Wednesday, March 28, 2012

Drug Innovation 1: On Cancer, Bioequivalence and Clinical Trials

To distinguish discussions related to intellectual property rights (IPR) like compulsory licensing, I am starting a new thread in this blog just on "Drug Innovation". This is slightly different from the thread on "IPR and Medicines".

My elder brother who died of prostate cancer more than five years ago would have been 57 years old this week had he survived the disease. His diabetes plus emotional sadness when his wife died several months earlier due to colon cancer further aggravated his condition.

My other relatives, wedding godparents, friends, family members of friends, also died of cancer. There are different types of cancer, probably about 200, and all of them are dangerous. Perhaps all of us have cancer cells in our body, but our immune system are just strong enough to kill those cells, or at least keep them at bay and prevent them from expanding and invading other organs of our body. Our immune system is our best physicians, our best medicines, our best disease examiner, all rolled into one. It is very important therefore, that we keep our immune system strong and efficient, by not injecting too many substances that can weaken them -- like cigarettes, alcohol, fatty food and so on. A little of these substances, like when we attend parties, would be fine and our immune system should be able to repair minor damages. It is the excessive use of such substances that can create more damages in our body.

Medicines and vaccines help boost our immune system in killing undesirable cells like cancer. Usually, old medicines are less efficient in doing this job as human understanding of each disease improve through time. Thus drug innovation is a must. Diseases mutate and evolve, so treatment against such diseases must also evolve.

The business of medicine innovation should be depoliticized whenever possible. There are existing rules governing patent, trademark, copyright and other IPRs, all players, innovator and generic manufacturers especially, understand those rules and do their respective business plans and marketing that are compliant with those rules. That is why I question and oppose moves or proposals that governments should issue compulsory licensing (CL) and related political schemes that disrespect private property rights.

What governments should do, is encourage the entry if not proliferation, of more innovator companies. If there  will be 20 or 50 different innovator companies that develop and roll out new medicines (on top of existing, off-patent drugs) per disease, then the patients will greatly benefit. Competition among such innovator companies will bring down prices of such innovator drugs. Then another round of competition will follow once the patent expires as dozens if not hundreds of generic producers come in to produce their own branded drugs for each disease category.

I am posting below three articles by Reiner Gloor in BusinessWorld on dates indicated. Reiner is the Executive Director of the Pharmaceutical and Healthcare Association of the Philippines (PHAP), the federation of mostly innovator pharma companies in the country. The three papers are:
1. Beating Cancer,
2. It all begins in innovation, and
3. The value of clinical trials.

The subject of bioequivalence and related tests for safety and efficacy of generic drugs before they will be introduced to the public are discussed. These are useful information that need to be shared to the public.

The most expensive drugs are those that do not work and hence, do not kill a particular disease, no matter how cheap they are. Because an ailing patient would have more complications as the disease inside his.her body is not treated and allowed to expand and inflict more damage in other internal organs of the patient.

Posted on 06:05 PM, February 02, 2012

Medicine Cabinet -- By Reiner W. Gloor

Beating cancer

Major non-communicable diseases were among the important health issues that gained the attention of world leaders in 2010. In a United Nations summit, political leaders agreed to a plan of action that sought to address alarming trends involving four major non-communicable diseases (NCD) that have developed to become the world’s biggest killers.

The four major NCDs are cardiovascular diseases, diabetes, chronic respiratory diseases, and cancers that have altogether prematurely claimed the lives of 38 million people, representing about 63% of the total global deaths in 2008. Studies indicate that the major NCDs are affecting the developing world and lower-income populations hardest.

This is particularly true for cancer, which accounted for about 7.6 million global deaths in 2008. By 2030, cancer deaths are also expected to soar to 11 million worldwide. The World Health Organization (WHO) also disclosed that about 70% of all cancer deaths occur in low- and middle-income countries.

Cancer can affect any part of the body. A defining feature of cancer is the rapid creation of abnormal cells that grow beyond their usual boundaries, and which can then invade adjoining parts of the body and spread to other organs. This process is referred to as metastasis which is the major cause of death from cancer, the WHO said.

Locally, the Department of Health recently led the observance of the National Cancer Awareness Week in a campaign to boost public consciousness on the disease. Such an awareness drive is important specifically for the Philippine Society of Medical Oncology (PSMO), which considers information as a keystone to preventing and treating cancer.
The need to raise awareness on cancer has become more evident with the GLOBOCAN Project report, which estimated that there had been more than 51,000 cancer deaths in the Philippines in 2010.

The GLOBOCAN Project, which provides global incidence of, mortality and prevalence from major types of cancer, reported that leading new cancer deaths among Filipinos in 2010 include those involving the lung, liver, breast, colon/rectum, leukemia stomach, cervix uteri, brain, prostate and pharynx.

Among Filipino men, lung and liver cancer comprise 43% of all new cancer deaths. These top two killer cancers affected more than 12,000 Filipino men.

On the other hand, breast cancer was the number one cause of new cancer deaths among Filipino women also in 2010. It is estimated that more than 4,000 Filipino women died of breast cancer or 18% of all total deaths during the same year. Around 2,197 women and 1,984 others succumbed to lung and cervical cancers, respectively.

Breast cancer also topped the list of new cancer cases in 2010 followed by lung, liver, colon/rectum, cervix, leukemia, stomach, prostate, brain and ovarian cancer. The top 10 leading sites comprise 68% of all new cases.

Despite the threats posed by cancer, the disease can be reduced and controlled by implementing strategies for prevention, early detection and care for patients with cancer. These include modifying key behavioral and dietary risk factors as well as early detection and screening tests which are important in the diagnosis and treatment before cancer becomes advanced. Vaccination against human papilloma virus (HPV) and hepatitis B virus also help in cancer prevention.

PSMO President Dr. Felycette Gay Martinez-Lapus explained that the fight against cancer requires a collaborative effort among the physician or physicians, the patient, the patient’s family and friends.

She added that treating cancer is a delicate balancing process. The general aim is to reduce tumor growth while ensuring that any potential side effects do not compromise the patient’s quality of life to the extent that the treatment does more harm than good.

Dr. Martinez-Lapus acknowledged that in recent years, there has been a surge of innovative drugs which has forever changed the landscape of cancer treatment.

She said that as opposed to about 40 years ago, life expectancy have increased with new medicines that target the cancer cells directly. Today, targeted therapy is more precise in that it is formulated to act against a specific type of cancer unlike previous treatments.

At the moment, researchers are working on more than 800 innovative medicines that are either undergoing clinical trials or regulatory review. Due to these developments, cancer can now be better managed and even beaten.

(2) September 30, 2011

Medicine Cabinet -- Reiner W. Gloor

It all begins in innovation

Since the enactment of the Generics Act (RA 6675) in September 1988, the month of September every year has been designated by the Department of Health (DoH) as the Generics Month. Every year programs with various activities were organized by the DoH with the objective of informing the public about measures to implement RA 6675 and encourage the use of generic medicines.

Early this month, the DoH, through the National Center for Pharmaceutical Access and Management, organized the 2nd Generic Medicines Summit and Expo with the theme “Generics Para sa Kalusugan, Gamot Pangkalahatan.”

During the summit, the role of pharmaceutical innovation was acknowledged as the lifeblood of medicine development, including generics. Following 12 to 15 years of research and development (R & D), only one out of the 5,000 to 10,000 compounds will be approved for marketing by the government. The R & D process, which consists of three phases of clinical trials, involves large human resource and costs an average of $1 billion.

With the huge investment for a worthy cause of finding preventions or cures for many of today’s diseases, manufacturers of innovator medicines are provided a 20-year patent protection to recoup investments and ensure the continuous search for new medicines.

The patent life begins shortly before the actual clinical trial stage which usually takes about eight and a half years until drug approval. In effect, manufacturers have about 11.5 years to exclusively market the newly discovered medicine. After this period, generic manufacturers are then allowed to make versions of the innovator products. The entry of generic versions results in more options for patients as well as stimulates market competition.

Even after patent expiry, pharmaceutical innovation continues in a hope that current medications will be better targeted and would help improve patient compliance to treatment. Pharmacovigilance also continues to monitor the effect of the drug on patients.

Generic manufacturers, on the other hand, will have the option to market the medicines either as branded generics or “generic generic.” Concerning generic medicines, one of the questions that often comes out is: “Are generic medicines as effective as the original formulation?”

Theoretically, yes. A generic drug must have the same active ingredient as the original formulation. Therefore, it is expected to show the same effect. But because there are other factors that affect the behavior of the drug within the body, such as the manufacturing process, the excipients used, the hardness or the moisture content of the tablet or capsule, among others, the World Health Organization (WHO) recommends that some oral dosage forms be subjected to bioavailability/bioequivalence studies.

A bioavailability study is done to determine what percent of the active pharmaceutical ingredient of an oral dose reaches systemic circulation. This is done “in vivo” with healthy subjects where one group takes the original formulation and another group takes the generic drug. When the results of the study show that the absorption rate of the generic drug is equivalent to that of the original formulation, the generic drug is said to be bioequivalent.

The World Health Organization classifies active pharmaceutical ingredients according to the Biopharmaceutics Classification System (BCS) as: BCS Class I, high solubility-high permeability; BCS Class II, low solubility-high permeability; BCS Class III, high solubility-low permeability; and BCS Class IV, low solubility-low permeability. Based on this classification, the Food and Drug Administration can identify formulations that may be eligible for testing through a procedure that does not require “in vivo” bioequivalent studies. This is known as a biowaiver.

Bioavailability for some medicines is a requirement under the ASEAN Harmonized System to achieve an ASEAN Economic Community by 2020. The Philippine National Drug Formulary (PNDF) 7th edition lists about 40 pharmaceutical products that are to be subject to “in vivo” bioequivalence studies as recommended by the WHO. Among those in the PNDF list are Nifedipine (calcium antagonist), Rifampicin (anti-tuberculosis), Theophylline (anti-asthmatic), Azithromycin (anti-infective), and Ciclosporin (immunosuppressant).

Innovator and generic medicines are now available for many of the known diseases today. About 95% of medicines under the WHO Essential Drug List are now off patent. This provides patients more options for treatment. But in spite of the existence of these medicines, studies show that they still do not reach the patients.

While potent medicines do exist, some barriers to medicine access remain. Issues such as availability, distribution, patient’s access to care and treatment adherence are among those that need to be worked out to fully benefit from the medicines we have today.

(3) 27 May 2011

Medicine Cabinet -- By Reiner W. Gloor

The value of clinical trials

The book Men Are from Mars, Women Are from Venus was a phenomenal success after author John Gray deviated from the convention. While almost all counselors look for similarities to enhance personal ties, the book asserted that relationships will only be successful when men and women recognize that they are different and unique from each other.

The recognition that men and women are different has also prompted medical researchers to study a number of diseases based on one’s gender. Researchers reveal that women are either more prone to certain diseases or their symptoms for certain diseases may be different.

For example, men who are having heart attack may experience chest pain that radiates down the arm. Women, on the other hand, may not have the exact symptom but may instead feel indigestion, extreme fatigue and nausea when having an attack.

Determined to address these gaps, the Pharmaceutical Research and Manufacturers of America (PhRMA) recently reported that 851 medicines are in development for diseases that exclusively or disproportionately affect women. In the pipeline are medicines for diseases such as osteoporosis, multiple sclerosis, depression, rheumatoid arthritis, and age-related macular degeneration. The list also includes 139 medicines in development for cancers that affect women and 110 for autoimmune diseases which affect women three times more often than men. PhRMA said that the medicines in development are all in human clinical trials or are pending review by the US Food and Drug Administration (FDA).

Clinical trials are an integral part of the research and development (R&D) process which refers to the study of medicine in humans. Prior to any clinical trials, an average of three to six years is spent for laboratory and animal testing to ensure that the medicine is safe enough for humans.
Clinical trials are crucial in answering specific scientific questions and are necessary to determine the benefits and risks of a new medical treatment to patients and the society in general.

In conducting clinical trials, all necessary steps are taken to respect and protect the safety of research participants. Laws and regulations govern the conduct of clinical trials which are guided by the principles set forth in the Declaration of Helsinki and the Guideline for Good Clinical Practice of the International Conference on Harmonization.

Clinical trials are also being closely monitored not only by the pharmaceutical industry but by regulatory agencies, medical professionals, hospitals and institutions, institutional review boards and ethics committees like the one set up by the Philippine Health Research Board, the national policy-making body on health research ethics under the Philippine National Health Research System.

An "informed consent" of the participant is likewise required before proceeding with the trial. The International Federation of Pharmaceutical Manufacturers & Associations explained that informed consent is the process of knowing the important details about the trial such as purpose, duration, procedures, risks and benefits, and key contacts. At any point in time before or during the trials, any participant could withdraw from the study.

Clinical trials are conducted in three phases with specific purposes to help researchers answer particular questions.

The goal in Phase I trials is to determine if the drug is safe in humans. It involves about 20 to 100 mainly healthy volunteers or in some cases, tests are studied among patients. In this phase, researchers focus on pharmacokinetics to answer how a drug is absorbed, metabolized and eliminated from the body. It also studies pharmacodynamics to find out the drug’s side effects and if it produces the desired effects.

In Phase II trials, the main goal is to explore the medicine’s therapeutic efficacy in patients. Studies in this phase involve 100 to 500 patients who are selected based on a criteria. Early estimates of dose strength response are expected during this phase. Researchers also look for possible side effects and other risks associated with the drug.

Meanwhile, Phase III trials test the candidate drug to about 1,000 to 5, 000 patients in a bid to gather more reliable studies about the safety, efficacy and the benefits and risks of the candidate drug. The objective of these trials is to confirm that the drug is safe and effective for the patients in its intended indication.

Following successful trials, the pharmaceutical company files a New Drug Application requesting FDA to approve a new drug. The FDA may decide to do any after rigorous review of the application: approve the medicine, send an "approvable" letter requesting the company to provide further studies or even deny approval.

When a drug is approved and already in the market, Phase IV clinical trial is set in motion to further establish the safety and efficacy of the new drug as more patients begin to use the medicine. (For more details about clinical trials, go to and the clinical trials portal of

Several sites across the globe participate in clinical trials to get data from as much diverse group of patients as possible. One of the trial sites include the Philippines with more than 200 clinical trials registered with the FDA in 2010. According to a report, the Philippines ranked third among Southeast Asian countries with most number of clinical trials after Thailand and Singapore.

Overall, clinical trials that put premium to the integrity and safety of research participants benefit the patients since they get to access new medicines and health care services. Clinical trials also contribute to the economy and research expertise of the communities and professionals involved in the studies. Most importantly, clinical trials are integral part of the R&D process to discover breakthrough medicines, including those that seek to address diseases that disproportionately affect women and other specific groups such as the children and elderly.

For more information, consult your doctor or you may log on to Join us on E-mail the author

See also:
IPR and Medicines 10: Innovator Drugs and Generics Complementation, July 13, 2011
IPR and medicines 11: When blockbusters' patent expires, September 07, 2011

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