugs were needed and HIV activist organizations expressed concerns about the time it took for the FDA to review and approve these vital drugs. Large protests were staged, including a confrontational one in October 1988 at the FDA campus resulting in nearly 180 arrests. By 1990, it was estimated that thousands of lives were lost each year due to delays in approval and marketing of drugs for cancer and AIDS.
In 1987, the FDA introduced Treatment INDs to allow promising new drugs to be made available to desperately ill patients as early in the drug development process as possible, once there is preliminary evidence of drug efficacy and the drug is intended to treat a serious or life-threatening disease, or if there is no alternative drug or therapy available. Treatment INDs are made available to doctors and their patients before general marketing begins, typically during phase 3 studies. They also allow the manufacturer and the FDA to obtain additional data on the drug’s safety and effectiveness.
Treatment INDs are rare. In the first 12 years only 39 such applications have been approved, of which 13 were for cancer and 11 were for HIV/AIDS. The accelerated approval rules were further expanded and codified in 1992.
All of the initial drugs approved for the treatment of HIV/AIDS were approved through accelerated approval mechanisms. For example, a treatment IND was issued for the first HIV drug, AZT, in 1985, and approval was granted just two years later in 1987. Three of the first five drugs targeting HIV were approved in the U.S. before they were approved in any other country.
The Critical Path Initiative, launched in 2004, is the FDA’s effort to stimulate and facilitate a national focus on modernizing how FDA-regulated products are developed, evaluated, and manufactured. Nonetheless, criticism of the time it takes the FDA to review and approve drugs continues. The AIDS crisis created political efforts to streamline the approval process, but these limited reforms were targeted for AIDS drugs, not the broader market. This led to the call for more enduring reforms that would allow patients to have access to drugs that have passed the first round of clinical trials. These would be patients suffering from rare and lethal diseases, and treatment would be under the care of doctors.
Oligomers in development for rare diseases are currently reviewed in the same way as other new drugs, and thus have required as much data to support their safety, especially toxicological data, as conventional drugs. When their clinical development plans advance, the number of patients with each rare disease, or each subset with any particular genetic variation, will be insufficient to meet the high hurdles that all drugs are expected to surpass.
The Center for Drug Evaluation and Research (CDER) has different requirements for the three main types of drug products: new drugs, generic drugs and over-the-counter drugs. A drug is considered “new” if it is made by a different manufacturer, uses different excipients or inactive ingredients, is used for a different purpose, or undergoes any substantial change. The most rigorous requirements apply to “new molecular entities” (NMEs): drugs that are not based on existing medications. All oligomers currently in development fall in this category and will receive extensive assessment before FDA approval in the NDA process.
In 2006, at the request of Congress, a committee was appointed by the Institute of Medicine to review pharmaceutical safety regulation in the U.S. It found major deficiencies in the current FDA system for ensuring the safety of marketed drugs and called for an increase in the regulatory powers, funding, and independence of the FDA. Some of the committee’s recommendations were incorporated into the Food and Drug Administration Act, which was signed into law in 2007. This law requires that the FDA review new drugs within ten months. It has been a successful piece of legislation, more than doubling the proportion of NDAs the FDA reviews within one year to 95% of those submitted. This has led to more companies submitting their NDAs to the FDA and aiming for launch in the U.S. first.
The FDA collects fees for the review of all NDAs, thus the Food and Drug Administration Act has generated more revenue for Uncle Sam from these.
The Safety of Drugs for Children
Prior to the 1990s, only twenty percent of all drugs prescribed for children had been tested for safety and efficacy in a pediatric population. This became a major concern of pediatricians as evidence accumulated that the physiological response of children to many drugs differed significantly from those seen in adults. For many drugs, children represented such a small proportion of the total potential market that such testing would not be cost-effective. There were also concerns about the feasibility and ethics of children providing informed consent. In addition, increased governmental and institutional hurdles for these clinical trials were encountered, as well as greater concerns about liability. Thus, for decades, most medicines prescribed to children were done so in an “off-label” manner, with dosages extrapolated from adult data through body weight and body-surface-area calculations.
After several initiatives proved unsuccessful at stimulating more widespread pediatric clinical studies, Congress used the 1997 Food and Drug Administration Modernization Act (FDAMA) to pass incentives which gave a six-month patent term extension to pharmaceutical manufacturers on new drugs submitted with pediatric trial data.
In a 2001 report, the General Accounting Office of the U.S. government confirmed that this law had been successful. Before 1997, up to eighty percent of drug labels had inadequate pediatric data. Within four years, the FDA had received 188 requests for the marketing extension allowable under FDAMA. These requests included data from 414 studies covering 23,200 children. New drugs were the subject of 33 of these requests, while 155 applications concerned drugs already approved but lacking pediatric data.
Most recently, in the Pediatric Research Equity Act of 2003, Congress codified the FDA’s authority to mandate manufacturer-sponsored pediatric drug trials as a “last resort” if incentives and publicly funded mechanisms proved inadequate. Several of the oligomers currently in advanced clinical development are for pediatric diseases.
History of the European Medicines Agency
The European Medicines Agency (EMA) was, until 2004, known as European Agency for the Evaluation of Medicinal Products (EMEA). The EMA is the pharmaceutical regulatory body of the European Union (EU). It’s based in London. Before the EMEA was established, each country in Europe relied on its own national regulatory authority to regulate drug approvals. Although the national authorities have not been disbanded they now work with the EMA, often in a sort of subcontractor role. The EMEA was born after more than seven years of negotiations among EU governments and replaced the Committee for Proprietary Medicinal Products (CPMP) and the Committee for Veterinary Medicinal Products. Both of these committees were reborn as the core scientific advisory committees within the newly formed EMEA.
Roughly parallel to the U.S. FDA, but without FDA-style centralization, the EMA was originally set up in 1995 with EU and pharmaceutical industry funding, as well as indirect subsidy from member states. The EMA is an attempt to harmonize (but not replace) the work of existing national European medicine and regulatory bodies and thereby reduce the $350 million annual cost drug companies incurred by having to win separate approvals from each member state. It was also hoped that the EMA’s creation would eliminate the protectionist tendencies of some states unwilling to approve new drugs manufactured by companies in other countries that might compete with domestic drug companies. The main responsibility and mission of the EMA is to coordinate the scientific resources of the 27 EU Member States, with a view to providing European citizens with high quality, safe, and effective medicines for humans and animals and, at the same time, to advance towards a single market for medicines. The European Union is currently the source of about one-third of the new drugs brought onto the world market each year.
The EMA is run by a management board that provides administrative oversight. It is responsible for approval of budgets and plans, and selection of the executive director. The board includes one representative from each of the 27 member states (Figure 9.1), two representatives of the European Commission, two representatives of the European Parliament, two representatives of patients’ organizations, one representative of doctors’ organizations and one representative of veterinarians’ organizations. The EMA works through a network of roughly 4500 EU experts to decentralize its scientific assessment of medicines and draws on resources from over forty National Competent Authorities (NCAs) from EU member states.
Companies can submit a single application to the agency to obtain a centralized approval valid in all EU and European Free Trade Association states (including Iceland, Liechtenstein and Norway). The centralized procedure is compulsory for all medicines derived from biotechnology and other high-tech processes, as well as for human medicines for the treatment of HIV/AIDS, cancer, diabetes, neurodegenerative diseases, auto-immune and other immune dysfunctions, and viral diseases. The therapeutic oligomers for rare diseases will be reviewed by this centralized procedure in due course.
Figure 9.1. The 27 EU Member states. Note Switzerland and Norway are not EU Member States.
A single centralized marketing authorization application (MAA) is submitted to the EMA and a single evaluation is carried out by the Committee for Medicinal Products for Human Use (CHMP). If the committee approves the drug, it’s virtually guaranteed that the European Commission will approve it for sale throughout the whole of the EU.
The CHMP is obliged by the Regulations to reach decisions within 210 days, although the clock is stopped when the applicant company is asked for clarification or further supporting data. This compares favorably with the average of 500 days taken by the FDA.
The Pediatric Committee (PDCO) deals with the implementation of the 2007 pediatric legislation which requires all new MAAs, or variations to existing authorizations, to either include data from pediatric studies (previously agreed with the PDCO), or to have received a waiver or a deferral for these studies from the PDCO. So, the EMA like the FDA is keen to ensure that new drugs will be made available for children and that pediatric data will be submitted as part of the MAA.
History of the Japanese PMDA
In Japan, the Ministry of Health, Labor, and Welfare establishes drug regulations. It was formed by the merger of the former Ministry of Health and Welfare and the Ministry of Labor, and began accepting submissions for new product approvals in July 2001.
Following the Reorganization and Rationalization Plan for Special Public Corporations that was approved in a Cabinet meeting in 2001, the Pharmaceuticals and Medical Devices Agency (PMDA) was established and came into service on April 1, 2004, the Japanese counterpart to FDA and EMA. The services of the Pharmaceuticals and Medical Devices Evaluation Center of the National Institute of Health Sciences, the Organization for Pharmaceutical Safety and Research, and part of the Japan Association for the Advancement of Medical Equipment were consolidated under the Law that established the PMDA.
The PMDA has three main areas of activity: Drug and Medical Device review, post-marketing safety and compensation for adverse drug effects. As with FDA and EMA, the PMDA has numerous departments and divisions.
International Conference on Harmonization
It became apparent during the 1960s, 70s and 80s that different requirements for drug development were being imposed on global pharmaceutical companies by the three main regulatory authorities. This led to inefficiency, some unnecessary duplication, greater expense, and delay in new drugs being registered in some markets. Harmonization of regulatory requirements was pioneered by the European Community (EC), in the 1980s, as the EC moved towards the development of a single market in Europe for pharmaceuticals.
The success achieved in Europe demonstrated that harmonization was feasible. At the same time there were bilateral discussions between Europe, Japan and the U.S. on possibilities for wider harmonization. At the 1989 World Health Organization (WHO) Conference of Drug Regulatory Authorities in Paris, specific planning for action started. Soon afterwards, the authorities approached the International Federation of Pharmaceutical Manufacturers and Associations to discuss a joint regulatory-industry initiative on international harmonization, and ICH was conceived.
The birth of ICH took place at a meeting in April 1990, hosted by the European Federation of Pharmaceutical Industries and Associations in Brussels. Representatives of the regulatory agencies and industry associations of Europe, Japan and the U.S. met, primarily, to plan an International Conference but the meeting also discussed the wider implications and terms of reference of ICH. It has evolved since its inception through its Global Cooperation Group, to respond to the increasingly global face of drug development. ICH’s mission is to achieve greater harmonization to ensure that safe, effective, and high quality medicines are developed and registered in the most resource-efficient manner.
Other countries, outside the original U.S., European and Japanese founders of ICH, are increasingly getting involved in ICH developments, bringing harmonization of regulatory requirements to an ever wider market. Authorities such as Health Canada, Australia’s Therapeutic Goods Administration and New Zealand’s Medsafe are closely aligned with the principals and practice of ICH. India, China and Brazil are all increasingly adopting FDA-like structures and operating practices in a bid to speed up access to new drugs in their domains. This is good news for pharmaceutical and biotech companies and for the patients suffering from rare diseases, their families and the healthcare professionals caring for them.
The Regulatory Authorities and Oligomers
In September 2009, AVI BioPharma (now Sarepta Therapeutics), and the other companies working on four specific neuromuscular diseases, were invited by TreatNMD to a preliminary discussion which they hosted at the EMA in London. At the time I was chief medical officer for AVI and we had an ongoing clinical study at London’s Great Ormond Street Hospital for Sick Children and the University of Newcastle in the UK.
TreatNMD (treat neuromuscular disease, www.treat-nmd.eu/about/network/) is a European network of academics, clinicians, charities and industry employees seeking ways to accelerate the development of new therapies in neuromuscular disease. The meeting aimed to bring regulators, academia, advocacy groups and industry together to discuss the issues raised by the development of therapeutic oligomers for the four lethal neuromuscular diseases: Duchenne muscular dystrophy (DMD), Spinal Muscular Atrophy (SMA), Amyotrophic Lateral Sclerosis (ALS) and Myotonic Dystrophy (MD). Each of these diseases is being tackled by disparate teams of scientists, researchers and companies scattered around the world. I was asked to present some of the emerging data with AVI-4658 in DMD, that I was responsible for overseeing, and other companies and academics presented data they had generated.
The outcome of, and hope generated at, this meeting was subsequently published (Muntoni. Neuromusc Dis 2010) and was then followed by a second meeting hosted by the U.S. National Institutes of Health (NIH) in Washington DC in October 2010. FDA attendance at this second meeting was much greater, with numerous staff from the Office of Orphan Product Development attending [http://www.fda.gov/AboutFDA/CentersOffices/OC/OfficeofScienceandHealthCoordination/OfficeofOrphanProductDevelopment/default.htm].
I was invited to sit on one of several panels at this second meeting that discussed the obstacles to successful development of oligomers and possible solutions to those problems. At both of these meetings, all parties agreed that the current regulations would need more flexible interpretation to allow drugs to be developed for very small populations of patients, in some cases less than one hundred. It was left for industry to prompt the agencies to consider the issues by engaging in dialogue early, repeatedly and frequently. Both the EMA and FDA have encouraged companies to approach them for advice to help design clinical studies and both have formal mechanisms for that advice to be requested and provided.
The regulations are there for a purpose, to safeguard the public. But while the long path to drug marketing approval has historically been the safe and cautious way to test new chemical entities, should the same path be adopted for rare diseases? The large numbers of patients required for today’s conventional safety testing will never be available for any one rare disease.
An interesting analogy was made at the TreatNMD/EMA meeting by the Dutch DMD Parent Project organization. “Society expects there to be traffic laws and for all cars to obey a restricted speed limit in towns. That makes it safer for other drivers, cyclists and pedestrians. But emergency vehicles, driven by carefully trained drivers, are given special dispensation to exceed these limits when rushing to or from an emergency. Why cannot we have a similar “fast track” process for drugs intended to treat rare diseases, especially those previously undruggable, currently untreatable and universally lethal?”
The good news is that the regulatory authorities do indeed have some “fast track” regulations, and perhaps yet faster paths to approval can and will be agreed over the next few years as the oligomers in development start to build some traction.
Current Path to Approval for a New Drug
People wonder why it takes so long to get a new drug to market. Sometimes press releases from an early research project suggesting possible future benefit from a drug may give the misleading impression that the drug will be available within days, weeks, or months. That is regrettable, as drug development is already very complex, highly regulated, subject to detailed and lengthy review by the regulatory agencies, and often only follows years of careful clinical research. That clinical research involves testing of the new drug in hundreds, sometimes thousands of patients with the disease of interest.
Here are the complicated steps that a new drug, from a new class, must go through before the dossier of results can be submitted to the FDA, EMA or PMDA for approval:
1. Drug Discovery
First a disease is identified that needs treatment. Understanding how the disease starts and what causes it is vital before a new drug can be sought to solve that problem. Then a series of chemicals may be investigated in the laboratory to see which, if any, may be effective in that disease. Currently much of that drug design looks at a target receptor that is key to how the disease affects people. Hopefully, the drug being sought will bind to that receptor and block it, or stimulate it. For the oligomers, which share a string of building blocks of synthetic nucleotides, this step can be skipped.
2. Basic Research
Long before a drug goes anywhere near a patient, early research must determine that it works in the test tube. For the oligomers, several patches may be tested to find the one that binds best to the target area of the faulty RNA. It is known, for instance that certain areas of pre-messenger RNA have sections that when read will initiate splicing, so called enhancer sites. These areas, and those immediately adjacent, are the focus of attention when alternative splicing needs to be triggered. Nowadays experiments can be run on several different patches at the same time to identify, in the laboratory, which seems to be the most efficient. The best result leads to that particular sequence being selected as the “drug candidate.”
The drug candidate in the test tube then needs to be tested in living cells to see if it does indeed do what is required of it. On passing this hurdle, if there are animal models of the disease, the drug will be tested in a whole live animal. It is important to confirm that the drug will indeed get into the cells and work.
3. Toxicology Studies in Animals
Next comes a toxicology program, using animals, to investigate how safe a drug is, long before it goes anywhere near a human. While it is regrettable that animals need to be used in these experiments, computer modeling is just not sophisticated enough to be able to predict and replicate how a whole animal, especially a mammal, will respond to a new drug.
Laboratory scientists are acutely aware of the issues and ethics of drug testing in animals and the vast majority of this early work is conducted under closely monitored conditions to minimize any suffering to the animals involved. Much of the early research for many drugs, but especially the new oligomers, is conducted in mice. These mice have often been specially bred for these experiments. Sometimes they have a mouse equivalent of the human disease, as in DMD. In other cases, sometimes a human gene is bred into the mice so that the effect of a new drug for human disease can be tested on the human gene, in the humanized mouse.
The toxicology testing program in animals is a complex process that often takes several years.
An early step is to assess the amount of a drug that is absorbed into the body of a mammal (especially if is given by mouth). When given directly by intravenous injection, this amount is assumed to be 100% of the dose. The researchers then try to determine where this dose is distributed and in which organs it accumulates. This will help to decide which organs should be more carefully examined in the general toxicology studies.
There are four key steps to predicting how a drug will behave in humans, which can easily be remembered using the acronym ADME:
A. Absorption: How much of a new drug is absorbed in to the body
D. Distribution: Where the drug then distributes to and what levels it accumulates to in the various tissues
M. Metabolism: Where and how the new drug is metabolized, for instance by the liver, and understanding what products the drug breaks up into
E. Elimination: How are the parent molecule and/or its metabolites eliminated
Another early step in the preclinical testing is a series of safety pharmacology studies, usually single dose. These look at specific organ systems in much greater depth than is undertaken in the routine toxicology testing. The cardiovascular, respiratory, and the neurological systems are usually the focus of these studies. Special studies may also be needed either before or during human testing to look at the effect of the new drug on cardiac conduction and other organ systems.
Generally, the FDA requires data on safety for a new drug to be generated in two species before human testing can commence. For most drugs one rodent, mouse or rat, and one larger species are needed. In many cases, specially bred beagle dogs, are the second species, but for oligomers, most companies choose small monkeys. Since they are genetically and physiologically closer to humans, their data may be more accurate at predicting safety in humans.
The program usually starts off in mammals of one species to determine the maximum tolerated dose (MTD). After the tolerability of a single dose has been determined, multiple doses will be tested, administered in the same way as it will be later in humans. The most common ways drugs are given are intravenously, orally or by inhalation, but there are other routes including subcutaneous or intramuscular injection. These chronic dosing studies are expected to identify the dose at which there are no side effects, called the “no adverse effect level” (NOAEL). The gap between the NOAEL and the MTD gives an indication of a drug’s safety. The wider the gap, the safer the drug is expected to be in subsequent human testing.
The toxicology program, especially the crucial multiple dose studies lasting for 14, 28, or 90 days must be conducted under very carefully controlled conditions. These programs are conducted in special facilities that have been carefully designed to control the environment and allow careful observation of the animals. These facilities may at any time be inspected by the company whose drug is being studied, by an auditor on behalf of the company, or by one or other of the regulatory authorities. The facilities also have to follow rules established by special animal use committees who oversee all animal experiments. This is to ensure that animals do not suffer unnecessarily in the quest to develop safer, more effective drugs for human use.
The FDA expects companies to take a fraction of NOAEL dose, ranging from as little as one percent to as much as five percent, as the starting dose in subsequent first-time-in-human single dose testing.
In addition to the data provided to enable human testing to begin, other more specialized toxicology studies may be required. Reproductive toxicology will be required for any drug that is being developed for possible use during pregnancy. Studies of juvenile animals are required if the drug is intended for children, and most drugs that are intended for chronic use in humans have to undergo longer term chronic testing, often up to nine months duration in two species. Another expensive study to conduct is the two-year carcinogenicity trial to determine if the drug causes cancer in animals. This is often irrespective of whether the early gene-toxicity showed any likelihood of damage to animal genes even at extremely high doses in the test tube. And this is by no means a comprehensive list of all the studies that may be required. Some of the work can be delayed, especially the nine months of chronic dosing and the carcinogenicity study, until early human results have been obtained. If single doses of the drug are not well tolerated by humans, then longer term testing will not be allowed, so these longer term studies in animals are not needed.
4. Chemistry, Manufacturing and Controls (CMC)
All drugs approved by the FDA have to pass stringent standards for purity and quality. The quality of a new drug and its purity and stability during storage and shipping, commonly known as the shelf life, must be assured before it can be tested in humans. The paper trail for a new drug has to go back to the very earliest ingredients that have been used to make the raw materials for even the first step in what, for oligomers, is a series of many complex steps. At each step, the manufacturing process has to be carefully documented and explained. Records must be reviewed that show the materials adhere to very tight specifications for stability and purity. The final product, intended for human use in the first set of safety studies has to have records that stretch back to the first basic ingredients. And they must be available for inspection and approval by the FDA.
The final product, the active pharmaceutical ingredient (API), has to be stored without degrading for periods of time considerably longer than those likely to be encountered in early clinical testing. In addition, the API, in its packaging, must be exposed to extremes of both temperature and humidity and yet remain pure and potent.
Most of the oligomers in development will be dry powders or solutions in glass vials with rubber stoppers. Other medicines use a variety of containers that you’re probably familiar with, including foil-backed blister packs or small screw-top bottles for pills, plastic ampules for liquid solutions, and metal canisters for inhaled drugs. These systems have to be studied to ensure that the material they are made of does not leak into the medicines. In addition, the medicine must not get absorbed onto the container’s walls.
This basic quality data is a vital part of the information required before any human testing can take place. As a drug goes through clinical testing in humans, the clinical studies get longer as the program advances. And these clinical studies will be conducted in patients over a wider geographical area. Thus CMC data generation continues to evolve in parallel to the clinical work during the long process from bench top to bedside. By the time a drug has completed a clinical development program, the CMC data fills many gigabytes of hard disc space. Also, the manufacturing process is refined and improved as development proceeds. But once clinical testing reaches its last step, the manufacturing process must be finalized. From then on it cannot be changed. This even includes the color of the ink on a label, for fear that a new pigment may leak in through the walls of the drug container and affect the purity of a compound that was tested.
5. Clinical Studies – in Humans
Once animal testing has provided sufficient safety data to enable human testing, an investigational new drug (IND) application is prepared and submitted to the FDA. There is an equivalent dossier, an Investigational Medicinal Product Dossier in Europe. These dossiers and their submission are a key landmark in the life of any company, but especially any small company. All the previous research, quality and animal toxicology data must be submitted. A protocol for the proposed first human study is also included. In the U.S., the FDA has a stipulated thirty days to review all this information and decide if the data is sufficient to allow the proposed human study to proceed. If the FDA is not satisfied, which sometimes happens, they impose a “clinical hold” on the program until the deficiencies have been addressed.
Human research is often divided into three phases:
Phase I: Single dose and then short term multiple-dose testing is often undertaken in otherwise healthy adult volunteers. The starting dose is a fraction of the NOAEL, discovered in animal trials, ranging from as little as one to five percent.
Frequently, an independent data safety monitoring board, or DSMB, will review the information from each step before permission is granted to escalate to a higher dose. The aim is to reach a dose where troubling side effects may start to appear, which is called “dose limiting toxicity.” This dose needs to be well above what the expected effective dose of the drug is, giving it a wide safety margin. Some drugs continue with testing even when this safety margin is rather narrow.
This phase may involve a small number of subjects, usually less than one hundred. In addition to very careful observation of all bodily functions, blood samples may be taken at frequent intervals over a period of hours or days after dosing to see how the volunteers eliminate the drug from the blood stream. This is the science of pharmacokinetics, what the body does to the drug. The close observation, often combined with intensive monitoring of some or all bodily systems, is the companion science of pharmacodynamics, what the drug does to the body.
New cancer drugs usually skip this phase because even at a low dose they will cause unpleasant side effects in human volunteers. Thus the early single and then multiple dose testing studies are conventionally conducted in small numbers of cancer patients.
The initial safety testing of the new oligomers will be done in patients with the specific disease they target, rather than healthy volunteers. The oligomers will patch the messenger RNA that is faulty by binding to a tiny section of it. If they were given to normal volunteers, they would bind to the same message that might have adverse consequences.
There are lots of questions. In August 2012, the first of several discussion papers was published in Nucleic Acid Therapeutics (NAT) by one of the subcommittees of the Oligonucleotide Safety Working Group (OSWG). The paper summarized the opinions of academic and industrial researchers and clinicians about how the safety of inhaled oligomers should be assessed.
The OSWG is a loosely knit think tank of over one hundred scientists from academia, industry and regulatory agencies, for which I act as volunteer publications coordinator. We are keen to develop guidelines about how best to assess the safety of these exciting new drugs in both animals and humans. Several more guidelines developed by various subgroups focusing on different areas of testing – mainly preclinical (i.e. before the oligomers are given to humans) are in development. In some cases the papers have been submitted to scientific journals for publication and over the coming years more debate and discussion will occur. Hopefully, consensus will emerge.
New gene patches being developed to block lethal viruses don’t need to skip phase I. Outbreaks of Ebola or Marburg hemorrhagic fever are likely to occur in populations where at least some of those infected will be otherwise healthy adults. The viral mRNA is unique to the virus and there is no identical message within the normal human genome. Thus phase I testing of the new antiviral translation suppressing oligomers (TSO) has been conducted in healthy volunteers.
Phase II: In phase II, different doses of the drug and different regimens such as once or twice daily, will be tested. In the case of oligomers, a lesser frequency may be tested, maybe once a week or less. Different formulations may also be tried and if the drug is given intravenously, different speeds of injection, ranging from a slow drip that takes over 12 hours to an injection that takes two minutes. This phase is conducted to confirm that the drug does works, and what doses it works at.
If the drug is designed to treat hypertension, lowering of the blood pressure is desired. How much is the blood pressure lowered? How soon after taking the drug? How long does the lowering affect last after each dose? All of these questions, and many more, need to be answered in this phase.
For many diseases, such as high blood pressure, methods for monitoring the effect, the recording of blood pressure, have been available for many years, and doctors and staff are familiar with how to record measurements. For rare diseases that is not always the case.
In the case of Duchenne muscular dystrophy (DMD), for example, there is no history of testing even mildly effective drugs and no experience with how to monitor beneficial effects. In this case, the phase II experiment measures different possible effects and explores which benefit is easiest to measure. It then looks at how much that measure changes in patients, and for how long. Because the clinical benefit of these new medicines may take weeks or even months to become apparent, doctors are looking for biomarkers, a biological effect that is easier to measure that will predict clinical benefit. For DMD, the ultimate clinical benefit is a longer life, but that may take up to thirty years to prove. Shorter term, the ability of the new oligomers to slow the loss of muscle function, halt decline or even restore muscle function would be an ideal marker to follow.
The problem is that boys with DMD have been without dystrophin in their muscles since birth. Is the new appearance of dystrophin in their muscles ten years down the road going to translate into an immediate clinical benefit, as measured by the distance they can walk in six minutes? That experiment has now been conducted by both companies working with DMD splice switching oligomers. Both Pronsena and Sarepta believe the answer is yes.
What is easier to demonstrate is the appearance of new dystrophin in the muscles of these boys, through the use of tissue biopsies. This may become a biomarker for other effective DMD oligomers in the future, should the levels of the novel dystrophin found prove to correlate with subsequent substantial clinical benefit.
One other note: In the case of all drugs (with the exception of those for cancer and oligomers), phase I is performed in healthy volunteers.
Phase II is conducted in patients who are ill with the disease for which the drug is intended.
A phase II program can be complex with multiple studies conducted over a period of several years. This is the phase where other specialized studies may need to be conducted: interaction with other drugs, possible effects on the electrical activity in the heart, and how well the drug works in patients who have another disease as well. These studies are usually longer than phase I and involve more subjects. Tens or even hundreds of patients are often studied in each phase II trial.
Phase III: Once an efficacy signal has been detected in phase II, there is often a meeting between the sponsoring company and the FDA. It is important at this meeting to agree on the signal, the benefit of the drug being tested, and the design of a pair of pivotal studies to confirm its beneficial effect. Thus phase III is the confirmatory phase of drug development which seeks to provide the pivotal data on which its approval will be based.
Depending on the disease being studied, the phase III program could be just this single pair of studies. But sometimes the company wants to prove benefit in more than one indication, or more than one type of patient. Depending on how different the types of patients are, the pair of studies may need to be analyzed in a more complicated way, either analyzing them by subset, or conducting additional, different studies. This phase is much larger, with several hundred to sometimes thousands of patients enrolled in a study. There are dozens, even hundreds of investigational centers, spread across many continents and countries. They are extremely expensive. An individual phase III study may cost anywhere from ten million to one hundred million dollars to conduct, and take many years to set up, execute and analyze. This is true even if the actual study period is only a few weeks.
The most likely oligomer to be reviewed next, now that mipomersen has been approved, is the Prosensa DMD drug, PRO051, which is being supported by GlaxoSmithKline. A phase III study of 180 Duchenne boys, which now appears to have fully enrolled, is currently ongoing at the time of this writing.
To avoid bias, phase III studies are often double blind and placebo controlled. That means that neither the doctors nor their staff, nor the volunteers with the disease know if they are receiving active drug or a placebo. Even rare disease drugs may be compared against a placebo, as is the case for PRO051. Such placebo controlled testing is regarded as the gold standard of drug study design.
At all phases of the clinical program, subjects, be they healthy volunteers or patients with mild, moderate or severe disease, must participate in the research voluntarily. Since the Geneva conventions after the Second World War, a process called informed consent has been enforced. Here the benefits and risks of the research has to be explained to and understood by the subjects. They must sign a voluntary agreement that states there has been no coercion. This consent process is a vital step before any study–related procedure can be conducted.
Investigational Review Boards/Ethics Committees
Another key protection that has been built into clinical research is the establishment of Investigational Review Boards (IRBs) in the U.S. In other parts of the world they are called “ethics committees,” but they have the same function. These committees are composed of doctors, attorneys, ethicists, and lay people who are not affiliated in any way with the company conducting the research, nor the investigational sites where the research is being executed. The members of the ethics committee may not be associated with any of the regulatory authorities. The IRB has the responsibility of ensuring that the research is conducted ethically and responsibly by all concerned. They review the language in the consent form which explains what is proposed to confirm that the explanation is understandable to the subjects.
Clinical Investigator Brochure
An important document is the Clinical Investigator Brochure (CIB, or just IB). It serves as a reference manual for the doctors in charge of supervising dosing throughout the clinical program. For the phase 1 studies, it summarizes the work carried out in animals as well as basic information about the disease for which the new drug is being tested. As the clinical program proceeds, the CIB is updated at least once a year.
Post-Approval Monitoring
FDA interest in drugs does not end however when a drug is approved. After NDA approval, the sponsor must review and report every ordinary adverse patient drug experience it learns of, at least quarterly. Unexpected serious and fatal adverse drug events must be reported within 15 days.
The FDA also receives “spontaneous reports” about possible adverse drug events through its MedWatch program. These voluntary reports are received directly from consumers and health professionals. This program has been the primary tool of post- market safety surveillance.
Vioxx, as discussed in Chapter 4, is a non-steroidal anti-inflammatory drug that was approved in the U.S. in 1999. However, several subsequent studies suggested that Vioxx might increase the risk of fatal heart attacks. In 2004, these fears were confirmed, leading to its much publicized, voluntary removal from the market by Merck.
More recently, the case of Avandia, a diabetes drug manufactured by GlaxoSmithKline, generated controversy. In June 2010, a retrospective study of 227,571 elderly American patients, comparing Avandia to other similar U.S. diabetes drugs was published. The authors concluded that Avandia was associated with “an increased risk of stroke, heart failure, and all-cause mortality.” Based on the study, only sixty patients needed to be treated with Avandia for one to come to harm.
In March 2011, a meta-analysis of observational studies, involving 810,000 patients, provided more evidence that Avandia was associated with a higher risk of heart failure, myocardial infarction and death than a similar drug, pioglitazone. Other reports comparing Avandia to other diabetes drugs (including the 2009 RECORD study published in the Lancet) were less unfavorable and were reviewed by an FDA panel. The controversy led to the FDA requiring stricter prescribing rules and patient warnings as well as calls for a general increase in the amount of pre- and post- approval safety data.
As a result of these highly publicized cases, FDA requirements for post-marketing risk management are increasing. As a condition of approval, a sponsor may be required to conduct additional clinical trials, called Phase IV trials. The FDA is increasingly requiring risk management plans for drugs as part of a development program that may call for additional studies, restrictions, or safety surveillance activities.
High profile public and scientific debates continue about whether new drugs should be evaluated on the basis of their absolute safety, or on their safety relative to existing treatments. The FDA is in an unenviable position. The public wants access to effective medicines as quickly as possible, yet serious safety concerns may not be detected by current standard development programs. What they may require is many thousands of patient-years of treatment. These conflicting requirements are impossible to resolve especially for drugs being developed for rare diseases.
Summary
The big three Regulatory Authorities, FDA, EMA, and PMDA, have all grown and evolved over recent decades. They are now large organizations responsible for approving the marketing of effective and safe drugs that have been manufactured to adequate levels of quality. Globalization of pharmaceutical development and approval has led to many national authorities in other countries taking their lead from the FDA.
Current requirements for registration of a new drug throughout the world have grown dramatically over the last half-century. Regulation was introduced to protect the public from the unscrupulous few, in this case doctors and pharmaceutical manufacturers. More recently, there has been additional scientific assessment of new drugs and increasing sophistication, as well as beneficial harmonization of the regulatory authorities. The path to approval for a new drug is now harder than ever, and discourages many companies. Between 2007 and 2009, thirty percent of all newly marketed medicines were modifications of already approved drugs. For instance, old drugs were reformulated and given as an injection instead of a tablet, or vice versa. Or old drugs were modified for a new indication but borrowed the safety record of the original drug. Many companies and their investors feel that it is a safer investment to wring more life out of old approved drugs than to try and develop new ones.
How will the high hurdles be overcome by the new wave of oligomers? How many patients with any one rare disease can these new drugs can be tested on? The answers will be provided over the next few years if the oligomers in development live up to their early promise.