Anthony I Idigbe SAN1
Clinical trials are studies of drugs that are still in development or have not yet been approved by the relevant food and drug regulatory agency for the use being studied. EU Clinical Trial Directive defines clinical trial as "an investigation to ascertain the efficacy or safety of a medicine in human subjects". A drug being studied in a clinical trial is called an experimental drug. The trial is conducted on the new drug to determine whether or not it is safe and effective.
Experimental/Investigational drugs: Is there a moral duty to participate in clinical study?
Experimental drugs are new drugs that are yet in the process of being tested for safety and effectiveness, and as such have not been approved by the relevant food and drug regulatory agency for general use. They are also called investigational drugs. These drugs are not available to be marketed to the general public as they pose unknown risk to users and their effectiveness has not been positively ascertained. These drugs may be available to patients as participants in a clinical trial or on the basis of compassionate use for patients with serious or life-threatening conditions who have not responded positively to otherwise approved drugs. According to Harris2  individuals have a moral duty to participate in scientific research as subjects for clinical studies as otherwise they have no right to enjoy the benefit of the safety and effectiveness of drugs which the clinical study process actually produces.
Protection of Right to Life
The world has seen its fair share of abuse of the right of human beings to life. Historically feudal society gave no regard to the life of the peasant. Wars, slavery with its savagery and recently the holocaust and ethnic cleansing waves around the world create conditions for abuse of human life. Ever so often these reoccur with frightening propensity. The effort at protection of human life has also been unrelenting. In connection with clinical studies the abuses of human subjects during the Second World War are well documented in the Nuremburg trials which drew international attention to the threat which clinical studies if not well regulated could pose to not only the right to life but also right to dignity and prevention of torture. The Nuremburg Trial of Germany doctors who used captured human subjects for experiment led to the Nuremburg Code of 1949 by which it was intended to set standard for future ethical research. The Code was followed by the Declaration of Helsinki in 1964. Recently in 2002 the Council for International Organisations of Medical Sciences issued the International Ethical Guidelines for Biomedical Research involving Human Subjects. According to Grubb, Laing and McHale  despite the promulgation of those lofty statements and principles on ethical standards of clinical studies, scientific research is still dogged with controversy3. They cited the notorious Tuskegee experiment on black US males for progression of syphilis when there was acceptable cure for the disease and the Ellen Roche incident at John Hopkins University in 2001.
Under common law certain remedies were available to protect the human being including the right to life in contract as well as in tort. Now, whether based on contract or tort the most common remedy is for clinical negligence in circumstances where the patient consented to the clinical study4. However tort provides other remedies such as trespass to the person, assault and battery which may be more suited where there was no consent to the medical procedure. According to Grubb, Laing and McHale "The law relating to consent is of central importance in medical law. Under common law the legality of a medical treatment or procedure will largely turn upon whether the patient has given a valid consent to it. Treatment without consent may amount to the tort of battery or the crime of assault." Of course common law also offers many defences to these sorts of actions such as Contributory Negligence, Volenti Non Fit Injuria, Ex Turpi Causa Non Oritur Actio, Limitation, Causation, Reasonableness, In Pari Delecto, etc. For instance in Kanu Okoro Ajegbu v Dr. E. S. Etuk5, Kaine P.J. of the High Court of the then Eastern Region of Nigeria held that having considered all the evidence before him with all the submissions of counsel and authorities cited before him the plaintiff (father of the deceased) on the whole failed to prove a case of negligence against the defendant a medical doctor for causing the death of the deceased. There was no post mortem to determine cause of death. Also allegation that operation took too long was not proved nor was there proof that length of operation could have resulted in delayed chloroform poisoning. On the other hand there was evidence that the deceased could have died from paralytic ileus due to peritonitis as a result of ruptured appendicitis.
The protection of human life and dignity has been considered so important that almost all countries have elevated the matter to status of inalienable or fundamental human rights inserted in their constitutions with special procedures for their protection. Countries without a written constitution such as the United Kingdom have had to enact special laws such as the Human Rights Act of the UK to provide the required special protection to fundamental human rights including the right to life and dignity.
In Nigeria the protection of human rights was domesticated by virtue of Chapter 4 of the 1999 Constitution as amended. Every citizen of Nigeria is guaranteed a right to life by Section 33(1) of the 1999 Constitution which provides that:
The law provides for a special procedure for enforcement of the fundamental human rights pursuant to which the Chief Justice of Nigeria has made the Fundamental Rights Enforcement Rules. This procedure provides for a quick intervention of the courts when there is threat of or actual abuse of fundamental human rights. An analysis of most of the cases brought under this procedure show that they concern mostly threat to freedom of movement rather than right to life. Perhaps the dearth of medical law related cases is responsible for the near absence of use of this procedure in cases of say non consensual clinical studies.
On the international level as said earlier following the revelations of the Second World War at the Nuremburg Trials various treaties and conventions have been signed at regional and global levels to strengthen protection of human life and punish abuses within normal domestic civil context or in times of war or strife that may be within or outside domestic regime. Perhaps fundamental to international law in this area is the United Nations Declaration of Human Rights. There are others such as the numerous Geneva Conventions on the Law of Wars. But our focus is on clinical experiments as they affect protection of human rights, so we will focus more on the Nuremburg Code6 and Declaration of Helsinki7 as the fundamental international documents for the ethical conduct of clinical trials consistent with the protection of human rights.
It remains to say that some regions of the world have done much better than others in translating the concepts of ethical research into their regional legislative framework than others. For instance, in Europe there is the European Convention on Human Rights and in Africa the African Charter on Human and Peoples Rights. Many of these regional treaties have been domesticated but the extent of implementation varies greatly from region to region as we will see later in this paper.
International Best Practices in Clinical Studies
There is no real contradiction between conducting clinical studies and protection of human life and human rights generally. As pointed out above the benefit of clinical trial or studies on experimental drugs to society is the steady supply of safe and effective medicines for medical treatment and procedures. The challenge of the process is prevention of abuses which is same as many or most processes in society which require regulation. The best practices derived from the various international codes, guidelines, declarations and practices can be summarized as follows:
- Every system for regulation of clinical studies must have a Research Governance Framework
- The Framework must provide for a distinct approval process clinical studies on experimental drugs apart from the licensing process for approved drugs
- The clinical studies approval process should provide for the research sponsor to provide a protocol for the research stating the objective of the study (the benefit must outweigh the risk)8 and the details of the procedure including provision of competent personnel to conduct the study
- The protocol should provide for informed consent of the participants9
- The protocol should protect the confidentiality of the participants
- The protocol should provide for an Ethics Committee approval by the research administering institution as distinct from the research sponsor
- Generally clinical study should be therapeutic except under special circumstances where it may be allowed to be non-therapeutic
- The Framework should provide for monitoring of the clinical studies by a designated approval authority including monitoring of various persons and authorities involved with research
- The Framework must provide for reporting obligations of the various stakeholder in the clinical study process
- The framework should avoid multiple regulatory authorities which can lead to conflicts in regulation.
- The Framework must provide for accountability and compensation in the event of damage or bad practice in scientific research.
Suffice to say that each of the above eleven (11) elements of best practices in clinical studies is the subject of massive jurisprudence. Also from them it is clear that maintaining best practice in clinical studies is not the responsibility of the research sponsor alone. The government and other research institutions such as universities, hospitals, care givers, researchers etc., have great roles to play in setting up the Framework. Where the government or the research administering institution fails in their roles then even the best intentioned research sponsor can be exposed to unnecessary litigation which is capable of detracting from the laudable objective of clinical studies. Lastly on the issue of informed consent we should state that this is also another complex area of the law. There is issue of consent by a competent adult absence of which can lead to actions in battery and or negligence. There is also issue of consent and participation of children or of illiterate persons even if they are adults. Then there are adults who may be incompetent to consent or participate because of their mental state. Availability of clear rules and procedures for getting required consent or ensuring that the consent is real would determine the effectiveness of each regulatory regime in ensuring ethical research and delivery of safe and effective medicines to the society. Where the rules are not clear there is likelihood that the objective of clinical trials will not be achieved and threat to life may exist. For instance where there are multiple regulators without clear allocation of responsibilities.
Is there a Right to insist on Unapproved Medical Treatment or Procedure or refuse Approved Procedure?
Necessarily proceeding from the above discussed constitutionally guaranteed right to life is the right to preserve that life. Taking it further is the argument that persons who are terminally ill have the right to take steps to protect their right to live which will include the right to take any available medical treatment to preserve their life. Article 25(1) of The Universal Declaration of Human Rights seems to be full support of this right as it provides as follows;
The above it seems provides a further backing to the already strong argument that patients with life-threatening and otherwise untreatable diseases have a constitutional right to seek experimental treatments for their ailment even though the efficacy of the treatment is not yet established. It is argued that government should not interfere with this right unless it proves that there is an overriding and compelling reason to do so. In the 1990 US case of In re GUARDIANSHIP OF Estelle M. BROWNING10, the court held that "fundamental right to the sole control of his or her person" and "the constitutional right to choose or refuse medical treatment, and that right extends to all relevant decisions concerning one's health". In that case the issue was whether the patient's wish not to be on life support should be respected. The patient had earlier signed a Will stating her preference not to be placed on any life support, but the State of Florida refused to honor that wish.
In that case it was clearly brought out that the individual's wishes regarding medical treatment should be respected and free of government intrusion except there is a compelling and overriding government interest. One of the compelling reasons has been identified by case law as preservation of right and protection of innocent third parties. These reasons clearly tilts in favour of the argument that an adequately informed patient should be free to have access to an experimental drug which he believes is capable of curing his ailment and elongating his life.
In another US case the contrary position seems to have been held. This is the case of Abigail Alliance for Better Access to Developmental Drugs Vs. Andrew Von Eschenbach, (in his official capacity as Commissioner, Food and Drug Administration, and Michael O. Leavitt, in his official capacity as Secretary, U.S. Department of Health and Human Services)11 where a panel of 10 judges of the Court of Appeal of the District of Columbia held that there was no constitutional right of terminally ill patients to unapproved drug.12
This case revolved around a 21 year old Abigail who died from head and neck cancer at the time she was denied permission by FDA to obtain an experimental new drug that possibly could have benefited her. Her father Frank Burrough formed the Abigail Alliance for Better Access to Developmental Drugs after the death of his daughter to champion the cause of terminally ill patients who want access to experimental drugs. The alliance is an advocacy group of terminally ill patients and their supporters who have sought to advance the notion that individuals should have a right to obtain drugs that are in a clinical trial phase before the FDA has given the manufacturer permission to market the drug in the United States. In its initial lawsuit filed in 2003, the alliance was given an adverse opinion from a federal district court judge. That court determined that there is no fundamental or constitutional right to access experimental drugs that have not yet been approved by the FDA for marketing to the general public.
Subsequently, a three-judge panel of the Court of Appeal reversed that decision agreeing with the Alliance that the right of a mentally competent, terminally ill adult patient to access potentially lifesaving post-Phase I investigational new drugs, upon a doctor's advice, even where that medication carries risks for the patient should be protected. The court stated that "upon examining our nation's history, legal traditions, and practices, the government has not blocked access to new drugs throughout the greater part of our history" and that "only in recent years has the government injected itself into consideration of the effectiveness of new drugs." The court determined that the Due Process clause of the U.S. Constitution protects "the right to access potentially life-sustaining medication where there are no alternative government-approved treatment options." The fundamental principal, according to these judges is "the patient's right to make the decision about her life free from government interference."
The FDA sought review of this decision by all of the judges in the Court of Appeals for the District of Columbia. The en banc panel reversed the opinion of the three judges and reinstated the holding of the original district court judge. These judges stated that "the nation's history and tradition did not establish a fundamental substantive due process right of access to experimental drugs for the terminally ill" and that "neither the common law doctrine of necessity, the tort of intentional interference with rescue, nor the right to self defense established a self-preservation right giving the terminally ill access to experimental drugs." The court went on to state, "The FDA's policy of limiting access to investigational drugs was rationally related to the legitimate state interest of protecting patients from potentially unsafe drugs with unknown therapeutic effects."
The case came to a sudden halt when the U.S. Supreme Court declined to hear an appeal from the en banc decision on January 14, 2008. In effect, this affirms the original district court opinion finding that there is no constitutional right to access experimental drugs that have not been approved by the FDA13. This will appear to be a volte face from the position taken by the court in Estelle Browning case (supra).
Also in the case of Perry v UK14the European Court of Human Rights held as follows:
In Nigeria the Supreme Court in the case of Medical and Dental Practitioners Disciplinary Tribunal v Okonkwo15, also upheld the right of a Jehovah Witness adherent to resist blood transfusion even though it would have saved the life of the patient who was his wife. In that case the patient, one Mrs. Martha Okorie was delivered of a baby at Kanayo Hospital, but was diagnosed of an ailment which required blood transfusion. But the patient and her husband refused the blood transfusion because their faith (Jehovah witness) does not support blood transfusion. Upon their refusal, the doctor discharged them. Upon her discharge, her husband got her admitted into another hospital, Jeno Hospital. It was once again diagnosed that she needed blood transfusion, but the patient and her husband bluntly refused same and gave an undertaking absolving the hospital from any liability. They also refused to be moved to another hospital. The Respondent performed the medical procedure and the patient died subsequently. The Respondent was charged before the Medical and Dental Practitioners Disciplinary Tribunal with attending to the patient in a negligent manner thereby conducting himself infamously in a professional respect. In its judgment, the Tribunal held that the Respondent was guilty for having held onto a patient knowing full well that the correct treatment cannot be given in the face of failure to obtain consent. He appealed to the Court of Appeal and the appeal was allowed. The Court of Appeal judgment was also upheld by the Supreme Court. Per Ayoola JSC "If I may proffer an opinion, gratuitous though it may be, it is that the medical profession and the public will profit more if more attention is paid to a consideration of what legal remedies may be available to make objecting competent adult patients, in appropriate cases, submit to life-saving medical treatment. If such remedies as there are, are found inadequate, the solution is to be found in making the legal system fashion adequate remedies. The solution, in my opinion, is not in, unwittingly, making a hapless practitioner a scapegoat of the consequence of whatever deficiency there may be in the remedy provided by our laws; nor is it in making the medical practitioner pay for failure of concerned relations of the patient to seek legal advice and such remedies as the law might have offered at the time when such might have made a difference. Had such remedies been sought the responsibility of deciding whether or not the decision of the patient should be over-ridden would have shifted to the courts which are the proper forum for such decisions. Besides, granted that the medical profession may offer guidance to its members at any time, it is unjust to find a practitioner guilty of infamous conduct on an issue on which there has been neither rules nor what can be regarded as standard practice, or for a conduct which is not inherently infamous"16
It seems that under Section 40 of the 1999 Constitution some interference that can be reasonably justified in a democratic system may be allowable in cases of safety of others for instance but as pointed out by Justice Ayoola JSC, the rules and laws to take advantage of the exception in section 40 still have to be made.
In concluding on this, the argument of the regulatory authorities in barring access to experimental drugs by patients, including terminally ill patient is the risk of seriously undermining the scientific basis for evidence-based medicine by undermining the whole system of clinical trials that ensures efficacy and safety17.
Regulatory Framework for Clinical Studies in Nigeria
Clinical Studies Regime
In Nigeria, the National Agency for Food and Drug Administration and Control (NAFDAC) and the National Health Research Ethics Committee (NHREC) are the two main regulatory agencies regulating clinical studies. NAFDAC is responsible for regulating food and drug related products. By virtue of Section 5 of Foods, Drugs and Related Products (Registration, etc) Act CAP F33 L.F.N. 2004, clinical trials as regulated in Nigeria. It provides as follows;
5. Clinical trials
(a) import or supply a drug, drug product, cosmetic or medical device; Or
(b) procure the importation or supply of a drug, drug product, cosmetic or medical device;
(c) procure the manufacture or assembly of a drug, drug product, cosmetic or medical device, for the purpose of a clinical test, unless he is a holder of a valid clinical trial, certificate and the trial is to be carried out in accordance with the terms of the certificate and the provisions of any regulation in force.
(2) Application for a clinical trial, certificate shall be made to the Agency in such from and manner as the Agency may prescribe by regulations.
So far all that NAFDAC has issued is a guideline for clinical trials titled - "Documentation Guidelines for Clinical Trial in Nigeria". In our view this document is merely a guideline for application for approval of clinical studies. Although it contained some best practices such as requirement for a protocol and ethics approval from NHREC, it is not a regulation and is not comprehensive enough to deal with the major issues of best practices. The regulatory agencies require that new drugs be shown to be safe and effective before being marketed to the public. This requirement is rooted in the ability of the agency to make science-based health and safety decisions about the medical products offered to the public. These sciencebased health and safety decisions about new drugs are a keystone of the informed consent process on which patients rely in deciding what type of medical treatment to pursue.
The requirement that a person wishing to sell to the public a product to prevent, cure or mitigate illness or injury must first prove that such product is safe, and is efficacious, is the single most important consumer protection provision of the regulations in this regard. The regulations are made to afford consumers the most effective protection against untested and unproven products. The evidence of safety and effectiveness usually is obtained through the conduct of controlled clinical trials. The argument for controlled clinical trial is that this disciplined, systematic, scientific conduct of such trials is the most effective and efficient means of getting the reliable data which will let the patient/consumer and his or her health care practitioner know how to use the new product so that it will have the most beneficial effect. Indeed it can be said that clinical studies actually protects the constitutional right to life by ensuring that the public is not exposed to medicines that can harm them because their safety and efficacy are undetermined.
NHREC is in charge of human subject protections and regulation of human subject and animal research with respect to their ethical conduct. It was established in 2006 with the following mandate:
- Determine guidelines for the functioning of health research ethics committee;
- Register and audit health research ethics committees;
- Set norms and standards for conducting research on humans and animals, including norms and standards for conducting clinical trials;
- Adjudicate in complaints about the functioning of health research ethics committees and hear any complaint by a researcher who believes that he has been discriminated against by a health research ethics committee;
- Refer to the relevant statutory health professional council matters involving the violation or potential violation of an ethical or professional rule by a health care provider;
- Institute such disciplinary action as may be prescribed against any person found to be in violation of any norms and standards, or guidelines, set for the conduct of research under this Act; and
- Advise the Federal Ministry of Health and State Ministries on any ethical issues concerning research.
Drug Licensing Regime
Apart from regulation of clinical studies, NAFDAC is also the licensing authority for approved drugs to be administered on patients in Nigeria. NAFDAC Guideline on Clinical Studies makes it clear that an approval for clinical study is not an approval to market the drug to the general public. This is in line with the intendment of clinical studies which is to ensure the safety and efficacy of the drug before it is made available to the general public. Section 5 of NAFDAC Act provides as follows:
5. Functions of the Agency.
(1) The Agency shall have the following functions, that is, to -
(a) regulate and control the importation, exportation, manufacture, advertisement, distribution, sale and use of food, drugs, cosmetics, medical devices, bottled water and chemicals.
(b) conduct appropriate tests and ensure compliance with standard specifications designated and approved by the Council for the effective control of the quality of food, drugs, cosmetics, medical devices, bottled water and chemicals and their raw materials as well as their production processes in factories and other establishments;
(c) undertaken appropriate investigations into the production premises and raw materials for food, drugs, cosmetics, medical devices, bottled water and chemical and establish relevant quality assurance systems, including certificate of the production sites and of the regulation products;
(d) undertake inspection of imported food, drugs, cosmetics, medical devices, bottled water and chemicals and establish relevant quality assurance systems, including certification of the production sites and of the regulated products
(e) compile standard specifications and guidelines for the production, importation, exportation, sale and distribution of food, drug, cosmetics, medical devices, bottled water and chemicals;
(f) undertake the registration of food, drugs, cosmetics, medical devices, bottled water and chemicals;
(g) control the exportation and issue quality certification of food, drugs, cosmetics, medical devices, bottled water and chemicals intended for export;
(h) establish and maintain relevant laboratories or other institutions in strategic areas of Nigeria as may be necessary for the performance of its functions under this Act;
(i) pronounce on the quality and safety of food, drugs, cosmetics, medical devices, bottled water and chemicals after appropriate analysis;
(j) undertake measures to ensure that the use of narcotic drugs and psychotropic substances are limited to medical and scientific purposes;
(k) grant authorisation for the import and export of narcotic drugs and psychotropic substances as well as other controlled substances,
(l) collaborate with the National Drug Law Enforcement Agency in measures to eradicate drug abuse in Nigeria;
(m) advise Federal, State and Local Governments, the private sector and other interested bodies regarding the quality, safety, and regulatory provisions on food, drugs, cosmetics, medical devices, bottled water and chemicals;;
(n) undertake and co-ordinate research programmes on the storage, adulteration, distribution and rational use of food, drugs, cosmetics, medical devices, bottled water and chemicals;
(o) issue guidelines on, approve and monitor the advertisement of food, drugs, cosmetics, medical devices, bottled water and chemicals;
(p) compile and publish relevant data resulting from the performance of the functions of the Agency under this Act or from other sources;
(q) sponsor such national and international conferences as it may consider appropriate;
(r) liase with relevant establishments within and outside Nigeria in pursuance of the functions of the Agency;
(s) determine the suitability or otherwise of medicines, drugs, food products, cosmetics, medical devices or chemicals for human and animal use; and.
(t) carry out such activities as are necessary or expedient for the performance of its functions under this Act.
It follows that in Nigeria there is convergence of authority with respect to licensing and clinical studies. It is important to note that these are not the same issues even if they are related. Licensing would relate to the sale and administration of approved product. Clinical study would usually require a Research Governance Framework which sets out the objectives to be achieved and the requirements for ethical, safe, humane and effective output of clinical research including the tracking of such research for regulatory purposes.
Challenges of Clinical Studies Regulation in Nigeria
Our experience indicates that NAFDAC is yet to develop a Research Governance Framework for Nigeria in the light of international best practices discussed above. Although NAFDAC has established a guideline for clinical trials titled - "Documentation Guidelines for Clinical Trial in Nigeria"; this does not in our opinion provide a proper Research Governance Framework. We are aware that NAFDAC has a draft "Good Clinical Practice Regulation", which is capable of providing the much needed research framework, but this is yet to be signed and enacted.
In furtherance of its mandate the NHREC has developed a "National Code for Health Research Ethics"18. This Code has been approved by the National Council on Health19, but its main challenge is that it has yet to receive statutory backing which is expected with the coming into force of the National Health Bill which was recently passed into law in February 2014 but is yet to receive the Presidential assent20. The statutory backing provides for sanctions for non-compliance.
The joint collaborative effort of NAFDAC and NHREC we believe will bring about a well regulated clinical trial regime in Nigeria in line with international best practices. Evidence of this collaboration can be seen from the NAFDAC guideline for clinical trial which has provided that application for clinical trial must be accompanied with NHREC approval.
Also although the law gave NAFDAC the power to make regulations on clinical studies it is yet to make such regulations. Of course to make effective regulations it should be as part of implementation of a Research Governance Framework. The universities and various institutes and hospitals are conducting one form of medical research or the other. Most of them claim the authority to conduct such medical research from their governing statute. For instance the National Institute for Medical Research was established by virtue of the Research Institutes (Establishment, etc) Order, a subsidiary legislation made pursuant to National Agency for Science and Engineering Infrastructure Act21 to undertaken medical research in the country; the University of Ibadan Act22 establishes a Post Graduate School of Medical Research. This posited that these research institutes/schools in undertaking their studies will in one way or the other deal with human study participants and it is critical that a clinical study regime is put in place to ensure that these studies are conducted in line with international best practices.
In the absence of a clear apex regulatory role for NAFDAC with reporting obligations set by regulation, NAFDAC is unable to collate data on on-going or past research particularly those that have thrown up damaging results to their subjects. Such information can be extremely useful for planning and regulation purposes. Also without clear statutory backing NHREC cannot effectively monitor these research institutions and hospitals to ensure they always have in place Ethics Committees including setting out regulations for the conduct of such committees which is vital to ethical research in consonance with protection of human rights. We can say more but the above are mentioned merely to highlight the need for NAFDAC to rise up to the challenge of developing a Research Governance Framework for Nigeria and for statutory backing to be provided for NHREC to carry out its responsibility. We think this workshop is a good start and that the country has the right mix of legal and medical practitioners to assist these agencies achieve their objectives.
Analysis of Other Jurisdictions
The Position in the US
Normally in the USA, a new drug goes through a regimented process of testing and clinical trial before it is approved for the market. In the development of the drug, the manufacturer/sponsor must ensure it is first tested on animals to determine toxicity. Then the manufacturer submits the result of this test to the regulatory agency along with full protocol for a clinical trial for approval to conduct a clinical trial on human beings. The sponsor then takes that animal testing data, along with additional information about the drug's composition and manufacturing, and develops a plan for testing the drug in humans. The testing plan generally is referred to as the protocol. The sponsor submits these data, along with its study plan, the qualifications of the investigators who will conduct the clinical studies, and assurances of informed consent and protection of the rights and safety of the human subjects, to FDA in the form of an Investigational New Drug application (IND).23
FDA reviews the IND for assurance that the proposed studies, generally referred to as clinical trials, do not suggest that human subjects might be exposed to unreasonable risk of harm. FDA also verifies that there are adequate assurances of informed consent and human subject protection. At that point, the first of three phases of study in humans can begin. Phase 1 studies primarily focus on the safety studies of the drug in humans. Phase 1 studies carefully assess how to safely administer and dose the drug with an emphasis on evaluation of the toxic manifestations of the therapy, how the body distributes and degrades the drug, and how side effects relate to dose. Phase 1 studies typically include fewer than 100 healthy volunteers or patients.
The next step, called Phase 2 studies, are clinical studies to evaluate the effectiveness of the drug for a particular indication and to determine common short-term side effects. Phase 2 studies typically involve a few hundred patients. Importantly, it is estimated that 80 percent of all drugs tested are abandoned by their sponsors after either Phase 1 or 2. Once Phase 2 studies are successfully completed, the drug's sponsor has learned much about the drug's safety and effectiveness. At this point Phase 3 studies, involving up to several thousand patients, may be conducted. These studies can examine additional uses, obtain further safety data including long-term experience, and consider additional population subsets, dose response, etc. FDA strongly encourages sponsors to work closely with the Agency in planning definitive Phase 3 clinical trials so as to help assure that the trials are designed to have the greatest likelihood of producing results sufficient to permit product marketing.
Once Phase 3 trials are completed, the sponsor submits the results to FDA in the form of an NDA. FDA's medical officers, chemists, statisticians, and pharmacologists review the application to determine if the sponsor's data in fact show that the drug is both safe and effective. The manufacturing facility is evaluated to confirm that the product can be produced consistently with high quality. This process can take up to 10 years to be completed. Formal FDA approval is obtained following Phase 3 clinical trials. However, it is almost always the case these days that as a condition of drug approval, the FDA requires post-approval clinical trials (often called Phase 4 trials) in certain populations that were not studied before approval (e.g., children, elderly, people with certain co-morbidities) and/or for certain conditions that were not studied. The idea is that it is not justified to withhold a potentially beneficial drug from the population as a whole, even though safety/efficacy has not yet been established in every sub-population, but the company agrees to conduct trials in those sub-populations after approval to confirm that no safety issues are noted.
The Position in the UK
In the UK there are established the National Research Ethics Service and the UK Ethics Committee Authority. The UK has implemented the EU Clinical Trials Directive by virtue of the Part 2 of the Medicines for Human Use (Clinical Trials) Regulations 2004, SI 2004/1031.
The National Research Ethics Service24 is essentially responsible for training of researchers and optimizing research ethics review whilst the UK Ethics Committee Authority monitors the various Ethics Committees of research institutions. At the heart of regulation of clinical studies is the Research Ethics Committee REC which reviews the research protocol and gives approval. The process is decentralized. The national authorities only set guidelines for the RECs to follow and they monitor the RECs and enforce reporting obligations.
There is no one model for regulation of clinical studies to ensure protection of human life and delivery of safe and effective evidence based medicines to the society at large. Some systems are decentratralised while others concentrate power in a central regulatory agency. Whatever the system, it is critical that capacity of researchers, research sponsors, care givers, research administrators and regulators are enhanced on best practices. It is also important that the institutions should be effective. For NAFDAC to be effective they have to be able to develop and implement a Research Governance Framework. In the absence of this framework, the consequence is that we seem to be groping in the dark when we seek to apportion liability in view of the few cases that have come up. On ethics, our current dilemma is that even though we have set clear standards and processes for ethical research, NHREC is yet to receive the necessary statutory backing which will empower it to enforce the Code. We seek to apply standards and practices in our systems which have not been properly domesticated under Nigerian law. Section 12 of the 1999 Constitution as amended stipulates that no international treaty, convention or declaration can form part of the municipal law of Nigeria unless it has been passed into law by the National Assembly. There lies the challenge. In the case of Abacha Vs Fawehinmi25 the Supreme Court of Nigeria held as follows;
The Court of Appeal in Nigeria followed the same line of decision in the case of Nnaji Vs. Nigerian Football Association26 when they held that by vrtue of Section 12 of the Constitution, no treaty between the Federation and any other country shall have the force of law except to the extent to which such treaty have been enacted into law by the National Assembly.
Therefore as good as the Nuremburg Code or Declaration of Helsinki may be they are not part of Nigerian domestic or municipal law and as such cannot be enforced.
Even the United States of America which was liberal in directly enforcing international law by virtue of the Alien Tort Claim Act, by allowing defendants to be sued in US for human rights violations committed outside the US has retreated from that Carte Blanche in the recent US Supreme Court case of Kiobel v. Royal Dutch Petroleum Co.27
Although the jurisprudence in Nigeria in the area of clinical trials is still developing, it should not depend solely on common law and the judges to making the law piece meal on a case by case basis. The country has the advantage of rich jurisprudence and legislative interventions available worldwide which it can utilize immediately to develop our process of regulation of clinical studies in such a way as to balance its law and practice in line with the constitutional protection of the fundamental rights to life, dignity, liberty and movement and encourage the industry to continue to produce life saving drugs and medicines. The regulatory environment we should seek to provide for clinical studies should be such that encourages ethical research and prevents dispute or rather anticipate them in such a way that it is easy to lay liability where disputes arise. It should also be able to deal from a regulatory standpoint with cases of abuses or conduct below stipulated standards of ethical research whilst affirming those above such ethical standards. Finally the frame work should encourage planning and capacity development.
1 Senior Partner PUNUKA Attorneys & Solicitors with research assistance from Ebelechukwu Enedah and Ndubuisi Okonta both Senior Associates at PUNUKA Attorneys & Solicitors
2 Harris, J, 'Scientific Research is a Moral Duty' (2005) 31 Journal of Medical Ethics 242 cited in Grubb Laing and McHale Principles of Medical Law 3rd Ed 2010 Oxford para 13.01
3 Grubb, Laing and McHale Principles of Medical Law 3rd Ed 2010 Oxford at 13.02 at p.726
4 For more detailed discussion on clinical negligence see Grubb, Laing and McHale Supra at Chapter 3
5 (1962) Vol. VI ENLR 196
6 Trials of War Criminals before the Nuremberg Military Tribunals under Control Council Law No. 10", Vol. 2, pp. 181-182. Washington, D.C.: U.S. Government Printing Office, 1949
7 World Medical Association. Declaration of Helsinki - Ethical Principles for Medical Research Involving Human Subjects. WMA General Assembly; Seoul: 2008. Oct
8 Declaration of Helsinki: Medical research involving human subjects should only be conducted if the importance outweighs the inherent risks and burdens to the subject. This is especially important where the human subjects are healthy volunteers.
9 See section 34 of 1999 Constitution against torture and inhuman treatment; Para 24 of Declaration of Helsinki; Cardozo J in Schloendorff v Society of New York Hospital (1914) 211 NY 125 at 126 as follows: Every human being of adult years and sound mind has a right to determine what shall be done with his own body; and a surgeon who performs an operation without his patient's consent commits an assault, for which he is liable in damages.
10 543 So. 2d 258, 261 (Fla. Dist. Ct. App. 1989).
11 Slip Op No. 04-5350, U.S. Ct App. DC, 495 F3d 695; 2007 U.S. App. Lexis 18688 (August 7, 2007, Decided) 12 Abigail Alliance for Better Access to Developmental Drugs web site. http://www.abigail-alliance.org/.
13 Following this state of the law US FDA passed the 2009 Amendment to FDA Rules Concerning Expanded Access for Investigational Drugs which now allows use of investigational drugs in emergency situations that is where the patient has serious or immediately life threatening diseases or conditions who lack other therapeutic options and may benefit from such investigational drugs provided the potential benefit justifies the risk and Expanded Access Submission is made.
14 Application 2346/02 (2002) 66 BMLR147 (ECtHR) at para 63
15 (2002) 7 NWLR (part 711) page 206
16At page 247 para A-C.
17 But see US FDA 2009 Amendment to FDA Rules Concerning Expanded Access for Investigational Drugs which now allows expanded access in limited circumstances.
18 This code is available on NHREC website - http://www.nhrec.net/nhrec/NCHRE_Aug%2007.pdf
19 Federal Ministry of Health (FMOH) FMOH; Proceedings of the 50th National Council on Health Meeting, Sheraton Hotel and Towers; Abuja, Nigeria. 2006.
20 It is noted that there are serious objections to the National Health Bill because of some of the provisions of the Bill vigorously opposed by anit abortion campaigners.
21 CAP N3, LFN 2004, Schedule 2
22 CAP 454, LFN 2004
23 Providing Access to Promising Therapies for Seriously Ill and Dying Patients - FDA Testimony before Committee on Government Reform and Oversight, U.S. House of Representatives (http://www.fda.gov/NewsEvents/Testimony/ucm115120.htm )
24 In Nigeria we have the National Code of Health Research Ethics 2007, which defines the roles and responsibilities of the National Health Research Ethics Committees, Institutional Health Research Ethics Committees, Healthcare Professionals, Universities; Health Researchers and Research sponsors in the protection of human research subjects.
25 (2000) 6 NWLR (part 660) page 228
26 (2010) 11 NWLR (part 1206) page 438
27 133 S.Ct. 1659 (2013); See also the decision of the US Court of Appeal in the case of Abdullah Vs Pfizer Docket Nos. 05-4863-cv(L), 05-6768-cv(CON).
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