Statements, sometimes attributable to senior government officials, have implied that neither the Medicines Control Council, nor the Ethics Committees operating in academic centers and hospitals, are competent or effective.

We object, in particular, to allegations implying that all clinical research conducted on behalf of multinational pharmaceutical companies is unethical, unlicensed and uncontrolled, and that local patients are exploited and exposed to dangerous medicines without adequate information about risks.

The MCC is the statutory Council and regulatory authority in South Africa charged with the registration and control of medicines. This includes the manner in which medicines are tested and the responsibility for approval of clinical trial protocols for new medicines.

The fact that these statements have been reported has resulted in grave concerns and anxiety to patients currently on well-controlled clinical trials with new medications, being conducted in SA at this time.

It is regrettable that many of the accusations have been made by persons unfamiliar with the specific reports of one study which resulted in a most unfortunate situation where certain patients died --- the FTC 302 study. In this study, which has been halted, it is unclear, as yet, whether any causality/direct link was established between one or more of the medicines used and the patient deaths. As these reports are available to the Government, it is recommended that the relevant sections be released and studied before public comment is made.

The PMA believes, therefore, that the public interest demands a general explanation on the conduct of clinical trials in South Africa.

We discuss below, briefly, why clinical trials are necessary, how these are conducted and controlled and the benefits they bring to the people of SA.

Clinical trials are tests done in human beings to ascertain whether a new medicine is effective and safe for treating patients with a specific disease.

In general the number of subjects included in a clinical trial could range from less than 20 at the initial stages to more than 10 000 in later phases of clinical testing.

Clinical trials are divided into various stages. The objective of the initial stage is to determine how the body reacts to the drugs (absorption, distribution, metabolism and excretion) by introducing the drug to a small number of volunteers. The next stage is to determine what the drug does to the body in terms of effectiveness and safety in a small number of patients under close observation. The third stage, before the drug is registered, includes large numbers of patients to collect additional safety and effectiveness data. Clinical trials conducted after the medicine is registered, are regarded as fourth stage studies.

Currently clinical trials are the only internationally scientific acceptable way of proving the safety and effectiveness of new medicines. At best, there is a cure for only approximately 25% of known diseases. For the rest, doctors can only treat the symptoms.

Clinical trials are the only way by which further cures can be developed or current treatment improved by the development of more effective or safer medicines. The result of these trials may not necessarily provide a cure but could enhance the quality of life for patients eg. arthritis was initially treated with medicines which had side effects which made approximately one third of patients treated ill. Through continuous improvement and the development of new medicines for arthritis, side effects have been dramatically reduced (to only about 2 %).

WHY PERFORM CLINICAL TRIALS IN SOUTH AFRICA?
SA has a diverse population presenting many different disease conditions. Some are diseases that do not present frequently in the developed world or for which there is currently no acceptable treatment.

• The South African Regulatory Authority [MCC] has been held in high esteem internationally and SA has been regarded as a country which had an excellent regulatory control system.
  

• Standards of medical practice in SA are high – results from clinical trials conducted in SA are acceptable by the Regulatory Authorities in many developed countries.
  
• The advantage for companies is that they can use the results obtained in South African clinical trials as part of their international registration dossiers thus speeding up the process and ensuring acceptability of the data submitted.

• Multi-centre [multi-country] clinical trials mean that the company can complete the trial faster, because it can enroll the total number of patients with a particular condition required for the trial sooner than if the company had to wait for enough patients with the indications for treatment to present in only one country or area.
  
• Research budgets are decided in the country of the company’s principal.
  Costs of conducting clinical trials in SA are influenced by many factors, for example, costs of consultation, laboratory fees, data management fees etc. All of these are further influenced by the type and duration of the clinical trial being conducted.

Clinical trials are conducted according to strictly controlled international and local standards of Good Clinical Practice. Approval to do the study is needed from two different bodies. These are the Medicines Control Council and one or more Ethics Committee. An Ethics Committee consists of doctors, legal advisers, community representatives or lay person/s, scientists and additional relevant advisors as required, for example, a pediatrician would be required for a study in children. The Ethics Committee’s function is primarily to protect the safety and rights of the patient.

Studies are conducted according to a clearly defined protocol, which outlines the conditions for the selection of patients. This includes all aspects including the medicine under study for that type and stage of disease, the gender, age, race, etc of patients.

For the conduct of clinical trials race and ethnicity/nationality may have relevance for certain conditions or products being studied. For example, the way the body reacts to drugs and food may vary between races [Japanese patients metabolise certain drugs at different rates to Caucasians, black people react differently to ACE inhibitors, or B-blockers and black babies absorb synthetic milk formulae differently. Secondary differences may also result from differences in the diet of the races which may result in differences in absorption – this usually relates to the fat content of the meal/diet]. It is fair to conclude that little value could be attached to a trial that selects patients from only one ethnic or racial group.

Clinical trials are often conducted in seriously ill patients who may die as a result of their clinical condition eg. cancer, HIV/AIDS patients, serious heart disease. It is therefore important to establish whether there is any link between the serious adverse event [death] and the medicines they have taken during the clinical trial. If they have taken more than one medicine it is also important to establish whether the death is linked directly to the new drug being studied, or if in fact, it was given in combination with one or more other medicines or treatments, and the combination resulted in death.

No patient enters a clinical trial without giving informed consent. The Informed Consent is obtained according to an internationally agreed standard, the Declaration of Helsinki. It is scrutinized by the Medicines Control Council and the Ethics Committees, which ensures that the information is in a format that the patient can clearly understand, giving a true reflection of what the patient can expect to experience if he/she participates in the clinical trial. The patient must also be told – in his/her home language - that they may receive the medicine under study or the standard treatment at the time of the trial.

In order to remove any bias, neither the doctor conducting the clinical trial nor the patient participating in "blinded" clinical trials, will know which medicine the patient is receiving. The code will only be broken at the conclusion of the clinical trial when the results are assessed. This is to remove any bias there might otherwise be, in observing and recording the effectiveness and side effects of the treatment.

Patients are not paid inducements for participating in clinical trials. They are, however, reimbursed for any expenses incurred, for example, travelling and accommodation costs, or for time off work.

Healthy human volunteers for Phase I studies [to determine the pharmacokinetics (absorption, distribution, metabolism and excretion) of a new drug] may be paid for participating in clinical trials. Most of the volunteers are medical or other students studying in a scientific discipline.

The patient’s condition is closely monitored throughout the clinical trial in accordance with internationally prescribed regulations. In addition, the patient’s safety is monitored, not only in terms of side effects but also by means of ongoing tests that are performed at specified time intervals. This ensures optimal patient safety.

Any serious adverse event is immediately reported by the doctor to the company who in turn is compelled to report the event to the Medicines Control Council. At this stage it may not be clear if the Adverse Event was as a result of the medicine being studied, or of any other treatment being used or of the conduct of the clinical trial. All serious adverse events are investigated and reports are compiled for the company, the Medicines Control Council and the relevant Ethics Committees. Appropriate action is taken when required.

WHO CONDUCTS A CLINICAL TRIAL

Clinical trials are conducted and sponsored by multi-national research-based pharmaceutical companies, academic foundations or individual researchers. If a pharmaceutical company sponsors a clinical trial, that company monitors the study at regular internationally acceptable intervals, or sometimes a Contract Research Organization will perform this task. The appointed investigating doctor responsible for the patient will see the patient at regular intervals as outlined in the protocol. Appropriately qualified and experienced persons are selected to conduct the clinical trials and compile reports.

The primary responsibility for the patient’s safety and care lies with the doctor conducting the study. The sponsoring company accepts full responsibility for events related to their product under investigation, if there is a proven direct link between the event and the conduct of the study or the medicines used in the study.

Data obtained from clinical trials conducted in SA have been accepted by the major regulatory authorities in the world. This enhances the academic stature of research institutions and researchers in SA and expands their knowledge base by providing the opportunity to participate in the forefront of research. Publications in respected international scientific journals also enhance the standing of SA researchers and institutions. This reported research also builds the reputation of the SA Regulatory Authority, the Medicines Control Council [MCC].

Company employees involved in clinical trials benefit from the transfer of knowledge and technology in terms of modern research methodology. New scientific equipment contributes to the research capacity of the country and thereby to the SA economy.

Clinical trials conducted in SA ensure the retention of research workers with skills and knowledge [developed at considerable cost to the SA tax payer] who might emigrate if denied the opportunity to conduct research in fields which interest them. These trials allow them to develop and expand their individual knowledge base.

Clinical trials account for around R400m per annum in Direct Foreign Investment - money brought into SA by multinational research based companies, some of which spend between 5 and 20 % of their total clinical research budgets in SA. This figure is disproportionately higher than the income generated by these companies from sales in SA (approximately 0,5 %- 1%).

Many countries compete for the right to conduct clinical trials due to the perceived value to the country and the benefit to patients. This direct foreign investment is at risk in SA due to unnecessary delays in the approval process and to other proposed measures which will make it more difficult to conduct clinical trials in SA than in European countries, and in many former Eastern bloc countries, as well as Australia.

It should be noted that there are international timelines for completion of clinical investigations including timelines for the enrolment of sufficient patients who fit the selection criteria - patients who have the condition for which the treatment is being investigated and fit other selection criteria, for example patients who are not on concomitant medication, do not have liver or kidney failure etc.

The loss of clinical trials to other countries would mean the loss of highly skilled investigators and auxiliary trained personnel. This represents a considerable capital loss to the country in all respects.

The clinical trials which have recently been conducted in this country or which are still on-going, include treatments for diseases which predominantly occur in the developing world, as well as treatments for diseases experienced in both the developed and developing countries. These include:

• treatments for malaria;

• multi-drug resistant Tuberculosis;
• new antibiotic treatment for pelvic inflammatory diseases [a condition which is common in the developing world];
• chancroid infection [a common Sexually Transmitted Disease (STD) ]
  Note: Patients suffering from STD’s are particularly vulnerable to infection with HIV/AIDS];
• multi-drug resistant Shigellosis [a type of virulent dysentery affecting children in particular as well as adults in the developing world];
• diabetes and hypertension [conditions which are particularly difficult to treat in black patients where these patients do not respond well to the standard therapies used in Caucasian populations. Local clinical research is therefore desirable];
• coronary heart disease and atherosclerosis.
  These are diseases which are increasing dramatically in the black population of this country as people move into the urban environment.
• clinical research into the medicinal treatment of head injuries [common in SA due to the violence in our society]
• HIV/AID’s

• research is also being done into vaccine development for primary immunisation [DTP].

It is false, therefore, to allege that multinational drug companies have no interest in conducting research into diseases prevalent in developing countries. While research into diseases prevalent in the developed world continues in South Africa this research is also directly relevant to a country like South Africa since the incidence of these diseases in an increasingly urban population in SA, is growing at an alarming rate among all members of the population.

On the global front, mention should be made of the substantial partnerships between the United Nations and the pharmaceutical industry to increase research and innovation for new malaria treatments, vaccines and more recently HIV/AIDS research and treatment. Companies in their individual capacities also continue the search for vaccines, treatments and cures for these diseases.

It should be noted that the price at which a new medicine will be sold when it is marketed is unknown at the time of the clinical investigation.

In many cases, patients benefit from local clinical trials because

• there may not have been an appropriate, effective treatment previously;

• patients may not have had access to standard therapy;
• patients may have not responded to currently accepted therapies;
• patients may have experienced unacceptable side effects from the current treatment.

The inclusion of a South African in a clinical trial, is generally of benefit to the group of patients to be treated, as they are guaranteed treatment with the trial drug [and frequently other medicines included in the treatment regimen] free of charge for the duration of the clinical trial. In many other countries, the State or medical insurers will agree to fund continued treatment. This does not happen in SA but even if the patient is not cured and cannot afford to continue with treatment after the trial, he or she may have experienced an improved quality of life for the duration of the trial and possibly an extension of life expectancy in certain conditions. Some companies ensure treatment after the completion of the trial where medication continues to be beneficial for the patient.

Delays in approval of clinical trials in SA, or onerous conditions not directly related to the safety of patients, may result in such trials being conducted in other countries. This would mean denial of new therapies and treatments to SA patients who may have to wait many years before the drug is eventually registered and marketed. This could be a particular disadvantage for the poorer sections of the population who cannot afford or may not have access to alternative treatments.

Several options are possible for the patient on conclusion of a trial. These include:

• Discontinuation of all medication;
• Continuation of all medication;
• Roll-over into a continuation study or a carry-over for a limited period or open period;

• Continuing with the trial medication only while there is still some benefit to the patient. The company is seldom, however, able to supply other medication which formed part of the study – this would become the responsibility of the State or other healthcare funders.